Abstract Central nervous system (CNS) tumors originate from neuroectodermal cells, display biological behaviors ranging from indolent lesions to highly aggressive malignancies. To understand how CNS tumors gain a survival benefits, we performed pathway-level analyses with primary omics datasets and found ISR as a most frequently activated program. ISR is a conserved, stress-adaptation pathway suppresses global protein synthesis while selectively promoting ATF4 translation in tumor cells, makes ISR a potentially targetable vulnerability. However, its relevance in CNS tumors remain understudied. Here, we interrogate multi-omics datasets in CNS tumors to define regulatory programs linked to ISR activation. We evaluated ISR activation using primary single-cell transcriptomes (scRNA-seq) and single-cell chromatin accessibility (scATAC-seq) data from multiple patient-derived pituitary adenomas (PA), schwannomas (SCH), and hemangioblastomas (HB). We used curated ATF4 target genes signature (∼200) to computed ISR activity, parallelly with differential expression analysis and single-cell transcription factor activity inference (SCENIC). Our analysis was expended utilizing publicly available scRNA-seq datasets spanning multiple CNS tumor types, including medulloblastomas (MB), meningiomas (MG), and ependymomas (EPN), alongside normal human spinal cord datasets. Chromatin accessibility of ISR related gene was evaluated using scATAC-seq, and DNA methylation profiling of ISR downstream genes was performed in PA and MG samples to explore epigenetic modulation. Across PA, EPN, MG, SCH, and HB, tumor cells showed significantly (p < 0.05) higher ISR activity compared to normal counterparts . Differential expression and functional enrichment analysis revealed upregulation of genes in tumor-cells related to protein translation, protein folding, ER stress, and proteostasis. ISR associated transcriptional program were activated, including ATF4 and related TFs such as DDIT3, ATF3, ATF5, ATF6, XBP1 and CEBPB. However, elements of the ATF4-DDIT axis linked apoptotic signaling were induced in selected tumor types (MG), tumor cells preferentially engaged with chronic ISR programs that survival, reflected by upregulation of ER stress-resolution and chaperone genes together with HSPA5, HERPUD1, PDIA3, PDIA6, DNAJB9, DNAJC3, SEC61A, CANX, and CALR. scATAC-seq analysis pinpoints increased promoter accessibility across multiple ISR-linked genes and DNA methylation analysis showd heterogeneous promoter methylation patterns, with both hypo and hypermethylation of ISR downstream genes in PA and MG, strongly supporting epigenetic reprogramming of ISR pathways. Overall, our findings demonstrate that ISR activation in CNS tumors (PA, EPN, MG, SCH, HB) contributes to tumor adaptation by enhancing protein homeostasis and stress resilience. Our study highlights adaptive ISR signaling as a key tumor adaptation mechanism and identifying the ISR axis as a potential therapeutic vulnerability in these CNS tumor entities. Only for language editing and grammatical correction AI tools were used. Citation Format: Santosh Kumar, Debjani Mandal, Kory R Johnson, Prashant Chittiboina. Integrated Stress Response (ISR) activation coupled to epigenetic reprogramming enables CNS tumor survival [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B018.

To evaluate the clinical, pathological, and immunohistochemical characteristics of schwannomas (SCHs) in the oral, maxillofacial, and cervical regions to provide a reference for their diagnosis and clinical management. We retrospectively analyzed 20 patients with oral, maxillofacial, and cervical SCHs treated at our institution between January 2019 and December 2025. Clinical history, presenting symptoms, and relevant auxiliary examinations were collected. Histopathological diagnoses were established using hematoxylin and eosin (H&E) staining and immunohistochemical analysis. Demographic data, clinical manifestations, surgical approaches, and pathological findings were descriptively analyzed. The tumors originated predominantly from branches of the trigeminal, the lingual, and facial nerves, as well as the cervical plexus. The most common clinical presentation was a painless mass in the oral-maxillofacial region. Some patients presented with tongue sensory disturbances, masticatory dysfunction, or facial muscle weakness, depending on the affected nerve. Histopathological examination revealed typical Antoni A and Antoni B patterns with Verocay bodies, and immunohistochemical findings confirmed the diagnosis of SCH. Surgical approaches were individualized according to tumor location and size. All patients had favorable postoperative outcomes. SCHs of the oral and maxillofacial region and neck exhibit diverse clinical manifestations, definitive diagnosis relies on histopathological and immunohistochemical evaluation. Awareness of the tumor’s anatomical origin and associated clinical features facilitates optimal surgical planning and informed clinical decision-making.

