Dysembryoplastic Neuroepithelial Tumor Research Articles

Can we use intraoperative high-frequency oscillations to guide tumor-related epilepsy surgery?

ObjectiveIn people with low‐grade intrinsic brain tumors, an epileptic focus is often located close to the lesion. High‐frequency oscillations (HFOs) in electrocorticography (ECoG) might help to delineate this focus. We investigated the relationship between HFOs and low‐grade brain tumors and their potential value for tumor‐related epilepsy surgery.MethodsWe analyzed pre‐ and postresection intraoperative ECoG in 41 patients with refractory epilepsy and a low‐grade lesion. Electrodes were designated as overlying the tumor, adjacent resected tissue (peritumoral), or outside the resection bed using magnetic resonance imaging (MRI) and intraoperative photographs. We then used a semiautomated approach to detect HFOs as either ripples (80–250 Hz) or fast ripples (250–500 Hz).ResultsThe rate of fast ripples was higher in electrodes covering tumor and peritumoral tissue than outside the resection (p = .04). Mesiotemporal tumors showed more ripples (p = .002), but not more fast ripples (p = .07), than superficial tumors. Rates of fast ripples were higher in glioma and extraventricular neurocytoma than in ganglioglioma or dysembryoplastic neuroepithelial tumor (DNET). The rate of ripples and fast ripples in postresection ECoG was not higher in patients with residual tumor tissue on MRI than those without. The rate of ripples in postresection ECoG was higher in patients with good than bad seizure outcome (p = .03). Fast ripples outside the resection and in post‐ECoG seem related to seizure recurrence.SignificanceFast ripples in intraoperative ECoG can be used to help guide resection in tumor‐related epilepsy surgery. Preresection fast ripples occur predominantly in epileptogenic tumor and peritumoral tissue. Fast ripple rates are higher in glioma and extraventricular neurocytoma than in ganglioglioma and DNET.

Clinico-Radiological Presentation of Angiocentric Neuroepithelial Tumor Associated with Pharmacoresistant Epilepsy: A Case Report

The World Health Organization (WHO) Classification of Central Nervous System describes several types of glioneuronal tumors, which are known to induce refractory partial seizures in children and adults [1]. The most frequent ones are Dysembryoplastic Neuroepithelial Tumors (DNETs) [2], gangliogliomas and oligodendrogliomas, but other types of complex glioneuronal lesions can be observed and are described as Low-Grade Epilepsy Associated Neuroepithelial Tumors (LEAT).

Factors associated with prognosis of dysembryoplastic neuroepithelial tumors patients after surgical resection: a retrospective observational study

Objective To explore factors that might be associated with prognosis of dysembryoplastic neuroepithelial tumors (DNTs). Methods DNTs patients who were admitted to the Department of Neurosurgery of Xiangya Hospital between 1 January 2010 and 31 December 2018 and underwent surgical resection were retrospectively analyzed. Clinical, neuroimaging, and pathological features of DNTs were compared among patients with different outcomes and analyzed using the Kaplan–Meier curves and univariable Cox regression analysis. Results Thirty-three DNTs patients were included finally, of which the average age at seizure onset was 11.59 ± 7.46 years old and the average duration of seizures prior to surgical resection was 3.00 ± 4.68 years. After surgical resection, the patients were followed up for 2.39 ± 1.97 years, and 28 patients (84.85%) were seizure-free (class I of the Engel Outcome Scale) while five patients (15.15%) were seizure-continuous (class II or III of the Engel Outcome Scale). When compared with seizure-free patients, seizure-continuous patients had greater age at seizure onset and longer duration of seizures before surgical resection (p < .05). No variables were found to be statistically significantly associated with prognosis in univariable Cox regression analysis, but patients with extra-temporal DNTs were found to have better prognosis than those with temporal DNTs (log-rank test p = .048). Conclusions Elder seizure onset age, longer duration of seizures prior to surgical resection, and a temporal location may be risk factors of poor prognosis for DNTs patients after surgical resection.

