Search

Background: EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors., Methods: We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts., Results: In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice., Conclusion: Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Drug-resistant epilepsy (DRE) can have devastating consequences for patients and families. Vagal nerve stimulation (VNS) is used as a surgical adjunct for treating DRE not amenable to surgical resection. Although VNS is generally safe, it has its inherent complications. With the increasing number of implantations, adequate patient education with discussion of possible complications forms a critical aspect of informed consent and patient counseling. There is a lack of large-scale reviews of device malfunction, patient complaints, and surgically related complications available to date., Materials and Methods: Complications associated with VNS implants performed between 2011 and 2021 were identified through a search of the United States Food and Drug Administration Manufacturer And User Facility Device Experience (MAUDE) data base. We found three models on the data base, CYBERONICS, INC pulse gen Demipulse 103, AspireSR 106, and SenTiva 1000. The reports were classified into three main groups, "Device malfunction," "Patient complaints," and "Surgically managed complications.", Results: A total of 5888 complications were reported over the ten-year period, of which 501 reports were inconclusive, 610 were unrelated, and 449 were deaths. In summary, there were 2272 reports for VNS 103, 1526 reports for VNS 106, and 530 reports for VNS 1000. Within VNS 103, 33% of reports were related to device malfunction, 33% to patient complaints, and 34% to surgically managed complications. For VNS 106, 35% were related to device malfunction, 24% to patient complaints, and 41% to surgically managed complications. Lastly, for VNS 1000, 8% were device malfunction, 45% patient complaints, and 47% surgically managed complications., Conclusion: We present an analysis of the MAUDE data base for adverse events and complications related to VNS. It is hoped that this description of complications and literature review will help promote further improvement in its safety profile, patient education, and management of both patient and clinician expectations., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: Total/near-total resection (TR/NTR) of complex lumbosacral lipomas (CSL) is reported to be associated with better long-term functional outcomes and lower symptomatic re-tethering rates. We report our institutional experience for CSL resection in affected children., Methods: This is a single-institution, retrospective study. Inclusion criteria consist of patients with CSL with dorsal, transitional and chaotic lipomas based on Pang et al's classification. The study population is divided into 2 groups: asymptomatic patients with a normal preoperative workup referred to as 'prophylactic intent' and 'therapeutic intent' for those with pre-existing neuro-urological symptoms. Primary aims are to review factors that affect post-operative clean intermittent catheterization (CIC), functional outcomes based on Necker functional score (NFS), and re-tethering rates., Results: 122 patients were included from 2000 to 2021. There were 32 dorsal lipomas (26.2 %), 74 transitional lipomas (60.7 %), and 16 chaotic lipomas (13.1 %). 82 % patients achieved TR/NTR. Favourable NFS at 1-year was 48.2 %. The re-tethering rate was 6.6 %. After multivariable analysis, post-operative CIC was associated with median age at surgery (p = 0.026), lipoma type (p = 0.029), conus height (p = 0.048) and prophylactic intent (p < 0.001). Next, extent of lipoma resection (p = 0.012) and the post-operative CSF leak (p = 0.004) were associated with re-tethering. Favourable NFS was associated with lipoma type (p = 0.047) and prophylactic intent surgery (p < 0.001)., Conclusions: Our experience shows that TR/NTR for CSL is a feasible option to prevent functional deterioration and re-tethering. Efforts are needed to work on factors associated with post-operative CIC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Cerebrospinal fluid (CSF) shunt failures in children are devastating. The primary aims of this study are to, firstly, review our institutional series of ventriculoperitoneal shunt (VPS) insertions and identify factors associated with shunt failure., Methods: This is a