Vestibular schwannomas (VS) are tumors arising from Schwann cells of the vestibulocochlear nerve, often leading to hearing loss, gait imbalance, and other neurological complications. Recently, molecular profiling of VS using bulk and single-cell transcriptional and epigenetic approaches has reshaped our understanding of VS pathogenesis and challenged the long-standing view of VS being molecularly homogeneous. These integrative, multi-omic approaches reveal significant differences within VS and highlight diverse Schwann cell subpopulations and their interactions with the tumor microenvironment. Interestingly, these analyses also uncover 2 molecularly distinct groups of VS, one containing Schwann cells with an "Injury-like" phenotype that drives VS progression through immune cell recruitment and another containing more quiescent Schwann cells with decreased immune cell infiltrate. In this review, we combine insights from modern molecular analyses of VS to provide an updated view of VS pathogenesis and mechanisms of tumor growth, which may be used to inform the development of novel treatments for VS.

Transcriptome Wide Association and Single-Cell Rnaseq Analysis Identifies 7 Novel Genes in Vestibular Schwannoma Tumors

Neurofibromatosis type 1 (NF1) and NF2 -related Schwannomatosis ( NF2 -SWN) are both inherited syndromes characterized by Schwann cell tumors. NF1 tumors harbor activated Ras/MEK/ERK, while NF2 -SWN tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD. To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations. VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus). The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the NF2 -SWN cell line SC4, with lower magnitudes in an NF1 cell line.

Wait-and-scan surveillance is now commonly employed for initial management of small- and medium-sized vestibular schwannomas. Although small differences in tumor size are unlikely to impact outcomes significantly, treatment with either radiosurgery or microsurgery is usually recommended following radiological detection of tumor growth. The objective of the current study was to identify potential inflection points in vestibular schwannoma tumor size, where the risks of treatment with single-fraction stereotactic radiosurgery (SRS) accelerate to inform timing of intervention. Adult (≥ 18 years old) patients with sporadic vestibular schwannoma who underwent SRS from 2000 through 2022 were included. A total of 749 patients with a median age at SRS of 62 years were studied, the majority (n = 566 [76%]) of whom had tumors extending into the cerebellopontine angle (CPA) at SRS. The optimal tumor size cut point to predict SRS failure and need for salvage treatment was 4 mm or more of CPA extension (c-index 0.59, HR 3.60, p = 0.01). The optimal tumor size cut point to predict the outcome of facial nerve paresis was 13 mm or more of CPA extension, resulting in a c-index of 0.63 (HR 2.88, p = 0.01). Among patients with at least 3 months of surveillance before SRS, those with a tumor growth rate ≥ 2.5 mm/year were more likely to undergo salvage treatment than those with a growth rate < 2.5 mm/year, although this difference did not achieve statistical significance (HR 1.82, p = 0.18). The risk of SRS failure requiring salvage treatment and the risk of post-SRS facial nerve paralysis increase at sizes of approximately 4 and 13 mm extension into the CPA, respectively, providing a size threshold anchor to help guide treatment decision-making regarding timing of SRS. Furthermore, rapid tumor growth during the initial wait-and-scan period may be associated with an increased risk of radiosurgical failure, which may influence choice of treatment.