The T2-FLAIR mismatch sign as a predictor of IDH-mutant, 1p/19q-noncodeleted lower-grade gliomas: a systematic review and diagnostic meta-analysis.

To evaluate the diagnostic performance of the T2-FLAIR mismatch sign for prediction of isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted lower-grade gliomas (LGGs) and review studies with false positive results. The MEDLINE and EMBASE databases were searched up to March 13, 2020, to identify articles reporting the diagnostic performance of the T2-FLAIR mismatch sign for prediction of IDH-mutant, 1p/19q-noncodeleted LGGs (IDHmut-Noncodel) using the search terms (T2 FLAIR mismatch). Pooled sensitivity, specificity, and correlation coefficient for interobserver agreement were calculated. Twelve studies including a total of 1053 patients were included. The median age was 43 (median; range, 14-56). The pooled sensitivity and specificity were 42% (95% CI, 28-58%) and 100% (95% CI, 88-100%), respectively. According to the HSROC curve, the area under the curve was 0.77 (95% CI, 0.73-0.80). Considerable heterogeneity was possible among the studies in terms of both sensitivity and specificity. A threshold effect was suggested and was considered to explain most of the heterogeneity. Four studies reported false positive results for the T2-FLAIR mismatch sign, including dysembryoplastic neuroepithelial tumor, pediatric-type gliomas, and non-neoplastic lesions. The 2 original articles with false positive results showed the highest sensitivities among the 10 studies included in the quantitative analysis, supporting the probability of the threshold effect. The pooled correlation coefficient was 0.87 (95% CI, 0.73-0.94). The T2-FLAIR mismatch sign had a high specificity and interobserver agreement for the prediction of IDHmut-Noncodel. However, the sign demonstrated low sensitivity, and a few studies with false positive cases were also reported. • The pooled sensitivity and specificity of the T2-FLAIR mismatch sign for prediction of IDH-mutant, 1p/19q-noncodeleted lower-grade gliomas were 42% and 100%, respectively. • Four studies reported false positive results. • The pooled correlation coefficient was 0.87, suggesting almost perfect interobserver agreement.

The spectrum of mitochondrial DNA (mtDNA) mutations in pediatric CNS tumors.

BackgroundWe previously established the landscape of mitochondrial DNA (mtDNA) mutations in 23 subtypes of pediatric malignancies, characterized mtDNA mutation profiles among these subtypes, and provided statistically significant evidence for a contributory role of mtDNA mutations to pediatric malignancies.MethodsTo further delineate the spectrum of mtDNA mutations in pediatric central nervous system (CNS) tumors, we analyzed 545 tumor-normal paired whole-genome sequencing datasets from the Children’s Brain Tumor Tissue Consortium.ResultsGermline mtDNA variants were used to determine the haplogroup, and maternal ancestry, which was not significantly different among tumor types. Among 166 (30.5%) tumors we detected 220 somatic mtDNA mutations, primarily missense mutations (36.8%), as well as 22 loss-of-function mutations. Different pediatric CNS tumor subtypes had distinct mtDNA mutation profiles. The number of mtDNA mutations per tumor ranged from 0.20 (dysembryoplastic neuroepithelial tumor [DNET]) to 0.75 (meningiomas). The average heteroplasmy was 10.7%, ranging from 4.6% in atypical teratoid/rhabdoid tumor (AT/RT) to 26% in diffuse intrinsic pontine glioma. High-grade gliomas had a significant higher number of mtDNA mutations per sample than low-grade gliomas (0.6 vs 0.27) (P = .004), with almost twice as many missense mtDNA mutations per sample (0.24 vs 0.11), and higher average heteroplasmy levels (16% vs 10%). Recurrent mtDNA mutations may represent hotspots which may serve as biologic markers of disease.ConclusionsOur findings demonstrate varying contributions of mtDNA mutations in different subtypes of CNS tumors. Sequencing the mtDNA genome may ultimately be used to characterize CNS tumors at diagnosis and monitor disease progression.

