Levels of nasal nitric oxide and nitric oxide synthase expression in chronic rhinosinusitis with nasal polyposis.

KEY POINTS: CRSwNP patients had decreased nNO and increased SNOT-22, endoscopy, and CT scores. CRSwNP patients exhibited decreased nNO despite elevated iNOS and eNOS mRNA expression. The mechanism behind lowered nNO in CRSwNP may not be related to NOS expression.

Effect of Cobalt-60 Treatment Dose Rate on Arteriovenous Malformation Obliteration After Stereotactic Radiosurgery With Gamma Knife.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) marginal dose is associated with successful obliteration of cerebral arteriovenous malformations (AVM). SRS dose rate-how old the cobalt-60 sources are-is known to influence outcomes for some neurological conditions and benign tumors. The objective of this study was to determine the association between cobalt-60 treatment dose rate and cerebral AVM obliteration in patients treated with SRS. METHODS: We performed a retrospective cohort study of 361 patients undergoing 411 AVM-directed SRS treatments between 2005 and 2019 at a single institution. Lesion characteristics, SRS details, obliteration dates, and post-treatment toxicities were recorded. Univariate and multivariate regression analyses of AVM outcomes regarding SRS dose rate (range 1.3-3.7 Gy, mean = 2.4 Gy, median = 2.5 Gy) were performed. RESULTS: At 10 years post-SRS, 68% of AVMs were obliterated on follow-up imaging. Dose rates >2.9 Gy/min were found to be significantly associated with AVM obliteration compared with those <2.1 Gy/min ( P = .034). AVM size, biologically effective dose, and SRS marginal dose were also associated with obliteration, with obliteration more likely for smaller lesions, higher biologically effective dose, and higher marginal dose. Higher dose rates were not associated with the development of post-SRS radiological or symptomatic edema, although larger AVM volume was associated with both types of edema. CONCLUSION: Patients with cerebral AVMs treated with higher SRS dose rates (from newer cobalt-60 sources) experience higher incidences of obliteration without a significant change in the risk of post-treatment edema.

Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Automated screening of computed tomography using weakly supervised anomaly detection.

BACKGROUND: Current artificial intelligence studies for supporting CT screening tasks depend on either supervised learning or detecting anomalies. However, the former involves a heavy annotation workload owing to requiring many slice-wise annotations (ground truth labels); the latter is promising, but while it reduces the annotation workload, it often suffers from lower performance. This study presents a novel weakly supervised anomaly detection (WSAD) algorithm trained based on scan-wise normal and anomalous annotations to provide better performance than conventional methods while reducing annotation workload. METHODS: Based on surveillance video anomaly detection methodology, feature vectors representing each CT slice were trained on an AR-Net-based convolutional network using a dynamic multiple-instance learning loss and a center loss function. The following two publicly available CT datasets were retrospectively analyzed: the RSNA brain hemorrhage dataset (normal scans: 12,862; scans with intracranial hematoma: 8882) and COVID-CT set (normal scans: 282; scans with COVID-19: 95). RESULTS: Anomaly scores of each slice were successfully predicted despite inaccessibility to any slice-wise annotations. Slice-level area under the curve (AUC), sensitivity, specificity, and accuracy from the brain CT dataset were 0.89, 0.85, 0.78, and 0.79, respectively. The proposed method reduced the number of annotations in the brain dataset by 97.1% compared to an ordinary slice-level supervised learning method. CONCLUSION: This study demonstrated a significant annotation reduction in identifying anomalous CT slices compared to a supervised learning approach. The effectiveness of the proposed WSAD algorithm was verified through higher AUC than existing anomaly detection techniques.

Validity and Usefulness of YouTube Videos Related to Endoscopic Transsphenoidal Surgery for Patient Information.

