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Cerebrospinal fluid (CSF) plays an important role in brain tumors, including medulloblastoma (MBL). Recent advancements in mass spectrometry systems and 'Omics' data analysis methods enable unbiased, high proteome depth research. We conducted proteomic profiling of the total CSF in MBL patients with the purpose of finding a potential diagnostic biomarker for MBL. We quantified 1112 proteins per CSF sample. Feature selection identified four elevated soluble proteins (SPTBN1, HSP90AA1, TKT, and NME1-NME2) in MBL CSF. Validation with ELISA confirmed that TKT was significantly elevated in MBL. Additionally, TKT-positive extracellular vesicles were significantly enriched in MBL CSF and correlated with the burden of leptomeningeal seeding. Our results provide insights into the proteomics data of the total CSF of MBL patients. Furthermore, we identified the significance of TKT within the total CSF and its presence within circulating EVs in the CSF. We suggest that TKT may serve as a biomarker for MBL., (© 2024. The Author(s).)

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions., (© 2024. The Author(s).)

Unexplained neurological deterioration is occasionally observed in patients with traumatic brain injuries (TBIs). We aimed to describe the clinical features of post-traumatic transient neurological dysfunction and provide new insight into its pathophysiology. We retrospectively collected data from patients with focal neurological deterioration of unknown origin during hospitalization for acute TBI for 48 consecutive months. Brain imaging, including computed tomography, diffusion-weighted imaging and perfusion-weighted imaging, and electroencephalography were conducted during the episodes. Fourteen (2.0%) patients experienced unexplained focal neurological deterioration among 713 patients who were admitted for traumatic intracranial hemorrhage during the study period. Aphasia was the predominant symptom in all patients, and hemiparesis or hemianopia was accompanied in three patients. These symptoms developed within 14 days after trauma. Structural imaging did not show any significant interval change, and electroencephalography showed persistent arrhythmic slowing in the corresponding hemisphere in most patients. Perfusion imaging revealed increased cerebral blood flow in the symptomatic hemisphere. Surgical intervention and anti-seizure medications were ineffective in abolishing the symptoms. The symptoms disappeared spontaneously after 4 h to 1 month. Transient neurological dysfunction (TND) can occur during the acute phase of TBI. Although TND may last longer than a typical transient ischemic attack or seizure, it eventually resolves regardless of treatment. Based on our observation, we postulate that this is a manifestation of spreading depolarization occurring in the injured brain, which is analogous to migraine aura.

Purpose: The present study aimed to evaluate the role of early and delayed surgery in congenital brain tumors and analyze the clinical outcomes of infantile brain tumors., Materials and Methods: We performed a retrospective cohort study on 69 infantile brain tumors at a single institution from January 2008 to June 2023. Outcomes were assessed as early mortality (within 30 days following surgery) to evaluate the risk of early surgery in congenital brain tumors. Outcomes of recurrence and overall survival were analyzed in infantile brain tumors., Results: Surgery-related early mortality appeared to occur in young and low-body-weight patients. Cut-off values of age and body weight were found to be 1.3 months and 5.2 kg to avoid early mortality. Three patients (3/10, 30%) showed early mortality in the early surgery group, and early mortality occurred in one patient (1/14, 7.14%) in the delayed surgery group, whose tumor was excessively enlarged. Younger age at diagnosis (< 3 months of age; hazard ratios [HR], 7.1; 95% confidence intervals [CI], 1.4 to 35.6; p=0.018) and leptomeningeal seeding (LMS; HR, 30.6; 95% CI, 3.7 to 253.1; p=0.002) were significant independent risk factors for high mortality in infantile brain tumors., Conclusion: We suggest delaying surgery until the patient reaches 1.3 months of age and weighs over 5.2 kg with short-term imaging follow-up unless tumors grow rapidly in congenital brain tumors. Younger ages and the presence of LMS are independent risk factors for high mortality in infantile brain tumors.

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level., (© 2024. The Author(s).)

Cerebral cavernous malformation (CCM) is a vascular anomaly commonly found in children and young adults. Common clinical presentations of pediatric patients with CCMs include headache, focal neurological deficits, and seizures. Approximately 40% of pediatric patients are asymptomatic. Understanding the natural history of CCM is crucial and hemorrhagic rates are higher in patients with an initial hemorrhagic presentation, whereas it is low in asymptomatic patients. There is a phenomenon known as temporal clustering in which a higher frequency of symptomatic hemorrhages occurs within a few years following the initial hemorrhagic event. Surgical resection remains the mainstay of treatment for pediatric CCMs. Excision of a hemosiderin-laden rim is controversial regarding its impact on epilepsy outcomes. Stereotactic radiosurgery is an alternative treatment, especially for deepseated CCMs, but its true efficacy needs to be verified in a clinical trial.

Choroid plexus hyperplasia (CPH), also known as diffuse villous hyperplasia of choroid plexus, is a rare condition characterized by excessive production of cerebrospinal fluid (CSF), resulting in hydrocephalus. Diagnosing CPH can be challenging due to the absence of clear imaging criteria for choroid plexus hypertrophy and the inability to assess CSF production non-invasively. As a result, many CPH patients are initially treated with a ventriculoperitoneal (VP) shunt, but subsequently require additional surgical intervention due to intractable ascites. In our study, we encountered two CPH patients who presented with significantly enlarged subarachnoid spaces, reduced parenchymal volume, and prominent choroid plexus. Initially, we treated these patients with a VP shunt, but eventually opted for endoscopic choroid plexus cauterization (CPC) to address the intractable ascites. Following the treatment with endoscopic CPC, we observed a gradual reduction in subarachnoid spaces and an increase in parenchymal volume. In cases where bilateral prominent choroid plexus, markedly enlarged subarachnoid spaces, and cortical atrophy are present, CPH should be suspected. In these cases, considering initial treatment with combined endoscopic CPC and shunt may help minimize the need for multiple surgical interventions.

