{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T14:02:49Z","timestamp":1781013769898,"version":"3.54.1"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T00:00:00Z","timestamp":1778889600000},"content-version":"vor","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurooncol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Although most vestibular schwannomas (VS) occur sporadically, both sporadic and hereditary tumors share common molecular features beyond the loss of\n                      <jats:italic>NF2<\/jats:italic>\n                      . New evidence highlights the role of interconnected signaling pathways and epigenetic regulation in Schwann cell tumorigenesis, pointing toward potential molecularly targeted therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review synthesizes preclinical, molecular, and clinical evidence to examine genetic and epigenetic mechanisms underlying VS, therapeutic strategies, and contributors to hearing loss. A structured search of ClinicalTrials.gov identified 21 Phase 1\u20133 interventional therapeutic trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      VS pathogenesis is driven by\n                      <jats:italic>NF2<\/jats:italic>\n                      loss and merlin deficiency, leading to dysregulation of Hippo\/YAP-TAZ, PI3K\/AKT\/mTOR, VEGF, MAPK, and adhesion pathways. Epigenetic alterations, including DNA methylation, chromatin remodeling, non-coding RNAs, and SOX10 dysfunction, further shape tumor behavior. Clinical trial analysis revealed a predominance of early-phase, non-comparative studies, limited progression to later-phase trials, and incomplete results reporting, indicating gaps in high-quality evidence. Bevacizumab remains the most consistent systemic therapy for select\n                      <jats:italic>NF2<\/jats:italic>\n                      -related cases, while other agents such as icotinib, lapatinib, everolimus, selumetinib, and brigatinib have shown modest activity, primarily disease stabilization. Emerging approaches, including TEAD inhibition, PI3K\/mTOR blockade, MEK inhibition, and combined signaling-epigenetic strategies, show preclinical promise. Hearing loss is multifactorial, involving tumor-secreted factors, inflammation, vascular changes, and inner ear damage alongside nerve compression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>VS biology reflects integrated genetic and epigenomic dysregulation. Advancing care will require multi-omic classification, biomarker-driven trials, and combination therapies targeting both signaling and epigenetic vulnerabilities. Future management is expected to shift toward personalized, mechanism-based strategies aimed at durable tumor control while preserving hearing and quality of life.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-026-05621-4","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T16:56:43Z","timestamp":1778950603000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vestibular schwannoma: genetic and epigenetic mechanisms, hearing loss, and emerging therapies"],"prefix":"10.1007","volume":"178","author":[{"given":"Franciska","family":"Otaner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3906-5317","authenticated-orcid":false,"given":"Vratko","family":"Himic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis O.","family":"Vargas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Abikenari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelesh","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayndhan","family":"Sivanathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Kalmanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Govindan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagoberto","family":"Estevez-Ordonez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeeva","family":"Jeyaretna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish H.