Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.

Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

Genetics of brain arteriovenous malformations and cerebral cavernous malformations.

Cerebrovascular malformations comprise abnormal development of cerebral vasculature. They can result in hemorrhagic stroke due to rupture of lesions as well as seizures and neurological defects. The most common forms of cerebrovascular malformations are brain arteriovenous malformations (bAVMs) and cerebral cavernous malformations (CCMs). They occur in both sporadic and inherited forms. Rapidly evolving molecular genetic methodologies have helped to identify causative or associated genes involved in genesis of bAVMs and CCMs. In this review, we highlight the current knowledge regarding the genetic basis of these malformations.

[Superficial Temporal Artery:Middle Cerebral Artery Bypass Technique as the Basis for Emergency Revascularization].

The superficial temporal artery-middle cerebral artery(STA-MCA)bypass technique is extremely important as the basis for both cerebral revascularization in chronic-stage ischemia and emergency surgical revascularization, including open surgical embolectomy. The sophisticated technique of microvascular bypass could also contribute to rescuing inadvertent vascular injuries, such as those occurring in difficult tumor surgery. Therefore, novice neurosurgeons should practice mastering the microvascular suturing technique.

Association Between the Onset Pattern of Adult Moyamoya Disease and Risk Factors for Stroke.

BACKGROUND AND PURPOSE: Few previous studies have comprehensively explored the relationship between the onset pattern of adult moyamoya disease and risk factors for stroke. We performed a retrospective analysis focusing on risk factors for stroke and related findings on magnetic resonance imaging/angiography with respect to the pattern of disease onset. We also examined whether risk factors for stroke were associated with an increased risk for symptomization in asymptomatic patients. METHODS: A total of 178 adult patients with moyamoya disease (asymptomatic, n=84; ischemic, n=71; hemorrhagic, n=23) at the University of Tokyo Hospital from 2000 to 2018 were included in this study. Data pertaining to patient background and magnetic resonance imaging findings were analyzed retrospectively. In the asymptomatic group, the effects of stroke-associated risk factors on symptom onset were analyzed. RESULTS: Comparisons among the 3 groups revealed no significant difference in the frequency of risk factors for stroke. The proportion of patients with magnetic resonance imaging/angiography findings indicating anterior choroidal artery anastomosis or microbleeds was significantly higher in the hemorrhagic group than in the asymptomatic or ischemic group. Among asymptomatic patients, the hazard ratios for symptomization with hypertension and dyslipidemia were 6.69 ([95% CI, 1.23-36.4] P=0.028) and 8.14 ([95% CI, 1.46-45.2] P=0.017), respectively. CONCLUSIONS: The development of anterior choroidal artery anastomosis and microbleeds on magnetic resonance imaging/angiography was significantly associated with hemorrhagic onset. Hypertension and dyslipidemia may increase the risk of cerebrovascular events in asymptomatic patients, and thus, early intervention to these factors may be important.

[Usefulness of CT in the Lateral Decubitus Position for Preoperative Evaluation of Cranioplasty].

Patients with massive brain swelling undergo external decompressive craniectomy to manage intracranial pressure. Following supratentorial craniectomy, and after the brain swelling is relieved, cranioplasty is performed. Although feasibility of the surgery is usually assessed by CT scanning in a supine position, it is sometimes difficult to determine whether the surgery can be performed safely. Although nine patients underwent a decompressive craniectomy during the study period, only six patients could undergo brain CT-first in a supine position and next in a lateral decubitus position with the surgical side upward-before cranioplasty. On CT images, the distance from the midline to the brain surface was measured on the image where brain bulging was maximal, and the bulging was calculated by comparing the image with the distance measured on the contralateral side. In all cases, brain bulging decreased with this change in position. The decrease ranged from 5.5-9.2mm(mean 7.1mm). Patients with brain bulging of 2.8-3.6mm in the lateral decubitus position needed no additional procedure, or only required drainage of a very small amount of cerebrospinal fluid(CSF)from the brain surface. Those with brain bulging of 5.1-12mm showed ventricular dilatation on CT images, and required ventricular puncture or spinal CSF drainage to decrease brain bulging for cranioplasty. We believe that the lateral decubitus position, with the surgical side upward, ameliorates the local brain shift induced by gravity. A lateral position during CT simulates the surgical head position for cranioplasty and can help to assess whether cranioplasty is feasible.

