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The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
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Glioma/genética , Adulto , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Progresión de la Enfermedad , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Polimorfismo de Nucleótido Simple , RecurrenciaRESUMEN
BACKGROUND: Meningiomas are the most common intracranial tumors. Recent advancements in the genetic profiling of tumors have allowed information including DNA copy number analysis, mutational analysis, and RNA sequencing to be more frequently reported, in turn allowing better characterization of meningiomas. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success. METHOD: We report DNA methylation profiling on meningiomas from 17 patients. Formalin-fixed paraffin-embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were processed through the the CNS tumor classifier developed by the Molecular Neuropathology group at the German Cancer Research Center (DKFZ). Corresponding genomics were captured using targeted sequencing panels. RESULT: Among the meningioma samples, 13 samples were classified as "benign," two samples as "intermediate," and the remaining three samples (from two patients) as "malignant," based on previously validated classification algorithms. In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (including size and location), surgical approaches, and mutational analysis. The two patients who provided the samples with "malignant" methylation classifications had tumor recurrence, reflecting a more aggressive disease course. CONCLUSION: In accordance with prior reports, our case series provides support that tumor DNA methylation profiling adds meaningful classification information and may be beneficial to incorporate in clinical practice. Our report also reveals that DNA methylation combined with WHO histology classification can more accurately predict tumor behavior than WHO classification alone.
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Neoplasias del Sistema Nervioso Central , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/diagnóstico , Meningioma/genética , Metilación de ADN/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genéticaRESUMEN
BACKGROUND: Meningiomas are the most common primary central nervous system tumor. Previous studies have characterized recurrent genetic alterations that can predict patient prognosis and potentially provide new avenues for therapeutic intervention. Continued efforts to characterize the genomic changes in meningioma samples can aid in the discovery of therapeutic targets and appropriate patient stratification. METHODS: We performed targeted genomic sequencing on 25 primary and 2 recurrent meningiomas using a 500-gene panel, including canonical meningioma drivers. We further detail the genomic profiles and relevant clinical findings in three cases of angiomatous meningiomas and two recurrent atypical meningiomas. RESULTS: Our approach uncovers a diverse landscape of genomic variants in meningioma samples including mutations in established meningioma-related genes NF2, AKT1, PIK3CA, and TRAF7. In addition to known meningioma drivers, we uncover variants in genes encoding other PI3K subunits, Notch/hedgehog/Wnt signaling pathway components, and chromatin regulators. We additionally identify 22 genes mutated across multiple samples. Three patients included in the study were diagnosed with angiomatous WHO grade I meningiomas, all three of which contained variants in the PI3K-AKT signaling pathway previously described to regulate tumor angiogenesis. Analysis of patient-matched primary and recurrent atypical meningiomas revealed clonal enrichment for mutations in the SWI/SNF complex subunits ARID1A and SMARCA4. CONCLUSIONS: Targeted genomics implemented in neuro-oncology care can enhance our understanding of the genetic underpinnings of central nervous system tumors, including meningiomas. These molecular signatures may be clinically useful in dictating treatment strategies and patient follow-up.
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Neoplasias Meníngeas , Meningioma , ADN Helicasas , Genómica , Humanos , Neoplasias Meníngeas/patología , Meningioma/patología , Recurrencia Local de Neoplasia , Proteínas Nucleares , Fosfatidilinositol 3-Quinasas/genética , Factores de TranscripciónRESUMEN
Pregnancy-associated meningiomas have unique considerations and features regarding their pathophysiology, location, genetic profile, and neurosurgical management. These tumours have been reported to undergo rapid growth during gestation and regression post-partum, implicating a role for female sex hormones in tumour physiology. In addition, these tumours occur at a higher incidence in the skull base compared to sporadic meningiomas in the general population, often impinging neurovascular structures and requiring emergent resection. While the genomics of sporadic meningiomas have been described, there are no reports characterizing the genetic features of those associated with pregnancy. Here we describe a patient diagnosed with a diphragma sellae meningioma early in the third trimester after presenting with rapidly deteriorating vision. At 32 weeks gestation the baby was delivered by caesarean section and the tumour subsequently removed. Genomic profiling of the tumour sample revealed variants of unknown significant (VUS) in six genes, none of which were in canonical meningioma drivers. We describe our surgical approach and discuss the relevant pathology and genomics, as well as medical and surgical management considerations of meningiomas in pregnancy.
