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International Journal of Molecular... May 2021Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal... (Review)
Review
Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.
Topics: Animals; Biomarkers, Tumor; Clinical Trials as Topic; Disease Models, Animal; Disease Susceptibility; Genes, Neurofibromatosis 1; Genes, Neurofibromatosis 2; Genetic Predisposition to Disease; Humans; Models, Biological; Molecular Targeted Therapy; Mutation; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis 2; Protein Kinase Inhibitors; Skin Neoplasms; Treatment Outcome
PubMed: 34072574
DOI: 10.3390/ijms22115850 -
Head and Neck Pathology Dec 2020Vestibular schwannoma (VS) is a Schwann cell-derived tumour arising from the vestibulocochlear nerve. Although benign, it represents a threat to intracranial structures... (Review)
Review
Vestibular schwannoma (VS) is a Schwann cell-derived tumour arising from the vestibulocochlear nerve. Although benign, it represents a threat to intracranial structures due to mass effect and carries a small risk of malignant transformation. VS therefore represents an important healthcare burden. We review the literature regarding pathogenesis, risk factors, and diagnosis of VS. The current and future potential management strategies are also discussed. A narrative review of all relevant papers known to the authors was conducted. The majority of VS remain clinically stable and do not require interventional procedures. Nevertheless, various surgical techniques exist for removing VS, the most common of which are translabyrinthine and retrosigmoid approaches. Due to surgical risks such as hearing loss, facial nerve dysfunction, post-operative headache, and cerebrospinal fluid leakage, a "watch and rescan" approach is adopted for most patients. Radiotherapy is a useful alternative and has been shown to have a similar response for growth restriction. Due to the heterogeneous nature of VS, there is a lack of consensus regarding management of tumours that are too large for conservative management but too small to indicate surgery. Emerging biologic therapies, such as Bevacizumab, Everolimus, and Lapatinib, as well as anti-inflammatories like aspirin are promising potential treatments; however, long-term evidence of their efficacy is required. The knowledge base regarding VS continues to improve. With increased understanding of the pathogenesis of these tumors, we believe future work should focus on pharmacologic intervention. Biologic therapies aimed toward improved patient outcomes are particularly promising.
Topics: Humans; Neuroma, Acoustic; Risk Factors
PubMed: 32232723
DOI: 10.1007/s12105-020-01155-x -
Neuro-oncology Jan 2020The level of evidence to provide treatment recommendations for vestibular schwannoma is low compared with other intracranial neoplasms. Therefore, the vestibular...
The level of evidence to provide treatment recommendations for vestibular schwannoma is low compared with other intracranial neoplasms. Therefore, the vestibular schwannoma task force of the European Association of Neuro-Oncology assessed the data available in the literature and composed a set of recommendations for health care professionals. The radiological diagnosis of vestibular schwannoma is made by magnetic resonance imaging. Histological verification of the diagnosis is not always required. Current treatment options include observation, surgical resection, fractionated radiotherapy, and radiosurgery. The choice of treatment depends on clinical presentation, tumor size, and expertise of the treating center. In small tumors, observation has to be weighed against radiosurgery, in large tumors surgical decompression is mandatory, potentially followed by fractionated radiotherapy or radiosurgery. Except for bevacizumab in neurofibromatosis type 2, there is no role for pharmacotherapy.
Topics: Humans; Neuroma, Acoustic
PubMed: 31504802
DOI: 10.1093/neuonc/noz153 -
Acta Neuropathologica Apr 2020Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from... (Review)
Review
Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDA-approved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research.
Topics: Central Nervous System Diseases; Genetic Predisposition to Disease; Humans; Neurofibromatosis 2
PubMed: 31161239
DOI: 10.1007/s00401-019-02029-5 -
JAMA Aug 2023Current guidelines for treating small- to medium-sized vestibular schwannoma recommend either upfront radiosurgery or waiting to treat until tumor growth has been... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Current guidelines for treating small- to medium-sized vestibular schwannoma recommend either upfront radiosurgery or waiting to treat until tumor growth has been detected radiographically.
OBJECTIVE
To determine whether upfront radiosurgery provides superior tumor volume reduction to a wait-and-scan approach for small- to medium-sized vestibular schwannoma.
DESIGN, SETTING, AND PARTICIPANTS
Randomized clinical trial of 100 patients with a newly diagnosed (<6 months) unilateral vestibular schwannoma and a maximal tumor diameter of less than 2 cm in the cerebellopontine angle as measured on magnetic resonance imaging. Participants were enrolled at the Norwegian National Unit for Vestibular Schwannoma from October 28, 2014, through October 3, 2017; 4-year follow-up ended on October 20, 2021.