Technique for rerouting a bridging vein that hinders the anterior interhemispheric approach: a technical note.

BACKGROUND: The frontal bridging vein, which is the venous drainage route of the frontal cortex into the superior sagittal sinus (SSS), sometimes poses an obstacle in the anterior interhemispheric approach during surgery for anterior cerebral artery aneurysms. Although severe complications including venous infarction or edema due to damage to the bridging vein are well known, only a few reports have discussed how to avoid venous injury when we must sacrifice the bridging vein to obtain an appropriate surgical field. This report describes a microvascular technique performed in two patients who underwent rerouting of the bridging vein to obtain an appropriate anterior interhemispheric surgical corridor to treat a ruptured anterior cerebral artery aneurysm. The hindering bridging vein was resected from the entrance to the SSS and anastomosed toward the adjacent cortical vein. METHODS: A 65-year-old male and a 43-year-old male were admitted to our hospital for sudden headache. Computed tomography, magnetic resonance angiogram, or digital subtraction angiography demonstrated a subarachnoid hemorrhage and an anterior cerebral artery aneurysm in both patients. In both cases, a relatively robust bridging vein, which appeared problematic to sacrifice, was draining into the SSS, resulting in a limited surgical corridor. Thus, we performed cortical vein reconstruction, and the aneurysms were successfully clipped under a wider surgical view. RESULTS: We confirmed completed clipping without postoperative venous complications. One patient demonstrated patency of reconstructed venous flow by digital subtraction angiography. No apparent cognitive impairment was seen in either patient. CONCLUSIONS: This technique may be useful for obtaining an appropriate surgical corridor when the frontal bridging vein may be damaged.

Clinical and radiological features of intracranial ancient schwannomas: a single-institution, retrospective analysis.

Ancient schwannoma (AS) is a subtype of schwannoma characterized by slow progression despite degenerative changes in pathology. Although it is considered a benign tumor, most previous reports have focused on extracranial AS; therefore, the clinical characteristics of intracranial AS is not clear. We included 174 patients who underwent surgery for sporadic intracranial schwannoma, and 13 patients (7.5%) were diagnosed with AS. Cysts were significantly more common in patients with AS than conventional schwannomas (92.3% vs. 44.7%, p < 0.001), as was bleeding (38.5% vs. 6.9%, p = 0.003) and calcification (15.4% vs. 1.3%, p = 0.029). The maximum tumor diameter was also larger in patients with AS (35 mm vs. 29 mm, p = 0.017). The median duration from symptom onset to surgery (7.0 vs. 12.5 months, p = 0.740) did not significantly differ between groups, nor did the probability of postoperative recurrence (p = 0.949). Intracranial AS was strongly associated with cyst formation and exhibited a benign clinical course with a lower rate of recurrence and need for salvage treatment. Extracranial AS is reportedly characterized by a slow progression through a long-term clinical course, whereas intracranial AS did not progress slowly in our study and exhibited different clinical features to those reported for extracranial AS.

POLR2A Mutation is a Poor Prognostic Marker of Cerebellopontine Angle Meningioma.

BACKGROUND AND OBJECTIVES: Recent molecular analyses have shown that the driver genetic mutations of meningiomas were associated with the anatomic location. Among these, POLR2A mutation is common among lesions in the skull base, mainly in the cerebellopontine angle (CPA). The objective of this study was to investigate the efficacy of POLR2A mutation as a prognostic marker for CPA meningiomas. METHODS: We retrospectively analyzed the clinical data of 70 patients who had World Health Organization grade I CPA meningiomas. Somatic DNA was analyzed by Sanger sequencing and microsatellite array to examine for NF2 , AKT1 , KLF4 , SMO , and POLR2A mutations and 22q loss. Genetic and clinical parameters were analyzed to identify the factors related with tumor recurrence. RESULTS: We detected clearly the clinical features of the CPA cases with POLR2A mutation. Compared with cases without POLR2A mutation, cases with POLR2A mutation had more meningothelial type ( P = 6.9 × 10 -4 ), and higher rate of recurrence ( P = .04). We found that the poor prognostic factors associated with the recurrence of CPA meningiomas were POLR2A mutation ( P = .03, hazard ratio [HR] 9.38, 95% CI 1.26-70.0) and subtotal resection (STR) ( P = 5.1 × 10 -4 , HR 63.1, 95% CI 6.09-655.0). In addition, in the group that underwent STR, POLR2A mutation was a poor prognostic factor associated with tumor recurrence ( P = .03, HR 11.1, 95% CI 1.19-103.7). CONCLUSION: POLR2A mutation and STR were the poor prognostic markers associated with the recurrence of CPA meningioma. For CPA meningioma cases that underwent STR, only POLR2A mutation was a poor prognostic factor. Detecting POLR2A mutation may be a cost-effective, easy, and useful marker for prognostication.