SEIZURES IN CHILDREN WITH LOW GRADE GLIOMA

Seizures are a common presentation of pediatric brain tumors. The incidence of pediatric brain tumor (Age 0-19 years) ranges from 1.12–5.26 cases per 100,000 persons. Low grade gliomas are an important subgroup of pediatric brain tumors causing epilepsy. Low-grade gliomas are largely slow-growing tumors and the manifestations are dependent on age, location, tumor type, size of tumor and rate of tumor growth. Seizures have been reported in up to 38 % of children with supratentorial tumors. The tumors are identified when work up of patients for epilepsy includes electrophysiological and imaging studies. The primary treatment modality remains surgical excision. Antiepileptic medications are used for control of seizures. Subsequent histopathological diagnosis is important for prognostication. The tumors commonly associated with long-term epilepsy in various studies were ganglioglioma, dysembryoplastic neuroepithelial tumor, pilocytic astrocytoma and pilocytic xanthoastrocytoma. The outcome of surgery with regards to seizure control is generally good. Though concomitantly antiepileptic medications will be needed for most of them. An attempt is made in this review to summarize the epidemiology, clinical features, pathology and treatment aspects of pediatric low grade gliomas presenting with seizures.

RARE-36. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS: A REVIEW OF CLINICAL AND MOLECULAR CHARACTERISTICS, AND OUTCOME IN A PEDIATRIC POPULATION AT A SINGLE CENTER

BACKGROUNDNeuronal and mixed neuro-glial tumors of the central nervous system (CNS) are relatively rare. Dysembryoplastic neuroepithelial tumor (DNET) is a benign, rare, slow-growing tumor, but in many cases is associated with intractable epilepsy.OBJECTIVETo report the experience with DNET at a single free-standing children’s institution.METHODSA retrospective chart review of 24 patients with confirmed DNET between 2001 and 2019 was performed. Data was collected on clinical characteristics, tumor location, surgical management, histopathological and molecular findings, and outcomes.RESULTSMean age at diagnosis was 10 years (range 2 to 19 years), with female predominance (54.2%). Most common presenting symptoms were seizures (79.2%) and headaches (12.5%). Location of the tumor was temporal (29.2%), frontal (25.0%), parietal (16.7%), cerebellar (12.5%) and occipital (4.2%). A gross total resection was achieved in half the cases. Recurrence occurred in 4 patients (16.7%), all of whom had subtotal resections. The average follow up since diagnosis was 4.6 years (range 0.3 to 14 years). Nineteen patients presented with seizures, of which 63.2% were seizure free after surgery. The samples with molecular genetic testing (microarrays or FISH), were all normal except one patient positive for BRAF V600E mutation.CONCLUSIONSThis is the first and largest review of pediatric DNETs in the last 10 years. Despite majority of patients having a favorable outcome after surgery, a subset of patients remains symptomatic. As molecular mechanisms in DNET remain unknown, future aim is to describe the molecular characteristics of our DNET population, and correlate with outcomes.