Objectives This article evaluates the completeness and accuracy of YouTube videos related to endoscopic transsphenoidal surgery (ETS) as a source for patient information. Design YouTube was searched using relevant terms pertaining to ETS. Videos were evaluated independently by two physician reviewers experienced in ETS. Video demographics including uploader source along with validity scores based on predetermined checklists were captured. Setting Internet. Participants Not applicable. Main Outcome Measures A novel ETS scoring checklist, the modified DISCERN criteria, and Journal of the American Medical Association (JAMA) benchmark score were used to measure completeness and accuracy of videos. video power index (VPI) was calculated to reflect popularity. Intraclass correlation coefficient was calculated for rater agreement. Results Seventy-nine videos were included in final scoring and analysis. The ETS score, DISCERN, JAMA, and mean VPI across all included videos were 5.0 ± 2.7, 2.4 ± 0.83, 2.19 ± 0.62, and 8.92 ± 18.1, respectively. Based on the ETS score checklist, 31 (39%) of the videos were rated as poor, 30 (38%) were moderately useful, 17 (22%) were useful, and 1 (1%) was exceptional. There was a significant positive correlation between the ETS, DISCERN, and JAMA scores ( p < 0.001), but no correlation with VPI and the validity scores. There were no significant differences comparing validity scores based on the uploader source. Conclusion YouTube videos related to ETS have limited usefulness and poor overall validity for patient information. Clinicians should direct patients to other validated sources of information and aim to improve the comprehensiveness of ETS-related videos.

Editor's Choice - Peri-Operative Outcomes of Carotid Endarterectomy are Not Improved on Dual Antiplatelet Therapy vs. Aspirin Monotherapy: A Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review and meta-analysis of the peri-operative outcomes of carotid endarterectomy (CEA) on dual antiplatelet therapy (DAPT) vs. aspirin monotherapy was carried out, to determine optimal peri-operative management with these antiplatelet agents. DATA SOURCES: The Web of Science, Pubmed, and Embase databases were searched from inception to July 2021. The corresponding authors of excluded articles were contacted to obtain additional data for possible inclusion. REVIEW METHODS: The main outcomes included ischaemic complications (stroke, transient ischaemic attack [TIA], and transcranial Doppler [TCD] measured micro-emboli), haemorrhagic complications (haemorrhagic stroke, neck haematoma, and re-operation for bleeding), and composite outcomes. Pooled estimates using odds ratios (ORs) were combined using a random or fixed effects model based on the results of the chi square test and calculation of I2. RESULTS: In total, 47 411 patients were included in 11 studies, with 14 345 (30.2%) receiving DAPT and 33 066 (69.7%) receiving aspirin only. There was no significant difference in the rates of peri-operative stroke (OR 0.87, 95% confidence interval [CI] 0.72 - 1.05) and TIA (OR 0.78, 95% CI 0.52 - 1.17) despite a significant reduction in TCD measured micro-emboli (OR 0.19, 95% CI 0.10 - 0.35) in the DAPT compared with the aspirin monotherapy group. Subgroup analysis did not reveal any significant difference in ischaemic stroke risk between patients with asymptomatic and symptomatic carotid artery stenosis. DAPT was associated with an increased risk of neck haematoma (OR 2.79, 95% CI 1.87 - 4.18) and re-operation for bleeding (OR 1.98, 95% CI 1.77 - 2.23) vs. aspirin. Haemorrhagic stroke was an under reported outcome in the literature. CONCLUSION: This meta-analysis found that CEA while on DAPT increased the risk of haemorrhagic complications, with similar rates of ischaemic complications, vs. aspirin monotherapy. This suggests that the risks of performing CEA on DAPT outweigh the benefits, even in patients with symptomatic carotid stenosis. The overall quality of studies was low, and improved reporting of CEA outcomes in the literature is necessary.

Importance of Cobalt-60 Dose Rate and Biologically Effective Dose on Local Control for Intracranial Meningiomas Treated With Stereotactic Radiosurgery.