Currently there are no therapeutic agents that are effective against both vestibular schwannoma and meningioma, the two most common tumour types affecting patients with the rare tumour predisposition syndrome NF2-related schwannomatosis. This study aimed to characterise the similarities and differences in the tumour immune microenvironments of meningioma and vestibular schwannoma to identify potential therapeutic targets viable for both tumour types. Publicly available bulk Affymetrix expression data for both meningioma (n = 22) and vestibular schwannoma (n = 31) were used to compare gene expression and signalling pathways, and deconvolved to predict the abundance of the immune cell types present. Publicly available single cell RNA sequencing data for both meningioma (n = 6) and vestibular schwannoma (n = 15) was used to further investigate specific T cell and macrophage subtypes for their signalling pathways, gene expression, and drug targets for predicted drug repurposing in both tumour types. Immune cells comprised a larger proportion of the vestibular schwannoma tumour microenvironment compared to meningioma and included a significantly higher abundance of alternatively activated macrophages. However, these alternatively activated macrophages, alongside other immune cell subtypes such as CD8 + T cells and classically activated macrophages, were predicted to be more active in meningioma than vestibular schwannoma. Despite these differences, T cells and tumour associated macrophages of both vestibular schwannoma and meningioma shared drug-target kinases amenable to drug repurposing with Food and Drug Administration (FDA) drugs approved for other conditions. These include bosutinib, sorafenib, mitoxantrone, and nintedanib which are yet to be clinically investigated for vestibular schwannoma or meningioma. Drug repurposing may offer an expedited route to the clinical translation of approved drugs effective for treating both meningioma and vestibular schwannoma to benefit NF2-related schwannomatosis patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02176-9.

Background and objectivesIn canonical knowledge, long-segment intraspinal schwannomas (SCHs) require laminectomies at all involved levels for complete exposure. To evaluate a minimally invasive, limited-exposure strategy for gross total resection (GTR) of multi-level intraspinal SCHs.MethodsA retrospective analysis was conducted on 11 patients with intraspinal SCHs involving ≥ 3 vertebral segments who underwent laminectomy confined to critical vertebrae, achieving gross total resection without full exposure of all involved levels. The surgical approach involved focused laminectomy targeting critical vertebrae, intracapsular decompression, and meticulous microsurgical dissection. Follow-up included clinical assessments and MRI evaluations at 3 months and 1-year post-surgery.ResultsThe cohort comprised 4 females and 7 males, with a median age of 50 years. Lesions were predominantly located in the cervical spine. Ten cases exhibited cystic lesions, while one presented a fully solid tumor. The average surgical time was 119 ± 15.6 minutes. Laminectomy was performed within 2 levels (6 cases) or 1 level (5 cases). All patients achieved complete symptom resolution at discharge, with no perioperative complications. During a mean follow-up of 23.5 ± 13.0 months, no cases of postoperative spinal instability or tumor recurrence were identified.ConclusionFor long-segment intraspinal SCHs, particularly cystic lesions, minimizing the number of laminectomy levels to achieve GTR is technically feasible and clinically safe.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00423-025-03932-0.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of multiple neurofibromas (NFs) throughout the body. Accurate segmentation of these tumors in whole-body magnetic resonance imaging (WB-MRI) is critical for quantifying tumor burden and clinical decision-making. This study aims to develop a pipeline for NF segmentation in fat-suppressed T2-weighted WB-MRI that incorporates anatomical context and radiomics to improve accuracy and specificity. The proposed pipeline consists of three stages: (1) anatomy segmentation using MRSegmentator and refinement with a high-risk NF zone; (2) NF segmentation using an ensemble of 3D anisotropic anatomy-informed U-Nets; and (3) tumor candidate classification using radiomic features to filter false positives. The study used 109 WB-MRI scans from 74 NF1 patients, divided into training and three test sets representing in-domain (3T), domain-shifted (1.5T), and low tumor burden scenarios. Evaluation metrics included per-scan and per-tumor Dice Similarity Coefficient (DSC), Volume Overlap Error (VOE), Absolute Relative Volume Difference (ARVD), and per-scan F1 score. Statistical significance was assessed using Wilcoxon signed-rank tests with Bonferroni correction. On the in-domain test set, the proposed ensemble of 3D anisotropic anatomy-informed U-Nets with tumor candidate classification achieved a per-scan DSC of 0.64, outperforming 2D nnU-Net (DSC: 0.52) and 3D full-resolution nnU-Net (DSC: 0.54). Performance was maintained on the domain-shift test set (DSC: 0.51) but declined on low tumor burden cases (DSC: 0.23). Preliminary inter-reader variability analysis showed model-to-expert agreement (DSC: 0.67-0.69) comparable to inter-expert agreement (DSC: 0.69). The proposed pipeline achieves the highest performance among established methods for automated NF segmentation in WB-MRI and approaches expert-level consistency. The integration of anatomical context and radiomics enhances robustness. Nonetheless, segmentation performance decreases in low tumor burden scenarios, indicating a key area for future methodological improvements. Additionally, the limited inter-reader agreement observed among experts underscores the inherent complexity and ambiguity of the NF segmentation task.

