Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other central nervous tumors such as meningiomas and spinal ependymomas. Symptoms vary according to the age at diagnosis and the location of these tumors. The diagnostic criteria of NF2 have been regularly revised and recently updated in 2022 with a new nomenclature "NF2-related schwannomatosis" to differentiate NF2 from other schwannoma predisposing disorders, such as SMARCB1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1)-, LZTR1 (leucine zipper-like transcription regulator 1)-, and 22q-related schwannomatosis. Addition to the clinical features, genetic testing for pathogenic variants in these genes became an important essence to support diagnosis of NF2 and other schwannomatosis, including mosaic conditions.

NF2-related Schwannomatosis (NF2 SWN) is a rare disease characterised by the growth of multiple nervous system neoplasms, including bilateral vestibular schwannoma (VS). VS tumours are characterised by extensive leucocyte infiltration. However, the immunological landscape in VS and the spatial determinants within the tumour microenvironment that shape the trajectory of disease are presently unknown. In this study, to elucidate the complex immunological networks across VS, we performed imaging mass cytometry (IMC) on clinically annotated VS samples from NF2 SWN patients. We reveal the heterogeneity in neoplastic cell, myeloid cell and T cell populations that co-exist within VS, and that distinct myeloid cell and Schwann cell populations reside within varied spatial contextures across characteristic Antoni A and B histomorphic niches. Interestingly, T-cell populations co-localise with tumour-associated macrophages (TAMs) in Antoni A regions, seemingly limiting their ability to interact with tumorigenic Schwann cells. This spatial landscape is altered in Antoni B regions, where T-cell populations appear to interact with PD-L1+ Schwann cells. We also demonstrate that prior bevacizumab treatment (VEGF-A antagonist) preferentially reduces alternatively activated-like TAMs, whilst enhancing CD44 expression, in bevacizumab-treated tumours. Together, we describe niche-dependent modes of T-cell regulation in NF2 SWN VS, indicating the potential for microenvironment-altering therapies for VS.

Endocytosis is a fundamental process by which cells take up extracellular materials, including nutrients, growth factors, and pathogens. Although several endocytic pathways, such as clathrin-mediated and caveolin-mediated endocytosis, are well-characterized, other endocytic pathways remain poorly understood. Therefore, in this study, we performed a genome-wide CRISPR-Cas9 screen to elucidate new endocytic pathways using dynamin conditional knockout cells. We identified genes that significantly reduced the cell numbers when knocked out simultaneously with dynamin. Among these, neurofibromin 2 (Nf2) and tumor necrosis factor receptor-associated factor 3 (Traf3), whose relationship with endocytosis was not well understood, were investigated for their roles in endocytosis activity. Nf2 and Traf3 knockout cells exhibited reduced non-specific fluid endocytosis in a dynamin-independent manner. However, Nf2 or Traf3 knockout did not affect the transferrin receptor-mediated endocytosis that depends on clathrin and dynamin. Moreover, Nf2 knockout cells showed reduced cholera toxin uptake in a dynamin-independent manner. Overall, this study highlights the roles of Nf2 and Traf3 in endocytosis.

Vestibular schwannoma (VS) is an intracranial tumor arising from the Schwann cells of the vestibular nerve and is an important cause of sensorineural hearing loss (SNHL) in humans. The mechanisms underlying this SNHL are incompletely understood and currently, there are no drugs FDA approved specifically for VS. This knowledge gap significantly limits the development of effective treatments aimed at preventing, stabilizing, or reversing VS-induced SNHL.

To identify effector molecules involved in VS-induced SNHL, we analyzed 47 immune-related factors secreted by tumor tissue in over 50 patients with sporadic VS and studied their correlation with preoperative hearing ability and tumor size. The most promising effector molecules were validated in vivo in an anatomically accurate mouse model of VS, and in vitro with mouse fibroblasts (L929) and auditory cell lines representing pro-sensory precursors of hair cells (UB-OC1) and auditory neuroblasts (US-VOT-N33).