single-institution, retrospective study conducted over a 12-year period. All patients under 18 years old with VPS inserted were included. Variables of interest such as patient characteristics, hydrocephalus aetiology, shunt implant details, and outcomes were subjected to statistical analyses., Results: A total of 214 VPS patients were selected for this study. The mean age at VPS insertion was 6 months with a mean follow-up duration of 44 months. The most common type of hydrocephalus was obstructive (n = 142, 66.4%), and the most frequent aetiology was tumour-related (n = 66, 30.8%). The 30-day shunt failure rate was 9.3%: 9 infections (4.2%), 7 occlusions (3.3%), and 4 others (1.9%). After multivariable analysis, only recent central nervous system (CNS) infection prior to VPS insertion remained significant (OR 15.4 (1.3-175), p = 0.028)., Conclusion: This is the first, large-scale local study focused on the shunt failure in Singaporean children. Significant findings in our study demonstrate that recently treated CNS infection is a factor associated with 30-day shunt failure while the values of CSF constituents were not contributory., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Overall survival (OS)for glioblastoma multiforme (GBM) has a known association with the extent of tumor resection with gross total resection (GTR) typically considered as the upper limit. In certain regions such as the anterior temporal lobe, more extensive resection by means of a lobectomy may be feasible. In our systematic review and meta-analysis, we aimed to compare the outcomes of lobectomy and GTR for GBM. PubMed and Embase were queriedfor studies that compared the outcomes after lobectomy or GTR for GBM. The primary outcomes were OS, progression-free survival (PFS), and Karnofksy Performance Status (KPS) score at the latest follow-up. The secondary outcomes were seizure control at the latest follow-up and complication rates. Meta-analysis for OS and PFS was performed using individual-participant data reconstructed from published Kaplan-Meier curves. Random-effect meta-analysis was performed for KPS. The secondary outcomes were pooled using descriptive statistics. Of the 795 records screened, 6 were included in our study. Meta-analysis revealed that anterior temporal, frontal, or occipital lobectomy was associated with significantly better OS (p < 0.001) and PFS (p < 0.001) than GTR, but not KPS (MD = 6.37; 95% CI=(-13.80, 26.54); p = 0.536). Anterior temporal lobectomy was associated with significantly better seizure control rates than GTR for temporal GBM (OR = 27; 95% CI=(1.4, 515.9); p = 0.002). There was no statistically significant difference in complication rates between anterior temporal, frontal, or occipital lobectomy and GTR. In conclusion, lobectomy was associated with significantly better OS, PFS, and seizure control than GTR for GBM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: None

The Publisher regrets that this article is an accidental duplication of an article that has already been published in WNEU, 172 (2023) 20066, https://doi.org/10.1016/j.wneu.2023.01.070. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Tethered cord due to focal nondisjunction of primary neuralisation (FNPN) is a rare form of spinal dysraphism. We present our institutional experience in managing children diagnosed with FNPN., Materials and Methods: This is a single institution, retrospective study approved by the hospital ethics board. Patients below 18 years of age diagnosed with CDS, LDM or their mixed lesions, and subsequently underwent intervention by the Neurosurgical Service, KK Women's and Children's Hospital, are included., Results: From 2001 to 2021, 16 FNPN patients (50% males) were recruited. Eight of them had CDS (50.0%), seven had LDM (43.8%), and one patient had a mixed CDS and LDM lesion (6.2%). The average duration of follow up was 5.7 years and the mean age of surgery was 6 months old. Thirteen patients underwent prophylactic intent surgery (81.2%) and three had therapeutic intent surgery (18.8%). All patients did not have new neurological deficit or required repeat surgery for cord retethering. We observed that detethering surgery performed at or less than three months old was associated with having a wound infection ( p  = .022)., Conclusions: Our study reports that early recognition and timely intervention are mainstays of management for FNPN. We advocate a multi-disciplinary approach for good outcomes.

