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.

Long-term outcomes of stereotactic radiosurgery for intracranial schwannoma in neurofibromatosis type 2: a genetic analysis perspective.

PURPOSE: Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas. METHODS: This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed. RESULTS: The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months).　The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016). CONCLUSION: SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

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.

Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis.

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

Single-Cell Phenotyping of CD73 Expression Reveals the Diversity of the Tumor Immune Microenvironment and Reflects the Prognosis of Bladder Cancer.

The cutting edge of cancer immunotherapy extends to ecto-5'-nucleotidase (CD73), a cell membrane enzyme that targets the metabolism of extracellular adenosine. We herein focused on the expression of CD73 to clarify the state of CD73 positivity in cancer immunity and tumor microenvironment, thereby revealing a new survival predictor for patients with bladder cancer (BCa). We used clinical tissue microarrays of human BCa and simultaneously performed the fluorescent staining of cell type-specific markers (CD3, CD8, Foxp3, programmed cell death protein 1, and programmed death-ligand 1 [PD-L1]) and CD73 together with DAPI for nuclear staining. In total, 156 participants were included. Multiplexed cellular imaging revealed a unique interaction between CD73 expression and CD8+ cytotoxic T cells (CTLs) and Foxp3+ regulatory T (Treg) cells in human BCa, showing the high infiltration of CD8+CD73+ CTLs and Foxp3+CD73+ Treg cells in tumors to be associated with tumorigenesis and poor prognosis in BCa. Interestingly, from a biomarker perspective, the high infiltration of CD73+ Treg cells in tumors was identified as an independent risk factor for overall survival in addition to clinicopathologic features. Regarding the relationship between immune checkpoint molecules and CD73 expression, both CD73+ CTLs and CD73+ Treg cells tended to coexpress programmed cell death protein 1 as tumor invasiveness and nuclear grade increased. Additionally, they may occupy a spatial niche located distantly from PD-L1+ cells in tumors to interfere less with the cancerous effects of PD-L1+ cells. In conclusion, the present results on the status of CD73 in cancer immunity suggest that CD73 expression on specific T-cell types has a negative immunoregulatory function. These findings may provide further insights into the immunobiological landscape of BCa, which may be translationally linked to improvements in future immunotherapy practice.

Clinical and Genetic Characteristics of Patients with Moyamoya Disease who Experienced Both Ischemic and Hemorrhagic Events.

OBJECTIVE: Cerebrovascular events in moyamoya disease are mainly classified into ischemic or hemorrhagic onset. It is rare for one patient to develop both ischemia and hemorrhage in moyamoya disease; detailed clinical course and genetic characteristics of such patients have not been elucidated. We aimed to clarify the clinical features of patients with both ischemic and hemorrhagic cerebrovascular events. METHODS: We analyzed the background factors, radiological features, and genotype of ring finger protein 213 c.14429 G > A (p.Arg4810Lys) of patients with moyamoya disease who visited our hospital between 1996 and 2020, and experienced both ischemic and hemorrhagic cerebrovascular events. Additionally, we analyzed factors that caused subsequent hemorrhage in adult-onset ischemic moyamoya disease. RESULTS: Of 262 patients, 12 presented with both ischemia and hemorrhage, of which, 4 exhibited pediatric onset and 8 had adult onset. In pediatric-onset subjects, ischemia was the initial event in all cases. Hemorrhagic events occurred at a median of 24.7 years postoperatively in patients who had undergone bypass surgery. In adult-onset subjects, ischemia preceded hemorrhage in 7 patients. In males, the interval to subsequent hemorrhage was significantly shorter for adult-onset ischemic moyamoya disease, and the hazard ratio for hemorrhagic events was 5.45. The ring finger protein 213 p.Arg4810Lys heterozygous variant was present in 9 patients. CONCLUSIONS: A majority of patients with moyamoya disease with both ischemia and hemorrhage experience an ischemic event first. Patients who developed ischemia in childhood may develop subsequent hemorrhage in approximately 20-25 years after bypass surgery. Male sex is a risk factor for a subsequent hemorrhagic event in adult-onset ischemic moyamoya disease.