We demonstrated that VS-induced SNHL was linked to increased secretion of TNF-α, IL-2R, CD163, eotaxin, and HGF, while larger tumor size was associated with higher levels of TNF-α, TNF-R2, IL-1α, IFN-α, MIP-1β, and IL-21 secretion. We identified heterogeneity among VS tumors in their capacity to secrete TNF-α. Tumors with high levels of TNF-α secretion released cytokines and chemokines that significantly correlated with poor hearing (TWEAK and eotaxin) or better hearing (LIF, GRO-α, MIP-1α, MIP-3α, and IL-1α). Among these, TWEAK was notably abundant, with levels exceeding those in normal nerve tissue, elevated in patients with non-serviceable hearing and strongly linked to poor hearing in patients with TNF-α high-secreting tumors. In vivo, we demonstrated that VS-secreted factors reach the inner ear, with elevated TNF-α and TWEAK in the perilymph and blood of tumor-bearing mice with impaired hearing. In vitro, TWEAK amplified TNF-α -mediated cytotoxicity in TNF-α sensitive cells (L929) and auditory cell lines (UB-OC1 and US-VOT-N33) at tumor-secreted concentrations.

This study provides compelling evidence that VS-secreted TNF-α and TWEAK act synergistically to drive tumor-induced SNHL. Targeting the TNF-α/TWEAK axis presents a promising new avenue for preventing VS-induced SNHL.

Schwannomas are tumors that originate from myelinating Schwann cells and can occur in cranial, spinal, and peripheral nerves. Although our understanding of the molecular biology underlying schwannomas remains incomplete, numerous studies have identified various molecular findings and biomarkers associated with schwannomas of the central nervous system (CNS). The development of these tumors is primarily linked to mutations in the NF2 gene. Merlin, the protein encoded by NF2, is integral to several signaling pathways, including Ras/Raf/MEK/ERK, PI3K/Akt/mTORC1, Wnt/β-catenin, and the Hippo pathway.

Recent research has also uncovered novel genetic alterations, such as the SH3PXD2A::HTRA1 fusion gene, VGLL-fusions in intraparenchymal CNS schwannomas, and the SOX10 mutation particularly in non-vestibular cranial nerve schwannomas. In addition to genetic alterations, research is also being conducted on gene expression and epigenetic regulation, with a focus on NF2 methylation and post-transcriptional silencing by micro RNA. Furthermore, the advent of advanced techniques like single-cell sequencing and multi-omics analysis has facilitated rapid discoveries related to the tumor microenvironment and tumor heterogeneity in schwannomas.

A deeper exploration of these molecular findings could clarify the mechanisms of schwannoma tumorigenesis and progression, ultimately guiding the development of new therapeutic targets. This review offers a comprehensive overview of the current molecular understanding of CNS schwannomas, emphasizing the insights gained from previous research, while addressing existing controversies and outlining future research and treatment perspectives.

Background: Unilateral (uVS) and bilateral vestibular schwannoma (bVS) are distinct disease types, yet share tumorigenic features. This study examined causative genetic alterations in three groups: patients with NF2-related schwannomatosis (NF2), young patients with uVS (≤30 years), and older patients with uVS (≥40 years). Methods: Lymphocyte and vestibular schwannoma DNA was genetically analyzed. Outcomes included gene involvement, pathogenicity classification, variant type, effect, and location, and loss of heterozygosity (LOH) of chromosome 22. Results: Among 93 patients, 17% had NF2, 39% were ≤30 years with uVS, and 44% were ≥40 years with uVS. In all patients with NF2 (100%), two or more hits were detected in the tumor DNA, whereas patients with uVS had a slightly lower detection rate (89-98%). NF2-related tumors had a higher frequency of nucleotide variants (76%), while LOH events were more common in uVS (64-69%). Variants were mostly identified in NF2, with nonsense variants over-represented in patients with NF2 (38%) and frameshift variants more prevalent in uVS (44-51%). Conclusions: Biallelic NF2 inactivation primarily drives vestibular schwannoma tumorigenesis. In patients with NF2, two pathogenic NF2 variants or one NF2 variant with LOH are common, whereas patients with uVS often exhibit one NF2 variant with LOH. Additionally, variant types differ between patient groups.