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo J.","family":"Komotar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Gampel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Dinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Ivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,16]]},"reference":[{"key":"5621_CR1","doi-asserted-by":"crossref","unstructured":"Li J, Wang Q, Zhang M et al (2021) Malignant transformation in vestibular schwannoma: clinical study with survival analysis. Front Oncol 11","DOI":"10.3389\/fonc.2021.655260"},{"key":"5621_CR2","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1056\/NEJMra2020394","volume":"384","author":"JLM L CM","year":"2021","unstructured":"L CM JLM (2021) Vestibular Schwannomas. N Engl J Med 384:1335\u20131348. https:\/\/doi.org\/10.1056\/NEJMra2020394","journal-title":"N Engl J Med"},{"key":"5621_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11060-025-05252-1","volume":"176","author":"O Bin-Alamer","year":"2025","unstructured":"Bin-Alamer O, Osama M, Sheehan JP (2025) The evolution of stereotactic radiosurgery for vestibular schwannomas: recent evidence and outcomes. J Neurooncol 176:1. https:\/\/doi.org\/10.1007\/s11060-025-05252-1","journal-title":"J Neurooncol"},{"key":"5621_CR4","doi-asserted-by":"crossref","unstructured":"Ohara K, Miyawaki S, Teranishi Y et al (2026) Genetic analysis of intracranial schwannomas: differential NF2 alteration frequencies in nonvestibular schwannomas versus vestibular schwannomas. Neurosurgery 98","DOI":"10.1227\/neu.0000000000003508"},{"key":"5621_CR5","unstructured":"Dhamija R, Plotkin S, Gomes A, Babovic-Vuksanovic D (2025) LZTR1-and SMARCB1-related schwannomatosis. Seattle"},{"key":"5621_CR6","unstructured":"Evans DG (1998) NF2-related schwannomatosis. National Library of Medicine"},{"key":"5621_CR7","doi-asserted-by":"publisher","first-page":"15021","DOI":"10.1038\/cddiscovery.2015.21","volume":"1","author":"A Colciago","year":"2015","unstructured":"Colciago A, Melfi S, Giannotti G et al (2015) Tumor suppressor Nf2\/merlin drives Schwann cell changes following electromagnetic field exposure through Hippo-dependent mechanisms. Cell Death Discov 1:15021. https:\/\/doi.org\/10.1038\/cddiscovery.2015.21","journal-title":"Cell Death Discov"},{"key":"5621_CR8","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40478-025-01937-w","volume":"13","author":"T Tsuchiya","year":"2025","unstructured":"Tsuchiya T, Miyawaki S, Teranishi Y et al (2025) Current molecular understanding of central nervous system schwannomas. Acta Neuropathol Commun 13:24. https:\/\/doi.org\/10.1186\/s40478-025-01937-w","journal-title":"Acta Neuropathol Commun"},{"key":"5621_CR9","doi-asserted-by":"crossref","unstructured":"Sanchez LD, Bui A, Klesse LJ (2021) Targeted therapies for the neurofibromatoses. Cancers (Basel) 13","DOI":"10.3390\/cancers13236032"},{"key":"5621_CR10","unstructured":"Mubbashir MS, De Jesus O (2023) Vestibular schwannoma. National Library of Medicine"},{"key":"5621_CR11","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1002\/gcc.22232","volume":"54","author":"M Torres-Mart\u00edn","year":"2015","unstructured":"Torres-Mart\u00edn M, Lassaletta L, de Campos JM et al (2015) Genome-wide methylation analysis in vestibular schwannomas shows putative mechanisms of gene expression modulation and global hypomethylation at the HOX gene cluster. Genes Chromosomes Cancer 54:197\u2013209. https:\/\/doi.org\/10.1002\/gcc.22232","journal-title":"Genes Chromosomes