Objective: Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain., Methods: We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome., Results: Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom., Significance: Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Endothelial colony-forming cells (ECFCs) have been reported to play an important role in the pathogenesis of moyamoya disease (MMD). We have previously observed stagnant growth in MMD ECFCs with functional impairment of tubule formation. We aimed to verify the key regulators and related signaling pathways involved in the functional defects of MMD ECFCs., Methods: ECFCs were cultured from peripheral blood mononuclear cells of healthy volunteers (normal) and MMD patients. Low-density lipoproteins uptake, flow cytometry, high content screening, senescence-associated β-galactosidase, immunofluorescence, cell cycle, tubule formation, microarray, real-time quantitative polymerase chain reaction, small interfering RNA transfection, and western blot analyses were performed., Results: The acquisition of cells that can be cultured for a long time with the characteristics of late ECFCs was significantly lower in the MMD patients than the normal. Importantly, the MMD ECFCs showed decreased cellular proliferation with G1 cell cycle arrest and cellular senescence compared to the normal ECFCs. A pathway enrichment analysis demonstrated that the cell cycle pathway was the major enriched pathway, which is consistent with the results of the functional analysis of ECFCs. Among the genes associated with the cell cycle, cyclin-dependent kinase inhibitor 2A (CDKN2A) showed the highest expression in MMD ECFCs. Knockdown of CDKN2A in MMD ECFCs enhanced proliferation by reducing G1 cell cycle arrest and inhibiting senescence through the regulation of CDK4 and phospho retinoblastoma protein., Conclusion: Our study suggests that CDKN2A plays an important role in the growth retardation of MMD ECFCs by inducing cell cycle arrest and senescence.

The aim of this study is to investigate the genetic profiles and methylation-based classifications of Embryonal tumor with multilayered rosettes (ETMR), with a specific focus on differentiating between C19MC amplified and C19MC-not amplified groups, including cases with DICER1 mutations. To achieve this, next-generation sequencing using a targeted gene panel for brain tumors and methylation class studies using the Epic850K microarray were performed to identify tumor subclasses and their clinicopathological characteristics. The study cohort consisted of four patients, including 3 children (a 4-months/F, a 9-months/M, and a 2 y/F), and one adult (a 30 y/Male). All three tumors in the pediatric patients originated in the posterior fossa and exhibited TTYH1:C19MC fusion and C19MC amplification. The fourth case in the adult patient involved the cerebellopontine angle with biallelic DICER1 mutation. Histopathological examination revealed typical embryonal features characterized by multilayered rosettes and abundant neuropils in all cases, while the DICER1 -mutant ETMR also displayed cartilage islands in addition to the classic ETMR pathology. All four tumors showed positive staining for LIN28A. The t-SNE clustering analysis demonstrated that the first three cases clustered with known subtypes of ETMR, specifically C19MC amplified, while the fourth case clustered separately to non-C19MC amplified subclass. During the follow-up period of 6~12 months, leptomeningeal dissemination of the tumor occurred in all patients. Considering the older age of onset in DICER1 -mutant ETMR, genetic counseling should be recommended due to the association of DICER1 mutations with germline and second-hit somatic mutations in cancer.

Background: Achondroplasia is an autosomal dominant disorder mainly affecting bony growth, typically resulting in markedly short stature. From a neurosurgical viewpoint, patients sometimes develop spinal cord compression at the narrowed foramen magnum and hydrocephalus. This study aims to construct growth references for height, weight, and head circumference (HC) of young achondroplasia patients in Korea and to evaluate the predictability of the necessity and timing of neurosurgical procedures through growth patterns., Methods: Growth data were collected from achondroplasia patients who visited our institution between January 2002 and August 2022. First, we constructed percentile growth curves of height, weight, and HC for the patients under 3 years of age with the generalized additive model for location, scale, and shape (GAMLSS). Second, the growth patterns of the patients with hydrocephalus who underwent neurosurgical procedures such as foramen magnum decompression (FMD) and ventriculoperitoneal (VP) shunt were analyzed., Results: There were 125 achondroplasia patients, including 67 males and 58 females. Among 125 patients, 46 underwent FMD, and 5 underwent VP shunt. As short stature and macrocephaly were typical characteristics of achondroplasia, the height of achondroplasia was lower than that of the general population, and HC in achondroplasia showed accelerated growth postnatally. There were no significant changes in HC in hydrocephalus patients before they underwent neurosurgical procedures. The influence of hydrocephalus on the growth patterns of HC in achondroplasia seemed insignificant., Conclusion: Growth references for height, weight, and HC in young achondroplasia patients were constructed. It is the first report of growth patterns of achondroplasia in Korea. Unlike other pediatric patients, the diagnosis of hydrocephalus and the necessity of neurosurgical procedures are hard to be predicted with HC in achondroplasia. Neuroimaging should be considered for achondroplasia patients with neurological symptoms., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Background: This study aims to elucidate clinical features, therapeutic strategies, and prognosis of pineal parenchymal tumors (PPT) by analyzing a 30-year dataset of a single institution., Methods: We reviewed data from 43 patients diagnosed with PPT at Seoul National University Hospital between 1990 and 2020. We performed survival analyses and assessed prognostic factors., Results: The cohort included 10 patients with pineocytoma (PC), 13 with pineal parenchymal tumor of intermediate differentiation (PPTID), and 20 with pineoblastoma (PB). Most patients presented with hydrocephalus at diagnosis. Most patients underwent an endoscopic third ventriculostomy and biopsy, with some undergoing additional resection after diagnosis confirmation. Radiotherapy was administered with a high prevalence of gamma knife radiosurgery for PC and PPTID, and craniospinal irradiation for PB. Chemotherapy was essential in the treatment of grade 3 PPTID and PB. The 5-year progression-free survival rates for PC, grade 2 PPTID, grade 3 PPTID, and PB were 100%, 83.3%, 0%, and 40%, respectively, and the 5-year overall survival rates were 100%, 100%, 40%, and 55%, respectively. High-grade tumor histology was associated with lower survival rates. Significant prognostic factors varied among tumor types, with World Health Organization (WHO) grade and leptomeningeal seeding (LMS) for PPTID, and the extent of resection and LMS for PB. Three patients experienced malignant transformations., Conclusion: This study underscores the prognostic significance of WHO grades in PPT. It is necessary to provide specific treatment according to tumor grade. Grade 3 PPTID showed a poor prognosis. Potential LMS and malignant transformations necessitate aggressive multimodal treatment and close-interval screening., Competing Interests: Seung-Ki Kim, Ji Hoon Phi, Chul-Kee Park, and Sung-Hye Park, contributing editors of Brain Tumor Research and Treatment, were not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology.)