Schwann cell tumors occur frequently in association with the vestibular nerves, leading to sensorineural hearing loss, and brainstem compression. In humans, unilateral vestibular schwannomas (VS) occur sporadically (VSspo)1, or bilaterally with neurofibromatosis type 2 syndrome (NF2) – VSnf2.2 VS formation is driven by sub-haploid NF2 gene dosage3, typically by biallelic loss.4,5 Loss of merlin promotes hippo/TEAD dependent transcriptional reprogramming, proliferation, and paracrine signaling that varies across time, and tumor volume.4,6 These variations lead to a clinically unpredictable course, and incomplete response to treatment. We hypothesized that Schwann cell merlin inactivation state determines cell-wise hippo/TEAD dependency and drives schwannoma pathogenesis. We analyzed clinical samples from VSspo and VSnf2 with a multi-omics approach and detected variation in merlin activity within tumor Schwann cell population. We found that tumor-driving merlin-depleted Schwann cells (Schwannmer-) exhibited elevated hippo activity that was predominantly driven by TEAD1. In-silico TEAD1 perturbation led to a reversal to merlin intact Schwann phenotype. These findings, and tumor cell growth suppression were confirmed in NF2fl/fl;Peri-Cre mouse model7, and in human derived schwannoma cells treated with a pan-TEAD auto palmitoylation inhibitor VT3989.8 Our computational and experimental results confirm that TEAD1 inhibition could be a potent, targeted strategy for schwannomas.

There is currently no effective treatment for malignant peripheral nerve sheath tumors (MPNSTs), half of which result from malignant progression of neurofibromas (NFs) in patients with neurofibromatosis type 1 (NF1). NFs are due to biallelic loss-of-function of NF1, which negatively regulates the RAS pathway, in the Schwann cell lineage. We generated a conditional Nf1-mutant mouse model where NFs spontaneously transform into MPNSTs, faithfully recapitulating the human situation. Single-cell transcriptomic profiling demonstrated progression of NFs into MPNSTs, with a glial-to-mesenchymal transition. Sox9 was identified as a marker of this transition and key player in tumor growth. The transition is followed by a loss of the tumor suppressor gene (TSG) Cdkn2a and acquisition of pathogenic variants of other TSGs. Finally, a proof-of-concept drug screen aimed at reducing Sox9 expression in tumor cells identified 12 FDA-approved drugs. Notably, several of these agents target the RAS signaling cascade, suggesting that multi-targeted inhibition of this pathway may represent a promising therapeutic strategy against MPNSTs.