NF2-related schwannomatosis, previously known as neurofibromatosis type 2, is a genetic disorder characterized by nerve tumors due to NF2 gene mutations. Mice with Nf2 deletion develop schwannomas slowly with low penetrance, hence inconvenient for preclinical studies. Here, we show that NF2, by recruiting E3 ubiquitin ligases β-TrCP1/2, promotes WWC1-3 ubiquitination and degradation. In NF2 mutated cells, WWC1-3 accumulation is a compensatory mechanism to prevent YAP/TAZ hyperactivation and rapid tumorigenesis. Accordingly, we generate a synthetic mouse model with complete penetrance and short latency by concurrently deleting Nf2 and Wwc1/2 in Schwann cells. This model closely resembles NF2-related schwannomatosis in patients, as confirmed by histological and single-cell transcriptome analysis. Moreover, a cell line from mouse schwannomas and a syngeneic tumor model in immune-competent mice are established. Furthermore, a screen using established models has identified candidate drugs that effectively suppress schwannoma progression. Hence, this work has developed rapid and transplantable models that will facilitate both basic and translational research on NF2-related schwannomatosis.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, presenting with heterogeneous clinical and molecular subtypes. While gene fusions are predominantly associated with alveolar RMS, spindle cell RMS, especially congenital and intraosseous variants, are also linked to specific gene fusions. Furthermore, recently, FGFR1 kinase-driven RMSs were published. Here, we describe a case of RMS harboring an EWSR1::NF2 gene fusion, a deletion-driven genetic alteration that has not been previously documented in RMS or other soft tissue tumors. The patient was a 29-year-old female who presented with a lobulated ankle mass. Histologic examination revealed a malignant round cell tumor extensively infiltrating large nerve bundles. Immunohistochemical analysis demonstrated rhabdomyoblastic differentiation, consistent with rhabdomyosarcoma. While some areas showed features resembling the sclerosing and others the embryonal subtypes, the overall findings were considered unclassifiable. Targeted RNA sequencing revealed EWSR1(exon 9):: NF2(exon 7) gene fusion, which was confirmed on whole genome and targeted DNA sequencing. The latter did not yield specific diagnostic insights but revealed mutations in TSC2 (p.T1330M), ZFHX3 (p.A301T), and a NOTCH3 rearrangement, all of unknown oncogenic significance. MYC gene amplification was detected, but there was no evidence of chromosome 8 amplification or chromosome 11p15 loss of heterozygosity. Whole genome sequencing revealed a low tumor mutation burden (2.69/Mb) and showed no other significant potentially oncogenic events. DNA methylation studies using dimensionality reduction and unsupervised clustering placed the case within the embryonal RMS subtype. Although the absence of other oncogenic driver alterations suggests that the fusion may have played a pivotal role in pathogenesis, we cannot exclude the possibility that it represents a passenger alteration rather than a true driver mutation. If the former is true, further studies will be required to determine whether this fusion represents a novel RMS subtype or a rare driver in existing subtypes of RMS.

Protein kinase A (PKA) is a basophilic kinase implicated in the modulation of many cell-signaling and physiological processes. PKA also contributes to cancer-relevant events such as growth factor action, cell cycle control, cell migration and tumor metabolism. Germline and somatic mutations in PKA, gene amplifications, and chromosome rearrangements that encode kinase fusions, are linked to a growing number of malignant neoplasms. Mislocalization of PKA by exclusion from A-Kinase Anchoring Protein (AKAP) signaling islands further underlies cancer progression. This article highlights the influence of AKAP signaling and local kinase action in selected hallmarks of cancer. We also feature the utility of kinase inhibitor drugs as frontline and future anti-cancer therapies.

Eosinophilic solid and cystic renal cell carcinoma is now defined in the 5th edition of the 2022 World Health Organization classification of urogenital tumors.

To perform morphologic, immunohistochemical, and preliminary genetic studies about this new entity in China for the purpose of understanding it better.

The study includes 18 patients from a regional tertiary oncology center in northern China (Tianjin, China). We investigated the clinical and immunohistochemical features of these cases.

The mean age of patients was 49.6 years, and the male to female ratio was 11:7. Macroscopically, 1 case had the classic cystic and solid appearance, whereas the others appeared purely solid. Microscopically, all 18 tumors shared a similar solid and focal macrocystic or microcystic growth pattern, and the cells were characterized by voluminous and eosinophilic cytoplasm, along with coarse amphophilic stippling. Immunohistochemically, most of the tumors had a predominant cytokeratin (CK) 20-positive feature, ranging from focal cytoplasmic staining to diffuse membranous accentuation. Initially, we separated these cases into different immunohistochemical phenotypes. Group 1 (7 of 18; 38.5%) was characterized by positive phospho-4EBP1 and phospho-S6, which can imply hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. Group 2 (4 of 18; 23%) was negative for NF2, probably implying a germline mutation of NF2. Group 3 (7 of 18; 38.5%) consisted of the remaining cases. One case had metastatic spread and exhibited an aggressive clinical course, and we detected cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation in this case; other patients were alive and without disease progression.