Cancer"},{"key":"5621_CR12","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s00401-025-02883-6","volume":"149","author":"F Zhao","year":"2025","unstructured":"Zhao F, Teng X-F, Zhang J et al (2025) Multiplatform molecular analyses reveal two molecular subgroups of NF2-related schwannomatosis vestibular schwannomas with distinct tumour microenvironment and therapeutic vulnerabilities. Acta Neuropathol 149:47. https:\/\/doi.org\/10.1007\/s00401-025-02883-6","journal-title":"Acta Neuropathol"},{"key":"5621_CR13","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1093\/neuonc\/nor072","volume":"13","author":"ML Bush","year":"2011","unstructured":"Bush ML, Oblinger J, Brendel V et al (2011) AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro Oncol 13:983\u2013999. https:\/\/doi.org\/10.1093\/neuonc\/nor072","journal-title":"Neuro Oncol"},{"key":"5621_CR14","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1093\/brain\/aws353","volume":"136","author":"RDS Doddrell","year":"2013","unstructured":"Doddrell RDS, Dun X-P, Shivane A et al (2013) Loss of SOX10 function contributes to the phenotype of human Merlin-null schwannoma cells. Brain 136:549\u2013563. https:\/\/doi.org\/10.1093\/brain\/aws353","journal-title":"Brain"},{"key":"5621_CR15","doi-asserted-by":"publisher","first-page":"e30418","DOI":"10.1371\/journal.pone.0030418","volume":"7","author":"JD Lee","year":"2012","unstructured":"Lee JD, Kwon TJ, Kim U-K, Lee W-S (2012) Genetic and Epigenetic Alterations of the NF2 Gene in Sporadic Vestibular Schwannomas. PLoS ONE 7:e30418","journal-title":"PLoS ONE"},{"key":"5621_CR16","doi-asserted-by":"crossref","unstructured":"Chiranth S, Langer SW, Poulsen HS, Urup T (2023) A systematic review of targeted therapy for vestibular schwannoma in patients with NF2-related schwannomatosis. Neurooncol Adv 5","DOI":"10.1093\/noajnl\/vdad099"},{"key":"5621_CR17","doi-asserted-by":"crossref","unstructured":"Rechberger JS, Price AL, Zhang L et al (2025) Chapter two - tumor-specific biology, diagnosis, and therapy. In: Abdelbaki MS, Fisher PB, Limbrick DD (eds) Advances in Cancer Research. Academic Press, pp 37\u201379","DOI":"10.1016\/bs.acr.2025.09.002"},{"key":"5621_CR18","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1136\/jmg.35.6.450","volume":"35","author":"DG Evans","year":"1998","unstructured":"Evans DG, Trueman L, Wallace A et al (1998) Genotype\/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet 35:450. https:\/\/doi.org\/10.1136\/jmg.35.6.450","journal-title":"J Med Genet"},{"key":"5621_CR19","doi-asserted-by":"publisher","first-page":"3446","DOI":"10.1200\/JCO.19.01367","volume":"37","author":"SR Plotkin","year":"2019","unstructured":"Plotkin SR, Duda DG, Muzikansky A et al (2019) Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma. J Clin Oncol 37:3446\u20133454. https:\/\/doi.org\/10.1200\/JCO.19.01367","journal-title":"J Clin Oncol"},{"key":"5621_CR20","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/s11060-014-1710-0","volume":"122","author":"S Goutagny","year":"2015","unstructured":"Goutagny S, Raymond E, Esposito-Farese M et al (2015) Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neurooncol 122:313\u2013320. https:\/\/doi.org\/10.1007\/s11060-014-1710-0","journal-title":"J Neurooncol"},{"key":"5621_CR21","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.3171\/2022.9.JNS22699","volume":"138","author":"F Zhao","year":"2023","unstructured":"Zhao F, Li S, Zhang S et al (2023) Phase II trial of icotinib in adult patients with neurofibromatosis type 2 and progressive vestibular schwannoma. J Neurosurg 138:1680\u20131687. https:\/\/doi.org\/10.3171\/2022.9.JNS22699","journal-title":"J Neurosurg"},{"key":"5621_CR22","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1093\/neuonc\/nos146","volume":"14","author":"MA