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BACKGROUND: Spinal arteriovenous fistula (AVF) represents the most common type of spinal vascular lesions and is often associated with progressive neurological dysfunction. METHOD: Here, we present a unique case of a spinal vascular malformation that does not fit the traditional classification schemes. The patient presented with progressive neurologic deficits resembling partial Brown-Sequard syndrome and was subsequently found to have a lesion resembling type I spinal AVF. However, this intradural fistula drained into the ventral venous plexus rather than dorsal. CONCLUSION: Recognizing these rare anatomical variants is paramount in achieving successful obliteration and improved functional outcome for patients.
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Fístula Arteriovenosa/cirugía , Drenaje/métodos , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias/prevención & control , Médula Espinal/cirugía , Drenaje/efectos adversos , Humanos , Procedimientos Neuroquirúrgicos/efectos adversos , Complicaciones Posoperatorias/etiologíaRESUMEN
The presence of gaseous air emboli in the vasculature has the potential to cause significant morbidity and mortality. Once viewed as a rare complication of high-risk surgeries, air embolism is now also being associated with even minor and routine procedures such as peripheral venous catheterization. With increasing recognition, various preventive measures have emerged, the most important of which is the use of air-eliminating filters. However, studies on these devices are currently lacking. Therefore, in this present study, we aimed to evaluate the effectiveness of two commercially available filters in removing air within intravenous (IV) lines. An IV infusion system was created, designed to resemble standard conditions used in real clinical practice. Testing was completed using a .9% NaCl solution at room temperature with a flow rate set at 75 mL/h and involving three different filter orientations. The test bed was configured to inject air every 2 minutes with volumes ranging between 5 and 600 µL. The two filter models tested were GVS .2-µM and Braun SUPOR membrane air-eliminating filters. Data was collected at pre-filter and post-filter sites. The Braun SUPOR membrane filter (B Braun, Bethlehem, PA) reduced air micro-emboli by 100.0% (p < .0001) both by volume and count compared with -.6 ± 3.5% by volume and -.8 ± 1.5% by count for the control. The reduction seen with the GVS .2-µM filter was 99.8 ± .2% (p < .0001) by volume and 86.2 ± 21.1% (p < .0001) by count compared with the control. There was no statistically significant difference in the removal efficacy between the two filter models. As the use of air-eliminating filters becomes a common standard of care, establishing the validity of the commercially available filter models is important to minimize the risk of vascular air embolism.
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Embolia Aérea , Humanos , Infusiones IntravenosasRESUMEN
INTRODUCTION: Dysphagia screening protocols have been recommended to identify patients at risk for aspiration. The American Heart Association convened an evidence review committee to systematically review evidence for the effectiveness of dysphagia screening protocols to reduce the risk of pneumonia, death, or dependency after stroke. METHODS: The Medline, Embase, and Cochrane databases were searched on November 1, 2016, to identify randomized controlled trials (RCTs) comparing dysphagia screening protocols or quality interventions with increased dysphagia screening rates and reporting outcomes of pneumonia, death, or dependency. RESULTS: Three RCTs were identified. One RCT found that a combined nursing quality improvement intervention targeting fever and glucose management and dysphagia screening reduced death and dependency but without reducing the pneumonia rate. Another RCT failed to find evidence that pneumonia rates were reduced by adding the cough reflex to routine dysphagia screening. A smaller RCT randomly assigned 2 hospital wards to a stroke care pathway including dysphagia screening or regular care and found that patients on the stroke care pathway were less likely to require intubation and mechanical ventilation; however, the study was small and at risk for bias. CONCLUSIONS: There were insufficient RCT data to determine the effect of dysphagia screening protocols on reducing the rates of pneumonia, death, or dependency after stroke. Additional trials are needed to compare the validity, feasibility, and clinical effectiveness of different screening methods for dysphagia.
