We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
Background: We performed a phase II trial of pembrolizumab in patients with NSCLC or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. Methods: This was an open-label, single-institution, phase 2 study. Eligible patients were ≥ 18 years of age with advanced NSCLC with ≥1 brain metastasis 5-20mm not previously treated or progressing after prior radiation, no neurologic symptoms or corticosteroid requirement, and performance status <2. Patients were treated with pembrolizumab 10 mg/kg IV every 2 weeks. Cohort 1 was for patients with PD-L1 ≥1% and cohort 2 PD-L1 <1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response. All treated patients were analyzed for response and safety endpoints. This study is closed to accrual and is registered with Clinicaltrials.gov, number NCT02085070. Here we report the updated results of the NSCLC cohort. Findings: Between March 31, 2014 and May 21, 2018, 42 patients were treated. Median followup was 8.3 months (IQR 4.5 to 26.2 months). Eleven of 37 patients in cohort 1 had a brain metastasis response (29.7% [95% CI, 15•9-47•0%]). There were no responses in cohort 2. Grade 3-4 AEs related to treatment included 2 patients with pneumonitis, and 1 each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycemia, and hypokalemia. Treatment-related serious adverse events occurred in 6 (14%) patients and included pneumonitis acute kidney injury, colitis, hypokalemia, and adrenal insufficiency. There were no treatment-related deaths. Interpretation: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression ≥1% and is safe in select patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted.
Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors1. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.
Our updated literature review demonstrates that despite more experience with endoscopic resection and skull base reconstruction, the literature still supports TCA over EEA with respect to the extent of resection and complications. EEA may be an option in selected cases where visual improvement is the main goal of surgery and postoperative anosmia is acceptable to the patient or in medium-sized tumors with existing preoperative anosmia. Nevertheless, based on our results, it seems more prudent at this time to use TCA for the majority of OGMs.
Sphenoorbital meningiomas (SOMs) are slow-growing tumors that originate from the sphenoidal wing and are associated with visual deterioration, extrinsic ocular movement disorders, and proptosis caused by hyperostosis of the lateral wall of the orbit. In some cases, the intracranial component is quite small or "en plaque," and the majority of the symptoms arise from adjacent hyperostosis. Craniotomy has traditionally been the standard of care, but new minimally invasive multiportal endoscopic approaches offer an alternative. In the current study, the authors to present their experience with the transorbital endoscopic eyelid approach for the treatment of 2 patients with SOMs and sphenoid wing hyperostosis. Clinical and radiological data for patients with SOMs who underwent a transorbital endoscopic eyelid approach were retrospectively reviewed. Surgical technique and clinical and radiographic outcomes were analyzed. The authors report the cases of 2 patients with SOMs and proptosis due to sphenoid wing hyperostosis. One patient underwent prior craniotomy to debulk the intracranial portion of the tumor, and the other had a minimal intracranial component. Both patients were discharged 2 days after surgery. MR images and CT scans demonstrated a large debulking of the hyperostotic bone. Postoperative measurement of the proptosis with the aid of an exophthalmometer demonstrated significant reduction of the proptosis in one of the cases. Persistence of intraconal tumor in the orbital apex limited the efficacy of the procedure in the other case. A review of the literature revealed 1 publication with 3 reports of the transorbital eyelid approach for SOMs. No measure of relief of proptosis after this surgery had been previously reported. The transorbital endoscopic approach, combined with endonasal decompression of the medial orbit, may be a useful minimally invasive alternative to craniotomy in a subset of SOMs with a predominantly hyperostotic orbital wall and minimal intracranial bulky or merely en plaque disease. In these cases, relief of proptosis and optic nerve compression are the primary goals of surgery, rather than gross-total resection, which may have high morbidity or be unachievable. In cases with significant residual intraconal tumor, orbital bone removal alone may not be sufficient to reduce proptosis.
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