Karajannis","year":"2012","unstructured":"Karajannis MA, Legault G, Hagiwara M et al (2012) Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 14:1163\u20131170. https:\/\/doi.org\/10.1093\/neuonc\/nos146","journal-title":"Neuro Oncol"},{"key":"5621_CR23","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1056\/NEJMoa2400985","volume":"390","author":"SR Plotkin","year":"2024","unstructured":"Plotkin SR, Yohay K, Nghiemphu P et al (2024) Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors. N Engl J Med 390:2284\u20132294. https:\/\/doi.org\/10.1056\/NEJMoa2400985","journal-title":"N Engl J Med"},{"key":"5621_CR24","doi-asserted-by":"publisher","first-page":"fcad197","DOI":"10.1093\/braincomms\/fcad197","volume":"5","author":"GE Gregory","year":"2023","unstructured":"Gregory GE, Jones AP, Haley MJ et al (2023) The comparable tumour microenvironment in sporadic and NF2-related schwannomatosis vestibular schwannoma. Brain Commun 5:fcad197. https:\/\/doi.org\/10.1093\/braincomms\/fcad197","journal-title":"Brain Commun"},{"key":"5621_CR25","doi-asserted-by":"publisher","first-page":"911","DOI":"10.3171\/2016.10.JNS161384","volume":"128","author":"AL H\u00e5vik","year":"2018","unstructured":"H\u00e5vik AL, Bruland O, Myrseth E et al (2018) Genetic landscape of sporadic vestibular schwannoma. J Neurosurg JNS 128:911\u2013922. https:\/\/doi.org\/10.3171\/2016.10.JNS161384","journal-title":"J Neurosurg JNS"},{"key":"5621_CR26","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1038\/ng.3688","volume":"48","author":"S Agnihotri","year":"2016","unstructured":"Agnihotri S, Jalali S, Wilson MR et al (2016) The genomic landscape of schwannoma. Nat Genet 48:1339\u20131348. https:\/\/doi.org\/10.1038\/ng.3688","journal-title":"Nat Genet"},{"key":"5621_CR27","doi-asserted-by":"publisher","first-page":"e70265","DOI":"10.1002\/lio2.70265","volume":"10","author":"T Wakabayashi","year":"2025","unstructured":"Wakabayashi T, Wasano K, Nakamura K et al (2025) Comprehensive Genetic Analysis of NF2 in Sporadic Vestibular Schwannoma. Laryngoscope Investig Otolaryngol 10:e70265. https:\/\/doi.org\/10.1002\/lio2.70265","journal-title":"Laryngoscope Investig Otolaryngol"},{"key":"5621_CR28","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1136\/jmg.2006.047753","volume":"44","author":"DGR Evans","year":"2007","unstructured":"Evans DGR, Ramsden RT, Shenton A et al (2007) Mosaicism in neurofibromatosis type 2: an update of risk based on uni\/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet 44:424. https:\/\/doi.org\/10.1136\/jmg.2006.047753","journal-title":"J Med Genet"},{"key":"5621_CR29","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.21873\/invivo.13929","volume":"39","author":"M Breun","year":"2025","unstructured":"Breun M, Schulz T, Monoranu CM et al (2025) Pathogenic Variants and Allele Loss of the NF2 and LZTR1 Gene in Sporadic Vestibular Schwannoma. Vivo (Brooklyn) 39:1251. https:\/\/doi.org\/10.21873\/invivo.13929","journal-title":"Vivo (Brooklyn)"},{"key":"5621_CR30","doi-asserted-by":"crossref","unstructured":"Zhang H, Cao X, Wang J et al (2021) LZTR1: a promising adaptor of the CUL3 family (review). Oncol Lett 22","DOI":"10.3892\/ol.2021.12825"},{"key":"5621_CR31","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1212\/WNL.0000000000003418","volume":"88","author":"MJ Smith","year":"2017","unstructured":"Smith MJ, Bowers NL, Bulman M et al (2017) Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology 88:87\u201392. https:\/\/doi.org\/10.1212\/WNL.0000000000003418","journal-title":"Neurology"},{"key":"5621_CR32","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/onc.2015.125","volume":"35","author":"AM