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Isquemia Encefálica , Trastornos de Deglución , Accidente Cerebrovascular , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Femenino , Humanos , Masculino , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapiaRESUMEN
INTRODUCTION: Endovascular thrombectomy is a highly efficacious treatment for large vessel occlusion (LVO). LVO prediction instruments, based on stroke signs and symptoms, have been proposed to identify stroke patients with LVO for rapid transport to endovascular thrombectomy-capable hospitals. This evidence review committee was commissioned by the American Heart Association/American Stroke Association to systematically review evidence for the accuracy of LVO prediction instruments. METHODS: Medline, Embase, and Cochrane databases were searched on October 27, 2016. Study quality was assessed with the Quality Assessment of Diagnostic Accuracy-2 tool. RESULTS: Thirty-six relevant studies were identified. Most studies (21 of 36) recruited patients with ischemic stroke, with few studies in the prehospital setting (4 of 36) and in populations that included hemorrhagic stroke or stroke mimics (12 of 36). The most frequently studied prediction instrument was the National Institutes of Health Stroke Scale. Most studies had either some risk of bias or unclear risk of bias. Reported discrimination of LVO mostly ranged from 0.70 to 0.85, as measured by the C statistic. In meta-analysis, sensitivity was as high as 87% and specificity was as high as 90%, but no threshold on any instruments predicted LVO with both high sensitivity and specificity. With a positive LVO prediction test, the probability of LVO could be 50% to 60% (depending on the LVO prevalence in the population), but the probability of LVO with a negative test could still be ≥10%. CONCLUSIONS: No scale predicted LVO with both high sensitivity and high specificity. Systems that use LVO prediction instruments for triage will miss some patients with LVO and milder stroke. More prospective studies are needed to assess the accuracy of LVO prediction instruments in the prehospital setting in all patients with suspected stroke, including patients with hemorrhagic stroke and stroke mimics.
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Isquemia Encefálica , Servicios Médicos de Urgencia/métodos , Procedimientos Endovasculares , Accidente Cerebrovascular , Trombectomía , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/cirugía , Procedimientos Endovasculares/instrumentación , Procedimientos Endovasculares/métodos , Femenino , Humanos , Masculino , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/cirugía , Trombectomía/instrumentación , Trombectomía/métodosRESUMEN
INTRODUCTION: Despite advancements in medical and surgical therapies, clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH) continue to be poor. Currently, aSAH pathophysiology remains poorly understood. No aSAH biomarkers are commonly used in the clinical setting. This exploratory study used metabolomics profiling to identify global metabolic changes and metabolite predictors of long-term outcome using cerebrospinal fluid (CSF) samples of aSAH patients. METHODS AND METHODS: Gas chromatography time-of-flight mass spectrometry was applied to CSF samples collected from 15 consecutive high-grade aSAH patients (modified Fisher grade 3 or 4). Collected CSF samples were analyzed at two time points (admission and the anticipated vasospasm timeframe). Metabolite levels at both time points were compared and correlated with vasospasm status and Glasgow Outcome Scale (GOS) of patients at 1 year post-aSAH. Significance level was defined as p < 0.05 with false discovery rate correction for multiple comparisons. RESULTS: Of 97 metabolites identified, 16 metabolites, primarily free amino acids, significantly changed between the two time points. These changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites (2-hydroxyglutarate, tryptophan, glycine, proline, isoleucine, and alanine) correlated with GOS at 1 year post-aSAH independent of vasospasm status. When predicting patients who had low disability (GOS 5 vs. GOS ≤4), 2-hydroxyglutarate had a sensitivity and specificity of 0.89 and 0.83 respectively. CONCLUSIONS: Our preliminary study suggests that specific metabolite changes occur in the brain during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcome in patients with aSAH. This is the first study to implicate 2-hydroxyglutarate, a known marker of tissue hypoxia, in aSAH pathogenesis.
