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Brain and Behavior Sep 2023The association between programed cell death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in vestibular schwannoma (VS) has been investigated in a few...
BACKGROUND
The association between programed cell death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in vestibular schwannoma (VS) has been investigated in a few studies. These published studies report a difference in the PD-L1 positivity rate in malignant peripheral nerve sheath tumors. We examined PD-L1 expression and lymphocyte infiltration in patients with VS who had undergone surgical resection and investigated the association between PD-L1 expression and clinicopathological features.
METHODS
The expression of PD-L1, CD8, and Ki-67 in 40 VS tissue specimens was investigated using immunohistochemistry, and a clinical review of the patients was performed.
RESULTS
Of the 40 VS samples, 23 (57.5%) were positive for PD-L1 and 22 (55%) were positive for CD8. No significant differences in age, tumor size, pure-tone audiometry, speech discrimination, or Ki-67 expression were observed between patients in the PD-L1-positive and PD-L1-negative groups. A higher level of CD8-positive cell infiltration was observed in PD-L1-positive tumors than in PD-L1-negative tumors.
CONCLUSION
We demonstrated that PD-L1 was expressed in VS tissues. Although no correlation was identified between clinical characteristics and PD-L1 expression, the association between PD-L1 and CD8 was confirmed. Thus, additional research on targeting PD-L1 is necessary to improve immunotherapy for VS in the future.
Topics: Humans; B7-H1 Antigen; Neuroma, Acoustic; Ki-67 Antigen; CD8-Positive T-Lymphocytes; Prognosis
PubMed: 37366935
DOI: 10.1002/brb3.3137 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2024Network connectivity, as mapped by the whole brain connectome, plays a crucial role in regulating auditory function. Auditory deprivation such as unilateral hearing loss...
Network connectivity, as mapped by the whole brain connectome, plays a crucial role in regulating auditory function. Auditory deprivation such as unilateral hearing loss might alter structural network connectivity; however, these potential alterations are poorly understood. Thirty-seven acoustic neuroma patients with unilateral hearing loss (19 left-sided and 18 right-sided) and 19 healthy controls underwent diffusion-weighted and T1-weighted imaging to assess edge strength, node strength, and global efficiency of the structural connectome. Edge strength was estimated by pair-wise normalized streamline density from tractography and connectomics. Node strength and global efficiency were calculated through graph theory analysis of the connectome. Pure-tone audiometry and word recognition scores were used to correlate the degree and duration of unilateral hearing loss with node strength and global efficiency. We demonstrate significantly stronger edge strength and node strength through the visual network, weaker edge strength and node strength in the somatomotor network, and stronger global efficiency in the unilateral hearing loss patients. No discernible correlations were observed between the degree and duration of unilateral hearing loss and the measures of node strength or global efficiency. These findings contribute to our understanding of the role of structural connectivity in hearing by facilitating visual network upregulation and somatomotor network downregulation after unilateral hearing loss.
Topics: Humans; Female; Male; Hearing Loss, Unilateral; Middle Aged; Adult; Connectome; Brain; Neuroma, Acoustic; Neural Pathways; Magnetic Resonance Imaging; Aged; Diffusion Tensor Imaging; Functional Laterality; Nerve Net
PubMed: 38896551
DOI: 10.1093/cercor/bhae220 -
Brazilian Journal of Otorhinolaryngology 2023To determine the cut-off point of the cochlear radiation dose as a risk factor for hearing loss in patients with vestibular schwannoma treated with radiosurgery. (Review)
Review
OBJECTIVES
To determine the cut-off point of the cochlear radiation dose as a risk factor for hearing loss in patients with vestibular schwannoma treated with radiosurgery.
METHODS
A systematic review of the literature was performed without language or publication year restrictions in the MEDLINE/PubMed, EMBASE, Web of Science, LILACS/VHL and Cochrane Library databases. Studies that met the following criteria were included: 1) population: adults of both sexes who underwent radiosurgery for vestibular schwannoma treatment; 2) exposure: cochlear radiation; 3) outcome: hearing loss; 4) type of study: cohort. Two independent reviewers conducted the entire review process. The registration number in PROSPERO was CRD42020206128.
RESULTS
From the 333 articles identified in the searches, seven were included after applying the eligibility criteria. There was no standardization as to how to measure exposure or outcome in the included studies, and most studies did not present sufficient data to enable meta-analysis.
CONCLUSION
It was not possible to determine a cut-off point for high cochlear dose that could be considered a risk factor for hearing loss.