SummaryBackgroundIntraspinal tumors (ISTs) pose diagnostic challenges due to their complex anatomy and reliance on subjective clinical imaging interpretation, while artificial intelligence-based methods offer significant potential for non-invasive ISTs diagnosis. We aimed to develop and validate an MRI-based deep learning model for IST differentiation.MethodsWe conducted a retrospective study across three hospitals in China between January 2010 and July 2025. This retrospective study included 1004 patients diagnosed with ISTs, categorized into Schwannoma (SCN), Meningioma (MNG), Astrocytoma (AST), Ependymoma (EPN), and Metastasis (MET). Patients from Center 1 (n = 723) formed the internal dataset, which was randomly divided into training, validation and internal test sets at a 7:1:2 ratio. Additionally, 281 patients from Centers 2 and 3 were used as an external test set. All patients underwent preoperative spinal MRI, including sagittal T1-weighted (T1W), T2-weighted (T2W), T2 fat-suppressed (T2FS) and axial T2W sequences. We proposed the ISMF-Net that integrates features from sequences and clinical data to differentiate ISTs. Diagnostic improvements with model assistance were evaluated through an observer study involving radiologists of different levels of experience.FindingsAmong 1004 patients, 22.6% had SCN, 21.8% had MNG, 14.9% had AST, 18.2% had EPN, and 22.5% had MET. The proposed ISMF-Net achieved micro-ACC of 0.859 [0.827, 0.889], 0.849 [0.826, 0.874], and 0.821 [0.801, 0.841] on the validation, internal test, and external test sets, respectively, outperforming existing methods. The highest performance was observed for SCN (F1: 0.905 [0.879, 0.930]–0.940 [0.910, 0.968]), while MET showed lower performance (F1: 0.757 [0.724, 0.790]–0.804 [0.746, 0.858]). Model assistance significantly improved diagnostic performance across all radiologists, with junior radiologists benefiting the most, showing increases of 7.9%, 20.1% and 4.9% in accuracy, sensitivity, and specificity, respectively. Additionally, preference analysis confirmed strong alignment between the model's predictions and radiologists' diagnostic tendencies.InterpretationThis study proposes a multi-modal DL approach integrating MRI and clinical data to improve IST diagnosis, providing a valuable tool for enhancing diagnostic accuracy in clinical practice.FundingThis study was funded by the General Program from Department of Education of Liaoning Province (JYTMS20230132), the National Natural Science Foundation of China (82304235) and the 10.13039/501100002858China Postdoctoral Science Foundation (2024M753641).

Schwannomas (SCH) and meningiomas (MEN), the two most common primary spinal cord tumors, present a clinical diagnostic challenge due to their overlapping clinical and radiological manifestations. To address this, we developed a deep learning-based object detection model for automated detection of these tumors using magnetic resonance imaging (MRI), which could facilitate early diagnosis and alleviate clinical decision-making burdens. Our study retrospectively analyzed MRI scans from 103 pathologically confirmed SCH and MEN cases at a local hospital (July 2015-August 2024). First, we took YOLOv8n as the baseline model, introduced selective kernel fusion (SKFusion) module to replace the feature fusion layer of the original neck part, added recursive gated convolution (gnConv), and then trained the improved feature fusion model (YOLOv8n-SKNeck). The proposed model achieved notable performance metrics: 91.20% mean accuracy, 90.92% mean recall, and 91.03% mean F1-score for SCH/MEN detection. These results demonstrate that our optimized deep learning framework can effectively automate the detection and differential diagnosis of spinal SCH and MEN through MRI analysis. Thus, the novel method holds significant potential for advancing computer-aided diagnosis and facilitating innovative applications in future clinical practice.