BACKGROUND: Radiosurgery dose rate and biologically effective dose (BED) are associated with outcomes after stereotactic radiosurgery (SRS) for functional neurosurgical conditions and some benign tumors. It is not known if these factors affect the efficacy of SRS for meningioma. OBJECTIVE: To determine the association between cobalt-60 dose rate and BED on outcomes in patients with meningioma treated with SRS. METHODS: A single-institution cohort of 336 patients treated between 2005 and 2018 with cobalt-based SRS for 414 separate meningioma lesions was assembled. BED was calculated using an SRS-specific monoexponential model accounting for treatment time per lesion, assuming α/ß = 2.47 Gy. Cumulative incidences of local failure (LF) were reported after considering the competing risk of death, on a per-lesion basis. Multivariable analysis of LF was performed using a proportional hazards model. RESULTS: The most common SRS dose was 12 Gy (n = 227); 140 lesions received 14 Gy. Five-year LF was 15.6% (95% confidence interval 10.4-21.9) and 4.3% (1.4-9.8) in patients who had a dose rate of <2.95 and ≥2.95 Gy/min, respectively (P = .0375). Among 354 grade I or unresected lesions treated with SRS, BED >50 Gy2.47 was associated with a lower incidence of LF (P = .0030). Each 1 Gy/min increase in dose rate was associated with an adjusted hazard ratio of 0.53 (95% confidence interval, 0.29-0.97, P = .041) for LF. Prescription dose >12 Gy was not associated with a lower incidence of LF. CONCLUSION: Patients with meningiomas treated with lower dose rates experienced a higher incidence of LF than those treated with higher dose rates.

Novel Dural-Splitting Operative Technique for Excision of Ventrally Located Spinal Meningiomas.

OBJECTIVE: Spinal meningiomas are one of the frequently seen intradural extramedullary spinal tumors. They are almost always World Health Organization grade I, and a complete removal of the tumor can be curative. However, ventrally located spinal meningioma removal can be challenging due to the position in front of the spinal cord through a narrow corridor provided by routine dorsal approaches. Incomplete excision of the relatively inaccessible dural attachment can consequently lead to recurrence. We describe a safe and reproducible technique used to achieve Simpson grade I removal of ventrally located spinal meningioma. METHODS: Since the spinal dura can be easily divided into inner and outer layers and the tumor usually spares the outer layer, we developed a simple technique to achieve total resection of the tumor and involved dura while leaving the outer dural layer intact. RESULTS: An advantage of this procedure is that it exploits an interdural approach to allow early devascularization of the tumor without cord manipulation and provides access to the ventral dura to achieve Simpson grade I excision. Another advantage is complete dural closure to minimize postoperative cerebrospinal fluid leak or ventral cord herniation without the need for dural substitutes. CONCLUSION: Its novel interdural approach can be used for all ages and all spinal meningiomas.

The Traumatic Brain Injury Model Systems National Database: A Review of Published Research.

The Traumatic Brain Injury Model Systems (TBIMS) is the largest longitudinal TBI data set in the world. Our study reviews the works using TBIMS data for analysis in the last 5 years. A search (2015-2020) was conducted across PubMed, EMBASE, and Google Scholar for studies that used the National Institute on Disability, Independent Living and Rehabilitation Research NIDILRR/VA-TBIMS data. Search terms were as follows: ["TBIMS" national database] within PubMed and Google Scholar, and ["TBIMS" AND national AND database] on EMBASE. Data sources, study foci (in terms of data processing and outcomes), study outcomes, and follow-up information usage were collected to categorize the studies included in this review. Variable usage in terms of TBIMS' form-based variable groups and limitations from each study were also noted. Assessment was made on how TBIMS' objectives were met by the studies. Of the 74 articles reviewed, 23 used TBIMS along with other data sets. Fifty-four studies focused on specific outcome measures only, 6 assessed data aspects as a major focus, and 13 explored both. Sample sizes of the included studies ranged from 11 to 15,835. Forty-two of the 60 longitudinal studies assessed follow-up from 1 to 5 years, and 15 studies used 10 to 25 years of the same. Prominent variable groups as outcome measures were "Employment," "FIM," "DRS," "PART-O," "Satisfaction with Life," "PHQ-9," and "GOS-E." Limited numbers of studies were published regarding tobacco consumption, the Brief Test of Adult Cognition by Telephone (BTACT), the Supervision Rating Scale (SRS), general health, and comorbidities as variables of interest. Generalizability was the most significant limitation mentioned by the studies. The TBIMS is a rich resource for large-sample longitudinal analyses of various TBI outcomes. Future efforts should focus on under-utilized variables and improving generalizability by validation of results across large-scale TBI data sets to better understand the heterogeneity of TBI.