Petrilli","year":"2016","unstructured":"Petrilli AM, Fern\u00e1ndez-Valle C (2016) Role of Merlin\/NF2 inactivation in tumor biology. Oncogene 35:537\u2013548. https:\/\/doi.org\/10.1038\/onc.2015.125","journal-title":"Oncogene"},{"key":"5621_CR33","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1038\/s41467-023-37226-0","volume":"14","author":"C Chiasson-MacKenzie","year":"2023","unstructured":"Chiasson-MacKenzie C, Vitte J, Liu C-H et al (2023) Cellular mechanisms of heterogeneity in NF2-mutant schwannoma. Nat Commun 14:1559. https:\/\/doi.org\/10.1038\/s41467-023-37226-0","journal-title":"Nat Commun"},{"key":"5621_CR34","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1097\/NEN.0000000000000238","volume":"74","author":"J-E Oh","year":"2015","unstructured":"Oh J-E, Ohta T, Satomi K et al (2015) Alterations in the NF2\/LATS1\/LATS2\/YAP Pathway in Schwannomas. J Neuropathol Exp Neurol 74:952\u2013959. https:\/\/doi.org\/10.1097\/NEN.0000000000000238","journal-title":"J Neuropathol Exp Neurol"},{"key":"5621_CR35","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1093\/brain\/awac342","volume":"146","author":"L Laraba","year":"2023","unstructured":"Laraba L, Hillson L, de Guibert JG et al (2023) Inhibition of YAP\/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma. Brain 146:1697\u20131713. https:\/\/doi.org\/10.1093\/brain\/awac342","journal-title":"Brain"},{"key":"5621_CR36","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.3171\/2014.6.JNS131433","volume":"121","author":"S Agnihotri","year":"2014","unstructured":"Agnihotri S, Gugel I, Remke M et al (2014) Gene-expression profiling elucidates molecular signaling networks that can be therapeutically targeted in vestibular schwannoma: Laboratory investigation. J Neurosurg JNS 121:1434\u20131445. https:\/\/doi.org\/10.3171\/2014.6.JNS131433","journal-title":"J Neurosurg JNS"},{"key":"5621_CR37","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1158\/1541-7786.MCR-11-0425-T","volume":"10","author":"MF James","year":"2012","unstructured":"James MF, Stivison E, Beauchamp R et al (2012) Regulation of mTOR Complex 2 Signaling in Neurofibromatosis 2\u2013Deficient Target Cell Types. Mol Cancer Res 10:649\u2013659. https:\/\/doi.org\/10.1158\/1541-7786.MCR-11-0425-T","journal-title":"Mol Cancer Res"},{"key":"5621_CR38","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1593\/neo.111600","volume":"14","author":"HK Wong","year":"2012","unstructured":"Wong HK, Shimizu A, Kirkpatrick ND et al (2012) Merlin\/NF2 regulates angiogenesis in schwannomas through a Rac1\/semaphorin 3F-dependent mechanism. Neoplasia 14:84\u201394. https:\/\/doi.org\/10.1593\/neo.111600","journal-title":"Neoplasia"},{"key":"5621_CR39","doi-asserted-by":"publisher","unstructured":"Gao X, Zhao Y, Stemmer-Rachamimov AO et al (2015) Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model. Proc Natl Acad Sci U S A 112:14676\u201314681. https:\/\/doi.org\/10.1073\/pnas.1512570112","DOI":"10.1073\/pnas.1512570112"},{"key":"5621_CR40","doi-asserted-by":"publisher","first-page":"vdad099","DOI":"10.1093\/noajnl\/vdad099","volume":"5","author":"S Chiranth","year":"2023","unstructured":"Chiranth S, Langer SW, Poulsen HS, Urup T (2023) A systematic review of targeted therapy for vestibular schwannoma in patients with NF2-related schwannomatosis. Neurooncol Adv 5:vdad099. https:\/\/doi.org\/10.1093\/noajnl\/vdad099","journal-title":"Neurooncol Adv"},{"key":"5621_CR41","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1056\/NEJMoa0902579","volume":"361","author":"SR Plotkin","year":"2025","unstructured":"Plotkin SR, Stemmer-Rachamimov AO, Barker IIFG et al (2025) Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2. N Engl J Med 