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Scientific Reports Dec 2023It is difficult to distinguish other pathologies mimicking Ménière's disease (MD) clinically. This study aims to investigate the differences of imaging findings and...
It is difficult to distinguish other pathologies mimicking Ménière's disease (MD) clinically. This study aims to investigate the differences of imaging findings and features between MD and other menieriform diseases via intravenous gadolinium-enhanced magnetic resonance imaging (MRI). 426 patients with menieriform symptoms, including MD, vestibular migraine (VM), and vestibular schwannoma (VS), underwent 3D-FLAIR and 3D-T2WI MRI 6 h after the intravenous gadolinium injection. MR images were analyzed for inner ear morphology, perilymphatic enhancement (PE), EH and other abnormalities. EH was observed at a higher rate in MD patients (85.71%) than patients with other menieriform diseases (VM group = 14.75%, VS group = 37.50%). The prevalence of unilateral EH as well as both cochlear and vestibular EH showed significant differences between MD and VM groups. The prevalence of cochlear EH (I and II) and vestibular EH (II and III) was different between MD and VM groups. The prevalence of PE was higher in MD than VM group. The degrees of cochlear and vestibular hydrops were higher in the definite than probable MD group (P < 0.05). Using these imaging features, MRI can be used to help differentiate MD from other menieriform diseases.
Topics: Humans; Meniere Disease; Endolymphatic Hydrops; Gadolinium; Vestibule, Labyrinth; Vertigo; Magnetic Resonance Imaging; Neuroma, Acoustic; Migraine Disorders
PubMed: 38057393
DOI: 10.1038/s41598-023-49066-5 -
Audiology Research Jul 2023to evaluate recent contributions to the literature on prognostic factors of hearing preservation in small vestibular schwannoma microsurgery. (Review)
Review
OBJECTIVE
to evaluate recent contributions to the literature on prognostic factors of hearing preservation in small vestibular schwannoma microsurgery.
METHODS
review of the most recent studies.
RESULTS
factors such as tumor size, preoperative hearing status, tumor growth rate, tumor origin, surgical approach, radiological characteristics, results of preoperative neurophysiological tests, preoperative symptoms and demographic features have been investigated and some of them reported to be significant in the prediction of hearing preservation.
CONCLUSIONS
tumor size and preoperative hearing status are the most impactful factors and play a key role in patient selection for hearing preservation surgery. Other features such as fundal extension, tumor origin and impaired ABR could have prognostic value on hearing preservation. Tumor growth rate, preoperative impedance, cVEMPs and age have also recently been found to be significant, but more studies are needed. The role of preoperative tinnitus, vertigo and gender is lacking and controversial, whereas the differences between available surgical approaches have been smoothed out in recent years.
PubMed: 37489378
DOI: 10.3390/audiolres13040042 -
Molecular Cancer Therapeutics Nov 2023Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor....
Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.
Topics: Humans; Neurofibromatosis 2; Neurofibromin 2; Phosphatidylinositol 3-Kinases; Focal Adhesion Protein-Tyrosine Kinases; Dasatinib; Phosphatidylinositol 3-Kinase; Neurilemmoma; Antineoplastic Agents; Cell Proliferation
PubMed: 37527526
DOI: 10.1158/1535-7163.MCT-23-0135 -
Journal of Clinical Neuroscience :... Oct 2023Acoustic neuroma (AN) research largely employs a medical framework to understand health outcomes. An alternative is to examine quality of life (QOL) outcomes. This study...
INTRODUCTION
Acoustic neuroma (AN) research largely employs a medical framework to understand health outcomes. An alternative is to examine quality of life (QOL) outcomes. This study explored whether mental well-being (i.e., anxiety and depression) were predictive of QOL in those with AN over and above symptomatology.
METHODS
A nationwide online survey was distributed to 24 community organisations. The inclusion criteria were a diagnosis of AN irrespective of the treatment approach. There were 52 respondents. Mental well-being was assessed using the Hospital Anxiety and Depression Scale (HADS), and quality of life was assessed using Penn Acoustic Neuroma QOL scale (PANQOL).
RESULTS
The most frequently reported symptoms reported were poor balance, tinnitus, hearing loss, and headache. Preliminary analyses suggested that headaches, tinnitus and mental well-being were significantly correlated with QOL. Hierarchical regression revealed that these two symptoms and mental well-being accounted for 18.7% and 51.1% of the variance in QOL, respectively. In addition, there was a significant difference in depression scores between management types, with the surgery group having a significantly higher depression score than the radiation group.
CONCLUSION
Symptoms and mood contribute to QOL for those diagnosed with AN. This can be understood through the common-sense model and fear of cancer recurrence. Screening for psychological difficulties should be provided from the point of diagnosis to post-treatment to allow for targeted management plans to mitigate the effects of these on QOL.
Topics: Humans; Quality of Life; Neuroma, Acoustic; Tinnitus; Psychological Well-Being; Mental Health; Headache
PubMed: 37597328
DOI: 10.1016/j.jocn.2023.08.005 -
Clinical Trials (London, England) Feb 2024Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for...
Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.
Topics: Animals; Humans; Neurofibromatosis 1; Neurofibromatosis 2; Neurofibromatoses; Neurilemmoma; Skin Neoplasms
PubMed: 37937606
DOI: 10.1177/17407745231207970 -
Nature Communications Jan 2024Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis...
Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.
Topics: Animals; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis 2; Schwann Cells; Drug Resistance, Neoplasm
PubMed: 38216572
DOI: 10.1038/s41467-024-44755-9 -
Frontiers in Neuroscience 2023To investigate potential differences in absolute deviation values of subjective visual vertical and horizontal between unilateral acoustic neuroma patients and healthy...
OBJECTIVE
To investigate potential differences in absolute deviation values of subjective visual vertical and horizontal between unilateral acoustic neuroma patients and healthy young adults under varying degrees of static head tilt, as well as the impact of proprioception on these values, with the aim of determining the effect of acoustic neuroma on gravity sensory pathway function in patients.
METHODS
We recruited 22 patients diagnosed with unilateral acoustic neuroma and 25 healthy young adults and employed virtual reality technology to assess the absolute deviation values of subjective visual vertical (SVV) and subjective visual horizontal (SVH) under eight different static tilted head positions (Head centered (0° tilt), PdP, Head tilt 15°, 30°, 45° to the left and right), then compare and analyze intergroup differences.
RESULTS
In the Head-centered position, both SVV and SVH absolute deviated values were significantly higher in the AN group compared to healthy young adults. The AN group exhibited significantly higher absolute deviation values of SVV compared to the healthy group when tilting their head 30° left and right. Additionally, when tilting their heads to the right at 15° and 45° the AN group showed significant increases in SVH absolute deviated values compared to healthy adults. The SVV and SVH absolute deviation values of LAN and SAN groups did not reach statistical significance. The results of the SVV test for PDP position did not show any significant differences among all groups. However, the SVH test revealed that the absolute deviation values of the LAN group was significantly higher than that of healthy individuals.
CONCLUSION
Our study shows that the gravity sensing function of patients with unilateral acoustic neuroma is affected to different degrees, however, the degree of gravity sensing function damage of patients has little relationship with tumor size. When acoustic neuroma is larger than 2 cm, the effect of proprioception on patients' SVH outcome is noteworthy. So, we should pay attention to the postoperative follow-up of patients with acoustic neuroma and the evaluation of vestibular rehabilitation effect. Meanwhile, for patients opting for conservative treatment, it is imperative to monitor the dynamic changes in vestibular function and seize timely opportunities for intervention.
PubMed: 37954872
DOI: 10.3389/fnins.2023.1264585 -
Fukushima Journal of Medical Science Aug 2023Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell... (Review)
Review
Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell proliferation signals due to abnormalities of the NF2 gene located on chromosome 22. About half of patients inherit a germline mutation from a parent, and nearly 60% of de novo NF2 patients are estimated to have somatic mosaicism. The development of technical methods to detect NF2 gene mutation, including targeted deep sequencing from multiple tissues, improved the diagnostic rate of mosaic NF2. With improved understanding of genetics and pathogenesis, the diagnostic criteria for NF2 were updated to assist in identifying and diagnosing NF2 at an earlier stage. The understanding of cell signaling pathways interacting with merlin has led to the development of molecular-targeted therapies. Currently, several translational studies are searching for possible therapeutic agents targeting VEGF or VEGF receptors. Bevacizumab, an anti-VEGF monoclonal antibody, is widely used in many clinical trials aiming for hearing improvement or tumor volume control. Currently, a randomized, double-masked trial to assess bevacizumab is underway. In this randomized control trial, 12 other Japanese institutions joined the principal investigators in the clinical trial originating at Fukushima Medical University. In this review, we will be discussing the latest research developments regarding NF2 pathophysiology, including molecular biology, diagnosis, and novel therapeutics.
Topics: Humans; Neurofibromatosis 2; Neurofibromin 2; Bevacizumab; Mutation; Genomics; Randomized Controlled Trials as Topic
PubMed: 37468280
DOI: 10.5387/fms.2023-05 -
Neuro-oncology Sep 2023Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and...
BACKGROUND
Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies.
METHODS
Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models.
RESULTS
Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential.
CONCLUSIONS
This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.
Topics: Animals; Humans; Mice; Meningeal Neoplasms; Meningioma; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2
PubMed: 36806881
DOI: 10.1093/neuonc/noad037 -
Science Advances Nov 2023Vestibular schwannoma (VS) is an intracranial tumor arising from neoplastic Schwann cells and typically presenting with hearing loss. The traditional belief that hearing...
Vestibular schwannoma (VS) is an intracranial tumor arising from neoplastic Schwann cells and typically presenting with hearing loss. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. We conducted profiling of patients' plasma for 66 immune-related factors in patients with sporadic VS ( > 170) and identified and validated candidate biomarkers associated with tumor size (S100B) and hearing (MCP-3). We further identified a nine-biomarker panel (TNR-R2, MIF, CD30, MCP-3, IL-2R, BLC, TWEAK, eotaxin, and S100B) with outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS, providing a unique diagnostic tool that may predict hearing change and tumor growth in VS patients, and may inform the timing of tumor resection to preserve hearing.
Topics: Humans; Neuroma, Acoustic; Hearing Loss; Hearing; Biomarkers; Deafness
PubMed: 37948527
DOI: 10.1126/sciadv.adf7295