Topics: Adult; Female; Humans; Male; Deafness; Hearing Loss; Neuroma, Acoustic; Radiation Dosage; Radiosurgery; Retrospective Studies; Treatment Outcome
PubMed: 37579571
DOI: 10.1016/j.bjorl.2023.101300 -
The Laryngoscope Sep 2023To systematically review and evaluate metformin's potential impact on vestibular schwannoma (VS) growth. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To systematically review and evaluate metformin's potential impact on vestibular schwannoma (VS) growth.
DATA SOURCES
PubMed, Cochrane Library, and Embase.
REVIEW METHODS
A retrospective cohort study was performed on sporadic VS patients undergoing initial observation who had at least two magnetic resonance imaging studies. Patients were stratified by metformin use during the observation period. Primary endpoint was VS growth, defined as at least a 2 mm increase in diameter. Survival free of tumor growth was evaluated between groups. Systematic review and meta-analysis were performed to produce a pooled odds ratio [OR]. Study heterogeneity was assessed and post-hoc power analysis was performed.
RESULTS
A total of 123 patients were included, of which 17% were taking metformin. Median patient age was 56.6 years (range, 25.1-84.5). There were no statistically significant differences between the groups. Survival analysis did not demonstrate a statistically significant difference in time to VS growth between groups (hazard ratio = 0.61, 95% confidence interval [CI] = 0.29-1.29). Furthermore, logistic regression analysis did not demonstrate a statistically significant difference between groups in the odds of VS growth (OR = 0.46, 95% CI = 0.17-1.27). Systematic review identified 3 studies. Meta-analysis suggested that metformin reduces the odds of developing VS growth (pooled OR = 0.45, 95% CI = 0.29-0.71). Studies demonstrated low between-study heterogeneity. Power analysis demonstrated a sample size of 220 patients with equal randomization would be required to prospectively identify a true difference with 80% power.
CONCLUSIONS
Metformin use may reduce the odds of VS growth. A randomized trial would be ideal to identify an unbiased estimate of metformin's effect on VS growth. Laryngoscope, 133:2066-2072, 2023.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Neuroma, Acoustic; Metformin; Retrospective Studies; Magnetic Resonance Imaging; Survival Analysis
PubMed: 36744870
DOI: 10.1002/lary.30601 -
Acta Neuropathologica Communications Sep 2023Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with...
Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.
Topics: Humans; Macrophages; Meningeal Neoplasms; Meningioma; Neurofibromatosis 2; Retrospective Studies
PubMed: 37752594
DOI: 10.1186/s40478-023-01645-3 -
Nature Communications Jun 2024Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors,...
Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.
Topics: Schwann Cells; Humans; CRISPR-Cas Systems; Glucosephosphate Dehydrogenase; Neurofibromin 2; Coenzyme A Ligases; Synthetic Lethal Mutations; Animals; Neurofibromatosis 2; NADP; Mice; Oxidation-Reduction
PubMed: 38879607
DOI: 10.1038/s41467-024-49298-7 -
International Journal of Molecular... Jun 2024NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular... (Review)
Review
NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.
Topics: Humans; Neurofibromatoses; Neurofibromin 2; Neurilemmoma; Skin Neoplasms; Animals; Neurofibromatosis 2; Mutation; Signal Transduction; Molecular Targeted Therapy
PubMed: 38928264
DOI: 10.3390/ijms25126558 -
World Neurosurgery Aug 2023To compare shallow machine learning models and deep neural network (DNN) model in prediction of vestibular schwannoma (VS) surgical outcome.
OBJECTIVE
To compare shallow machine learning models and deep neural network (DNN) model in prediction of vestibular schwannoma (VS) surgical outcome.
METHODS
One hundred eighty-eight patients with VS were included; all underwent suboccipital retrosigmoid sinus approach, and preoperative magnetic resonance imaging recorded a series of patient characteristics. Degree of tumor resection was collected during surgery, and facial nerve function was evaluated on the eighth day after surgery. Potential predictors of VS surgical outcome were obtained by univariate analysis, including tumor diameter, tumor volume, tumor surface area, brain tissue edema, tumor property, and tumor shape. This study proposes a DNN framework to predict the prognosis of VS surgical outcomes based on potential predictors and compares it with a series of classic machine learning algorithms including logistic regression.