The Role of Growth Hormone in Depression: A Human Model.

BACKGROUND: Although the relationship between acromegaly and depression has been ascribed to the effects of chronic disease, the role of growth hormone (GH), and insulin like growth factor-1 (IGF-1) is not clear. OBJECTIVE: To determine whether related hormones levels in acromegalics are correlated with depressive symptoms and whether these symptoms are ameliorated following surgery. MATERIALS AND METHODS: A prospective cohort study was conducted on patients diagnosed with acromegaly (n = 15) or non-functioning pituitary adenomas (NFPA; n = 20, as controls) and undergoing first-time surgery, who completed the Center for Epidemiological Studies Depression (CES-D) questionnaire both pre-surgery and post-surgery. The primary outcome was the patient's severity of depression symptomatology using the CES-D score; GH, IGF-1 levels, and tumor characteristics were also measured. RESULTS: Hormone levels (GH and IGF-1) and depression scores in acromegaly patients showed significant reductions following surgery (p < 0.05). The average change in CES-D score was 5.73 ± 2.58 (mean ± SE). A moderate correlation was found between GH levels and CES-D scores (r = 0.52, p < 0.01). The depressed affect subscale accounted for the most improvement in CES-D scores postoperatively and correlated most highly with GH levels. We did not find similar declines in the matched cohort of NFPA patients. CONCLUSION AND RELEVANCE: Surgical resection of the pituitary tumor in acromegaly patients leads to reduction in GH levels that is correlated with reduction in CES-D scores. The results suggest a role for GH in depression and provide a stronger foundation on which to build the hypothesis that GH impacts affect. The study also suggests that hormones should be factored into the matrix that entails the neuro-biological underpinnings of depressive disorders. Future work could explore the mechanisms involved, further brain and neuropeptide interactions, and, novel potential therapeutic targets in depressive and other mental health disorders.

Radiation Dose Rate, Biologically Effective Dose, and Tumor Characteristics on Local Control and Toxicity After Radiosurgery for Acoustic Neuromas.

OBJECTIVE: To evaluate the relationships between calibration dose rate, calculated biologically effective dose (BED), and clinical factors and tumor control after stereotactic radiosurgery (SRS) for acoustic neuroma. METHODS: We performed a retrospective study of all patients with acoustic neuromas treated with frame-based cobalt-60 SRS at a single institution between 2005 and 2019. The calibration dose rate and cobalt-60 half-life were used to calculate the nominal dose rate during treatment. An SRS-specific monoexponential model accounting for treatment time per lesion was used to estimate BED. RESULTS: The study included 607 patients with 612 acoustic neuromas. Median follow-up was 5.0 years. There was no association between dose rate or BED with local failure (LF), radiologic edema, or symptomatic edema. Cystic tumors (adjusted hazard ratio 0.26, P = 0.028) were associated with lower LF, while use of SRS as salvage treatment for growing tumors (adjusted hazard ratio 4.9, P < 0.0001) was associated with higher LF. LF occurred more frequently in larger-diameter tumors, while radiologic or symptomatic edema occurred more frequently in larger-volume tumors. CONCLUSIONS: Radiosurgery dose rate and BED were not associated with tumor control or radiologic or symptomatic edema. Salvage SRS and larger tumors were associated with a higher LF rate, while cystic tumors were associated with a lower LF rate. Patients with larger tumors should be counseled appropriately about potential side effects and when to seek follow-up care.