Central neurocytoma (CN) is a low-grade neuronal tumor that mainly arises from the lateral ventricle (LV). This tumor remains poorly understood in the sense that no driver gene aberrations have been identified thus far. We investigated immunomarkers in fetal and adult brains and 45 supratentorial periventricular tumors to characterize the biomarkers, cell of origin, and tumorigenesis of CN. All CNs occurred in the LV. A minority involved the third ventricle, but none involved the fourth ventricle. As expected, next-generation sequencing performed using a brain-tumor-targeted gene panel in 7 CNs and whole exome sequencing in 5 CNs showed no driver mutations. Immunohistochemically, CNs were robustly positive for FGFR3 (100%), SSTR2 (92%), TTF-1 (Nkx2.1) (88%), GLUT-1 (84%), and L1CAM (76%), in addition to the well-known markers of CN, synaptophysin (100%) and NeuN (96%). TTF-1 was also positive in subependymal giant cell astrocytomas (100%, 5/5) and the pituicyte tumor family, including pituicytoma and spindle cell oncocytoma (100%, 5/5). Interestingly, 1 case of LV subependymoma (20%, 1/5) was positive for TTF-1, but all LV ependymomas were negative (0/5 positive). Because TTF-1-positive cells were detected in the medial ganglionic eminence around the foramen of Monro of the fetal brain and in the subventricular zone of the LV of the adult brain, CN may arise from subventricular TTF-1-positive cells undergoing neuronal differentiation. H3K27me3 loss was observed in all CNs and one case (20%) of LV subependymoma, suggesting that chromatin remodeling complexes or epigenetic alterations may be involved in the tumorigenesis of all CNs and some ST-subependymomas. Further studies are required to determine the exact tumorigenic mechanism of CN., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The goal of this study was to analyze the clinical outcomes of endoscopic third ventriculostomy (ETV) and endoscopic septostomy when shunt malfunction occurs in a patient who has previously undergone placement of a ventriculoperitoneal shunt., Methods: From 2001 to 2020 at Seoul National University Children's Hospital, patients who underwent ETV or endoscopic septostomy for shunt malfunction were retrospectively analyzed. Initial diagnosis (etiology of hydrocephalus), age at first shunt insertion, age at endoscopic procedure, magnetic resonance or computed tomography image, subsequent shunting data, and follow-up period were included., Results: Thirty-six patients were included in this retrospective study. Twenty-nine patients, 18 males and 11 females, with shunt malfunction underwent ETV. At the time of shunting, the age ranged from 1 day to 15.4 years (mean, 2.4 years). The mean age at the time of ETV was 13.1 years (range, 0.7 to 29.6 years). Nineteen patients remained shunt revision free. The 5-year shunt revisionfree survival rate was 69% (95% confidence interval [CI], 0.54-0.88). Seven patients, three males and four females, with shunt malfunction underwent endoscopic septostomy. At the time of shunting, the age ranged from 0.2 to 12 years (mean, 3.9 years). The mean age at the time of endoscopic septostomy was 11.9 years (range, 0.5 to 29.5 years). Four patients remained free of shunt revision or addition. The 5-year shunt revision-free survival rate was 57% (95% CI, 0.3-1.0). There were no complications associated with the endoscopic procedures., Conclusion: The results of our study demonstrate that ETV or endoscopic septostomy can be effective and safe in patients with shunt malfunction.

Pediatric nondysraphic intramedullary lipoma is very rare, and only limited cases have been reported. In the present case, we present two infant patients with these pathologies who were surgically treated. Previous literature on 20 patients with these diseases who had undergone surgical treatments was analyzed. Surgical treatment should be considered in most symptomatic patients, and laminoplastic laminotomy and internal debulking of the lipoma under intraoperative neurophysiological monitoring are mostly recommended.

Patients with Crouzon syndrome have increased risks of cerebrospinal fluid rhinorrhea and meningoencephalocele after LeFort III osteotomy. We report a rare case of meningoencephalocele following LeFort III midface advancement in a patient with Crouzon syndrome. Over 10 years since it was incidentally found during transnasal endoscopic orbital decompression, the untreated meningoencephalocele eventually led to intermittent clear nasal discharge, frontal headache, and seizure. Computed tomography and magnetic resonance imaging demonstrated meningoencephalocele in the left frontal-ethmoid-maxillary sinus through a focal defect of the anterior cranial base. Through bifrontal craniotomy, the meningoencephalocele was removed and the anterior cranial base was reconstructed with a pericranial flap and split calvarial bone graft. Secondary frontal advancement was concurrently performed to relieve suspicious increased intracranial pressure, limit visual deterioration, and improve the forehead shape. Surgeons should be aware that patients with Crouzon syndrome have the potential for an unrecognized dural injury during LeFort III osteotomy due to anatomical differences such as inferior displacement and thinning of the anterior cranial base., Competing Interests: Conflict of Interest None declared., (The Korean Society of Plastic and Reconstructive Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Dysembryoplastic neuroepithelial tumor (DNET) is a low-grade brain tumor commonly associated with drug-resistant epilepsy. About half of DNETs are accompanied by tiny nodular lesions separated from the main mass. The existence of these satellite lesions (SLs) has shown a strong association with tumor recurrence, suggesting that they are true tumors. However, it is not known whether SLs represent multiple foci of progenitor tumor cell extension and migration or a multifocal development of the main DNET. This study was designed to elucidate the histopathology and pathogenesis of SLs in DNETs. Separate biopsies from the main masses and SLs with DNET were analyzed. We performed comparative lesion sequencing and phylogenetic analysis. FGFR1 K656E and K655I mutations or duplication of the tyrosine kinase domain was found in all 3 DNET patients and the main masses and their SLs shared the same FGFR1 alterations. The phylogenic analysis revealed that the SLs developed independently from their main masses. It is possible that the main mass and its SLs were separated at an early stage in oncogenesis with shared FGFR1 alterations, and then they further expanded in different places. SLs of DNET are true tumors sharing pathogenic mutations with the main masses. It is plausible that multifocal tumor development takes place in the dysplastic cortex containing cells with a pathogenic genetic alteration., (© 2023. The Author(s).)

Purpose: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method., Methods: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made., Results: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results., Conclusions: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field., (© 2022. The Author(s).)

According to the new 2021 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) the classification of the primary intramedullary spinal cord tumors (IM-SCT) follows that of CNS tumors. However, since the genetics and methylation profile of ependymal tumors depend on the location of the tumor, the 'spinal (SP)' should be added for the ependymoma (EPN) and subependymoma (SubEPN). For an evidence-based review, the authors reviewed SCTs in the archives of the Seoul National University Hospital over the past decade. The frequent pathologies of primary IM-SCT were SP-EPN (45.1%), hemangioblastoma (20.0%), astrocytic tumors (17.4%, including pilocytic astrocytoma [4.6%] and diffuse midline glioma, H3 K27-altered [4.0%]), myxopapillary EPN (11.0%), and SP-subEPN (3.0%) in decreasing order. IDH-mutant astrocytomas, oligodendrogliomas, glioneuronal tumors, embryonal tumors, and germ cell tumors can occur but are extremely rare in the spinal cord. Genetic studies should support for the primary IM-SCT classification. In the 2021 WHO classifications, extramedullary SCT did not change significantly but contained several new genetically defined types of mesenchymal tumors. This article focused on primary IM-SCT for tumor frequency, age, sex difference, pathological features, and genetic abnormalities, based on a single-institute experience.