Objective: The role of prophylactic detethering a fibrofatty filum terminale (FFT) remains equivocal. Furthermore, long-term studies focusing on urological outcomes are sparse. The aims of this study were to present an institutional experience on the perioperative and long-term outcomes of FFT surgery and to assess for factors that contribute to postoperative clean intermittent catheterization (CIC)., Methods: This was a single-institution, retrospective study conducted over a 20-year period. Patients younger than 19 years of age who underwent surgery for FFT were included. Variables of interest included patient demographics, clinical presentation, radiological findings, postoperative complications, and long-term need for CIC. Outcomes were measured using the Necker functional score and modified Hoffer Functional Ambulation scale score at 3, 6, and 12 months postdischarge., Results: A total of 164 surgeries were performed for FFT from 2000 to 2020. The median age at surgery was 1.1 years, and the mean follow-up duration was 8.3 years. There were 115 patients (70.1%) who underwent prophylactic-intent surgery and 49 patients (29.9%) who underwent therapeutic-intent surgery. The proportion of therapeutic-intent surgeries increased significantly with age percentiles (0-20th, 21.9%; 20th-40th, 9.1%; 40th-60th, 18.2%; 60th-80th, 36.4%; and 80th-100th, 63.6% [p < 0.001]). Thirty patients (18.3%) had an associated syndrome, the most common (n = 19, 11.6%) being VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities). Forty-eight patients (29.3%) had an associated malformation (anorectal anomaly = 37, urogenital anomaly = 16, and sacral anomaly = 3). Cutaneous manifestation was the most common presentation (n = 96, 58.5%), followed by lower-limb neurological deficits (n = 21, 12.8%). A low-lying conus was present in 36.0% of patients (n = 59), and 16.5% had an associated syrinx (n = 27). There were 26 patients (18.8%) with an abnormal preoperative urodynamic study. Three patients (1.8%) had postoperative complications that required repeat surgery. There were no cases of CSF leakage. One patient (0.6%) developed retethering requiring another surgery. Postoperative CIC was required in 11 patients (6.7%). Multivariable analyses showed that an abnormal preoperative urodynamic study (adjusted OR 5.5 [95% CI 1.27-23.9], p = 0.023) and having an intraspinal syrinx (adjusted OR 5.29 [95% CI 1.06-26.4], p = 0.042) were associated with the need for CIC., Conclusions: The authors' results demonstrate that detethering surgery for FFT is a relatively safe procedure and can be performed prophylactically. Nonetheless, the risks of postoperative CIC should be emphasized during the preoperative counseling process.

Purpose: Abusive head trauma (AHT) is a major cause of morbidity and mortality in children. Studies on pediatric head injury observe that AHT patients often have a higher incidence of malignant cerebral oedema and, overall, worse prognosis. There are limited studies with a focus on the outcome of decompressive surgery in children with AHT. This is a study undertaken to review our institutional experience on the role of decompressive surgery in AHT patients and objectively assess its outcomes, in corroboration with current literature., Methods: This is an ethics-approved, retrospective study. Inclusion criteria consist of all children with a diagnosis of AHT managed by the Neurosurgical Service, KK Women's and Children's Hospital. Demographical and clinical variables are incorporated in the statistical analyses., Results: From 2011 to 2021, a total of 7 patients required decompressive surgery for AHT. Mean age of the cohort was 17.1 months (with the majority of patients being male (n = 5, 71.4%). During the follow-up period, there was 1 mortality (14.3%), 3 patients developed cerebral palsy (42.9%), and 3 patients had post-traumatic epilepsy (42.9%). With regards to functional outcome, 4 patients (57.1%) had a favorable KOSCHI score at 6 months follow-up., Conclusion: Decompressive surgery in children with AHT presents with its own unique challenges. We therein present our neurosurgical experience in decompressive surgery for this extremely vulnerable group of patients. Given the potential role of decompressive surgery in AHT, the development of an objective marker to select such patients who may benefit most from intervention should be the way forward., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Paediatric brain tumours (PBTs) are the most common solid tumours in children. Previous publications reflect variations in incidence rates and frequency of histological types in different global populations. However, there are limited studies on the epidemiology of PBTs in Singapore. This study aims to summarise the epidemiology of paediatric brain tumours managed in Singapore. This is an ethics-approved retrospective study of all patients below 19 years old diagnosed with PBTs managed by Singapore's 2 tertiary paediatric neurosurgical centres, KK Women's and Children's Hospital (KKH) and the National University Hospital (NUH) over a 15-year period from 01 January 2002 to 31 December 2017. Data collected was analysed for age, gender, tumour characteristics, presenting complaints, location, treatment modalities, 1-year and 5-year overall survival (OS). A total of 396 patients were included. The mean age of diagnosis was 7.05 years (0.25-18; ± 4.83) and male-to-female ratio was 1.41:1. Top histological groups were astrocytic (30.6%), embryonal (26.0%), germ cell (11.1%), ependymoma (30, 7.58%) and craniopharyngioma (27, 6.82%). Outcomes included recurrence rate (31.2%), 1-year OS (89.5%) and 5-year OS (72.2%). Poorer 5-year OS were noted in embryonal tumours (47.0%; p < 0.001) and ependymoma (50.0%; p = 0.0074) patients. Of note, the following cohorts also had poorer OS at 5 years: supratentorial tumours (76.2%; p = 0.0426), radiotherapy (67.4%; p = 0.0467) and surgery (74.9%, HR; p < 0.001). Overall, our data reflects patient demographics, presenting complaints, treatment modalities and survival outcomes, that are comparable to other international paediatric neurosurgical centres., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Epileptogenic triggers are multifactorial and not well understood. Here we aimed to address the hypothesis that inappropriate pro-inflammatory mechanisms contribute to the pathogenesis of refractory epilepsy (non-responsiveness to antiepileptic drugs) in human patients. We used single-cell cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to reveal the immunotranscriptome of surgically resected epileptic lesion tissues. Our approach uncovered a pro-inflammatory microenvironment, including extensive activation of microglia and infiltration of other pro-inflammatory immune cells. These findings were supported by ligand-receptor (LR) interactome analysis, which demonstrated potential mechanisms of infiltration and evidence of direct physical interactions between microglia and T cells. Together, these data provide insight into the immune microenvironment in epileptic tissue, which may aid the development of new therapeutics., (© 2022. The Author(s).)