Successful Mechanical Thrombectomy for Isolated Internal Carotid Artery Occlusion in a Patient with Monocular Blindness: A Case Report.

We report a rare case of isolated internal carotid artery occlusion complicated by central retinal artery occlusion that was successfully treated with mechanical thrombectomy for internal carotid artery occlusion. A 59-year-old man visited the emergency room because of right monocular blindness. Magnetic resonance imaging showed multiple acute small embolic infarctions in the right frontal lobe, and magnetic resonance angiography revealed right internal carotid artery occlusion without the associated occlusion of the circle of Willis, which indicates the patency of the anterior and middle cerebral arteries. An electrocardiogram showed atrial fibrillation. Therefore, we performed mechanical thrombectomy with a stent retriever under continuous manual aspiration with a balloon-guiding catheter and confirmed complete recanalization, anterograde flow in the right ophthalmic artery, and retinal brush. The procedure was completed without complications, and the patient noticed an improvement in visual acuity immediately after the procedure. When a patient with atrial fibrillation complains of monocular blindness, it is important to consider internal carotid artery occlusion due to cardioembolism, to perform an examination promptly, and to consider early treatment, including mechanical thrombectomy.

Endoscopic Extended Transsphenoidal Surgery Aiming for Radical Resection of Skull Base Tumors Involving Cavernous Sinus: Assessment of Resectability and Risks of Complications.

BACKGROUND AND OBJECTIVES: Surgical resection of tumors invading the cavernous sinus (CS) still shows therapeutic challenges. For "nonadenomatous" skull base tumors invading in CS, there were only a few reports showing the outcomes of radical resection. Therefore, the outcomes of endoscopic transsphenoidal surgery (ETS) aiming for radical resection thus remain largely unknown regarding resectability and functional results of the cranial nerves. METHODS: We performed ETS aiming for radical resection in 35 skull base tumors involving CS (17 chondrosarcomas, 12 chordomas, 3 meningiomas, and 3 trigeminal schwannomas; median follow-up 36.5 months ranging from 12 to 91 months). Gross total resection (GTR) is attempted in all the cases for real-time findings from electrophysiological monitoring of the cranial nerves. When the tumor was strongly adherent to the cranial nerves or internal carotid artery, maximum volume reduction of the tumor was attempted. RESULTS: GTR was achieved in 28 patients (80.0%), subtotal resection in 3 (8.6%), and partial resection in 4 (11.4%). One patient experienced internal carotid artery injury during surgery. After ETS, 15 patients showed symptom improvement (51.7% in all 29 patients with preoperative cranial nerve symptoms, CNS). Four (11.4%) transiently developed abducens nerve palsy, and one required repair surgery for cerebrospinal leakage. In univariate analyses, extension to the lateral compartment of CS ( P = .04) was significantly associated with reduced achievement of GTR. Previous transcranial surgery was associated with reduced possibility of improvement and worsening in CNS. Eleven patients underwent stereotactic radiosurgery, at a median of 12 months after ETS. 32 patients (91.4%) did not show recurrence at the final follow-up. CONCLUSION: ETS can achieve sufficient surgical resection in most of the patients, with acceptable neurological complications. For patients with CNS, ETS may offer the opportunity for improving CNS. We should also always prioritize avoidance of critical situations by preventing internal carotid artery injury.

Long-Term Outcomes of Stereotactic Radiosurgery for Postoperative World Health Organization Grade I Skull Base Meningioma: Utility of Ki-67 Labeling Index as a Prognostic Indicator.

