Browsing by Subject "Schwannoma"

Now showing 1 - 5 of 5
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    The importance of nerve microenvironment for schwannoma development
    (Springer-Verlag, 2016-08) Schulz, Alexander; Büttner, Robert; Hagel, Christian; Baader, Stephan L.; Kluwe, Lan; Salamon, Johannes; Mautner, Victor-Felix; Mindos, Thomas; Parkinson, David B.; Gehlhausen, Jeffrey R.; Clapp, D. Wade; Morrison, Helen; Department of Pediatrics, IU School of Medicine
    Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous nf2 gene deletion in Schwann cells and in animals with heterozygous nf2 knockout in both Schwann cells and axons. However, patient-mimicking schwannomas could only be provoked in animals with combined heterozygous nf2 knockout in Schwann cells and axons. We identified a severe re-myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation-emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas.
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    An Investigation of Molecular Pathways to Aid in Therapeutic Development for Neurofibromatosis Type 2
    (2019-05) Hawley, Eric Thomas; Clapp, D. Wade; Goebl, Mark G.; Harrington, Maureen A.; Mirmira, Raghu G.
    Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition in which loss of heterozygosity at the NF2 gene locus leads to the development of tumors of neural crest derived origin, most commonly bilateral vestibular schwannomas. There are currently no FDA approved chemotherapeutic agents for treatment in patients with NF2. Development of therapeutic agents has been hampered by our incomplete knowledge of how Merlin, the protein product of the NF2 gene, functions as a tumor suppressor. In order develop a deeper understanding for how loss of Merlin leads to oncogenic transformation in Schwann cells we have developed a genetically engineered mouse model (GEMM) of Neurofibromatosis Type 2 in which functional expression of Merlin is lost in Schwann cell precursors. In parallel studies utilizing these mice, we have sought to understand the pathophysiology driving tumor formation in Merlin deficient Schwann cells. In Chapter 1, we explore the role of Merlin as a negative regulator of the Group A p21 activated kinases, PAK1 and PAK2. We demonstrate that PAK1, a previously well established oncogene in solid tumors and Merlin binding partner, is hyperactivated in Merlin deficient schwannomas. Through therapeutic interventions and genetic manipulations we demonstrate that inhibition of PAK1 was capable of reducing tumor formation and alleviating sensorineural hearing loss in our NF2 GEMM. In Chapter 2, we investigate the role of NF-kB inducing kinase (NIK) and NF-kB signaling in the formation and growth of Merlin deficient Schwann cell tumors. Prior work in our lab as well as by others demonstrated elevated NF-kB signaling in Merlin deficient Schwann cell tumors. We observed accumulation of a catalytically active fragment of NF-kB inducing kinase and present data that accumulation of a 55Kd constitutively active fragment of NIK is sufficient trigger wild type Schwann cells to form tumors. In vivo however, Schwann cell intrinsic expression of NIK is not required for tumor formation or growth.
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    Phenotypic and molecular characterization of a novel mouse model of neurofibromatosis type 2
    (2015-05) Gehlhausen, Jeff R.; Clapp, D. Wade; Goebl, Mark G.; Harrington, Maureen A.; Nalepa, Grzegorz J.
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    Schwannoma-associated third nerve palsy: A pediatric case report
    (Elsevier, 2022-03-30) Moeller, Ashley A.; Sokol, Louis A.; Ho, Chang Y.; Neurology, School of Medicine
    Acquired third nerve palsies are infrequently seen in children, but are often associated with serious pathologies. This article presents a pediatric case of tumor-associated, isolated third nerve palsy, which took two years to diagnose. The patient initially presented with an isolated, dilated pupil and progressed over several months to a complete third nerve palsy. In this case, high-resolution neuroimaging eventually led to the diagnosis of a presumed schwannoma as the cause of her third nerve palsy. We review her case, the importance of high-resolution imaging, and management options.
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    Surgical Management of Craniovertebral Junction Schwannomas: A Systematic Review
    (MDPI, 2022-07-09) Palmisciano, Paolo; Ferini, Gianluca; Watanabe, Gina; Conching, Andie; Ogasawara, Christian; Scalia, Gianluca; Bin-Alamer, Othman; Haider, Ali S.; Passanisi, Maurizio; Maugeri, Rosario; Hoz, Samer S.; Baldoncini, Matias; Campero, Alvaro; Salvati, Maurizio; Cohen-Gadol, Aaron A.; Umana, Giuseppe E.; Neurological Surgery, School of Medicine
    Background: Craniovertebral junction (CVJ) schwannomas are rare, with surgery and stereotactic radiosurgery (SRS) being effective yet challenging options. We systematically reviewed the literature on CVJ schwannomas. Methods: PubMed, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA statement to include studies reporting CVJ schwannomas. Clinical features, management, and outcomes were analyzed. Results: We collected 353 patients from 101 included articles. Presenting symptoms were mostly neck pain (30.3%) and headache (26.3%), with most cranial neuropathies involving the XII (31.2%) and X (24.4%) nerves. Most tumors originated from C2 (30.9%) and XII (29.4%) nerves, being extracranial (45.1%) and intradural-extradural (44.2%). Erosion of C1–C2 vertebrae (37.1%), the hypoglossal canal (28.3%), and/or jugular foramen (20.1%) were noted. All tumors were operated, preferably with the retrosigmoid approach (36.5%), with the far-lateral approach (29.7%) or with the posterior approach and cervical laminectomy (26.9%), far-lateral approaches (14.2%), or suboccipital craniotomy with concurrent cervical laminectomy (14.2%). Complete tumor resection was obtained most frequently (61.5%). Adjuvant post-surgery stereotactic radiosurgery was delivered in 5.9% patients. Median follow-up was 27 months (range, 12–252). Symptom improvement was noted in 88.1% of cases, and cranial neuropathies showed improvement in 10.2%. Post-surgical complications occurred in 83 patients (23.5%), mostly dysphagia (7.4%), new cranial neuropathies (6.2%), and cerebrospinal fluid leak (5.9%). A total of 16 patients (4.5%) had tumor recurrence and 7 died (2%), with median overall survival of 2.7 months (range, 0.1–252). Conclusions: Microsurgical resection is safe and effective for CVJ schwannomas. Data on SRS efficacy and indications are still lacking, and its role deserves further evaluation.