Background: The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues., Methods: Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups., Results: We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression., Conclusions: This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies., (© 2022. The Author(s).)

Background: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes., Methods: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken., Results: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had β-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%)., Conclusions: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dysembryoplastic neuroepithelial tumor (DNET) is a distinct type of low-grade glioneuronal tumor. Clinically, DNET is highly associated with intractable epilepsy in young children and adolescents. Therefore, the burden of the tumor comprises oncological concerns (recurrence), seizure control, and quality of life. The pathology of DNET is characterized by glioneuronal elements and floating neurons. Grossly, many DNETs harbor separate nodules on the medial side of the mass. Some of the satellite lesions are bone fide tumor nodules that grow during the follow-up. Therefore, removing all satellite lesions may be important to prevent tumor progression. Seizure control is highly dependent on the complete removal of tumors, and the presence of satellite lesions also exerts a negative impact on seizure outcomes., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology.)

Background: Advances in surgical techniques based on in-depth anatomical knowledge of the skull base have broadened the indications for endoscopic skull base surgery (ESS) with the advantage of wide and direct surgical exposure while minimizing invasiveness. However, the low incidence of the indicated diseases and narrow surgical corridors in children have limited the popularization of ESS. In addition, surgical complications and preventive interventions are not yet well known. Therefore, we retrospectively investigated the complications and prevention methods of ESS in children with a comprehensive review., Methods: We retrospectively analyzed the medical records of pediatric patients who underwent ESS for sellar and parasellar tumors at Seoul National University Children's Hospital from July 2010 to December 2020. Visual and endocrine status, extent of resection, complications, and recurrences were investigated depending on the pathology of the tumor. In addition, a comprehensive literature review regarding the complications of pediatric ESS was performed., Results: A total of 98 patients were enrolled. The median age of the patients was 12 years, and 52 patients were male. Preoperative visual disturbance was found in 53 patients, anterior pituitary function deficit in 69, and diabetes insipidus in 32. Gross total resection was attempted in 67 patients and achieved in 62 (93%). Biopsy and cyst fenestration were the goals of surgery in 26 patients, and all were achieved as planned. Regarding outcomes, visual disturbance worsened in two patients (2%), endocrine status was aggravated in 34 (35%) patients, and new-onset diabetes insipidus occurred in 27 (41%) patients. The overall surgical complication rate (other than aggravation of visual or endocrine status) was 17%. Postoperative meningitis (12%) was the most common complication, followed by cerebrospinal fluid leakage (2%), vasospasm, hemorrhage and infarction. By pathological diagnosis, craniopharyngioma had the highest complication rate of 29%. All but one patient with postoperative hemorrhage showed no permanent deficits., Conclusion: ESS in children is feasible and relatively safe. More attention and different postoperative management protocols are required in children to avoid complications, especially in craniopharyngiomas. However, the complications can be mostly managed conservatively without permanent neurologic deficits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Kim, Phi, Kim and Wang.)

Objective: To develop and evaluate a deep learning-based artificial intelligence (AI) model for detecting skull fractures on plain radiographs in children., Materials and Methods: This retrospective multi-center study consisted of a development dataset acquired from two hospitals (n = 149 and 264) and an external test set (n = 95) from a third hospital. Datasets included children with head trauma who underwent both skull radiography and cranial computed tomography (CT). The development dataset was split into training, tuning, and internal test sets in a ratio of 7:1:2. The reference standard for skull fracture was cranial CT. Two radiology residents, a pediatric radiologist, and two emergency physicians participated in a two-session observer study on an external test set with and without AI assistance. We obtained the area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity along with their 95% confidence intervals (CIs)., Results: The AI model showed an AUROC of 0.922 (95% CI, 0.842-0.969) in the internal test set and 0.870 (95% CI, 0.785-0.930) in the external test set. The model had a sensitivity of 81.1% (95% CI, 64.8%-92.0%) and specificity of 91.3% (95% CI, 79.2%-97.6%) for the internal test set and 78.9% (95% CI, 54.4%-93.9%) and 88.2% (95% CI, 78.7%-94.4%), respectively, for the external test set. With the model's assistance, significant AUROC improvement was observed in radiology residents (pooled results) and emergency physicians (pooled results) with the difference from reading without AI assistance of 0.094 (95% CI, 0.020-0.168; p = 0.012) and 0.069 (95% CI, 0.002-0.136; p = 0.043), respectively, but not in the pediatric radiologist with the difference of 0.008 (95% CI, -0.074-0.090; p = 0.850)., Conclusion: A deep learning-based AI model improved the performance of inexperienced radiologists and emergency physicians in diagnosing pediatric skull fractures on plain radiographs., Competing Interests: Young Hun Choi and Jung-Eun Cheon who is on the editorial board of the Korean Journal of Radiology was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Korean Society of Radiology.)

Objective: Nosocomial bacterial meningitis is one of the major complications after neurosurgery. We performed nanopore 16S amplicon sequencing from cerebrospinal fluid (CSF) to evaluate bacterial meningitis in patients who underwent neurosurgery., Methods: Among the patients who visited the neurosurgery department of Seoul National University Hospital between July 2017 and June 2020, those with clinically suspected bacterial meningitis were included. 16S rDNA PCR was performed from the CSF, and nanopore sequencing was performed for up to 3 h. The reads were aligned to the BLAST database. In each case, the culture and the 16S rRNA gene amplicon analysis were simultaneously performed and compared with each other, and we retrospectively reviewed the medical records. Genuine infection was determined by the identical results between conventional culture study and the sequencing, or clinically determined in cases with inconsistent results between the two methods., Results: Of the 285 samples obtained from 178 patients who had 16S rDNA PCR, 41 samples (14.4%) were diagnosed with genuine infection. A total of 56.1% (23/41) of the samples with genuine infection showed a false-negative culture test. In particular, 16S amplicon sequencing was useful in evaluating patients at the initial tests who had infection with intraventricular hemorrhage (Culture false-negative rate = 100%), subarachnoid hemorrhage (Culture false-negative rate = 77.8%), and systemic cancer (Culture false-negative rate = 100%), which are risk factors for central fever. Moreover, 16S amplicon sequencing could suggest the possibility of persistent bacterial meningitis in empirical antibiotic use., Conclusion: CSF nanopore 16S sequencing was more effective than conventional CSF culture studies in postoperative bacterial meningitis and may contribute to evidence-based decisions for antibiotic maintenance and discontinuation., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities., Materials and Methods: Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole brain (WB), and whole ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months., Results: The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in 10 patients (5.3%) with a latency of 20 years (range, 4 to 26 years) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction., Conclusion: De-intensifying extended-field rather than involved-field or total scheme of RT will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.