BACKGROUND: Gross total resection, without causing neurological deficits, is challenging in skull base meningioma (SBM). Therefore, stereotactic radiosurgery (SRS) is an important approach for SBMs; however, it is difficult to predict the long-term prognosis. OBJECTIVE: To identify the predictive factors for tumor progression after SRS for World Health Organization (WHO) grade I SBMs, focusing on the Ki-67 labeling index (LI). METHODS: In this single-center retrospective study, factors affecting progression-free survival rates (PFSs) and neurological outcomes in patients undergoing SRS for postoperative SBMs were evaluated. Based on the Ki-67 LI, patients were classified into 3 groups: low (<4%), intermediate (4%-6%), and high LI (>6%). RESULTS: In the 112 patients enrolled, the cumulative 5- and 10-year PFSs were 93% and 83%, respectively. The PFSs were significantly higher in the low LI group (95% at 10 years) compared with the other groups (intermediate LI, 60% at 10 years, P = .007; high LI, 20% at 10 years, P = .001). Multivariable Cox proportional hazard analysis demonstrated that the Ki-67 LI was significantly associated with the PFSs (low vs intermediate LI; hazard ratio, 6.00; 95% CI, 1.41-25.54; P = .015; low vs high LI; hazard ratio, 31.90; 95% CI, 5.59-181.77; P = .001). CONCLUSION: Ki-67 LI may be a useful predictor of long-term prognosis in SRS for postoperative WHO grade I SBM. SRS provides excellent long- and mid-term PFSs in SBMs with Ki-67 LIs <4% or 4% to 6%, with a low risk of radiation-induced adverse events.

Case report and literature review: exploration of molecular therapeutic targets in recurrent malignant meningioma through comprehensive genetic analysis with Todai OncoPanel.

Background: Despite accumulating research on the molecular characteristics of meningiomas, no definitive molecularly targeted therapy for these tumors has been established to date. Molecular mechanisms underlying meningioma progression also remain unclear. Comprehensive genetic testing approaches can reveal actionable gene aberrations in meningiomas. However, there is still limited information on whether profiling the molecular status of subsequent recurrent meningiomas could influence the choice of molecular-targeted therapies. Case presentation: We report a case of meningioma with malignant progression and multiple recurrences. We performed matched tumor pair analysis using the Todai OncoPanel to investigate the possibility of additional standard treatments. The loss of several chromosomal regions, including NF2 and CDKN2A, which is associated with aggressive meningiomas, was considered a significant driver event for malignant progression. Using additional matched tumor pair analysis, mutations in TRAF7, ARID1A, and ERBB3 were identified as subclonal driver events at the time of recurrence. No genetic aberrations were found for which evidence-based targeted therapy was applicable. We also reviewed previous reports of molecular therapies in meningioma to discuss issues with the current molecular testing approach. Conclusion: Gene panel testing platforms such as the Todai OncoPanel represent a powerful approach to elucidate actionable genetic alterations in various types of tumors, although their use is still limited to the diagnosis and prediction of prognosis in meningiomas. To enable targeted molecular therapy informed by gene-panel testing, further studies including matched tumor pair analyses are required to understand the molecular characteristics of meningiomas and develop treatments based on genetic abnormalities.

Meningiomas in patients with neurofibromatosis type 2 predominantly comprise 'immunogenic subtype' tumours characterised by macrophage infiltration.

Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.

Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study.

The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world's first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from > 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G > A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10-10). Stratified analysis within ICAS cases demonstrated that clinical features of those with and without the risk allele were different. PheWAS indicated that high blood pressure and angina were significantly associated with RNF213 rs112735431. The first GWAS of ICAS, which stratifies subpopulations within the ICAS cases with distinct clinical features, revealed that RNF213 rs112735431 was the most significant variant associated with ICAS. Thus, RNF213 rs112735431 shows potential as an important clinical biomarker that characterizes pleiotropic risk in various vascular diseases, such as blood pressure and angina, thereby facilitating personalized medicine for systemic vascular diseases in East Asian populations.

Distal radial artery approach is safe and effective for cerebral angiography and neuroendovascular treatment: A single-center experience with ultrasonographic measurement.