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Biomarcadores/metabolismo , Metabolómica , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Femenino , Escala de Coma de Glasgow , Hospitalización , Humanos , Masculino , Metaboloma/fisiología , Persona de Mediana Edad , Estudios Prospectivos , Hemorragia Subaracnoidea/mortalidad , Hemorragia Subaracnoidea/cirugía , Resultado del Tratamiento , Vasoespasmo Intracraneal/mortalidad , Adulto JovenRESUMEN
OBJECTIVE: To report rates of cerebrospinal fluid leak, wound infection, and other complications after repair of retrosigmoid craniotomy with hydroxyapatite bone cement. METHODS: Retrospective case review at tertiary referral center of patients who underwent retrosigmoid craniotomy from 2013 to 2016 with hydroxyapatite cement cranioplasty. OUTCOME MEASURES: Presence of absence of cerebrospinal fluid leak, wound infection, and other complications. RESULTS: Twenty cases of retrosigmoid craniotomy repaired with hydroxyapatite cement were identified. Median length of follow up was 9.8months. No cases of cerebrospinal fluid leak were identified. One patient developed a wound infection which was thought to be related to a chronic inflammatory response to the implanted dural substitute. No other major complications were noted. CONCLUSIONS: A method and case series of suboccipital retrosigmoid cranioplasty using hydroxyapatite cement and a are reported. Hydroxyapatite cement cranioplasty is a safe and effective technique for repair of retrosigmoid craniotomy defects.
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Cementos para Huesos/uso terapéutico , Craneotomía , Hidroxiapatitas/uso terapéutico , Procedimientos de Cirugía Plástica , Complicaciones Posoperatorias/epidemiología , Cráneo/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Osteomas and exostoses are benign tumors of the bone that occur in the head and neck region but are rarely found within the internal auditory canal (IAC). In this report, we review the literature on bony lesions of the IAC and present two cases: one case of bilateral compressive osteomas and one case of bilateral compressive exostoses of the IAC.
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Neoplasias Óseas/diagnóstico por imagen , Conducto Auditivo Externo , Exostosis/diagnóstico por imagen , Osteoma/diagnóstico por imagen , Hueso Temporal , Adulto , Anciano de 80 o más Años , Neoplasias Óseas/complicaciones , Diagnóstico Diferencial , Exostosis/complicaciones , Femenino , Humanos , Osteoma/complicaciones , Tomografía Computarizada por Rayos XRESUMEN
Hemifacial spasm (HFS) is characterized by involuntary unilateral contractions of the muscles innervated by the ipsilateral facial nerve, usually starting around the eyes before progressing inferiorly to the cheek, mouth, and neck. Its prevalence is 9.8 per 100,000 persons with an average age of onset of 44 years. The accepted pathophysiology of HFS suggests that it is a disease process of the nerve root entry zone of the facial nerve. HFS can be divided into two types: primary and secondary. Primary HFS is triggered by vascular compression whereas secondary HFS comprises all other causes of facial nerve damage. Clinical examination and imaging modalities such as electromyography (EMG) and magnetic resonance imaging (MRI) are useful to differentiate HFS from other facial movement disorders and for intraoperative planning. The standard medical management for HFS is botulinum neurotoxin (BoNT) injections, which provides low-risk but limited symptomatic relief. The only curative treatment for HFS is microvascular decompression (MVD), a surgical intervention that provides lasting symptomatic relief by reducing compression of the facial nerve root. With a low rate of complications such as hearing loss, MVD remains the treatment of choice for HFS patients as intraoperative technique and monitoring continue to improve.