SURG-17. CLINICAL CHARACTERISTICS AND OUTCOMES OF EPILEPSY-RELATED BRAIN TUMOR IN CHILDREN

OBJECTIVEEpilepsy is one of the earliest symptoms in pediatric brain tumor. Gross total resection (GTR) of the tumor does not necessarily achieve seizure free, therefore it is controversial whether surrounding epileptic foci should be resected at the initial surgery. The aims of this study are to report clinical characteristics and outcome of pediatric epilepsy-related brain tumor (ERBT) and to discuss treatment strategy.METHODSSubjects were children less than 18 years old who underwent surgery for ERBT. Patients in whom epilepsy had been controlled before surgery were excluded. Data were collected from medical record and retrospectively reviewed.RESULTSTwenty-one children (8 boys and 13 girls) were analyzed in this study. The mean age at surgery was 6.8 years. Tumor was astrocytic tumor in 10, gangliogioma in 4 and dysembryoplastic neuroepithelial tumor in 3. Intracranial subdural electrodes were placed prior to tumor resection in 5 cases. GTR was achieved in 14 (67%). Seizure free was achieved in 15 (71.4%). GTR was significantly associated with seizure free (p=0.002).CONCLUSIONIn most of ERBT, seizure free can be achieved by lesionectomy alone. However, the resection of surrounding epileptic foci is required in some cases. Detailed examinations to detect the epileptic foci should be performed in ERBT, particularly in case of drug-resistant intractable epilepsy.

LGG-46. MOLECULAR CHARACTERIZATION OF HEMISPHERIC LOW-GRADE GLIOMAS IN CHILDREN

BACKGROUNDHeterogeneous pathology in hemispheric low-grade gliomas (hemLGG) stress the importance of molecular testing in terms of prognosis prediction and targeted therapy options.METHODSDemographic data was collected and targeted genomic approach was employed in the single institutional study. RT-PCR was used to screen for KIAA1549-BRAF fusion and FGFR1 tyrosine-kinase domain duplication (FGFR1-ITD). Direct sequencing evaluated point mutations (BRAF ex15 and ex11, FGFR1 ex12 and ex14). Samples with no detected alteration were subjected to panel RNA-sequencing (FusionPlex Archer Diagnostics).RESULTSWithin 2000–2019 were diagnosed 76 patients with hemLGG (median age 11.1y, range 0.0y–18.5y) comprising predominantly of ganglioglioma, dysembryoplastic neuroepithelial tumors, and diffuse astrocytoma. 40 % of hemLGG were characterized by BRAF alterations with over 2/3 of those cases harboring BRAF point mutations (two BRAFex11, 12 BRAFV600E). Notably, BRAF fusions were uncommon and detected only in six patients (two KIAA-BRAF fusion, two minor oncogenic BRAF variants, two non-KIAA BRAF fusion). 25 % of alterations were found in genes for receptor tyrosine kinases, consisting of seven patients with FGFR1-ITD, three FGFR2/3 fusions, two FGFR1 mutations, two ALK fusions, and one ROS fusion. Out of MAP kinase pathway, the most frequent alteration was IDH1 mutations (n=9). Two angiocentric gliomas were characterized by MYB-QKI fusion.CONCLUSIONTargeted sequencing combined with RNA-sequencing is feasible to establish molecular diagnosis in majority of cases and reveal new and rare alterations. Significant prevalence of non-BRAF alterations explains heterogeneity among hemLGG.

SURG-19. COMPLETE RESOLUTION OF ADHD AFTER GROSS TOTAL RESECTION OF DYSEMBRYIOPLASTIC NEUROEPITHELIAL TUMOR

A 3-year-old boy with a history of attention-deficit/hyperactivity disorder (ADHD) presented a single focal tonic seizure. A thorough physical examination revealed no neurological deficit. A contrast enhanced MRI showed an isointense lesion in the anterior part of the cingulate gyrus extending through the left frontal lobe. After initial evaluation, the parents refused surgical treatment and a close follow up was then considered. At the age of five, the ADHD become more evident and the patient was started on methylphenidate. Poor clinical response was seen with the initiation of stimulant. The boy presented a second generalized seizure and the parents agreed surgical management. An interhemispheric approach was then performed and a gross total resection was achieved. The histopathological diagnosis corresponded to a dysembryoplastic neuroepithelial tumor (DNET). Four years after the resection, the patient is seizure free and the ADHD has also resolved without the need of medication. The disappearance of seizures is common after surgical resection of DNET tumors, but this case establishes an association with ADHD.