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

Development and validation of a patient-centered, meningioma-specific quality-of-life questionnaire.

OBJECTIVE: Meningiomas can have significant impact on health-related quality of life (HRQOL). Patient-centered, disease-specific instruments for assessing HRQOL in these patients are lacking. To this end, the authors sought to develop and validate a meningioma-specific HRQOL questionnaire through a standardized, patient-centered questionnaire development methodology. METHODS: The development of the questionnaire involved three main phases: item generation, item reduction, and validation. Item generation consisted of semistructured interviews with patients (n = 30), informal caregivers (n = 12), and healthcare providers (n = 8) to create a preliminary list of items. Item reduction with 60 patients was guided by the clinical impact method, multiple correspondence analysis, and hierarchical cluster analysis. The validation phase involved 162 patients and collected evidence on extreme-groups validity; concurrent validity with the SF-36, FACT-Br, and EQ-5D; and test-retest reliability. The questionnaire takes on average 11 minutes to complete. RESULTS: The meningioma-specific quality-of-life questionnaire (MQOL) consists of 70 items representing 9 domains. Cronbach's alpha for each domain ranged from 0.61 to 0.91. Concurrent validity testing demonstrated construct validity, while extreme-groups testing (p = 1.45E-11) confirmed the MQOL's ability to distinguish between different groups of patients. CONCLUSIONS: The MQOL is a validated, reliable, and feasible questionnaire designed specifically for evaluating QOL in meningioma patients. This disease-specific questionnaire will be fundamentally helpful in better understanding and capturing HRQOL in the meningioma patient population and can be used in both clinical and research settings.

PRMT5 inhibition disrupts splicing and stemness in glioblastoma.

Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.

Pediatric multicompartmental trigeminal schwannoma: illustrative case.

BACKGROUND: Trigeminal schwannoma (TS) is an uncommon and histologically benign intracranial lesion that can involve any segment of the fifth cranial nerve. Given its often impressive size at diagnosis and frequent involvement of critical neurovascular structures of the skull base, it represents a challenging entity to treat. Pediatric TS is particularly rare and presents unique challenges. Similarly, tumors with extension into multiple compartments (e.g., middle cranial fossa, posterior cranial fossa, extracranial spaces) are notoriously difficult to treat surgically. Combined or staged surgical approaches are typically required to address them, with radiosurgical treatment as an adjunct. OBSERVATIONS: The authors presented the unusual case of a 9-year-old boy with a large, recurrent multicompartmental TS involving Meckel's cave, the cerebellopontine angle, and the infratemporal fossa. Near-total resection was achieved using a frontotemporal-orbitozygomatic craniotomy with a combined interdural and extradural approach. LESSONS: The case report adds to the current literature on multicompartmental TSs in children and their management. The authors also provided a simplified classification of TS that can be generalized to other skull base tumors. Given a lack of precedent, the authors intended to add to the discussion regarding surgical management of these rare and challenging skull base lesions.

Gradient of Developmental and Injury Response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity.

Glioblastomas harbor diverse cell populations, including rare glioblastoma stem cells (GSCs) that drive tumorigenesis. To characterize functional diversity within this population, we performed single-cell RNA sequencing on >69,000 GSCs cultured from the tumors of 26 patients. We observed a high degree of inter- and intra-GSC transcriptional heterogeneity that could not be fully explained by DNA somatic alterations. Instead, we found that GSCs mapped along a transcriptional gradient spanning two cellular states reminiscent of normal neural development and inflammatory wound response. Genome-wide CRISPR-Cas9 dropout screens independently recapitulated this observation, with each state characterized by unique essential genes. Further single-cell RNA sequencing of >56,000 malignant cells from primary tumors found that the majority organize along an orthogonal astrocyte maturation gradient yet retain expression of founder GSC transcriptional programs. We propose that glioblastomas grow out of a fundamental GSC-based neural wound response transcriptional program, which is a promising target for new therapy development.

Setting standards of performance expected in neurosurgery residency: A study on entrustable professional activities in competency-based medical education.