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Descompresión Quirúrgica , Nervio Facial/cirugía , Espasmo Hemifacial/cirugía , Síndromes de Compresión Nerviosa/cirugía , Adulto , Edad de Inicio , Toxinas Botulínicas Tipo A/uso terapéutico , Electromiografía , Nervio Facial/irrigación sanguínea , Nervio Facial/efectos de los fármacos , Nervio Facial/fisiopatología , Femenino , Espasmo Hemifacial/tratamiento farmacológico , Espasmo Hemifacial/epidemiología , Espasmo Hemifacial/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Microcirugia/métodos , Persona de Mediana Edad , Síndromes de Compresión Nerviosa/tratamiento farmacológico , Síndromes de Compresión Nerviosa/epidemiología , Síndromes de Compresión Nerviosa/fisiopatología , Fármacos Neuromusculares/uso terapéuticoRESUMEN
BACKGROUND: Intracranial aneurysms are prevalent, particularly with advancing age. De novo aneurysms, occurring independently from the initial lesion, pose a unique challenge because of their unpredictable nature. Although risk factors such as female sex, smoking history, and hypertension have been proposed, the mechanisms underlying de novo aneurysm development remain unclear. OBSERVATIONS: A 79-year-old female developed a de novo saccular aneurysm within a year after management of a ruptured vertebral artery dissecting aneurysm. Her complex clinical course involved subarachnoid hemorrhage with diffuse vasospasm, stent occlusion of a dissecting aneurysm, discovery of a right 7- to 8-mm de novo middle cerebral artery aneurysm at the 1-year magnetic resonance angiography follow-up, and successful coil embolization. LESSONS: This rare occurrence challenges established timelines, as most de novo aneurysms manifest over a longer interval. Studies have attempted to identify risk factors, yet consensus remains elusive, particularly regarding the influence of treatment modality on de novo formation rates. This unique case urges reconsideration of posttreatment surveillance protocols, proposing shorter intervals for imaging and more vigilant follow-up strategies to detect asymptomatic de novo aneurysms. Timelier identification could significantly impact patient outcomes by averting potential ruptures. This emphasizes the need for further research to delineate effective monitoring and preventive measures for these enigmatic lesions.
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BACKGROUND: Sir Rickman John Godlee (1849-1925) was widely known for performing the first documented surgery to resect a tumor from the brain. METHODS: The case was performed on November 25, 1884, on a 25-year-old farmer who presented with a left-sided Jacksonian March seizure. RESULTS: The case was highly publicized because the tumor was localized by Dr. Hughes Bennett and subsequently resected by Sir Godlee based on the patient's clinical presentation and physical examination alone. CONCLUSIONS: Aside from this widely publicized case, little has been written about Sir Godlee. Sir Godlee was also known to be an outstanding anatomist who displayed exceptional skills in surgical dissection. He was known for being an excellent teacher. Sir Godlee was deeply influenced by his uncle, Lord Joseph Lister, a renowned physician who popularized antiseptic methods. Sir Godlee was also known for publishing his uncle's biography, Lord Lister.
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Neoplasias Encefálicas , Masculino , Humanos , Adulto , Neoplasias Encefálicas/cirugía , Convulsiones , Disección , Familia , Examen FísicoRESUMEN
BACKGROUND: Many patients with transverse myelitis suffer from sensory loss below the spinal level of the lesion. This is commonly associated with chronic neuropathic pain. However, the presence of somatic pain below a complete thoracic sensory level after transverse myelitis is exceptionally rare, and it is unclear if surgical decompression is an effective form of treatment for these patients. CASE PRESENTATION: In this report, we describe a 22-year-old Caucasian female who suffered from chronic lumbar back pain despite a complete thoracic sensory level secondary to prior transverse myelitis. Imaging demonstrated multilevel central stenosis below the sensory level, and her pain improved after surgical decompression. To our knowledge, this is the first reported case of symptomatic lumbar stenosis below a sensory level after transverse myelitis successfully treated with surgical decompression. CONCLUSION: This is the first reported case of a patient with symptomatic lumbar stenosis after transverse myelitis whose lower back pain and quality of life improved following surgical decompression and fusion. This case provides evidence that typical lumbago is possible in patients with sensory loss from transverse myelitis, and standard lumbar decompression may provide benefit for these patients.
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Dolor de la Región Lumbar , Mielitis Transversa , Fusión Vertebral , Estenosis Espinal , Humanos , Femenino , Adulto Joven , Adulto , Estenosis Espinal/complicaciones , Estenosis Espinal/diagnóstico por imagen , Estenosis Espinal/cirugía , Constricción Patológica/complicaciones , Mielitis Transversa/complicaciones , Mielitis Transversa/diagnóstico por imagen , Mielitis Transversa/cirugía , Calidad de Vida , Dolor de Espalda/etiología , Dolor de Espalda/cirugía , Dolor de la Región Lumbar/etiología , Descompresión Quirúrgica/métodos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
This article reviews the major devices, individuals, and other historical landmarks in the development of suction in the field of neurosurgery, where the operating fields are characteristically deep and narrow. Our review spans the 159 years since the first use of aspiration in surgery to modern applications. This report exemplifies a comprehensive history of suction, the minute iteration of devices, and the massive impact this technological development has had on medicine and neurosurgery.