Introduction: The treatment of pediatric optic pathway gliomas (OPG) is challenging. At present, most centers provide individualized treatment to maximize progression free survival (PFS) and minimize morbidity. We aim to report our experience in the management of pediatric OPG, and investigate factors associated with an increased duration of remission after treatment., Methods: This is a single-institution study approved by the hospital ethics board. A retrospective review of consecutive OPGs managed from 2000 to 2020 was performed. Patients were divided into those managed with monomodality treatment (MT) and those who received combined therapy (CT). MT included various forms of surgery, chemotherapy and radiotherapy given alone, while CT involves a combination of surgery and adjuvant chemotherapy and/or radiotherapy., Results: Twenty-two patients were selected for this study. They had 40 treatment cycles; and a total follow up duration of 194.8 patient-years. Most of them were male (63.6%) and presented with visual deficits (72.7%). The mean age at initial presentation was 65 months and majority (86.4%) had their tumors arising directly from the optic chiasm, with 77.3% with hypothalamic extension. One patient had Neurofibromatosis type I (4.5%). The most common histological diagnosis was pilocytic astrocytoma (90.9%), followed by pilomyxoid astrocytoma (9.1%). The 5- and 10- year PFS were 46.2% and 36.4% respectively, while the 5- and 10-year OS were both 100%. When accounting for treatment type, there were 24 treatment cycles with MT (60.0%) and 16 CT (40.0%). After adjustment, treatments with MT were shown to have a shorter mean duration of remission (MT: 45 ± 49, CT: 84 ± 79 months; p  = 0.007). Cox regression curve plotted after adjusting for patient's age at treatment demonstrated a significantly longer PFS in the CT group ( p  = 0.037)., Conclusions: Our results suggest a significant survival benefit of CT over MT for affected patients due to the prolonged the duration of disease remission, for both primary and subsequent treatments. Nonetheless, we acknowledge that our study reflects the outcomes of treatment strategies that have evolved over time. We emphasize the need for collective efforts from a dedicated multidisciplinary team and international collaborations for better disease understanding., 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 Lim, Tan, Ng, Seow, Chang, Wong, Looi, Low and Low.)

