Molecular biology of sporadic vestibular schwannomas including genetic and epigenetic alterations

2020 ◽  
Vol 9 (3) ◽  
pp. 23-29
Author(s):  
Maria Makuszewska ◽  
Małgorzata Litwiniuk-Kosmala ◽  
Robert Bartoszewicz ◽  
Kazimierz Niemczyk
Keyword(s):  
Molecular Biology ◽  
Current Knowledge ◽  
Expression Profiles ◽  
Neurofibromatosis Type ◽  
Nerve Fibers ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Slow Growth Rate ◽  
Brainstem Compression ◽  
Altered Gene

Introduction: Vestibular schwannomas (VSs) are benign tumors, developing from neoplastic Schwann cells, that produce myelin sheath covering vestibular nerve fibers. The majority of these tumors are sporadic VS and very rarely they can be associated with neurofibromatosis type 2 (NF2). VSs are usually characterized with slow growth rate, however some of them appear to have a cystic structure, grow more rapidly, can cause facial nerve palsy and brainstem compression. The molecular hallmark of both sporadic and NF-2 associated VS is the inactivation of supresor gene NF-2, also called merlin gene. Aim: In this review we summarize the current knowledge on the molecular biology of VS, including genetic and epigenetic aberrations, altered gene expression and specific microRNA expression profiles.

scholarly journals Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4575
Author(s):  
Torin P. Thielhelm ◽  
Stefania Goncalves ◽  
Scott M. Welford ◽  
Eric A. Mellon ◽  
Erin R. Cohen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Current Knowledge ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Intracranial Tumors ◽  
Treatment Protocols ◽  
Cycle Arrest ◽  
Microsurgical Resection ◽  
Cranial Nerve Viii ◽  
Key Events

Vestibular schwannomas (VS) are benign tumors arising from cranial nerve VIII that account for 8–10% of all intracranial tumors and are the most common tumors of the cerebellopontine angle. These tumors are typically managed with observation, radiation therapy, or microsurgical resection. Of the VS that are irradiated, there is a subset of tumors that are radioresistant and continue to grow; the mechanisms behind this phenomenon are not fully understood. In this review, the authors summarize how radiation causes cellular and DNA injury that can activate (1) checkpoints in the cell cycle to initiate cell cycle arrest and DNA repair and (2) key events that lead to cell death. In addition, we discuss the current knowledge of VS radiobiology and how it may contribute to clinical outcomes. A better understanding of VS radiobiology can help optimize existing treatment protocols and lead to new therapies to overcome radioresistance.

Clinical, pathologic, and radiologic response in patients with neurofibromatosis type 2 (NF2) undergoing bevacizumab treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13049-e13049
Author(s):  
Niamh Coleman ◽  
Megan Greally ◽  
Lynda O' Riordan ◽  
Teresa Doyle ◽  
Oscar S. Breathnach ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Energy Levels ◽  
Neurofibromatosis Type ◽  
Vestibular Schwannomas ◽  
Response To Treatment ◽  
Benign Tumors ◽  
Subjective Response ◽  
Mri Imaging ◽  
Profound Hearing Loss ◽  
Bevacizumab Treatment

e13049 Background: NF2 is a rare inherited genetic condition characterized by multiple "benign" tumors in the peripheral and central nervous system. Profound hearing loss as a result of bilateral vestibular schwannomas is a major debilitating complication with a profound effect on quality of life. Vascular endothelial growth factor (VEGF) has been shown to be produced by vestibular schwannoma tumor cells. Bevacizumab, a humanized monoclonal antibody against VEGF, has been proposed as a treatment for patients with advanced NF2, who are poor candidates for surgery and radiation therapy. The aim of this study was to investigate and assess the benefit of treatment with bevacizumab in the treatment of patients with advanced NF2. Methods: Five patients with inoperable NF2 were assessed prospectively from 03/12-01/13. Pathological assessment of tissue for vascularity was performed in each of the patients’ tissue. Objective assessments, including audiogram and MRI brain, were performed pre- and during therapy. Qualitative assessments were undertaken to assess subjective response to treatment. Results: We identified 5 patients with advanced NF2 [n=5], 3 female 2 male with a median age 40 years [range 28 – 52] as outlined in the Table. Tumor-volume reduction of >20% was noted on MRI imaging in the vestibular schwannomas of 2 patients. 2 patients showed objective improvement on audiogram with subjective hearing improvement also noted. Other subjective responses noted include increased energy levels, less headaches, better concentration. Conclusions: Bevacizumab treatment in patients with advanced NF2 resulted in some symptomatic improvement, tumour shrinkage, improvement in disability. Patients with vestibular schwannomas appeared to receive the most benefit, and so in terms of palliation, the benefits may be most significant in patients with specific disabilities, such as hearing loss. [Table: see text]

The molecular biology and novel treatments of vestibular schwannomas

2011 ◽  
Vol 115 (5) ◽  
pp. 906-914 ◽  
Author(s):  
Brendan Fong ◽  
Garni Barkhoudarian ◽  
Patrick Pezeshkian ◽  
Andrew T. Parsa ◽  
Quinton Gopen ◽  
...  
Keyword(s):  
Molecular Biology ◽  
Vestibular Schwannoma ◽  
Cranial Nerve ◽  
Molecular Mechanisms ◽  
Tumor Burden ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Novel Therapies ◽  
Phase Ii Trials

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin. Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development. Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment. In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus with E3 ubiquitin ligase CRL4DCAF1. A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma. Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation. With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.