Purpose: Atypical teratoid/rhabdoid tumor (AT/RT) is arising typically in young children and is associated with a dismal prognosis which there is currently no curative chemotherapeutic regimen. Based on previous studies showing high histone deacetylase 1 (HDAC1) expression in AT/RT, the HDAC1 inhibitor CI-994 was used as a novel treatment strategy in this study. We assessed the anticancer effects of CI-994 and conventional drugs (etoposide, cisplatin or 4-HC) in AT/RT cells., Methods: AT/RT patient-derived primary cultured cells and cell lines were prepared. HDAC1 was estimated by real-time quantitative polymerase chain reaction (RT-qPCR). The interaction of the drugs was analyzed using isobologram analysis. Cell viability, apoptosis, HDAC enzyme activity and western blot assays were carried out., Results: HDAC1 was overexpressed in AT/RT compared to medulloblastoma. The combination index (CI) of CI-994 with etoposide revealed a synergistic effect in all AT/RT cells, but no synergistic effect was observed between CI-994 and cisplatin or 4-HC. CI-994 effectively reduced not only Class I HDAC gene expression but also HDAC enzyme activity. The combination treatment of CI-994 with etoposide significantly increased apoptosis compared to the single treatment. The enhanced effect of apoptosis by this combination treatment is related to a signaling pathway which decreases topoisomerase (Topo) II and increases histone H3 acetylation (Ac-H3)., Conclusion: We demonstrate that the combination treatment of CI-994 with etoposide exerts a synergistic anticancer effect against AT/RT by significantly inducing apoptosis through Topo II and Ac-H3 regulation., Clinical Relevance: This combination treatment might be considered a viable therapeutic strategy for AT/RT patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, Choi, Koh, Kim, Phi, Lee and Kim.)

Slit ventricle syndrome (SVS) is a well-known complication of long-standing shunts. Patients develop intermittent severe headache, vomiting with other symptoms of increased intra-cranial pressure. Brain computed tomography (CT) usually reveals slit-like ventricles with nearly obstructed proximal catheters. Treatment for SVS usually involves upgrading the shunt valve pressure setting. Currently, many patients carry programmable shunts and pressure setting can be adjusted noninvasively. However, when the programmable valve pressure setting is upgraded, some patients with SVS experience worsened symptoms. This is caused by the time gap between ICP increase and real ventricular expansion (and freeing proximal catheter) after shunt upgrading. Therefore, it is important to control a patient's symptoms during the transition period. We report our experience in controlling ICP in a patient with SVS using external ventricular drainage., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2021.)

Objective: Few studies exist on primary spinal cord tumors (PSCTs) in pediatric patients. The purpose of this study was to perform descriptive analysis and detailed survival analysis for PSCTs., Methods: Between 1985 and 2017, 126 pediatric patients (male : female, 56 : 70) with PSCTs underwent surgery in a single institution. We retrospectively analyzed data regarding demographics, tumor characteristics, outcomes, and survival statistics. Subgroup analysis was performed for the intramedullary (IM) tumors and extradural (ED) tumors separately., Results: The mean age of the participants was 6.4±5.04 years, and the mean follow-up time was 69.5±46.30 months. The most common compartment was the ED compartment (n=57, 45.2%), followed by the IM (n=43, 34.1%) and intradural extramedullary (IDEM; n=16, 12.7%) compartments. Approximately half of PSCTs were malignant (n=69, 54.8%). The most common pathologies were schwannomas (n=14) and neuroblastomas (n=14). Twenty-two patients (17.5%) died from the disease, with a mean disease duration of 15.8±15.85 months. Thirty-six patients (28.6%) suffered from progression, with a mean period of 22.6±30.81 months. The 10-year overall survival (OS) rates and progression-free survival (PFS) rates were 81% and 66%, respectively. Regarding IM tumors, the 10-year OS rates and PFS rates were 79% and 57%, respectively. In ED tumors, the 10-year OS rates and PFS rates were 80% and 81%, respectively. Pathology and the extent of resection showed beneficial effects on OS for total PSCTs, IM tumors, and ED tumors. PFS was affected by both the extent of removal and pathology in total PSCTs and ED tumors; however, pathology was a main determinant of PFS rather than the extent of removal in IM tumors. The degree of improvement in the modified McCormick scale showed a trend towards improvement in patients with IM tumors who achieved gross total removal (p=0.447)., Conclusion: Approximately half of PSCTs were malignant, and ED tumors were most common. The most common pathologies were schwannomas and neuroblastomas. Both the pathology and extent of resection had a decisive effect on OS. For IM tumors, pathology was a main determinant of PFS rather than the extent of removal. Radical excision of IM tumors could be a viable option for better survival without an increased risk of worse functional outcomes.

Background and Purpose: In certain cases of pediatric patients with Moyamoya disease undergoing encephaloduroarteriosynangiosis (EDAS) treatment, the posterior auricular artery can be used as an alternative when the parietal branch of the superficial temporal artery is unavailable. In this study, anatomic variations of the superficial temporal and posterior auricular arteries in pediatric patients with Moyamoya disease and postoperative outcomes of posterior auricular artery-EDAS are explored., Materials and Methods: Medical records of 572 patients with Moyamoya disease who underwent surgical procedures from 2007 to 2017 at the Seoul National University Children's Hospital were reviewed. Anatomic classifications of the superficial temporal and posterior auricular arteries were based on previous classifications. Postoperative hemodynamic changes of posterior auricular artery-EDAS were analyzed using the Matsushima grade. Also, Karnofsky Performance Scale and mRS scores of posterior auricular artery-EDAS cases were reviewed to identify postoperative clinical outcomes., Results: Among 1144 hemispheres, 24 were considered posterior auricular artery-EDAS candidates (2.1%). Of those, 10 hemispheres underwent posterior auricular artery-EDAS (41.7%, in total hemispheres 0.9%). Comparing the Matsushima grades of the superficial temporal artery-EDAS and posterior auricular artery-EDAS groups showed similar postoperative revascularization. Postoperative Karnofsky Performance Scale and mRS scores of patients having undergone posterior auricular artery-EDAS did not show deterioration., Conclusions: In approximately 2% of pediatric patients with Moyamoya disease for whom the superficial temporal artery is unavailable as the EDAS donor, the posterior auricular artery can be considered an alternative. On the basis of the results, the clinical outcome of posterior auricular artery-EDAS was not inferior to that of superficial temporal artery-EDAS. Hence, we suggest an in-depth consideration of the posterior auricular artery as the donor artery if the superficial temporal artery parietal branch is unavailable., (© 2021 by American Journal of Neuroradiology.)