Our research proposes that eosinophilic solid and cystic renal cell carcinoma exhibits prototypical pathologic features with CK20 positivity and has aggressive potential.

NF2-related schwannomatosis (NF2; previously termed neurofibromatosis type 2) is a tumor-prone disorder characterized by development of multiple schwannomas and meningiomas. The diagnostic criteria of NF2 have been regularly revised. Clinical criteria for NF2 were first formulated at the National Institutes of Health Consensus Conference in 1987 and revised in 1990. Revised criteria were also proposed by the Manchester group in 1992 and by the National Neurofibromatosis Foundation (NNFF) in 1997. The 2011 Baser criteria improved the sensitivity of diagnostic criteria, particularly for patients without bilateral vestibular schwannomas. Revisions to the Manchester criteria were published in 2019, with replacement of "glioma" by "ependymoma," removal of "neurofibroma," addition of an age limit of 70 years for development of vestibular schwannomas, and introduction of molecular criteria, which led to the most widely used criteria. In 2022, the criteria were reviewed and updated by the international committee of NF experts. In addition to changes in diagnostic criteria, the committee recommended the use of "schwannomatosis" as an umbrella term for conditions that predispose to schwannomas. Each type of schwannomatosis was classified by the gene containing the disease-causing pathogenic variant. Molecular data from NF2 patients led to further clarification of the diagnostic criteria for NF2 mosaic phenotypes. Given all these changes, the diagnostic criteria of NF2 may be confusing. Herein, to help healthcare professionals who diagnose NF2 conditions in the clinical setting, we review the historical development of diagnostic criteria.

The neurofibromatosis type 2 (NF2) gene, known for encoding the tumor suppressor protein Merlin, is central to the study of tumorigenesis and associated cellular processes. This review comprehensively examines the multifaceted role of NF2/Merlin, detailing its structural characteristics, functional diversity, and involvement in various signaling pathways such as Wnt/β-catenin, Hippo, TGF-β, RTKs, mTOR, Notch, and Hedgehog. These pathways are crucial for cellular growth, proliferation, and differentiation. NF2 mutations are specifically linked to the development of schwannomas, meningiomas, and ependymomas, although the precise mechanisms of tumor formation in these specific cell types remain unclear. Additionally, the review explores Merlin's role in embryogenesis, highlighting the severe developmental defects and embryonic lethality caused by NF2 deficiency. The potential therapeutic strategies targeting these genetic aberrations are also discussed, emphasizing inhibitors of mTOR, HDAC, and VEGF as promising avenues for treatment. This synthesis of current knowledge underscores the necessity for ongoing research to elucidate the detailed mechanisms of NF2/Merlin and develop effective therapeutic strategies, ultimately aiming to improve the prognosis and quality of life for individuals with NF2 mutations.

To evaluate long-term hearing outcomes following cochlear implantation in patients with neurofibromatosis type 2 and ipsilateral vestibular schwannoma.

Retrospective study.

Tertiary general hospital.

Twenty-two patients undergoing cochlear implantation between 2004 and 2018 with at least 1 year of follow-up were included. Patients were categorized as "users" or "nonusers" of their cochlear implant (CI). For users, speech perception (disyllabic words) without lip-reading was assessed in quiet conditions 1-year postimplantation, and annually thereafter. CI users were classified into 2 groups on the basis of speech intelligibility (≥40% or <40%). Demographic data, treatment options, and tumor size were also recorded.

One year after implantation, 16 (73%) patients used their CI daily. Twelve of these patients had a speech intelligibility ≥40% (mean: 74 ± 21.9%). Three had a Koos stage IV tumor. At the last visit (mean duration of follow-up: 6 ± 5 years), 12 of these 16 patients were still using their implant daily, and 6 had a speech intelligibility ≥40%. No predictive factors for good performance at 1 year or performance stability were identified.

Neurofibromatosis type 2 is a complex disease profoundly affecting patient quality of life, and cochlear implantation should always be considered on a case-by-case basis. In some individuals, cochlear implantation can provide good speech intelligibility for extended periods, even posttreatment or in cases of large tumors.

Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.

Successful regeneration of missing tissues requires seamless integration of positional information along the body axes. Planarians, which regenerate from almost any injury, use conserved, developmentally important signaling pathways to pattern the body axes. However, the molecular mechanisms which facilitate cross talk between these signaling pathways to integrate positional information remain poorly understood. Here, we report a p21-activated kinase (smed-pak1) which functionally integrates the anterior-posterior (AP) and the medio-lateral (ML) axes. pak1 inhibits WNT/β-catenin signaling along the AP axis and, functions synergistically with the β-catenin-independent WNT signaling of the ML axis. Furthermore, this functional integration is dependent on warts and merlin-the components of the Hippo/Yorkie (YKI) pathway. Hippo/YKI pathway is a critical regulator of body size in flies and mice, but our data suggest the pathway regulates body axes patterning in planarians. Our study provides a signaling network integrating positional information which can mediate coordinated growth and patterning during planarian regeneration.

Neurofibromatosis type 2-related schwannomatosis is a genetic disease characterized by the development of bilateral vestibular schwannomas, ependymomas, meningiomas, and cataracts. Mild to profound hearing loss and tinnitus are common symptoms reported by individuals with neurofibromatosis type 2. While tinnitus is known to have a significant and negative impact on the quality of life of individuals from the general population, the impact on individuals with neurofibromatosis type 2 is unknown. Consensus regarding the selection of suitable patient-reported outcome measures for assessment could advance further research into tinnitus in neurofibromatosis type 2 patients. The purpose of this work is to achieve a consensus recommendation by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration for patient-reported outcome measures used to evaluate quality of life in the domain of tinnitus for neurofibromatosis type 2 clinical trials.

The Response Evaluation in Neurofibromatosis and Schwannomatosis Patient-Reported Outcomes Communication Subgroup systematically evaluated patient-reported outcome measures of quality of life in the domain of tinnitus for individuals with neurofibromatosis type 2 using previously published Response Evaluation in Neurofibromatosis and Schwannomatosis rating procedures. Of the 19 identified patient-reported outcome measures, 3 measures were excluded because they were not validated as an outcome measure or could not have been used as a single outcome measure for a clinical trial. Sixteen published patient-reported outcome measures for the domain of tinnitus were scored and compared on their participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials.

The Tinnitus Functional Index was identified as the most highly rated measure for the assessment of tinnitus in populations with neurofibromatosis type 2, due to strengths in the areas of item content, psychometric properties, feasibility, and available scores.

Response Evaluation in Neurofibromatosis and Schwannomatosis currently recommends the Tinnitus Functional Index for the assessment of tinnitus in neurofibromatosis type 2 clinical trials.

Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.

Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas.

This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed.

The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months).　The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016).

SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.

We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.

We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.

We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

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.

Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic nerve (VIII cranial nerve), in the cochlea are present the hair cells, the spiral ganglion neurons, the glia-like supporting cells, and the Schwann cells (SCs), which alterations have been considered cause of HL. Notably, a benign SC-derived tumor of the acoustic nerve, named vestibular schwannoma (VS), has been indicated as cause of HL. Importantly, SCs are the main glial cells ensheathing axons and forming myelin in the peripheral nerves. Following an injury, the SCs reprogram, expressing some stemness features. Despite the mechanisms and factors controlling their biological processes (i.e., proliferation, migration, differentiation, and myelination) have been largely unveiled, their role in VS and HL was poorly investigated. In this review, we enlighten some of the mechanisms at the base of SCs transformation, VS development, and progression, likely leading to HL, and we pose great attention on the environmental factors that, in principle, could contribute to HL onset or progression. Combining the biomolecular bench-side approach to the clinical bedside practice may be helpful for the diagnosis, prediction, and therapeutic approach in otology.