SURG-06. AWAKE CRANIOTOMY FOR BRAIN TUMOR IN PEDIATRIC PATIENTS

BACKGROUNDThe challenge of surgery in neurooncology is to achieve the maximum extent of resection while preserving eloquent functions. Intra-operative cortical mapping during resection of a brain tumor allows direct stimulation in eloquent areas with a reduction in postoperative deficits. This procedure has been performed in adults and children down to the age of 11 years. There are only two cases reported on the literature of an 8-year-old and 9-year-old child submitted to an awake craniotomy for brain tumor resection. Pediatric patients are prone to more risks than adults because they become easily agitated after pain sensation. Extensive preparation for the procedure is essential for pediatric patients in order to avoid a lack of cooperation. CASE PRESENTATION: Two patients, with 9-year-old presented with seizures due to a tumor in the left temporoparietal region. In order to identify language and motor–controlling areas during resection, we proposed an awake craniotomy. Because of their ages, they were prepared by a multidisciplinary team. The children’s cooperation during the mapping procedure and tumor resection were exceptional. Postoperative cranial MRI confirmed partial resection of the lesion, whose remnant was located in the left motor area. No seizures occurred during the postoperative period, and both were discharged without a neurological disability on the fifth day after the surgery. Histology revealed a dysembryoplastic neuroepithelial tumor (WHO grade I).CONCLUSIONBrain mapping during resection of a tumor in an awake pediatric patient is feasible and can be safely performed even in patients under 11-year-old.

LGG-02. A BRAIN TUMOR DIAGNOSED AFTER TRANSITION TO THE DEPARTMENT OF ADULT NEUROSURGERY FROM THE DEPARTMENT OF PEDIATRICS

The patient was a 17-year-old boy with a history of 4 non-febrile convulsions at 15 and 16 years of age. He visited the Department of Pediatrics at a pediatric hospital. An electroencephalogram showed right frontal spike discharge. MRI was performed and judged to show no abnormality. The pediatric doctor diagnosed him with epilepsy. At 17 years old, he was referred to our Department of Adult Neurosurgery for transition. Physical and neurological examinations showed no abnormalities. Brain MRI showed right frontal cortical small tumor, with T1 low, T2 high, diffusion-weighted imaging low, and partial contrast enhancement. We diagnosed him with a brain tumor and symptomatic epilepsy. We surgically removed a right frontal cortical tumor. A pathological examination finalized the diagnosis of dysembryoplastic neuroepithelial tumor. MRI confirmed the total removal of the tumor. Anticonvulsant was started before surgery. No epileptic seizure was observed, so the anticonvulsant medication was gradually tapered and stopped at two years after the surgery. No epilepsy nor recurrence has been observed thus far. The problem with the initial management of this case at the Department of Pediatrics in the pediatric hospital was that the brain tumor was missed despite an MRI examination. Had the transition not happened, this brain tumor might not have been diagnosed. A brain tumor is a rare disease, and epilepsy is a common disease. However, in cases of non-febrile convulsion, a brain tumor should be considered. Collaboration within a single department, hospital and local area should be established.

Cutaneous adverse events to immune checkpoint inhibitors in pediatric populations: A retrospective cohort study

Cutaneous adverse events to immune checkpoint inhibitors in pediatric populations: A retrospective cohort study

Cognitive impairment in temporal lobe epilepsy: contributions of lesion, localization and lateralization.