Abstract Central nervous system (CNS) tumors originate from neuroectodermal cells and cause a significant burden of neurological and systemic disease in humans. CNS tumors exhibit diverse biological behaviors, ranging from benign, slow-growing masses to highly aggressive, infiltrative malignancies. We found activation of integrated stress response (ISR) in tumor cells. ISR is the final common pathway activated in response to a range of cellular stressors. ISR activation suppresses global protein translation except ATF4, leading to apoptosis in normal cells. Tumors can evade ISR activation to support proliferation, making ISR targetable. The relevance of ISR activation in the context of CNS tumors is unknown. ISR activation was analyzed with single cell transcriptomes (scRNAseq) and single cell ATAC seq (scATACseq) of pituitary adenomas (PA), schwannomas (SCH), and ependymomas (EPN) tumors from our patients. Analysis was supplemented with publicly available datasets including scRNAseq from medulloblastomas (MB) and meningiomas (MG), and corresponding human normal tissue datasets. ISR activity scores were significantly (p&amp;lt;0.05) higher in PA, EPN and MG tumor cells compared to their normal counterparts. Global functional enrichment analysis between tumor and normal cells revealed upregulation of translation, protein folding, and ER stress-related pathways. ATF4 target genes ATF6, and XBP1 were upregulated in tumor cells. These genes mediate ER stress resolution and drive the expression of HSPA5 (BiP), a molecular chaperone. HSPA5 itself was upregulated in tumor cells as well. scATACseq revealed increased promoter accesibility in several ISR-regulated genes including HSPA5, XBP1, and DDIT3 suggesting broad epigenetic reprogramming that allows ISR escape. Our findings suggests that ISR activation in some CNS tumors (PA, EPN, and MG) may play a critical role in tumor adaptation by enhancing protein homeostasis and stress resilience. These findings highlight the ISR escape as a tumor adaptation mechanism and potential therapeutic target in CNS tumors like PA, EPN, and MG.

Abstract INTRODUCTION This investigator-initiated study evaluated tozuleristide (Blaze Bioscience, Inc.), a tumor-targeting near-infrared fluorescence-guided surgery (FGS) imaging agent in combination with the Canvas imaging system (Blaze Bioscience, Inc.), to aid in safe and effective resection of enhancing vestibular schwannoma tumors in the cerebellopontine angle. METHODS Adults undergoing initial resection of suspected vestibular schwannomas received 24 mg of tozuleristide 16-20 hours pre-operatively. The Canvas imaging system was used intraoperatively to visualize tumor fluorescence. The protocol specified that the surgeon biopsy regions of interest (ROI) identified under white light as definite tumor. Intraoperative fluorescence assessments of ROIs were obtained and compared to post-operative histopathology to correlate fluorescence with tumor. Subjects were not selected for capacity to safely achieve gross total resection (GTR). RESULTS Preliminary results from 3 subjects who underwent all study procedures indicate that 3/3 tumors were fluorescent. All biopsies were consistent with vestibular schwannoma by histopathology examination and were highly fluorescent. The facial nerve was identified and stimulated in all patients. In all patients, resection of tumor capsule was stopped when the facial nerve was no longer visualized due to being covered in fluorescent tissue. Two patients underwent GTR and near GTR (maximum tumor diameter 20.8mm and 25.5 mm) and one patient underwent subtotal resection (STR) (maximum tumor diameter 41.8mm). Near GTR patients had post-operative House Brackmann (HB) scores of 2 and 4 which improved to HB 1 and 2 within 6 months. The STR patient had HB score of 1. No residual fluorescence was seen in the patient with GTR. After administration of 24 mg tozuleristide pre-operatively, 100% of vestibular schwannomas exhibited fluorescence. The utility of tozuleristide fluorescence appears to be in distinguishing fluorescent tumor capsule and nerve. Further investigation in a larger study is warranted and may be generalizable to patients with other enhancing tumors of the skull base.

Schwannomas are benign tumors that arise from Schwann cells of the nerve sheath, and their management presents a significant clinical challenge, particularly in genetic conditions like NF2-related schwannomatosis (NF2-SWN). Although current treatments, including surgery, radiation, and repurposed pharmacological agents, can be effective, they are often limited by issues such as tumor recurrence and the risk of nerve function impairment. This study aims to evaluate the potential of recombinant human Neuregulin1 beta 1 (rhNRGβ1) to inhibit schwannoma growth and promote Schwann cell differentiation in preclinical models. We investigated the therapeutic potential of rhNRGβ1, a recombinant human epidermal growth factor (EGF)-like domain of Neuregulin1 beta 1, as a growth-inhibitory agent for schwannomas. Two distinct mouse models were used to assess its efficacy, with both histological and functional endpoints analyzed. Both systemic and local administration of rhNRGβ1 resulted in a significant reduction in schwannoma tumor growth. Mechanistically, rhNRGβ1 not only inhibited tumor proliferation, but also promoted the differentiation of both proliferative and de-differentiated Schwann cells, suggesting a dual action of growth inhibition and cellular maturation. These findings highlight the therapeutic potential of rhNRG1-β1 in managing schwannomas, not only by reducing tumor growth, but also by promoting the maturation and functional restoration of Schwann cells. This dual effect provides a promising avenue for novel therapeutic strategies aimed at addressing both the growth and cellular differentiation challenges associated with schwannomas in NF2-SWN and other related conditions. ANN NEUROL 2026;99:369-381.