While the neural crest cell population gives rise to an extraordinary array of derivatives, including elements of the craniofacial skeleton, skin pigmentation, and peripheral nervous system, it is today increasingly recognized that Schwann cell precursors are also multipotent. Two mammalian paralogs of the SWI/SNF (switch/sucrose nonfermentable) chromatin-remodeling complexes, BAF (Brg1-associated factors) and PBAF (polybromo-associated BAF), are critical for neural crest specification during normal mammalian development. There is increasing evidence that pathogenic variants in components of the BAF and PBAF complexes play central roles in the pathogenesis of neural crest-derived tumors. Transgenic mouse models demonstrate a temporal window early in development where pathogenic variants in Smarcb1 result in the formation of aggressive, poorly differentiated tumors, such as rhabdoid tumors. By contrast, later in development, homozygous inactivation of Smarcb1 requires additional pathogenic variants in tumor suppressor genes to drive the development of differentiated adult neoplasms derived from the neural crest, which have a comparatively good prognosis in humans.

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.

NF2 (moesin-ezrin-radixin-like [MERLIN] tumor suppressor) is frequently inactivated in cancer, where its NF2 tumor suppressor functionality is tightly coupled to protein conformation. How NF2 conformation is regulated and how NF2 conformation influences tumor suppressor activity is a largely open question. Here, we systematically characterized three NF2 conformation-dependent protein interactions utilizing deep mutational scanning interaction perturbation analyses. We identified two regions in NF2 with clustered mutations which affected conformation-dependent protein interactions. NF2 variants in the F2-F3 subdomain and the α3H helix region substantially modulated NF2 conformation and homomerization. Mutations in the F2-F3 subdomain altered proliferation in three cell lines and matched patterns of disease mutations in NF2 related-schwannomatosis. This study highlights the power of systematic mutational interaction perturbation analysis to identify missense variants impacting NF2 conformation and provides insight into NF2 tumor suppressor function.

Neurofibromatosis type 2 (NF2) is a genetic condition marked by the development of multiple benign tumors in the nervous system. The most common tumors associated with NF2 are bilateral vestibular schwannoma, meningioma, and ependymoma. The clinical manifestations of NF2 depend on the site of involvement. Vestibular schwannoma can present with hearing loss, dizziness, and tinnitus, while spinal tumor leads to debilitating pain, muscle weakness, or paresthesias. Clinical diagnosis of NF2 is based on the Manchester criteria, which have been updated in the last decade. NF2 is caused by loss-of-function mutations in the NF2 gene on chromosome 22, leading the merlin protein to malfunction. Over half of NF2 patients have de novo mutations, and half of this group are mosaic. NF2 can be managed by surgery, stereotactic radiosurgery, monoclonal antibody bevacizumab, and close observation. However, the nature of multiple tumors and the necessity of multiple surgeries over the lifetime, inoperable tumors like meningiomatosis with infiltration of the sinus or in the area of the lower cranial nerves, the complications caused by the operation, the malignancies induced by radiotherapy, and inefficiency of cytotoxic chemotherapy due to the benign nature of NF-related tumors have led a march toward exploring targeted therapies. Recent advances in genetics and molecular biology have allowed identifying and targeting of underlying pathways in the pathogenesis of NF2. In this review, we explain the clinicopathological characteristics of NF2, its genetic and molecular background, and the current knowledge and challenges of implementing genetics to develop efficient therapies.

The NF2 tumor suppressor gene is a frequent somatically mutated gene in mesothelioma, with 30%-40% mesotheliomas showing NF2 inactivation. NF2 encodes merlin, a member of the ezrin, radixin, and moesin (ERM) family of proteins that regulate cytoskeleton and cell signaling. Recent genome analysis revealed that NF2 alteration may be a late event in mesothelioma development, suggesting that NF2 mutation confers a more aggressive phenotype to mesothelioma cells and may not be directly caused by asbestos exposure. The Hippo tumor-suppressive and mTOR prooncogenic signaling pathways are crucial cell-signaling cascades regulated by merlin. Although the exact role and timing of NF2 inactivation in mesothelioma cells remain to be elucidated, targeting the NF2/merlin-Hippo pathway may be a new therapeutic strategy for patients with mesothelioma.

Vestibular schwannomas continue to cause hearing loss, facial nerve paralysis, imbalance, and tinnitus. These symptoms are compounded by germline neurofibromatosis type 2 (NF2) gene loss and multiple intracranial and spinal cord tumors associated with NF2-related schwannomatosis. The current treatments of observation, microsurgical resection, or stereotactic radiation may prevent catastrophic brainstem compression but are all associated with the loss of cranial nerve function, particularly hearing loss. Novel targeted treatment options to stop tumor progression include small molecule inhibitors, immunotherapy, anti-inflammatory drugs, radio-sensitizing and sclerosing agents, and gene therapy.