BACKGROUND: The transradial artery approach to cerebral angiography can reduce both patient stress following examination and the risk of major complications due to hematoma. Recently, the distal radial artery approach (DRA) has garnered attention in cardiology as a minimally invasive method. DRA is also considered applicable to neurosurgery, although concerns about procedural difficulty and complications persist. Therefore, this study aimed to evaluate the efficacy of the DRA in cerebral angiography and neuroendovascular treatment. METHODS: We retrospectively selected 30 consecutive patients for whom the DRA was attempted for cerebral angiography at our hospital. The patients' age, sex, height, weight, and medical history information was collected and correlated with successful puncture and complications. The diameter of the distal radial artery (RA) was measured using ultrasonography. RESULTS: The median patient age was 67 years (range, 32-87 years) and 21 (70%) were men. The median diameter of the distal RA was 2.3 mm (range, 1.7-3.2 mm). Distal RA puncture was successful in 23 patients (77%) and no complications were noted; however there was no significant correlation between successful puncture and any of the patient factors. Carotid artery stenting and preoperative tumor embolization were performed via DRA in six and three cases, respectively. Although puncture site hematoma occurred in only one case, all treatments were successful, and no major complications were observed. CONCLUSION: DRA can be safely used for cerebral angiography and neuroendovascular treatment.

STA-A3 Bypass Using Radial Artery Graft for Progressive Cerebral Infarction of Bilateral ACA Region after STA-MCA Bypass Surgery for Moyamoya Disease.

Direct revascularization surgery, such as superficial temporal artery (STA)-middle cerebral artery (MCA) bypass, is effective in preventing ischemia and hemorrhage for moyamoya disease. On the other hand, when ischemia of the anterior cerebral artery (ACA) region progresses after ipsilateral STA-MCA bypass, it is difficult to perform revascularization from the viewpoint of the donor artery. A 55-year-old woman with right hemiparesis was diagnosed with cerebral infarction due to moyamoya disease. Left STA-MCA bypass was performed with no postoperative complications, but memory impairment and decreased motivation were observed 2 months after the operation. Magnetic resonance imaging and angiography revealed new infarction in the bilateral ACA area and deterioration in the signal intensity of bilateral ACAs. Revascularization of the bilateral ACA regions was considered necessary, but the left STA was already used in the previous surgery. Therefore, STA-radial artery (RA)-A3 bypass using RA graft combined with right STA-MCA bypass was performed. STA-A3 bypass using an RA graft may be the optimal treatment for ischemia of the ACA region that progresses after STA-MCA bypass.

NF2 Alteration/22q Loss Is Associated with Recurrence in WHO Grade 1 Sphenoid Wing Meningiomas.

Sphenoid wing meningiomas account for 11−20% of all intracranial meningiomas and have a higher recurrence rate than those at other sites. Recent molecular biological analyses of meningiomas have proposed new subgroups; however, the correlation between genetic background and recurrence in sphenoid wing meningiomas has not yet been fully elucidated. In this study, we evaluated the clinical characteristics, pathological diagnosis, and molecular background of 47 patients with sphenoid wing meningiomas. Variants of NF2, AKT1, KLF4, SMO, POLR2A, PIK3CA, TRAF7, and TERT were determined using Sanger sequencing, and 22q loss was detected using multiplex ligation-dependent probe amplification. Alterations were localized at NF2 in 11 cases, had other genotypes in 17 cases, and were not detected in 12 cases. Interestingly, WHO grade 1 meningiomas with NF2 alteration/22q loss (p = 0.008) and a MIB-1 labeling index > 4 (p = 0.03) were associated with a significantly shorter recurrence-free survival, and multivariate analysis revealed that NF2 alteration/22q loss was associated with recurrence (hazard ratio, 13.1). The duration of recurrence was significantly shorter for meningiomas with NF2 alteration/22q loss (p = 0.0007) even if gross-total resection was achieved. Together, these findings suggest that NF2 alteration/22q loss is associated with recurrence in WHO grade 1 sphenoid wing meningiomas.

Advances in Molecular Biological and Translational Studies in World Health Organization Grades 2 and 3 Meningiomas: A Literature Review.