ObjectiveTo summarize the outcomes of 1000 consecutive microsurgical resection of cerebellopontine angle tumors.Study DesignRetrospective cohort study.SettingSingle tertiary care institution.MethodsWe analyzed 1000 patients who underwent microsurgical resection of cerebellopontine angle tumors between November 2017 and August 2024. Patient and tumor‐related characteristics are summarized, and the extent of resection, facial nerve function, hearing preservation, and postoperative complications are described. Volumetric analysis was used to assess resection completeness.ResultsThe median patient age was 49 years (interquartile range [IQR] 40‐58), with 62% female and 74% Caucasian. Surgical approaches included 46.5% translabyrinthine (TL), 24.6% retrosigmoid (RS), 24.1% middle cranial fossa (MCF), and 4.8% other. The median tumor size was 19 mm (IQR 12‐27), and 52% were left‐sided. Overall, volumetric analysis for vestibular schwannoma tumors revealed that 88% of patients had ≤2% tumor volume remaining, 4% had >2% and ≤5%, 4% had >5% and ≤10%, and 4% had >10%. Additionally, the average extent of resection was 98% volume reduction. The most common postoperative complication was cerebrospinal fluid leak (10%), with 77% of cases treated by lumbar drain. Postoperative House‐Brackmann (HB) scores of I or II were achieved in 88% of patients, which had improved to 90% at the time of last follow‐up. Hearing preservation was 62% for MCF and 33% for RS cases.ConclusionMicrosurgical resection of cerebellopontine angle tumors yields favorable outcomes, particularly in preserving facial nerve function and hearing. Tumor size and surgical approach impacted hearing preservation, with the middle fossa approach being most effective for smaller tumors.

BackgroundAccurate monitoring of tumor progression is crucial for optimizing outcomes in neurofibromatosis type 2–related schwannomatosis. Standard 2D linear analysis on magnetic resonance imaging is less accurate than 3D volumetric analysis, but since 3D volumetric analysis is time-consuming, it is not widely used. To shorten the time required for 3D volumetric analysis, our lab has been developing an automated artificial intelligence–driven 3D volumetric tool.ObjectiveThe objective of the study was to survey and interview clinicians treating neurofibromatosis type 2–related schwannomatosis to understand their views on current 2D analysis and to gather insights for the design of an artificial intelligence–driven 3D volumetric analysis tool.MethodsInterviews examined for the following themes: (1) shortcomings of the currently used linear analysis, (2) utility of 3D visualizations, (3) features of an interactive 3D modeling software, and (4) lack of a gold standard to assess the accuracy of 3D volumetric analysis. A Likert scale questionnaire was used to survey clinicians’ levels of agreement with 25 statements related to 2D and 3D tumor analyses.ResultsA total of 14 clinicians completed a survey, and 12 clinicians were interviewed. Specialties ranged across neurosurgery, neuroradiology, neurology, oncology, and pediatrics. Overall, clinicians expressed concerns with current linear techniques, with clinicians agreeing that linear measurements can be variable with the possibility of two different clinicians calculating 2 different tumor sizes (mean 4.64, SD 0.49) and that volumetric measurements would be more helpful for determining clearer thresholds of tumor growth (mean 4.50, SD 0.52). For statements discussing the capabilities of a 3D volumetric analysis and visualization software, clinicians expressed strong interest in being able to visualize tumors with respect to critical brain structures (mean 4.36, SD 0.74) and in forecasting tumor growth (mean 4.77, SD 0.44).ConclusionsClinicians were overall in favor of the adoption of 3D volumetric analysis techniques for measuring vestibular schwannoma tumors but expressed concerns regarding the novelty and inexperience surrounding these techniques. However, clinicians felt that the ability to visualize tumors with reference to critical structures, to overlay structures, to interact with 3D models, and to visualize areas of slow versus rapid growth in 3D would be valuable contributions to clinical practice. Overall, clinicians provided valuable insights for designing a 3D volumetric analysis tool for vestibular schwannoma tumor growth. These findings may also apply to other central nervous system tumors, offering broader utility in tumor growth assessments.