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BACKGROUND: Dorsal thoracic arachnoid web is a rare diagnosis and is not commonly seen in neurosurgical practice. Patients can present with symptoms and signs of thoracic myelopathy in the setting of an arachnoid cyst and a presyrinx state. OBSERVATIONS: A 57-year-old male with a 10-year history of worsening bilateral leg weakness and chronic back pain re-presented to the neurosurgery clinic after being seen by neurology and orthopedic spine surgery. Initial imaging was concerning for myelomalacia and syringomyelia, and repeat delayed computed tomography myelography findings were consistent with an evolving thoracic arachnoid web, now demonstrating spinal cord compression secondary to arachnoid cyst formation and consistent with the signs of thoracic myelopathy. Intraoperative ultrasound displayed the arachnoid web as the cause of the evolving arachnoid cyst, edematous spinal cord, and a presyrinx-like state. The patient underwent surgical decompression, which restored cerebrospinal fluid (CSF) dynamics, resulting in clinical improvement. LESSONS: Dorsal thoracic arachnoid web is a dynamic condition that can occur in the setting of an arachnoid cyst. There appears to be a relationship between dorsal thoracic arachnoid web formation and the presence of an arachnoid cyst resulting from a ball-valve mechanism leading to the creation of a pressure gradient effect that alters CSF fluid dynamics. https://thejns.org/doi/10.3171/CASE24313.
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BACKGROUND: Early clinical trials validating endovascular therapy (EVT) for emergent large vessel occlusion (ELVO) ischemic stroke in the anterior circulation initially focused on patients with small or absent completed infarctions (ischemic cores) to maximize the probability of detecting a clinically meaningful and statistically significant benefit of EVT. Subsequently, real-world experience suggested that patients with large core ischemic strokes (LCS) at presentation may also benefit from EVT. Several large, retrospective, and prospective randomized clinical trials have recently been published that further validate this approach. These guidelines aim to provide an update for endovascular treatment of LCS. METHODS: A structured literature review of LCS studies available since 2019 and grading the strength and quality of the evidence was performed. Recommendations were made based on these new data by consensus of the authors, with additional input from the full SNIS Standards and Guidelines Committee and the SNIS Board of Directors. RESULTS: The management of ELVO strokes with large ischemic cores continues to evolve. The expert panel agreed on several recommendations: Recommendation 1: In patients with anterior circulation ELVO who present within 24 hours of last known normal with large infarct core (70-149 mL or ASPECTS 3-5) and meet other criteria of RESCUE-Japan LIMIT, SELECT2, ANGEL-ASPECT, TESLA, TENSION, or LASTE trials, thrombectomy is indicated (Class I, Level A). Recommendations 2-7 flow directly from recommendation 1. Recommendation 2: EVT in patients with LCS aged 18-85 years is beneficial (Class I, Level A). Recommendation 3: EVT in patients with LCS >85 years of age may be beneficial (Class I, Level B-R). Recommendation 4: Patients with LCS and NIHSS score 6-30 benefit from EVT in LCS (Class I, Level A). Recommendation 5: Patients with LCS and NIHSS score <6 and >30 may benefit from EVT in LCS (Class IIa, Level A). Recommendation 6: Patients with LCS and low baseline mRS (0-1) benefit from EVT (Class I, Level A). Recommendation 7: Patients with LCS and time of last known well 0-24 hours benefit from EVT (Class I, Level A). Recommendation 8: It is recommended that patients with ELVO LCS who also meet the criteria for on-label or guideline-directed use of IV thrombolysis receive IV thrombolysis, irrespective of whether endovascular treatments are being considered (Class I, Level B-NR). CONCLUSIONS: The indications for endovascular treatment of ELVO strokes continue to expand and now include patients with large ischemic cores on presentation. Further prospective randomized studies, including follow-up to assess the population-based efficacy of treating patients with LCS, are warranted.
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BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology. METHODS: This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. RESULTS: We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. CONCLUSIONS: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.