Cognitive impairment is an importantcomorbidityof refractory temporal lobe epilepsy (TLE). We aimed to explore the impact of (i) specific lesions, such as dysembryoplastic neuroepithelial tumor (DNET), dysplasia, or hippocampal sclerosis, (ii) focus localization (medial versus lateral) and (iii) focus lateralization (right versus left) on the neuropsychological profile of refractory TLE adult patients. We examined the neuropsychological characteristics of 312 adults with refractory TLE: 100 patients without hippocampal sclerosis (HS) and 212 with HS. Scores on tests of intelligence (Global IQ, Verbal IQ and Performance IQ), working memory, episodic memory (verbal and visual learning and forgetting), executive functions and language abilities were analyzed. Three main factors influenced the neuropsychological profile of refractory TLE patients: (i) the lesion, patients with HS obtaining poorer cognitive performances than patients without HS and specifically DNET patients performing better than patients with HS, (ii) the focus side, that seems only relevant for verbal memory abilities which are affected in left but not right TLE patients and (iii) the localization of seizure focus, patients with medial TLE exhibiting lower memory performances than patients with lateral TLE. Lesion, localization and lateralization are major contributors of the cognitive impairment depicted in TLE. Hippocampal sclerosis appears as the main contributor.

PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR

Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

Dysembryoplastic Neuroepithelial Tumor: A Rare Brain Tumor with Excellent Seizure Control after Surgical Resection

Abstract Introduction Dysembryoplastic neuroepithelial tumor (DNET) is a rare cause of intractable epilepsy, which has excellent results in terms of seizure control after surgical resection. We present one such case, because of its rarity, to highlight the effect of tumor removal on seizure control, particularly DNET. Materials and Methods/Case Summary A 9-year-old male patient presented with sudden onset of partial seizures for the past 6 months. There were five episodes. In each episode, the patient engaged in irrelevant talk, followed by deviation of mouth to left and twitching movements. The episode lasted 5 minutes and there was no loss of consciousness. There was no aura or tongue bite, and in one of the episodes, the patient lost consciousness. There was no other significant positive history. On examination, the child was consciously alert, without focal neurological deficit or features of meningitis. There was no papilledema. The patient was on phenytoin sodium, phenobarbitone and clobazam. Magnetic resonance imaging (MRI) of brain was done with and without contrast. MRI revealed a lesion approximately 4.1 × 3.6 × 3.2 cm in the right medial temporal lobe. It was hypointense to brain on T1 and fluid-attenuated inversion recovery (FLAIR), and hyperintense on T2-weighted images. Diffusion restriction was present and there was minimal contrast uptake. There was no evidence of mass effect or midline shift After discussing the risks and benefits with parents, the patient underwent preanesthetic checkup, and was taken up for craniotomy and excision of tumor. Gross total excision was done. The child was started orally on day 1 postoperatively and ambulated. There were no further seizure episodes. The patient was continued on phenytoin and clobazam, and phenobarbitone was tapered gradually. At 6 months, the child was seizure-free. Conclusions DNET are rare tumors occurring early in life and presenting with intractable seizures. Surgical resection offers a good and safe chance for long-term seizure control.

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

Coupling between infraslow activities and high-frequency oscillations precedes seizure onset.

Infraslow activities and high‐frequency oscillations (HFOs) are observed in seizure‐onset zones. However, the relation between them remains unclear. In this study, we investigated phase‐amplitude coupling between infraslow phase (0.016‐1 Hz) and HFOs' amplitude of focal impaired awareness seizures followed by focal to bilateral tonic‐clonic seizures, in a 28‐year‐old right‐handed man with a dysembryoplastic neuroepithelial tumor. We recorded five habitual seizures. After the time of seizure onset, a significant increase in the power of HFOs was observed, and the power was significantly coupled with θ (4‐8 Hz) phase. In contrast, coupling of infraslow activities and HFOs surged a few minutes before the seizure‐onset time, and ictal HFOs discharged after that. Collectively, our results show that coupling of infraslow activities and HFOs precedes the seizure‐onset time. We infer that such coupling may be a potential biomarker for seizure prediction.

Evaluating H3F3A K27M and G34R/V somatic mutations in a cohort of pediatric brain tumors of different and rare histologies.