The treatment of World Health Organization (WHO) grades 2 and 3 meningiomas remains difficult and controversial. The pathogenesis of high-grade meningiomas was expected to be elucidated to improve treatment strategies. The molecular biology of meningiomas has been clarified in recent years. High-grade meningiomas have been linked to NF2 mutations and 22q deletion. CDKN2A/B homozygous deletion and TERT promoter mutations are independent prognostic factors for WHO grade 3 meningiomas. In addition to 22q loss, 1p, 14p, and 9q loss have been linked to high-grade meningiomas. Meningiomas enriched in copy number alterations may be biologically invasive. Furthermore, several new comprehensive classifications of meningiomas have been proposed based on these molecular biological features, including DNA methylation status. The new classifications may have implications for treatment strategies for refractory aggressive meningiomas because they provide a more accurate prognosis compared to the conventional WHO classification. Although several systemic therapies, including molecular targeted therapies, may be effective in treating refractory aggressive meningiomas, these drugs are being tested. Systemic drug therapy for meningioma is expected to be developed in the future. Thus, this review aims to discuss the distinct genomic alterations observed in WHO grade 2 and 3 meningiomas, as well as their diagnostic and therapeutic implications and systemic drug therapies for high-grade meningiomas.

Clinical significance of NF2 alteration in grade I meningiomas revisited; prognostic impact integrated with extent of resection, tumour location, and Ki-67 index.

NF2 alteration is the most commonly-found genetic abnormality in meningiomas and is known to initiate events for aggressive-type meningiomas. Whereas the prognosis of meningiomas differs depending on their epigenomic/transcriptomic profile, the effect of NF2 alteration on the prognosis of benign meningiomas is not fully elucidated. This study aimed to probe the importance of NF2 alteration in prognosis of WHO grade I meningiomas. A long-term retrospective follow-up (5.3 ± 4.5 years) study involving 281 consecutive WHO grade I meningioma patients was performed. We assessed tumour recurrence in correlation with extent of resection (EOR), histopathological findings, tumour location, and NF2 alteration. "NF2 meningioma" was defined as meningiomas with presence of NF2 mutation and/or 22q loss. Overall, NF2 meningioma per se was not a predictor of prognosis in the whole cohort; however, it was a predictor of recurrence in supratentorial meningiomas, together with EOR and Ki-67. In a striking contrast, NF2 meningioma showed a better prognosis than non-NF2 meningioma in infratentorial lesion. Supratentorial NF2 meningiomas had higher Ki-67 and forkhead box protein M1 expression than those of others, possibly explaining the worse prognosis in this subtype. The combination of NF2 alteration, high Ki-67 and supratentorial location defines subgroup with the worst prognosis among WHO grade I meningiomas. Clinical connotation of NF2 alteration in terms of prognosis of WHO grade I meningioma differs in an opposite way between supratentorial and infratentorial tumors. Integrated anatomical, histopathological, and genomic classifications will provide the best follow-up schedule and proactive measures.

Early prediction of functional prognosis in neurofibromatosis type 2 patients based on genotype-phenotype correlation with targeted deep sequencing.

Regardless of treatment, the clinical progression of neurofibromatosis type 2 (NF2), particularly in terms of hearing, swallowing, and gait, tend to worsen throughout the patients' lives. We performed a retrospective analysis of functional outcomes in Japanese NF2 patients to predict their functional prognosis. We analyzed genotype-phenotype correlation based on genetic data from a cohort of 57 patients with a mean follow-up of 14.5 ± 6.0 years. Their functional outcomes, including hearing, swallowing, and ambulation, were reviewed. Performing a targeted deep sequencing, germline NF2 mutations were identified in 28 patients (49.1%), and mosaic NF2 was identified in 20 patients (20, 35.0%). The functional preservation period and outcome differed significantly depending on clinical/genetic factors. Among these factors, "Truncating", "Mosaic", and "Age of symptom onset ≥ 25" had the most significant effects on functional disability. By applying a combination of an NF2 mutation type/location, and age of symptom onset, we classified different degrees of functional preservation and progression, schwannoma growth rate and total interventions per year per patient. The prediction of detailed functional outcomes in NF2 patients can plan better strategies for life-long disease management and social integration.