INTERVENTIONS
Participants were randomized to receive either upfront radiosurgery (n = 50) or to undergo a wait-and-scan protocol, for which treatment was given only upon radiographically documented tumor growth (n = 50). Participants underwent 5 annual study visits consisting of clinical assessment, radiological examination, audiovestibular tests, and questionnaires.
MAIN OUTCOMES AND MEASURES
The primary outcome was the ratio between tumor volume at the trial end at 4 years and baseline (V4:V0). There were 26 prespecified secondary outcomes, including patient-reported symptoms, clinical examinations, audiovestibular tests, and quality-of-life outcomes. Safety outcomes were the risk of salvage microsurgery and radiation-associated complications.
RESULTS
Of the 100 randomized patients, 98 completed the trial and were included in the primary analysis (mean age, 54 years; 42% female). In the upfront radiosurgery group, 1 participant (2%) received repeated radiosurgery upon tumor growth, 2 (4%) needed salvage microsurgery, and 45 (94%) had no additional treatment. In the wait-and-scan group, 21 patients (42%) received radiosurgery upon tumor growth, 1 (2%) underwent salvage microsurgery, and 28 (56%) remained untreated. For the primary outcome of the ratio of tumor volume at the trial end to baseline, the geometric mean V4:V0 was 0.87 (95% CI, 0.66-1.15) in the upfront radiosurgery group and 1.51 (95% CI, 1.23-1.84) in the wait-and-scan group, showing a significantly greater tumor volume reduction in patients treated with upfront radiosurgery (wait-and-scan to upfront radiosurgery ratio, 1.73; 95% CI, 1.23-2.44; P = .002). Of 26 secondary outcomes, 25 showed no significant difference. No radiation-associated complications were observed.
CONCLUSION AND RELEVANCE
Among patients with newly diagnosed small- and medium-sized vestibular schwannoma, upfront radiosurgery demonstrated a significantly greater tumor volume reduction at 4 years than a wait-and-scan approach with treatment upon tumor growth. These findings may help inform treatment decisions for patients with vestibular schwannoma, and further investigation of long-term clinical outcomes is needed.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02249572.
Topics: Female; Humans; Male; Middle Aged; Neuroma, Acoustic; Radiosurgery; Retrospective Studies; Treatment Outcome; Watchful Waiting; Magnetic Resonance Imaging; Cerebellopontine Angle; Salvage Therapy; Microsurgery
PubMed: 37526718
DOI: 10.1001/jama.2023.12222 -
International Journal of Molecular... Jan 2021Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common... (Review)
Review
Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.
Topics: Animals; Apoptosis; Brain Neoplasms; Cell Proliferation; Humans; Meningeal Neoplasms; Meningioma; Mutation; Neurofibromatosis 2; Neuroma, Acoustic
PubMed: 33445724
DOI: 10.3390/ijms22020690 -
International Journal of Molecular... May 2022Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the... (Review)
Review
Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS.
Topics: High-Temperature Requirement A Serine Peptidase 1; Humans; Neurilemmoma; Neurofibromatosis 2; Neuroma, Acoustic; Phosphatidylinositol 3-Kinases; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 35628268
DOI: 10.3390/ijms23105462 -
Environment International May 2024Some have looked forward to the publication of the results of the COSMOS study on brain tumors, because the potential biases from retrospective investigations...
Some have looked forward to the publication of the results of the COSMOS study on brain tumors, because the potential biases from retrospective investigations predominating the search for brain tumor risks of mobile phone use since the late 1990 s were deemed unresolvable by further investigations of that type. Indeed, prospective cohort studies typically have the advantage of being not or less affected by differential exposure misclassification, recall and selection bias, and, as they proceed in the direction of the time arrow, results are more easily interpreted in terms of causation. However, results of the COSMOS study published now in this journal are not of help for the risk assessment of mobile phone use and do not support the conclusions of the authors that their findings "suggest that the cumulative amount of mobile phone use is not associated with the risk of developing glioma, meningioma, or acoustic neuroma".
Topics: Brain Neoplasms; Humans; Cell Phone; Prospective Studies; Cohort Studies; Bias; Risk Assessment; Glioma; Meningioma; Neuroma, Acoustic; Radiation Exposure; Young Adult; Adult; Middle Aged; Aged
PubMed: 38677087
DOI: 10.1016/j.envint.2024.108665