Abstract Intradural extramedullary spinal neoplasms account for ∼40% of all diagnosed spinal tumors. Of that, meningioma and schwannoma are the most common. However, improving the surgical outcomes for these spinal neoplasms requires precise intraoperative diagnosis provided by highly trained neuropathologists. Through a retrospective study of n=257 patient specimens, we demonstrate that 10-second picosecond infrared laser mass spectrometry (PIRL-MS) can robustly and objectively diagnose commonly occurring spinal tumor types with the sensitivity and specificity values of (93±1)% and (97±2)%, respectively. This classification utilizes n=41 cellular lipids including phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, and ceramides, whose identities were established using high-resolution tandem mass spectrometry. The identified lipids form a ‘molecular array’ for robust diagnosis of meningioma and schwannoma tumors by non-pathologists in a manner like genomic, transcriptomic, or methylomic arrays used to diagnose brain cancer types, albeit on a faster timescale of seconds as opposed to hours. Furthermore, when subjected to the presence of additional intradural extramedullary spinal tumor types in the differential diagnosis, the generalizability and robustness of the identified molecular array rendered correct classification even in the presence of data not seen previously by the model. PIRL-MS mediated pathology stratifies the resection risk such that complete removal of certain spinal neoplasms such as meningioma tumors with dural excision could be justified to improve the surgical outcomes. Thus, providing informed surgical care even in the absence of intraoperative consults, addressing the human resource limitations in settings that are understaffed in neuropathology. Here, the current state of PIRL-MS device development allows operation by anyone with basic laboratory skills. Citation Format: Alexa Fiorante, Michael Woolman, David Munoz, Taira Kiyota, Lan Anna Ye, Yasamine Farahmand, Darah Vlaminck, Francis Talbot, Sunit Das, Gelareh Zadeh, Howard Ginsberg, Ahmed Aman, Arash Zarrine-Afsar. A 10-second lipidomic based approach to diagnose common spinal tumor types with picosecond infrared laser mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 678.

Vertebrate embryogenesis requires the precisely timed specification of 3 germ cell layers- ectoderm, mesoderm, and endoderm- which give rise to tissues and organs in the developing organism. The tumor suppressor gene NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (Nf2) is expressed in all 3 germ layers during mouse development and its homozygous deletion causes embryonic lethality. People with heterozygous NF2 mutations typically develop Schwann cell tumors, especially vestibular schwannoma, but the specific role of NF2 in human embryonic development is unclear. Here, human induced pluripotent stem cells (hiPSCs) are used to demonstrate that NF2 is essential for endoderm specification and formation in humans. Although endoderm differentiation is not impaired in hiPSCs with heterozygous NF2 mutation, NF2 knockout (NF2-/-) abolished the capacity to form endoderm in vitro, confirmed by loss of expression of endoderm-related genes and proteins, or teratomas in vivo. This defect is mediated by the nuclear translocation of yes-associated protein 1 (YAP1), a transcription co-activator regulating lineage fate via the Hippo pathway and subsequent YAP1-mediated shutdown of Activin/Nodal signaling. Endoderm formation can be rescued via YAP1 knockdown or forced re-expression of NF2 in NF2-/- cells. Taken together, the essential role of NF2 during endoderm specification in human embryogenesis as a regulator of YAP1 is reported.