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.

Effects of an extended photoperiod on body composition of young Thoroughbreds in training.

The effects of an extended photoperiod (EP) on body composition of Thoroughbreds colts and fillies from December at one year old to April at two years old were investigated. Seventy-three Thoroughbreds reared and trained in Hidaka Training and Research Center, Japan Racing Association, Hokkaido were used. Forty-one horses were under the EP conditions from December 20 to April 15, and the 32 horses were under natural light alone as the control group. Body weight (BW), rump fat thickness (RFT), fat free mass (FFM) and percentage of fat (%F) were used as parameters of body composition. The present study revealed that BW and FFM increased with age in the EP group in colts. In fillies, BW increased with age in both the EP and the control group, however FFM increased with age only in the EP group. From December to April, only colts had a higher rate of increase in both BW and FFM in the EP group than in the control group. However, according to the mean rates of increase in FFM from January to March, the EP group was significantly higher than the control group in both sexes. Furthermore, monthly increase rate of FFM in March was significantly higher in the EP group than in the control group in both sexes. These results suggests that EP treatment to young Thoroughbreds in training at Hokkaido, which is shorter daylength in winter, accelerate the increase of FFM, representing muscle mass.

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.

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.

Transuncal Selective Amygdalohippocampectomy by an Inferolateral Preseptal Endoscopic Approach Through Inferior Eyelid Conjunctival Incision: An Anatomic Study.

BACKGROUND: Transorbital endoscopic approaches have been described for pathologies of anterior and middle fossae. Standard lateral orbitotomy gives access to mesial temporal lobe, but the axis of work is partially obscured by the temporal pole and working corridor is limited. OBJECTIVE: To evaluate the usefulness of an inferolateral orbitotomy to provide a more direct corridor to perform a transuncal selective amygdalohippocampectomy. METHODS: Three adult cadaveric specimens were used for a total of 6 dissections. A step-by-step description and illustration of the transuncal corridor for a selective amygdalohippocampectomy were performed using the inferolateral orbitotomy through an inferior eyelid conjunctival incision. The anatomic landmarks were demonstrated in detail. Orbitotomies and angles of work were measured from computed tomography scans, and the area of resection was illustrated by postdissection MRI. RESULTS: Inferior eyelid conjunctival incision was made for exposure of the inferior orbital rim. Inferolateral transorbital approach was performed to access the transuncal corridor. Endoscopic selective amygdalohippocampectomy was performed through the entorhinal cortex without damage to the temporal neocortex or Meyer's loop. The mean horizontal diameter of the osteotomy was 14.4 mm, and the vertical one was 13.6 mm. The mean angles of work were 65° and 35.5° in the axial and sagittal planes, respectively. Complete amygdalohippocampectomy was achieved in all 6 dissections. CONCLUSION: Transuncal selective amygdalohippocampectomy was feasible in cadaveric specimens using the inferolateral transorbital endoscopic approach avoiding damage to the temporal neocortex and Meyer's loop. The inferior eyelid conjunctival incision may result in an excellent cosmetic outcome.

Surgical morbidity of the extradural anterior petrosal approach: the Lariboisière experience.

OBJECTIVE: Concerns about the approach-related morbidity of the extradural anterior petrosal approach (EAPA) have been raised, especially regarding temporal lobe and venous injuries, hearing impairment, facial nerve palsy, cerebrospinal fluid fistula, and seizures. There is lack in the literature of studies with detailed analysis of surgical complications. The authors have presented a large series of patients who were treated with EAPA, focusing on complications and their avoidance. METHODS: The authors carried out a retrospective review of patients who underwent EAPA at their institution between 2012 and 2021. They collected preoperative clinical characteristics, operative reports, operative videos, findings on neuroimaging, histological diagnosis, postoperative course, and clinical status at last follow-up. For pathologies without petrous bone invasion, the amount of petrous apex drilling was calculated and classified as low (< 70% of the volume) or high (≥ 70%). Complications were dichotomized as approach related and resection related. RESULTS: This study included 49 patients: 26 with meningiomas, 10 brainstem cavernomas, 4 chondrosarcomas, 4 chordomas, 2 schwannomas, 1 epidermoid cyst, 1 cholesterol granuloma, and 1 osteoblastoma. The most common approach-related complications were temporal lobe injury (6.1% of patients), seizures (6.1%), pseudomeningocele (6.1%), hearing impairment (4.1%), and dry eye (4.1%). Approach-related complications occurred most commonly in patients with a meningioma (p = 0.02) and Meckel's cave invasion (p = 0.02). Gross-total or near-total resection was correlated with a higher rate of tumor resection-related complications (p = 0.02) but not approach-related complications (p = 0.76). Inferior, lateral, and superior tumoral extension were not correlated with a higher rate of tumor resection-related complications. No correlation was found between high amount of petrous bone drilling and approach- or resection-related complications. CONCLUSIONS: EAPA is a challenging approach that deals with critical neurovascular structures and demands specific skills to be safely performed. Contrary to general belief, its approach-related morbidity seems to be acceptable at dedicated skull base centers. Morbidity can be lowered with careful examination of the preoperative neuroradiological workup, appropriate patient selection, and attention to technical details.

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.

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.

Probable Sporadic Creutzfeldt-Jakob Disease Presenting as Refractory Status Epilepticus in a Poststroke Epilepsy Patient: A Case Report.