Objectives: Paediatric brain arteriovenous malformation (bAVM) is a rare and distinct clinical entity. There is a growing body of literature that support the success of multimodality approaches for this difficult condition. The authors aim to firstly, describe our institutional experience with a consecutive series of patients and next, corroborate our results with current literature., Material and Methods: This is a single institution, retrospective study conducted over a 20-year period. Patients less than 19 years old with bAVM were included. Variables of interest included patient demographics, clinical presentation, neuroimaging features, bAVM characteristics and treatment modality. Functional outcomes were measured with modified Rankin scale (mRS)., Results: There were 58 paediatric bAVMs, presenting at a mean age of 8.7 ± 4.2 years, and followed up for a mean duration of 7.7 years. Thirty-six patients (62.1%) underwent microsurgical resection, 10 patients had stereotactic radiosurgery (17.2%) and 2 patients had endovascular treatment (3.4%). 50 patients (86.2%) had a favourable outcome at 1-year follow up. Microsurgical resection and SRS had similar obliteration rates (resection 83.3%; SRS 80.0%) and recurrence (resection 10.0%; SRS 12.5%). There were 6 cases of bAVM recurrence (12.8%). This subgroup was noted to be less than 7.5 years old at presentation (OR 15.0, 95% CI 1.56 - 144), and less likely to present with bAVM rupture (OR 0.11, 95% CI 0.01 - 0.96)., Conclusion: This study describes our experience in managing paediatric bAVM, whereby monomodal therapy can still be effective. Of note, we also demonstrate the role of extended surveillance to detect recurrence., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Primary intraventricular neoplasms are rare tumors that originate from the ependymal or subependymal, septum pellucidum, choroid plexus and the supporting arachnoid tissue. Knowledge of the common locations of these tumors within the ventricular system, together with key imaging characteristics and presentation age, can significantly narrow the differential diagnosis. In 2016, the WHO reorganized the classification of several primary CNS tumors by combining histopathological and molecular data. This study highlights the imaging characteristics, histopathological and molecular data, treatment strategies and post-treatment changes of primary intraventricular tumors. Molecular-based diagnosis can not only aid in patient stratification and personalized treatment, but it can also provide prognostic and predictive value independent of WHO classification., (Copyright © 2021 Elsevier Inc. All rights reserved.)

(1) Background: pediatric hydrocephalus is a challenging condition. Programmable shunt valves (PSV) have been increasingly used. This study is undertaken to firstly, to objectively evaluate the efficacy of PSV as a treatment modality for pediatric hydrocephalus; and next, review its associated patient outcomes at our institution. Secondary objectives include the assessment of our indications for PSV, and corroboration of our results with published literature. (2) Methods: this is an ethics-approved, retrospective study. Variables of interest include age, gender, hydrocephalus etiology, shunt failure rates and incidence of adjustments made per PSV. Data including shunt failure, implant survival, and utility comparisons between PSV types are subjected to statistical analyses. (3) Results: in this case, 51 patients with PSV are identified for this study, with 32 index and 19 revision shunts. There are 3 cases of shunt failure (6%). The mean number of adjustments per PSV is 1.82 times and the mean number of adjustments made per PSV is significantly lower for MEDTRONIC™ Strata PSVs compared with others ( p = 0.031). Next, PSV patients that are adjusted more frequently include cases of shunt revisions, PSVs inserted due to CSF over-drainage and tumor-related hydrocephalus. (4) Conclusion: we describe our institutional experience of PSV use in pediatric hydrocephalus and its advantages in a subset of patients whose opening pressures are uncertain and evolving.

Arachnoid cysts (AC) are reported to have a prevalence of up to 2.6% in children. Most AC remain indolent, but others may expand or rupture to cause life-threatening symptoms of raised intracranial pressure. Currently, there are 2 controversial topics with regards to the management of ACs: the indications for surgery and the choice of surgical procedure. We therein report our institution's neurosurgical experience for symptomatic AC over a 22-year period and corroborate our results with published literature. This is a single institution, retrospective study conducted at KK Women's and Children's Hospital from 01 January 1998 to 31 December 2019. A total of 38 patients with ACs that required surgery were recruited. The 3 most common anatomical locations were in the middle cranial fossa (40.5%), posterior fossa (24.3%) and interhemispheric (13.5%). Typical clinical presentations included symptoms of raised intracranial pressure (34.2%), obstructive hydrocephalus (28.9%) and AC rupture (21.1%). Surgical approaches included 17 craniotomy-based procedures, 7 endoscopic fenestrations, 11 cystoperitoneal shunts, 2 burrhole drainage operations and 1 excision of spinal AC. Thirteen patients (34.2%) underwent either another operation due to the lack of resolution of their AC-related symptoms or secondary to complications directly related to their initial surgery. Average length of followup from time of first operation was 84.1 months. Overall, our results demonstrate similarities in epidemiology, clinical presentation and surgical experience, in comparison to larger cohort studies. We advocate collaborative efforts to better understanding of the pathophysiology of paediatric ACs, particularly for deciding between the various surgical treatment modalities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Germinomas (IG) account for up to 50% of all intracranial germ cell tumours. These tumours are reputed to be more prevalent in Oriental populations in comparison to Western cohorts. Biological characteristics of IG in other ethnic groups are unknown. Singapore is a multi-ethnic country with diverse cultures. Owing to inter-racial heterogeneity, the authors hypothesize there are molecular differences between paediatric IG patients in our local population. The aims of this study are exploratory: firstly, to identify molecular characteristics in this tumour type and circulating CSF unique to different racial cohorts; and next, to corroborate our findings with published literature., Methods: This is a single-institution, retrospective study of prospectively collected data. Inclusion criteria encompass all paediatric patients with histologically confirmed IG. Excess CSF and brain tumour tissues are collected for molecular analysis. Tumour tissues are subjected to a next generation sequencing (NGS) targeted panel for KIT and PDGRA. All CSF samples are profiled via a high-throughput miRNA multiplexed workflow. Results are then corroborated with existing literature and public databases., Results: In our cohort of 14 patients, there are KIT exon variants in the tumour tissues and CSF miRNAs corroborative with published studies. Separately, there are also KIT exon variants and miRNAs not previously highlighted in IG. A subgroup analysis demonstrates differential CSF miRNAs between Chinese and Malay IG patients., Conclusion: This is the first in-depth molecular study of a mixed ethnic population of paediatric IGs from a Southeast Asian cohort. Validation studies are required to assess the relevance of novel findings in our study.