Neurofibromatosis 2 (NF2) is an autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas (VS), meningiomas, ependymomas, spinal and peripheral schwannomas, optic gliomas, and juvenile cataracts. Ongoing studies provide new insight into the role of the NF2 gene and merlin in VS tumorigenesis.

As NF2 tumor biology becomes increasingly understood, therapeutics targeting specific molecular pathways have been developed and evaluated in preclinical and clinical studies. NF2-associated VS are a source of significant morbidity with current treatments including surgery, radiation, and observation. Currently, there are no FDA-approved medical therapies for VS, and the development of selective therapeutics is a high priority. This manuscript reviews NF2 tumor biology and current therapeutics undergoing investigation for treatment of patients with VS.

MPM has a uniquely poor somatic mutational landscape, mainly driven by environmental selective pressure. This feature has dramatically limited the development of effective treatment. However, genomic events are known to be associated with MPM progression, and specific genetic signatures emerge from the exceptional crosstalk between neoplastic cells and matrix components, among which one main area of focus is hypoxia. Here we discuss the novel therapeutic strategies focused on the exploitation of MPM genetic asset and its interconnection with the surrounding hypoxic microenvironment as well as transcript products and microvesicles representing both an insight into the pathogenesis and promising actionable targets.

Cohesion between sister chromatids by the cohesin protein complex ensures accurate chromosome segregation and enables recombinational DNA repair. Sister chromatid cohesion is promoted by acetylation of the SMC3 subunit of cohesin by the ESCO2 acetyltransferase, inhibiting cohesin release from chromatin. The interaction of ESCO2 with the DNA replication machinery, in part through PCNA-interacting protein (PIP) motifs in ESCO2, is required for full cohesion establishment. Recent reports have suggested that Cul4-dependent degradation regulates the level of ESCO2 protein following replication. To follow up on these observations, we have characterized ESCO2 stability in Xenopus egg extracts, a cell-free system that recapitulates cohesion establishment in vitro. We found that ESCO2 was stable during DNA replication in this system. Indeed, further challenging the system by inducing DNA damage signaling or increasing the number of nuclei undergoing DNA replication had no significant impact on the stability of ESCO2. In transgenic somatic cell lines, we also did not see evidence of GFP-ESCO2 degradation during S phase of the cell cycle using both flow cytometry and live-cell imaging. We conclude that ESCO2 is stable during DNA replication in both embryonic and somatic cells.

Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. Although there are few therapeutic options for brain tumors, enhanced biological understanding and unexampled innovations in targeted therapies and immunotherapies have considerably improved patients' prognoses. Nonetheless, the reduced response rates and unavoidable drug resistance of currently available treatment approaches have become a barrier to further improvement in brain tumor (glioma, meningioma, CNS germ cell tumors, and CNS lymphoma) treatment. Previous literature data revealed that several different signaling pathways are dysregulated in brain tumor. Importantly, a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies. Thus, there is an urgent need for a more comprehensive understanding of the pathogenesis of these brain tumors, which might result in greater progress in therapeutic approaches. This paper began with a brief description of the epidemiology, incidence, risk factors, as well as survival of brain tumors. Next, the major signaling pathways underlying these brain tumors' pathogenesis and current progress in therapies, including clinical trials, targeted therapies, immunotherapies, and system therapies, have been systemically reviewed and discussed. Finally, future perspective and challenges of development of novel therapeutic strategies in brain tumor were emphasized.

Benign spinal intradural tumors are relatively rare and include intramedullary tumors with a favorable histology such as low-grade astrocytomas and ependymomas, as well as intradural extramedullary tumors such as meningiomas and schwannomas. The effect on the neural tissue is usually a combination of mass effect and neuronal involvement in cases of infiltrative tumors. The new understanding of molecular profiling of different tumors allowed us to better define central nervous system tumors and tailor treatment accordingly. The mainstay of management of many intradural spinal tumors is maximal safe surgical resection. This goal is more achievable with intradural extramedullary tumors; yet, with a meticulous surgical approach, many of the intramedullary tumors are amenable for safe gross-total or near-total resection. The nature of these tumors is benign; hence, a different way to measure outcome success is pursued and usually depends on functional rather than oncological or survival outcomes.