Stereotactic radiosurgery for recurrent pleomorphic adenoma of the lacrimal gland: a case report.

Lacrimal gland pleomorphic adenomas (LGPAs) are common, benign, and intraorbital tumours that cause exophthalmos, ptosis, and visual disturbances. The curative treatment for LGPAs is gross total resection, and radiotherapy is considered adjunctive for recurrence or an alternative for inoperable LGPAs. Stereotactic radiosurgery (SRS) can be used for precise delivery of high radiation doses to the tumour, crucial in the treatment of intra-and extracranial neoplasms. Here, we present a 95-year-old woman who had a rapidly growing, recurrent LGPA and was successfully treated with SRS. The tumour was controlled without any adverse events over 21 months following SRS. SRS is a potential alternative treatment for recurrent LGPA.

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.

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.

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.

Long-term progression-free survival achieved in the skull base metastasis of gastrointestinal stromal tumor with introduction of tyrosine kinase inhibitor: illustrative case.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are common subepithelial tumors that rarely metastasize to the intracranial space. Because the standard treatment for metastatic intracranial GISTs has not been established, multimodal therapies are needed, especially in the case of skull base metastasis. However, its outcome has not always been favorable. The authors report the longest known surviving case of skull base metastasis of GIST treated with imatinib only. OBSERVATIONS: A 52-year-old male with a history of GIST presented with left facial swelling and numbness. Examinations revealed a 70-mm tumor occupying the left middle cranial fossa and the orbit. The authors performed transnasal endoscopic tumor biopsy for definitive diagnosis and reintroduced imatinib treatment. The tumor significantly decreased in size early after the introduction of imatinib, and symptoms completely disappeared within several weeks. The lesion has remained shrunk radiologically for 63 months, and the patient is continuously being followed up under imatinib treatment. LESSONS: The authors reported a rare case of skull base metastasis of GIST successfully treated solely with systemic therapy with a tyrosine kinase inhibitor, achieving tumor control for over 5 years. This case suggests that tyrosine kinase inhibitors might play a key role in the multidisciplinary treatment for skull base metastases of GIST.

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.

Symptomatic and Stenotic Developmental Venous Anomaly with Pontine Capillary Telangiectasia: A Case Report with Genetic Considerations.

Stenotic developmental venous anomalies (DVAs) often present with neurological deficits. In addition, cerebral capillary telangiectasia (CCT) coexisting with DVA is rarely encountered, and its pathophysiology, including the underlying genetics, and appropriate management remain uncertain. A 46-year-old man without any medical history of note was referred to our hospital with gradually worsening cerebellar ataxia. Two months after symptom onset, ataxic dysarthria and gait emerged. Brain magnetic resonance imaging showed CCT occupying the pons and left cerebellar peduncle. Subsequent catheter angiography demonstrated a DVA leading from the mass into the cavernous sinus with marked outlet stenosis and flow stagnation. We hypothesized that venous congestion was the source of gradual neurological deterioration and therefore initiated anticoagulation. Symptoms showed mild improvement, and his neurological status has remained stable as of 1 year after symptom onset. Whole-exome sequencing of germline DNA did not reveal any rare variants in genes previously reported as pertinent to vascular malformations. Anticoagulation may be a useful option in patients with non-thrombotic, stenotic DVA for whom neurological status did not improve under expectant management. Genetic analysis of this patient did not reveal any pathogenic mutations, and further investigation of somatic mutations is necessary to elucidate potential genetic causes.

[Molecular Biological Background of Neurofibromatosis Type 2].

Neurofibromatosis type 2(NF2)is a hereditary tumor syndrome characterized by bilateral acoustic nerve tumors, multiple schwannomas, and multiple meningiomas. About half of the patients develop familial onset through an autosomal dominant mode of inheritance. The causative gene of NF2 is the NF2 gene, and those who have a germline mutation of the said gene invariably develop the disease. On the other hand, about half of NF2 patients are sporadic cases. It is thought that the somatic mosaic of the NF2 gene is involved in most of the sporadic cases, in which germline mutation of NF2 is not detected. It is becoming clear that the clinical features, such as the life and functional prognoses of NF2 patients, differ depending on the genotype of the causative gene.