Molecular biology of familial and sporadic vestibular schwannomas: implications for novel therapeutics

2011 ◽  
Vol 114 (2) ◽  
pp. 359-366 ◽  
Author(s):  
Michael E. Sughrue ◽  
Andrea H. Yeung ◽  
Martin J. Rutkowski ◽  
Steven W. Cheung ◽  
Andrew T. Parsa
Keyword(s):  
Molecular Biology ◽  
Cranial Nerve ◽  
Single Gene ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Genetic Mutations ◽  
Chromosome 22 ◽  
Novel Therapeutics ◽  
Broad Variety ◽  
Cranial Nerve Viii

Vestibular schwannomas (VSs) are benign tumors arising from the sheath of cranial nerve VIII. The pathogenesis underlying most familial and sporadic VSs has been linked to a mutation in a single gene, the neurofibromin 2 (NF2) gene located on chromosome 22, band q11–13.1. In this review, the authors summarized what is known about the epidemiology of NF2 mutations and patients with VSs. The authors also discuss the function of the NF2 gene product, merlin, and describe the known and hypothetical effects of genetic mutations that lead to merlin dysfunction on a broad variety of cellular and histological end points. A better understanding of the molecular pathobiology of VSs may lead to novel therapeutics to augment current modalities of treatment while minimizing morbidity.

Surgical Management of Vestibular Schwannomas in Neurofibromatosis Type 2

2012 ◽  
Vol 73 (S 02) ◽  
Author(s):  
J. Tysome ◽  
R. MacFarlane ◽  
J. Durie-Gair ◽  
N. Donnelly ◽  
R. Mannion ◽  
...  
Keyword(s):  
Surgical Management ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas

scholarly journals Biologically effective dose correlates with linear tumor volume changes after upfront single-fraction stereotactic radiosurgery for vestibular schwannomas

2021 ◽  
Author(s):  
Constantin Tuleasca ◽  
Mohamed Faouzi ◽  
Philippe Maeder ◽  
Raphael Maire ◽  
Jonathan Knisely ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Effective Dose ◽  
Stereotactic Radiosurgery ◽  
Tumor Volume ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Biologically Effective Dose ◽  
Volume Changes ◽  
Single Fraction

AbstractVestibular schwannomas (VSs) are benign, slow-growing tumors. Management options include observation, surgery, and radiation. In this retrospective trial, we aimed at evaluating whether biologically effective dose (BED) plays a role in tumor volume changes after single-fraction first intention stereotactic radiosurgery (SRS) for VS. We compiled a single-institution experience (n = 159, Lausanne University Hospital, Switzerland). The indication for SRS was decided after multidisciplinary discussion. Only cases with minimum 3 years follow-up were included. The Koos grading, a reliable method for tumor classification was used. Radiosurgery was performed using Gamma Knife (GK) and a uniform marginal prescription dose of 12 Gy. Mean BED was 66.3 Gy (standard deviation 3.8, range 54.1–73.9). The mean follow-up period was 5.1 years (standard deviation 1.7, range 3–9.2). The primary outcome was changes in 3D volumes after SRS as function of BED and of integral dose received by the VS. Random-effect linear regression model showed that tumor volume significantly and linearly decreased over time with higher BED (p < 0.0001). Changes in tumor volume were also significantly associated with age, sex, number of isocenters, gradient index, and Koos grade. However, the effect of BED on tumor volume change was moderated by time after SRS and Koos grade. Lower integral doses received by the VSs were inversely correlated with BED in relationship with tumor volume changes (p < 0.0001). Six (3.4%) patients needed further intervention. For patients having uniformly received the same marginal dose prescription, higher BED linearly and significantly correlated with tumor volume changes after SRS for VSs. BED could represent a potential new treatment paradigm for patients with benign tumors, such as VSs, for attaining a desired radiobiological effect. This could further increase the efficacy and decrease the toxicity of SRS not only in benign tumors but also in other SRS indications.

Management of Neurofibromatosis Type 2 Associated Vestibular Schwannomas

2021 ◽  
Vol 9 (2) ◽  
pp. 170-176
Author(s):  
Huan Jia ◽  
Ghizlene Lahlou ◽  
Hao Wu ◽  
Olivier Sterkers ◽  
Michel Kalamarides
Keyword(s):  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas
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