361:358\u2013367. https:\/\/doi.org\/10.1056\/NEJMoa0902579","journal-title":"N Engl J Med"},{"key":"5621_CR42","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1200\/JCO.2015.64.3817","volume":"34","author":"JO Blakeley","year":"2016","unstructured":"Blakeley JO, Ye X, Duda DG et al (2016) Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2\u2013Associated Vestibular Schwannomas. J Clin Oncol 34:1669\u20131675. https:\/\/doi.org\/10.1200\/JCO.2015.64.3817","journal-title":"J Clin Oncol"},{"key":"5621_CR43","doi-asserted-by":"crossref","unstructured":"Hatley MG, Yohay KH, Roland JT Jr, Segal D (2026) The association between age and outcomes of bevacizumab treatment in NF2-related schwannomatosis. Otol Neurotol 47","DOI":"10.1097\/MAO.0000000000004759"},{"key":"5621_CR44","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s11060-016-2276-9","volume":"131","author":"KA Morris","year":"2017","unstructured":"Morris KA, Golding JF, Blesing C et al (2017) Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort. J Neurooncol 131:117\u2013124. https:\/\/doi.org\/10.1007\/s11060-016-2276-9","journal-title":"J Neurooncol"},{"key":"5621_CR45","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1093\/neuonc\/noz002","volume":"21","author":"MA Fuse","year":"2019","unstructured":"Fuse MA, Dinh CT, Vitte J et al (2019) Preclinical assessment of MEK1\/2 inhibitors for neurofibromatosis type 2\u2013associated schwannomas reveals differences in efficacy and drug resistance development. Neuro Oncol 21:486\u2013497. https:\/\/doi.org\/10.1093\/neuonc\/noz002","journal-title":"Neuro Oncol"},{"key":"5621_CR46","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1136\/jmedgenet-2017-104519","volume":"54","author":"D Halliday","year":"2017","unstructured":"Halliday D, Emmanouil B, Pretorius P et al (2017) Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet 54:657. https:\/\/doi.org\/10.1136\/jmedgenet-2017-104519","journal-title":"J Med Genet"},{"key":"5621_CR47","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s00401-016-1540-6","volume":"131","author":"M R\u00f6hrich","year":"2016","unstructured":"R\u00f6hrich M, Koelsche C, Schrimpf D et al (2016) Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol 131:877\u2013887. https:\/\/doi.org\/10.1007\/s00401-016-1540-6","journal-title":"Acta Neuropathol"},{"key":"5621_CR48","doi-asserted-by":"publisher","unstructured":"Huegel J, Dinh CT, Martinelli M, et al (2022) CUDC907, a dual phosphoinositide-3 kinase\/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells. Oncotarget 13:890\u2013904. Published 2022 Jul 19. https:\/\/doi.org\/10.18632\/oncotarget.28254","DOI":"10.18632\/oncotarget.28254"},{"key":"5621_CR49","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.1038\/s41388-024-03144-8","volume":"43","author":"MA Gonz\u00e1lez-Rodriguez","year":"2024","unstructured":"Gonz\u00e1lez-Rodriguez MA, Troutman S, Bayle S et al (2024) Synergistic effects of combined BET and FAK inhibition against Vestibular Schwannomas in NF2-related Schwannomatosis. Oncogene 43:2995\u20133002. https:\/\/doi.org\/10.1038\/s41388-024-03144-8","journal-title":"Oncogene"},{"key":"5621_CR50","doi-asserted-by":"publisher","unstructured":"Petrilli A, Bott M, Fern\u00e1ndez-Valle C (2013) Inhibition of SIRT2 in merlin\/NF2-mutant Schwann cells triggers necrosis. Oncotarget 4(12):2354\u20132365. https:\/\/doi.org\/10.18632\/oncotarget.1422","DOI":"10.18632\/oncotarget.1422"},{"key":"5621_CR51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065868","author":"M Torres-Martin","year":"2013","unstructured":"Torres-Martin M, Lassaletta L, de Campos JM et al (2013) Global Profiling in Vestibular Schwannomas Shows Critical Deregulation of MicroRNAs and Upregulation in Those Included in Chromosomal Region 14q32. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0065868. 8:","journal-title":"PLoS ONE"},{"key":"5621_CR52","doi-asserted-by":"publisher","first-page":"e25","DOI":"10.1016\/j.wneu.2020.11.043","volume":"147","author":"X Yin","year":"2021","unstructured":"Yin X, Huo Z, Yan S et al (2021) MiR-205 Inhibits Sporadic Vestibular Schwannoma Cell Proliferation by Targeting Cyclin-Dependent Kinase 14. World Neurosurg 147:e25\u2013e31. https:\/\/doi.org\/10.1016\/j.wneu.2020.11.043","journal-title":"World Neurosurg"},{"key":"5621_CR53","doi-asserted-by":"publisher","first-page":"e66","DOI":"10.1016\/j.wneu.2021.09.094","volume":"157","author":"J Shi","year":"2022","unstructured":"Shi J, Lu D, Gu R et al (2022) Integrated Analysis of Transcriptome and Differential Methylation of Neurofibromatosis Type 2 Vestibular Schwannomas. World Neurosurg 157:e66\u2013e76. https:\/\/doi.org\/10.1016\/j.wneu.2021.09.094","journal-title":"World Neurosurg"},{"key":"5621_CR54","doi-asserted-by":"publisher","first-page":"4301","DOI":"10.1080\/21655979.2022.2031410","volume":"13","author":"G Xiao","year":"2022","unstructured":"Xiao G, Huang B, Guo M et al (2022) Long non-coding RNA BRCAT54 sponges microRNA-21 in vestibular schwannoma to suppress cell proliferation. Bioengineered 13:4301\u20134308. https:\/\/doi.org\/10.1080\/21655979.2022.2031410","journal-title":"Bioengineered"},{"key":"5621_CR55","doi-asserted-by":"publisher","unstructured":"Fujita T, Seist R, Kao SY et al (2023) miR-431 secreted by human vestibular schwannomas increases the mammalian inner ear\u2019s vulnerability to noise trauma. Front Neurol 14. https:\/\/doi.org\/10.3389\/fneur.2023.1268359","DOI":"10.3389\/fneur.2023.1268359"},{"key":"5621_CR56","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1007\/s00701-020-04238-4","volume":"162","author":"HCR Sass","year":"2020","unstructured":"Sass HCR, Hansen M, Borup R et al (2020) Tumor miRNA expression profile is related to vestibular schwannoma growth rate. Acta Neurochir (Wien) 162:1187\u20131195. https:\/\/doi.org\/10.1007\/s00701-020-04238-4","journal-title":"Acta Neurochir (Wien)"},{"key":"5621_CR57","doi-asserted-by":"crossref","unstructured":"Altuna X, Lopez JP, Yu MA et al (2011) Potential role of imatinib mesylate (Gleevec, STI-571) in the treatment of vestibular schwannoma. Otol Neurotol 32","DOI":"10.1097\/MAO.0b013e3182009665"},{"key":"5621_CR58","doi-asserted-by":"publisher","first-page":"e39412","DOI":"10.1371\/journal.pone.0039412","volume":"7","author":"N Sabha","year":"2012","unstructured":"Sabha N, Au K, Agnihotri S et al (2012) Investigation of the In Vitro Therapeutic Efficacy of Nilotinib in Immortalized Human NF2-Null Vestibular Schwannoma Cells. PLoS ONE 7:e39412","journal-title":"PLoS ONE"},{"key":"5621_CR59","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/nbt.3781","volume":"35","author":"LD Landegger","year":"2017","unstructured":"Landegger LD, Pan B, Askew C et al (2017) A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol 35:280\u2013284. https:\/\/doi.org\/10.1038\/nbt.3781","journal-title":"Nat Biotechnol"},{"key":"5621_CR60","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1177\/0194599815601070","volume":"154","author":"C H\u0131zl\u0131 \u00d6mer","year":"2016","unstructured":"H\u0131zl\u0131 \u00d6mer C, Sebahattin K, Serdar et al (2016) Quantitative Vestibular Labyrinthine Otopathology in Temporal Bones with Vestibular Schwannoma. Otolaryngology\u2013Head Neck Surg 154:150\u2013156. https:\/\/doi.org\/10.1177\/0194599815601070","journal-title":"Otolaryngology\u2013Head Neck Surg"},{"key":"5621_CR61","doi-asserted-by":"publisher","first-page":"14118","DOI":"10.1038\/s41598-024-64352-6","volume":"14","author":"J