RESULTS
The results showed that 3 predictors of tumor diameter, tumor volume, and tumor surface area were the most important prognostic factors for VS surgical outcomes, followed by tumor shape, while brain tissue edema and tumor property were the least influential. Different from shallow machine learning models, such as logistic regression with average performance (area under the curve: 0.8263; accuracy: 81.38%), the proposed DNN shows better performance, where area under the curve and accuracy were 0.8723 and 85.64%, respectively.
CONCLUSIONS
Based on potential risk factors, DNN can be exploited to achieve preoperative automatic assessment of VS surgical outcomes, and its performance is significantly better than other methods. It is therefore highly warranted to continue to investigate their utility as complementary clinical tools in predicting surgical outcomes preoperatively.
Topics: Humans; Neuroma, Acoustic; Retrospective Studies; Neural Networks, Computer; Algorithms; Treatment Outcome; Facial Nerve
PubMed: 36966911
DOI: 10.1016/j.wneu.2023.03.090 -
Otology & Neurotology : Official... Dec 2023Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for...
BACKGROUND AND AIM
Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for growth. The role of the stroma and particularly fibroblasts, in the progression of VS, is not completely understood. This study examines the profile of fibroblasts in VS.
METHODS
Seventeen patients undergoing surgical excision of VS were recruited into the study. Reverse transcription with quantitative polymerase chain reaction (RT-qPCR) was performed on VS tissue samples and fibroblast-associated molecules examined. Immunofluorescence and immunohistochemistry in VS tissue were used to study the expression of fibroblast markers CD90 and podoplanin in situ. Fibroblast cultures were established from VS, and RT-qPCR analysis was performed on a panel of fibroblast markers on VS and control tissue fibroblasts.
RESULTS
Several fibroblast-associated molecules including members of galectin family and matrix metalloproteinases were found to be expressed in VS tissue on RT-qPCR analysis. In situ, expression of CD90 and podoplanin was observed in VS tissue both on immunohistochemistry and immunofluorescence. RT-qPCR analysis of fibroblasts from VS and control vestibular neuroepithelium (NE) showed a higher expression of several molecules of the galectin and matrix metalloproteinases family on VS fibroblasts compared with NE fibroblasts.
CONCLUSION
This work examines fibroblasts from VS and shows qualitative differences from NE fibroblasts on RT-qPCR. Further understanding of the fibroblast function in the progression of VS will potentially unveil new targets to manage VS growth.
Topics: Humans; Neuroma, Acoustic; Fibroblasts; Matrix Metalloproteinases; Galectins
PubMed: 37733967
DOI: 10.1097/MAO.0000000000004011 -
Journal of Korean Medical Science Oct 2023Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral...
BACKGROUND
Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral hearing loss were first reported in 1998, there has been no report of a comprehensive analysis of what has changed in GKS practice.
METHODS
We performed a retrospective study of the long-term outcomes of 106 patients with unilateral sporadic ANs who underwent GKS as an initial treatment. The mean patient age was 50 years, and the mean initial tumor volume was 3.68 cm (range, 0.10-23.30 cm). The median marginal tumor dose was 12.5 Gy (range, 8.0-15.0 Gy) and the median follow-up duration was 153 months (range, 120-216 months).
RESULTS
The tumor volume increased in 11 patients (10.4%), remained stationary in 27 (25.5%), and decreased in 68 patients (64.2%). The actuarial 3, 5, 10, and 15-year tumor control rates were 95.3 ± 2.1%, 94.3 ± 2.2%, 87.7 ± 3.2%, and 86.6 ± 3.3%, respectively. The 10-year actuarial tumor control rate was significantly lower in the patients with tumor volumes of ≥ 8 cm ( = 0.010). The rate of maintaining the same Gardner-Robertson scale grade was 28.6%, and that of serviceable hearing was 46.4%. The rates of newly developed facial and trigeminal neuropathy were 2.8% and 4.7%, respectively. The patients who received marginal doses of less than 12 Gy revealed higher tumor control failure rates ( = 0.129) and newly occurred facial or trigeminal neuropathy rates ( = 0.040 and 0.313, respectively).
CONCLUSION
GKS as an initial treatment for ANs could be helpful in terms of tumor control, the preservation of serviceable hearing, and the prevention of cranial neuropathy. It is recommended to perform GKS as soon as possible not only for tumor control in unilateral ANs with hearing loss but also for hearing preservation in those without hearing loss.
Topics: Humans; Middle Aged; Neuroma, Acoustic; Radiosurgery; Retrospective Studies; Follow-Up Studies; Hearing Loss; Trigeminal Nerve Diseases; Treatment Outcome
PubMed: 37846791
DOI: 10.3346/jkms.2023.38.e332