In this study, we report on a case of probable sporadic Creutzfeldt-Jakob disease (sCJD) diagnosed after a difficult course of status epilepticus (SE) in a patient with poststroke epilepsy. The patient was admitted with progressive cognitive decline and convulsive SE; therefore, it was initially thought that the patient had developed SE due to nonadherence to antiseizure medication (ASM) use, but despite treatment with ASMs after admission, no improvement was noted in consciousness disturbance or lateralized periodic discharges (LPDs) on electroencephalogram (EEG) examination. After a refractory course, the progression of LPDs to generalized periodic discharges (GPDs) on EEG and abnormal magnetic resonance imaging (MRI) findings met the diagnostic criteria of sCJD. Even if the patient had epilepsy, such as poststroke epilepsy, as in this case, it is essential to consider other underlying causes, including CJD in cases of superrefractory SE.

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.

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.

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.

The mini-combined transpetrosal approach: an anatomical study and comparison with the combined transpetrosal approach.

BACKGROUND: The combined transpetrosal approach (CTPA) is a versatile technique suitable for challenging skull base pathologies. Despite the advantages provided by a wide surgical exposure, the soft tissue trauma, complex and time-consuming bony work, and cosmetic issues make it far from patient expectations. In this study, the authors describe a less invasive modification of the CTPA, the mini-combined transpetrosal approach (mini-CTPA), and perform a quantitative comparison between these two approaches. METHODS: Five human specimens were used for this study. CTPA was performed on one side and mini-CTPA on the opposite side. The surgical freedom, petroclival and brainstem area of exposure, and maneuverability for 6 anatomical targets, provided by the CTPA and mini-CTPA, were calculated and statistically compared. The bony volumes corresponding to each anterior petrosectomy were also measured and compared. Three clinical cases with an operative video are also reported to illustrate the effectiveness of the approach. RESULTS: The question-mark skin incision done along the muscle attachments permits an optimal cosmetic result. Even though the limited incision, the smaller craniotomy, and the less extensive bone drilling of mini-CTPA provide a smaller area of surgical freedom, the areas of exposure of petroclival region and brainstem were not statistically different between the two approaches. The antero-posterior maneuverability for the oculomotor foramen (OF), Meckel's cave (MC) and the REZ of trigeminal nerve, and the supero-inferior maneuverability for OF, MC, Dorello's canal, and REZ of CN VII are significantly reduced by the smaller opening. The bony volume of anterior petrosectomy resulted similar among the approaches. CONCLUSIONS: The mini-CTPA is an interesting alternative to the CTPA, providing comparable surgical exposure both for petroclival region and for brainstem. Although the lesser soft tissue dissection and bony opening decrease the surgical maneuverability, the mini-CTPA may reduce surgical time, potential approach-related morbidities, and improve cosmetic and functional outcomes for the patients.

[A case of primary intramedullary spinal cord lymphoma diagnosed by spinal cord biopsy of long spinal cord lesions showing persistent gadolinium contrast enhancement].

An 82-year-old man presented with subacute bilateral lower limb paralysis, deep sensory disturbance, and vesico-rectal disturbance. MRI of the spinal cord revealed a large gray matter-dominant lesion extending from the medulla oblongata to the lower thoracic spinal cord. The patient was treated with steroid-pulse therapy for myelitis, but without symptomatic improvement. A spinal cord biopsy was performed for treatment-resistant myelopathy, and histopathology revealed a diffuse large B-cell lymphoma, that was diagnosed as a primary intramedullary spinal cord lymphoma because systemic examination didn't show any other findings suggestive of malignant lymphoma. A spinal cord biopsy is necessary for the definitive diagnosis of this disease, but in the case of poor response to treatment and a progressive course, intramedullary malignant lymphoma should be considered if there is a persistent elevation of CSF IL-10 or a prolonged contrast effect.

The Rostral Mucosa: The Door to Open and Close for Targeted Endoscopic Endonasal Approaches to the Clivus.

BACKGROUND: Extended endoscopic endonasal approaches (EEAs) have progressively widened the armamentarium of skull base surgeons. In order to reduce approach-related morbidity of EEAs and closure techniques, the development of alternative strategies that minimize the resection of normal tissue and alleviate the use of naso-septal flap (NSF) is needed. We report on a novel targeted approach to the clivus, with incision and closure of the mucosa of the rostrum, as the initial and final step of the approach. OBJECTIVE: To present an alternative minimally invasive approach and reconstruction technique for selected clival chordomas. METHODS: Three cases of clival chordomas illustrating this technique are provided, together with an operative video. RESULTS: The mucosa of the rostrum is incised and elevated from the underlying bone, as first step of surgery. Following tumor resection with angled scope and instruments, the mucosa of the sphenoid sinus (SS) is removed and the tumor cavity and SS are filled with abdominal fat. The mucosal incision of the rostrum is then sutured. A hangman knot is prepared outside the nasal cavity and tightened after the first stitch and a running suture is performed. CONCLUSION: We propose, in this preliminary report, a new targeted approach and reconstruction strategy, applying to EEAs the classic concept of skin incision and closure for transcranial approaches. With further development in the instrumentations and visualization tools, this technique may become a valuable minimally invasive endonasal approach for selected lesions.

Associations of pathological diagnosis and genetic abnormalities in meningiomas with the embryological origins of the meninges.

Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10-10). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10-12). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10-2, Hazard Ratio 4.08, 95% Confidence Interval 1.28-13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2.

BACKGROUND: Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2. METHODS: We performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype-phenotype correlation. RESULTS: Twenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma. CONCLUSION: We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with 'unilateral vestibular schwannoma' or 'multiple meningiomas' presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.