Edvardsson Rasmussen","year":"2024","unstructured":"Edvardsson Rasmussen J, Li P, Laurell G et al (2024) Hearing loss and its association with the proteome of perilymph, cerebrospinal fluid, and tumor tissue in patients with vestibular schwannoma. Sci Rep 14:14118. https:\/\/doi.org\/10.1038\/s41598-024-64352-6","journal-title":"Sci Rep"},{"key":"5621_CR62","doi-asserted-by":"publisher","first-page":"18599","DOI":"10.1038\/srep18599","volume":"5","author":"S Dilwali","year":"2015","unstructured":"Dilwali S, Landegger LD, Soares VYR et al (2015) Secreted Factors from Human Vestibular Schwannomas Can Cause Cochlear Damage. Sci Rep 5:18599. https:\/\/doi.org\/10.1038\/srep18599","journal-title":"Sci Rep"},{"key":"5621_CR63","doi-asserted-by":"crossref","unstructured":"Breun M, Monoranu CM, Kessler AF et al (2019) [68Ga]-pentixafor PET\/CT for CXCR4-mediated imaging of vestibular schwannomas. Front Oncol 9","DOI":"10.3389\/fonc.2019.00503"},{"key":"5621_CR64","doi-asserted-by":"crossref","unstructured":"Early S, Brown A, Xu L, Stankovic KM (2025) Angiotensin-receptor blockers prevent vestibular schwannoma\u2013associated hearing loss. Otol Neurotol 46","DOI":"10.1097\/MAO.0000000000004376"},{"key":"5621_CR65","doi-asserted-by":"publisher","first-page":"6595","DOI":"10.1038\/s41598-023-33812-w","volume":"13","author":"N Oishi","year":"2023","unstructured":"Oishi N, Noguchi M, Fujioka M et al (2023) Correlation between genotype and phenotype with special attention to hearing in 14 Japanese cases of NF2-related schwannomatosis. Sci Rep 13:6595. https:\/\/doi.org\/10.1038\/s41598-023-33812-w","journal-title":"Sci Rep"},{"key":"5621_CR66","doi-asserted-by":"crossref","unstructured":"Lassaletta L, Calvino M, Morales-Puebla JM et al (2019) Biomarkers in vestibular schwannoma\u2013associated hearing loss. Front Neurol 10","DOI":"10.3389\/fneur.2019.00978"},{"key":"5621_CR67","doi-asserted-by":"publisher","first-page":"e46132","DOI":"10.1371\/journal.pone.0046132","volume":"7","author":"AR Asthagiri","year":"2012","unstructured":"Asthagiri AR, Vasquez RA, Butman JA et al (2012) Mechanisms of Hearing Loss in Neurofibromatosis Type 2. PLoS ONE 7:e46132","journal-title":"PLoS ONE"},{"key":"5621_CR68","doi-asserted-by":"publisher","unstructured":"Lassaletta L, Bello MJ, Del R\u00edo L et al (2006) DNA methylation of multiple genes in vestibular schwannoma: Relationship with clinical and radiological findings. Otol Neurotol 27(8):1180\u20131185. https:\/\/doi.org\/10.1097\/01.mao.0000226291.42165.22","DOI":"10.1097\/01.mao.0000226291.42165.22"},{"key":"5621_CR69","doi-asserted-by":"publisher","unstructured":"Pozniak CD, Radinovic S, Yang A et al (2000) An Anti-Apoptotic Role for the p53 Family Member, p73, During Developmental Neuron Death. Sci (1979) 289:304\u2013306. https:\/\/doi.org\/10.1126\/science.289.5477.304","DOI":"10.1126\/science.289.5477.304"}],"container-title":["Journal of Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11060-026-05621-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11060-026-05621-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11060-026-05621-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:40:53Z","timestamp":1781012453000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11060-026-05621-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":69,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["5621"],"URL":"https:\/\/doi.org\/10.1007\/s11060-026-05621-4","relation":{},"ISSN":["0167-594X","1573-7373"],"issn-type":[{"value":"0167-594X","type":"print"},{"value":"1573-7373","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"27 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}