We encountered siblings with familial Majewski osteodysplastic primordial dwarfism type II (MOPD II) with acute myocardial infarction in adolescence and in their early 20s. We successfully performed percutaneous and surgical coronary interventions. From these cases, we were able to better understand coronary artery disease of MOPD II and provide better management. ( Level of Difficulty: Intermediate. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Sacrococcygeal teratoma (SCT) is an extragonadal germ cell tumor (GCT) that develops in the fetal and neonatal periods. SCT is a type I GCT in which only teratoma and yolk sac tumors arise from extragonadal sites. SCT is the most common type I GCT and is believed to originate through epigenetic reprogramming of early primordial germ cells migrating from the yolk sac to the gonadal ridges. Fetal SCT diagnosed in utero presents many obstetrical problems. For high-risk fetuses, fetal interventions (devascularization and debulking) are under development. Most patients with SCT are operated on after birth. Complete surgical resection is the key for tumor control, and the anatomical location of the tumor determines the surgical approaches. Incomplete resection and malignant histology are risk factors for recurrence. Approximately 10-15% of patients have a tumor recurrence, which is frequently of malignant histology. Long-term surveillance with monitoring of serum alpha fetoprotein and magnetic resonance imaging is required. Survivors of SCT may suffer anorectal, urological, and sexual sequelae later in their life, and comprehensive evaluation and care are required.

Purpose: Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years., Materials and Methods: A search of medical records from seven centers was performed between January 2005 and December 2016., Results: Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01)., Conclusion: Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.

Background: Cervical myelopathy and hydrocephalus occasionally occur in young children with achondroplasia. However, these conditions are not evaluated in a timely manner in many cases. The current study presents significant predictors for cervical myelopathy and hydrocephalus in young children with achondroplasia., Methods: A retrospective analysis of 65 patients with achondroplasia who visited Seoul National University Children's Hospital since 2012 was performed. The patients were divided into groups according to the presence of cervical myelopathy and hydrocephalus, and differences in foramen magnum parameters and ventricular parameters by magnetic resonance imaging between groups were analyzed. Predictors for cervical myelopathy and hydrocephalus were analyzed, and the cut-off points for significant ones were calculated., Results: The group with cervical myelopathy showed foramen magnum parameters that indicated significantly lower cord thickness than in the group without cervical myelopathy, and the group with hydrocephalus showed significantly higher ventricular parameters and 'Posterior indentation' grade than the group without hydrocephalus. 'Cord constriction ratio' (OR 5199.90, p = 0.001) for cervical myelopathy and 'Frontal horn width' (OR 1.14, p = 0.001) and 'Posterior indentation' grade (grade 1: OR 9.25, p = 0.06; grade 2: OR 18.50, p = 0.01) for hydrocephalus were significant predictors. The cut-off points for cervical myelopathy were 'Cord constriction ratio' of 0.25 and 'FM AP' of 8 mm (AUC 0.821 and 0.862, respectively) and 'Frontal horn width' of 50 mm and 'Posterior indentation' grade of 0 (AUC 0.788 and 0.758, respectively) for hydrocephalus., Conclusion: 'Cord constriction ratio' for cervical myelopathy and 'Frontal horn width' and 'Posterior indentation' grade for hydrocephalus were significant predictors and may be used as useful parameters for management. 'Posterior indentation' grade may also be used to determine the treatment method for hydrocephalus.

Background: Extracellular vesicles (EVs) secreted by tumours, including exosomes, are important factors that regulate cell-cell interactions in oncogenesis. Although EV studies are ongoing, the biological understanding of EV-miRNAs derived from brain tumour spheroid-forming cells (BTSCs) of medulloblastoma is poor., Purposes: We explored the specific cellular miRNAs and EV-miRNAs in medulloblastoma BTSCs to determine their potential biological function., Methods: Bulk tumor cells (BTCs) and BTSCs were cultured under different conditions from medulloblastoma tissues (N = 10)., Results: Twenty-four miRNAs were simultaneously increased in both cells and EVs derived from BTSCs in comparison to BTCs. After inhibition of miR-135b or miR135a which were the most significantly increased in BTSCs, cell viability, self-renewal and stem cell marker expression decreased remarkably. Through integrated analysis of mRNAs and miRNAs data, we found that angiomotin-like 2 (AMOTL2), which was significantly decreased, was targeted by both miR-135b and miR-135a. STAT6 and GPX8 were targeted only by miR-135a. Importantly, low expression of AMOTL2 was significantly associated with overall poor survival in paediatric Group 3 and Group 4 medulloblastoma patients., Conclusion: Our results indicated that inhibition of miR-135b or miR-135a leads to suppress stemness of BTSC through modulation of AMOTL2.

Background: Central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy., Methods: We retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children's Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients' choice., Results: The median age at diagnosis was 11.9 (range, 3.8-25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p < 0.001) and OS (77.9 ± 9.8%, p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy., Conclusion: The strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.

Background and Purpose- In pediatric moyamoya disease, there are few reports on the efficacy of surgical intervention for stroke prevention. We evaluated the long-term outcomes of indirect bypass surgery on a relatively large number of children with moyamoya disease in a single center. Methods- From August 1988 to December 2012, 772 children underwent indirect bypass surgery. This study included 629 patients who were followed up for >5 years, excluding patients with moyamoya syndrome. The mean clinical follow-up duration was 12 years (range, 5-29 years). Cross-sectional analysis was performed based on either Karnofsky Performance Scale or Lansky Play Performance Scale to evaluate overall clinical outcomes and factors associated with unfavorable outcomes. To analyze the longitudinal effect of surgery, the annual risk of symptomatic infarction or hemorrhage on the operated hemisphere after indirect bypass surgery was calculated with a person-year method, and the event-free survival rate was evaluated using the Kaplan-Meier method. Results- The overall clinical outcome was favorable in 95% of the patients. The annual risks of symptomatic infarction and hemorrhage on the operated hemispheres were 0.08% and 0.04%, respectively. Furthermore, the 10-year event-free survival rates for symptomatic infarction and hemorrhage were 99.2% and 99.8%. Conclusions- Indirect bypass surgery could provide satisfactory long-term improvement in overall clinical outcome and prevention of recurrent stroke in children with moyamoya disease.