Somatic mutations on H3 histone are currently considered a genetic hallmark for midline pediatric high-grade gliomas (HGGs). Yet, different tumor histologies have been occasionally described to carry these mutations. Since histone modifications can lead to major epigenetic changes with direct impact on prognosis and treatment, we thought to investigate the occurrence of H3F3A K27M and G34R/V mutations in a cohort of pediatric tumors which included HGGs, low-grade gliomas, ependymomas, medulloblastomas, and a series of rare brain tumor lesions of different histologies. A total of 82 fresh-frozen pediatric brain tumor samples were evaluated. PCR or RT-PCR followed by Sanger sequencing for the exon 2 of H3F3A (containing both K27 and G34 hotspots) were obtained and aligned to human genome. Loss of trimethylation mark (H3K27me3) in H3F3A/K27M-mutant samples was confirmed by immunohistochemistry. We found H3F3A/K27M mutation in 2 out of 9 cases of HGGs; no H3F3A/K27M mutations were detected in low-grade gliomas (27), ependymomas (n = 10), medulloblastomas (n = 21), or a series of rare pediatric brain tumors which included meningiomas, dysembryoplastic neuroepithelial tumors (DNETs), central nervous system (CNS) germ-cell tumors, choroid plexus tumors, cortical hamartoma, subcortical tubers, and schwannomas (n = 15). H3F3A/G34R/V mutation was not observed in any of the samples. Our investigation reinforces the low frequency of H3F3A somatic mutations outside the HGG setting. Interestingly, an atypical focal brainstem glioma carrying H3F3A K27M mutation that showed protracted clinical course with late-onset tumor progression was identified.

Orbitofrontal epilepsy: distinct neuronal networks underlying electroclinical subtypes and surgical outcomes.

The aim of this study was to characterize the clinical and electrophysiological findings of epilepsy originating from the orbitofrontal cortex (OFC) as well as its surgical outcomes. The authors retrospectively reviewed 27 consecutive cases of patients with drug-resistant orbitofrontal epilepsy (OFE) who underwent tailored resective surgery after a detailed presurgical workup. Demographic features, seizure semiology, imaging characteristics, resection site, pathological results, and surgical outcomes were analyzed. Patients were categorized according to semiology. The underlying neural network was further explored through quantitative FDG-PET and ictal stereo-electroencephalography (SEEG) analysis at the group level. FDG-PET studies between the semiology group and the control group were compared using a voxel-based independent t-test. Ictal SEEG was quantified by calculating the energy ratio (ER) of high- and low-frequency bands. An ER comparison between the anterior cingulate cortex (ACC) and the amygdala was performed to differentiate seizure spreading patterns in groups with different semiology. Scalp electroencephalography (EEG) and MRI were inconclusive to a large extent. Patients were categorized into the following 3 semiology groups: the frontal group (n = 14), which included patients with hyperactive automatisms with agitated movements; the temporal group (n = 11), which included patients with oroalimentary or manual automatisms; and the other group (n = 2), which included patients with none of the abovementioned or indistinguishable manifestations. Patients in the frontal and temporal groups (n = 23) or in the frontal group only (n = 14) demonstrated significant hypometabolism mainly across the ipsilateral OFC, ACC, and anterior insula (AI), while patients in the temporal group (n = 9) had hypometabolism only in the OFC and AI. The ER results (n = 15) suggested distinct propagation pathways that allowed us to differentiate between the frontal and temporal groups. Pathologies included focal cortical dysplasia, dysembryoplastic neuroepithelial tumor, cavernous malformation, glial scar, and nonspecific findings. At a minimum follow-up of 12 months, 19 patients (70.4%) were seizure free, and Engel class II, III, and IV outcomes were observed in 4 patients (14.8%), 3 patients (11.1%), and 1 patient (3.7%), respectively. The diagnosis of OFE requires careful presurgical evaluation. Based on their electrophysiological and metabolic evidence, the authors propose that varied semiological patterns could be explained by the extent of involvement of a network that includes at least the OFC, ACC, AI, and temporal lobe. Tailored resections for OFE may lead to a good overall outcome.