Background: Metastatic medulloblastoma (MB) portends a poor prognosis. Amongst the 4 molecular subtypes, Group 3 and Group 4 patients have a higher incidence of metastatic disease, especially involving the neuroaxis. At present, mechanisms underlying MB metastasis remain elusive. Separately, inflammation has been implicated as a key player in tumour development and metastasis. Cytokines and their inflammation-related partners have been demonstrated to act on autocrine and, or paracrine pathways within the tumour microenvironment for various cancers. In this study, the authors explore the involvement of cerebrospinal fluid (CSF) cytokines in Group 3 and 4 MB patients with disseminated disease., Methods: This is an ethics approved, retrospective study of prospectively collected data based at a single institution. Patient clinicpathological data and corresponding bio-materials are collected after informed consent. All CSF samples are interrogated using a proteomic array. Resultant expression data of selected cytokines are correlated with each individual's clinical information. Statistical analysis is employed to determine the significance of the expression of CSF cytokines in Group 3 and 4 patients with metastatic MB versus non-metastatic MB., Results: A total of 10 patients are recruited for this study. Median age of the cohort is 6.6 years old. Based on Nanostring gene expression analysis, 5 patients have Group 3 as their molecular subtype and the remaining 5 are Group 4. There are 2 non-metastatic versus 3 metastatic patients within each molecular subtype. Proteomic CSF analysis of all patients for both subtypes show higher expression of CCL2 in the metastatic group versus the non-metastatic group. Within the Group 3 subtype, the MYC-amplified Group 3 MB patients with existing and delayed metastases express higher levels of CXCL1, IL6 and IL8 in their CSF specimens at initial presentation. Furthermore, a longitudinal study of metastatic Group 3 MB observes that selected cytokines are differentially expressed in MYC-amplified metastatic Group 3 MB, in comparison to the non-MYC amplified metastatic Group 3 MB patient., Conclusion: This study demonstrates higher expression of selected CSF cytokines, in particular CCL2, in metastatic Group 3 and 4 MB patients. Although our results are preliminary, they establish a proof-of-concept basis for continued work in a larger cohort of patients affected by this devastating disease.