Objective: Intracranial aneurysms are not common in young age patients. We sought to find the characteristics of the intracranial aneurysms in patients under 20 years of age., Methods: We reviewed 23 consecutive patients ≤20 years of age treated for their intracranial aneurysms during the period from 1995 to 2017. From medical records and imaging studies, we gathered data on age, sex, presentation, associated medical condition, location and characteristics of aneurysms, treatment and clinical outcomes., Results: The patients' ages ranged from 13 months to 20 years (median, 14 years). There were 16 males and seven females (male to female ratio, 2.3 : 1) with 31 aneurysms. Clinical presentations included sudden severe headache in 61%, followed by altered mentality in 17% and seizure in 17%. More than one-fourth patients had specific medical conditions related to the development of the cerebral aneurysms. The majority of aneurysms occurred in the anterior circulation (71%), and were saccular (71%). There were each three patients with false aneurysms (13%) and giant aneurysms (13%), and only one patient with multiple aneurysms (4%). We treated 22 patients : 21 aneurysms with the endovascular methods, three with open surgery, and one with combined treatment. Good functional outcome could be achieved in 86% during the follow-up period., Conclusion: In this series, the young-age patients with intracranial aneurysms were characterized by male predominance, related specific medical conditions, low incidence of multiple aneurysms, high incidence of giant aneurysms and good functional outcome after treatment.

Background: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets., Methods: Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines., Results: WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells., Conclusions: We propose that NPM1 is a novel therapeutic target for AT/RTs.

Background: Using a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma., Method: Based on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data., Results: In SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4., Conclusions: The results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4.

Epilepsy is one of the major chronic neurological diseases affecting many patients. Resection surgery is the most effective therapy for medically intractable epilepsy, but it is not feasible in all patients. Vagus nerve stimulation (VNS) is an adjunctive neuromodulation therapy that was approved in 1997 for the alleviation of seizures; however, efforts to control epilepsy by stimulating the vagus nerve have been studied for over 100 years. Although its exact mechanism is still under investigation, VNS is thought to affect various brain areas. Hence, VNS has a wide indication for various intractable epileptic syndromes and epilepsyrelated comorbidities. Moreover, recent studies have shown anti-inflammatory effects of VNS, and the indication is expanding beyond epilepsy to rheumatoid arthritis, chronic headaches, and depression. VNS yields a more than 50% reduction in seizures in approximately 60% of recipients, with an increase in reduction rates as the follow-up duration increases. The complication rate of VNS is 3-6%, and infection is the most important complication to consider. However, revision surgery was reported to be feasible and safe with appropriate measures. Recently, noninvasive VNS (nVNS) has been introduced, which can be performed transcutaneously without implantation surgery. Although more clinical trials are being conducted, nVNS can reduce the risk of infection and subsequent device failure. In conclusion, VNS has been demonstrated to be beneficial and effective in the treatment of epilepsy and various diseases, and more development is expected in the future.

Brain tumors are the second most common type of structural brain lesion that causes chronic epilepsy. Patients with low-grade brain tumors often experience chronic drug-resistant epilepsy starting in childhood, which led to the concept of long-term epilepsy-associated tumors (LEATs). Dysembryoplastic neuroepithelial tumor and ganglioglioma are representative LEATs and are characterized by young age of onset, frequent temporal lobe location, benign tumor biology, and chronic epilepsy. Although highly relevant in clinical epileptology, the concept of LEATs has been criticized in the neuro-oncology field. Recent genomic and molecular studies have challenged traditional views on LEATs and low-grade gliomas. Molecular studies have revealed that lowgrade gliomas can largely be divided into three groups : LEATs, pediatric-type diffuse low-grade glioma (DLGG; astrocytoma and oligodendroglioma), and adult-type DLGG. There is substantial overlap between conventional LEATs and pediatric-type DLGG in regard to clinical features, histology, and molecular characteristics. LEATs and pediatric-type DLGG are characterized by mutations in BRAF, FGFR1, and MYB/MYBL1, which converge on the RAS-RAF-MAPK pathway. Gene (mutation)-centered classification of epilepsyassociated tumors could provide new insight into these heterogeneous and diverse neoplasms and may lead to novel molecular targeted therapies for epilepsy in the near future.

Epilepsy has been known to humankind since antiquity. The surgical treatment of epilepsy began in the early days of neurosurgery and has developed greatly. Many surgical procedures have stood the test of time. However, clinicians treating epilepsy patients are now witnessing a huge tide of change. In 2017, the classification system for seizure and epilepsy types was revised nearly 36 years after the previous scheme was released. The actual difference between these systems may not be large, but there have been many conceptual changes, and clinicians must bid farewell to old terminology. Paradigms in drug discovery are changing, and novel antiseizure drugs have been introduced for clinical use. In particular, drugs that target genetic changes harbor greater therapeutic potential than previous screening-based compounds. The concept of focal epilepsy has been challenged, and now epilepsy is regarded as a network disorder. With this novel concept, stereotactic electroencephalography (SEEG) is becoming increasingly popular for the evaluation of dysfunctioning neuronal networks. Minimally invasive ablative therapies using SEEG electrodes and neuromodulatory therapies such as deep brain stimulation and vagus nerve stimulation are widely applied to remedy dysfunctional epilepsy networks. The use of responsive neurostimulation is currently off-label in children with intractable epilepsy.