BACKGROUND: Competency-based medical education requires evaluations of residents' performances of tasks of the discipline (ie. entrustable professional activities (EPAs)). Using neurosurgical Faculty perspectives, this study investigated whether a sample of neurosurgical EPAs accurately reflected the expectations of general neurosurgical practice. METHOD: A questionnaire was sent to all Canadian neurosurgery Faculty using a SurveyMonkey® platform. RESULTS: The proportion of respondents who believed the EPAs were representative of general neurosurgery competences varied significantly across all EPAs [47%-100%] (p < 0.0001). For 9/15 proposed EPAs, ≥75% agreed they were appropriate for general neurosurgery training and expected residents to attain the highest standard of performance. However, a range of 27-53% of the respondents felt the other six EPAs would be more appropriate for fellowship training and thus, require a lower standard of performance from graduating residents. CONCLUSION: The shift towards subspecialization in neurosurgery has implications for curriculum design, delivery and certification of graduating residents.

Sinonasal Chondrosarcoma Presenting With Isolated Severe Vision Loss.

ABSTRACT: A 24-year-old man presented with a 2-month history of progressive, painless vision loss in the right eye, with no history of headache, nasal congestion, rhinorrhea, or epistaxis. His visual acuity was counting fingers at 1 ft in the right eye and 20 of 20 in the left eye with a right relative afferent pupillary defect and mild temporal optic disc pallor. MRI of the brain and orbits showed a mass involving bilateral ethmoid and sphenoid sinuses and right nasal cavity. He underwent urgent extended endoscopic endonasal transsphenoidal approach for resection of the sinonasal skull base tumor and photon radiation therapy. Pathology revealed a well-differentiated cartilaginous neoplasm with focal areas of entrapped native bone, consistent with a chondrosarcoma WHO grade I/III. At 6-month follow-up after surgery, he had a visual acuity of 20/40 in the right eye and 20/20 in the left eye. Malignant tumors from the sinonasal area should be kept in the differential diagnosis for compressive optic neuropathies and may present with vision loss even in the absence of nasal or sinus symptoms.

Gene Expression Signatures Identify Biologically Homogenous Subgroups of Grade 2 Meningiomas.

INTRODUCTION: Meningiomas are the most common brain tumor, with prevalence of approximately 3%. Histological grading has a major role in determining treatment choice and predicting outcome. While indolent grade 1 and aggressive grade 3 meningiomas exhibit relatively homogeneous clinical behavior, grade 2 meningiomas are far more heterogeneous, making outcome prediction challenging. We hypothesized two subgroups of grade 2 meningiomas which biologically resemble either World Health Organization (WHO) grade 1 or WHO grade 3. Our aim was to establish gene expression signatures that separate grade 2 meningiomas into two homogeneous subgroups: a more indolent subtype genetically resembling grade 1 and a more aggressive subtype resembling grade 3. METHODS: We carried out an observational meta-analysis on 212 meningiomas from six distinct studies retrieved from the open-access platform Gene Expression Omnibus. Microarray data was analyzed with systems-level gene co-expression network analysis. Fuzzy C-means clustering was employed to reclassify 34 of the 46 grade 2 meningiomas (74%) into a benign "grade 1-like" (13/46), and malignant "grade 3-like" (21/46) subgroup based on transcriptomic profiles. We verified shared biology between matching subgroups based on meta-gene expression and recurrence rates. These results were validated further using an independent RNA-seq dataset with 160 meningiomas, with similar results. RESULTS: Recurrence rates of "grade 1-like" and "grade 3- like" tumors were 0 and 75%, respectively, statistically similar to recurrence rates of grade 1 (17%) and 3 (85%). We also found overlapping biological processes of new subgroups with their adjacent grades 1 and 3. CONCLUSION: These results underpin molecular signatures as complements to histological grading systems. They may help reshape prediction, follow-up planning, treatment decisions and recruitment protocols for future and ongoing clinical trials.