Neurofibromatosis type 2 (NF-2) is an inherited disease, linked with abnormalities in the NF-2 gene, which is located on chromosome 22 and involved in merlin production. Many craniospinal tumors are common in individuals with NF-2. We present a case of NF-2 with the rapid symptomatic progression of multiple craniospinal tumors.

A 12-year-old male complained of headache and hearing impairment in the right ear for 7 months. Brain magnetic resonance imaging (MRI) revealed a right frontal meningioma, bilateral vestibular and trigeminal schwannomas, and a brainstem tumor. He was diagnosed with NF-2 and underwent brain surgery and radiotherapy for chordoid meningioma. He complained of right leg motor weakness 5 months post-surgery. The spine MRI showed multiple heterogeneously enhanced masses spreading over the entire spinal cord. The symptomatic intradural extramedullary mass at the cervicothoracic area was removed and the histological finding was schwannoma. His leg motor weakness was relieved after surgery. At the 6-month follow-up, brain MRI revealed the progression of the vestibular schwannoma, trigeminal schwannoma, and brainstem tumor. The patient was treated with bevacizumab (5 mg/kg) every 2 weeks for 6 months. For 2 years, all of the craniospinal tumors were stable without neurological deterioration after the completion of chemotherapy.

Meningiomas and schwannomas grow slowly in most patients with NF-2, but these multiple craniospinal tumors can show sudden rapid growth and manifest as neurological symptoms in a pediatric patient. These tumors could be controlled with local symptomatic and systemic bevacizumab treatments.

The literature on neurofibromatosis (NF) has never been systematically assessed using bibliometric analytic methodologies. We quantitatively analyzed the major trends and scientific output regarding NF, highlighting potential avenues for research.

An Elsevier's Scopus database search was performed for all indexed studies related to NF from 1898 to 2021. Validated bibliometric parameters were analyzed using productivity, citation, and keyword analysis, including text mining, content analysis, and collaboration network mapping from inception to date on R 4.1.2.

Our search yielded 15,024 documents. Annual scientific production has grown at a compounded rate of 5.86%, with the largest occurring in 2021 (n = 626). Journals with the most publications on NF include the Journal of Medical Genetics (n = 117) and Neurology (n = 113). The topmost cited author was Gutmann DH (n = 295). The United States had the most international collaboration (n = 435; multiple country publications). Identification of citation classics revealed a shift in recent decades towards understanding genetic and molecular pathways of NF tumorigenesis. Macro-level and micro-level text mining revealed the top 20 genetic and molecular pathways, and syndromes, associated with NF.

Our study exemplifies a quantitative method for understanding the historical and current state of academic efforts regarding NF. There has been a shift of treatment strategies towards targeting specific pathways involved in tumorigenesis. We highlight the top 20 genetic and molecular pathways in the literature as well as the top 20 associated syndromes. This data is encouraging as increased research in molecular targeted therapies aimed at NF pathogenesis may allow advances in disease control.

Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models.

Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees.

Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment.

The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.

Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5-100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

Vestibular schwannomas are benign, slow-growing tumors that often reduce patient quality of life by compressing nearby nerves. Neurological function preservation is one of the indicators of treatment success, with hearing preservation being the most difficult to obtain. This paper provides a bibliometric analysis of hearing preservation in treating acoustic neuromas and a greater understanding of the most highly cited articles, which have enhanced our understanding of this topic.

Key terms of "acoustic neuroma," "vestibular schwannoma," and "hearing preservation" were queried through Web of Science. Articles were sorted by citation frequency, and the top 100 articles were recorded for title, name of first author, journal title, year of publication, total number of citations (and associated rank), average number of citations per year, country of the first author's associated institution, and type of study.

The top 100 cited articles were published from 1980 to 2014. The United States had the highest involvement as a country (55%), the University of Pittsburgh as an institution (13%), and The Journal of Neurosurgery as a publishing source (27%). Fourteen were reviews, and 86 were clinical papers. Of the 86, 73 were retrospective studies.

Bibliometric analyses summarize and assess potential areas of strength and knowledge gaps within the literature. Studies on hearing preservation in vestibular schwannomas mostly consist of retrospective reviews that assess postoperative outcomes of microsurgery and radiosurgery. Prospective studies and novel treatment options for hearing preservation in vestibular schwannomas are needed to increase current literature diversity.