Background and Purpose: This study investigated the seizure recurrence rate and potential predictors of seizure recurrence following antiepileptic drug (AED) withdrawal after resective epilepsy surgery in children with focal cortical dysplasia (FCD)., Methods: We retrospectively analyzed the records of 70 children and adolescents with FCD types I, II, and IIIa who underwent resective epilepsy surgery between 2004 and 2015 and were followed for at least 2 years after surgery., Results: We attempted AED withdrawal in 40 patients. The median time of starting the AED reduction was 10.8 months after surgery. Of these 40 patients, 14 patients (35%) experienced seizure recurrence during AED reduction or after AED withdrawal. Half of the 14 patients who experienced recurrence regained seizure freedom after AED reintroduction and optimization. Compared with their preoperative status, the AED dose or number was decreased in 57.1% of patients, and remained unchanged in 14.3% after surgery. A multivariate analysis found that incomplete resection ( p =0.004) and epileptic discharges on the postoperative EEG ( p =0.025) were important predictors of seizure recurrence after AED withdrawal. Over the mean follow-up duration of 4.5 years after surgery, 34 patients (48.6% of the entire cohort) were seizure-free with and without AEDs., Conclusions: Children with incomplete resection and epileptic discharges on postoperative EEG are at a high risk of seizure recurrence after drug withdrawal. Complete resection of FCD may lead to a favorable surgical outcome and successful AED withdrawal after surgery., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2019 Korean Neurological Association.)

Background: Recently, modern technology such as diffusion tensor imaging (DTI), neuro-navigation and intraoperative neurophysiological monitoring (IOM) have been actively adopted for the treatment of thalamic tumors. We evaluated surgical outcomes and efficacy of the aforementioned technologies for the treatment of pediatric thalamic tumors., Methods: We retrospectively reviewed clinical data from 37 children with thalamic tumors between 2004 and 2017. There were 44 operations (27 tumor resections, 17 biopsies). DTI was employed in 17 cases, neuro-navigation in 23 cases and IOM in 14 cases. All diagnoses were revised according to the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Progression-free survival (PFS) and overall survival (OS) rates were calculated, and relevant prognostic factors were analyzed. The median follow-up duration was 19 months., Results: Fifteen cases were gross total resections (GTR), 6 subtotal resections (STR), and 6 partial resections (PR). Neurological status did not worsen after 22 tumor resections. There were statistically significant differences in terms of the extent of resection between the groups with DTI, neuro-navigation and IOM (n=12, GTR or STR=12) and the group without at least one of the three techniques (n=15, GTR or STR=9, p =0.020). The mean PFS was 87.2±38.0 months, and the mean OS 90.7±36.1 months. The 5-year PFS was 37%, and the 5-year OS 47%. The histological grade ( p ≤0.001) and adjuvant therapy (done vs. not done, p =0.016) were significantly related to longer PFS. The histological grade ( p =0.002) and the extent of removal (GTR/STR vs. PR/biopsy, p =0.047) were significantly related to longer OS., Conclusion: Maximal surgical resection was achieved with acceptable morbidity in children with thalamic tumors by employing DTI, neuro-navigation and IOM. Maximal tumor resection was a relevant clinical factor affecting OS; therefore, it should be considered the initial therapeutic option for pediatric thalamic tumors., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2018 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology.)

Cavernous malformations (CMs) are angiographically occult vascular lesions, and their clinical presentations vary widely according to location of the lesion. Here, we reviewed three cases of CM located at the optic apparatus. All three patients experienced visual deterioration and underwent surgical resection. One achieved complete resection of the CM, whereas the others achieved subtotal resection. Visual symptoms of the two patients who achieved subtotal resection improved, but the visual symptom of the patient who achieved complete resection remained unchanged. One patient with subtotal resection presented postoperative improvement of visual symptoms but experienced deterioration in two years after surgical resection due to rebleeding from the remnant lesion, and he required a second operation. We recommend total resection of CM when feasible and regular follow-up after subtotal resection due to the risk of rebleeding., Competing Interests: Disclosure: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Background and Purpose: The pathogenesis of moyamoya disease (MMD) remains poorly understood, and no reliable molecular biomarkers for MMD have been identified to date. The present study aimed to identify epigenetic biomarkers for use in the diagnosis of MMD., Methods: We performed integrated analyses of gene expression profiles and DNA methylation profiles in endothelial colony forming cells (ECFCs) from three patients with MMD and two healthy individuals. Candidate gene mRNA expression and DNA methylation status were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and pyrosequencing analysis of an expanded ECFC sample set from nine patients with MMD and ten controls. We evaluated the diagnostic accuracy of the potential biomarkers identified here using receiver operating characteristic curve analyses and further measured major angiogenic factor expression levels using a tube formation assay and RT-qPCR., Results: Five candidate genes were selected via integrated analysis; all five were upregulated by hypomethylation of specific promoter CpG sites. After further validation in an expanded sample set, we identified a candidate biomarker gene, sortilin 1 (SORT1). DNA methylation status at a specific SORT1 promoter CpG site in ECFCs readily distinguished patients with MMD from the normal controls with high accuracy (area under the curve 0.98, sensitivity 83.33%, specificity 100%). Furthermore, SORT1 overexpression suppressed endothelial cell tube formation and modulated major angiogenic factor and matrix metalloproteinase-9 expression, implying SORT1 involvement in MMD pathogenesis., Conclusion: s Our findings suggest that DNA methylation status at the SORT1 promoter CpG site may be a potential biomarker for MMD.

Background and Purpose: Sudden neurological deterioration which cannot be explained by structural change, ischemia or seizure is often observed among neurosurgical patients. We aimed to provide new insight into the pathophysiology of postoperative transient neurologic dysfunction., Methods: We describe prolonged but fully reversible focal neurologic dysfunction of unknown origin based on the initial evaluation in 8 patients who had received encephalo-duro-arterio-synangiosis for moyamoya disease. We performed brain imaging, including diffusion weighted imaging and perfusion magnetic resonance imaging or single photon emission computed tomography, and electroencephalography (EEG) during the episodes and after resolution of the symptoms., Results: The symptoms consisted of dysarthria, hemiparesis, or hemiparesthesia of limbs contralateral to the operated side. These symptoms developed between 12 hours and 8 days after surgery and lasted between 12 hours and 17 days. Structural imaging did not show any significant interval change compared with the immediate postoperative images. Perfusion imaging showed increased cerebral blood flow in the symptomatic hemisphere. EEG revealed low amplitude arrhythmic slowing in the corresponding hemisphere. Follow-up imaging and EEG after recovery did not show any abnormalities., Conclusions: Transient neurologic dysfunction can occur during the postoperative period of brain surgery. Although this may last more than usual transient ischemic attack or seizure, it eventually resolves regardless of treatment. Based on our observation, we propose that this is the manifestation of the transient cortical depression triggered by mechanical stimulation, analogous to migraine aura associated with cortical spreading depression., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2018 Korean Neurological Association.)