Background: Intraoperative magnetic resonance imaging (iMRI) has been recognized as a useful adjunct for brain tumor surgery in pediatric patients. There is minimal data on the use of an offsite intraoperative magnetic resonance imaging operating theater (iMRI OT), whereby vehicle transfer of patients is involved. The primary aim of this study is to validate the feasibility of perioperative patient transfer to use an offsite iMRI OT for patients with pediatric brain tumor. Secondary objectives include the assessment of tumor resection efficacy and perioperative outcomes in our patient cohort., Methods: This is a retrospective, single-institution clinical study of prospectively collected data from Singapore's largest children hospital. Variables of interest include issues encountered during interhospital transfer, achievement of surgical aims, length of stay in hospital, and postoperative complications. Our findings were compared with results of related studies published in the literature., Results: From January 1, 2009 to December 31, 2018, a total of 35 pediatric operative cases were performed in our offsite iMRI OT. Within this cohort, 24 of these were brain tumor surgery cases. For all the patients in this study, use of the iMRI OT influenced intraoperative decisions. Average ambulance transport time from parent hospital to the iMRI OT was 30.5 minutes, and from iMRI OT back to the parent hospital after surgery was 27.7 minutes. The average length of hospitalization stay was 7.9 days per patient. There were no ferromagnetic accidents during perioperative iMRI scanning and no airway/hemodynamic incidents in patients encountered during interhospital transfer., Conclusions: In our local context, the use of interhospital transfers for access to iMRI OT is a safe and feasible option in ensuring good patient outcomes for a select group of patients with pediatric brain tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Paediatric meningiomas are extremely rare. These tumours constitute only 2 to 3% of all childhood brain tumours. Despite similarities in histological features between PMs and their adult counterparts, there are important distinctions between them. In this case series, the authors describe their experience in paediatric meningiomas in Singapore's 2 children's hospitals from 1998 to 2018. The primary aim of this retrospective study is to evaluate the clinical, radiological and pathological characteristics, and associated outcomes of paediatric patients diagnosed with meningioma managed in our local institutions. Following that, the study's findings are secondary aims are corroborated with published literature. A total of 10 patients (4 males and 6 females) were identified for this study within the period of 01 January 1998 to 31 December 2018. Their ages ranged from 1 year old to 18 years old (median age 10.5 years old). Two of the patients had NF1 and NF2 respectively. There were 9 intracranial and 1 intraspinal paediatric meningiomas. Seven patients achieved gross total resection and 3 patients had subtotal resection. Eight patients did not have tumour recurrence or increase in size of tumour remnant during the course of their follow-up. In congruency with the literature, up to 40% of our patients had higher grade meningiomas and 55.6% had large tumour volumes more than 30 cm 3 . Owing to the paucity of knowledge for this unusual tumour, the authors emphasize the need for closer surveillance and in-depth genomic studies to identify novel therapies for this challenging condition., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Spontaneous intracranial hypotension is uncommon. There is a lack of understanding of its exact pathophysiology along with significant variability in its clinical management., Case Description: The authors report the case of a previously well man with cervicogenic headache associated with magnetic resonance imaging features of intracranial hypotension. The salient features of this case include the details of various treatments prescribed for his condition and the therapeutic difficulties encountered., Conclusion: Owing to the infrequency of the diagnosis, the challenges of clinical management for this patient are discussed in relationship to current literature. Next, the highlights of this unusual case in an individual add to the growing body of literature reports for better understanding of this disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The natural history of Chiari I malformation (C1M) in the paediatric population is poorly understood. There are conflicting reports with regards to surgical indications, operative techniques and peri-operative prognostic indicators. In this paper, we report our institutional experience in the management of paediatric C1M., Methods: The workflow process which includes preferred imaging modalities, surgical techniques and indications for intervention is discussed. In particular, we describe one of our current projects-an in-house designed Seow Operative Score (SOS) as a feasibility scoring system for neurosurgical intervention in our local cohort of paediatric C1M patients., Results: In our series, we have 2 groups: 10 non-operated patients versus 19 operated patients. In the non-operated group, the majority of patients had a SOS of 0 to 1. One patient had a score of 2.5 and was kept under close surveillance. Follow-up imaging demonstrated resolution of the cerebellar herniation and intraspinal syrinx. In the operated group, 17 patients had a SOS of 3 or more. Two patients had a SOS of 2. For these 2, 1 developed progressive symptoms, and the other had an extensive cervico-thoracic syrinx. Decision was made for surgery after a period of surveillance., Conclusions: In this paper, we report our institutional experience in managing paediatric C1M and, at the same time, highlight salient points of our practices. Meanwhile, we advocate collective global efforts and in-depth research for better disease understanding of this challenging condition.

Background: Pediatric intracranial aneurysms are extremely rare. In this age group, cerebral vascular anomalies have been associated with the development of intracranial aneurysms., Case Description: We present a case of a previously well 11-year-old boy who presented with seizures secondary to a giant, unruptured, and partially thrombosed right middle cerebral artery (MCA) aneurysm. Extensive workup for underlying infective and autoimmune etiology was negative. Of interest, this vascular lesion was found to originate from an anomalous M2 branch, which ran an aberrant parallel course within the Sylvian fissure to the main and distally bifurcating MCA. The patient underwent successful surgical clipping and excision of the giant aneurysm., Conclusions: Because of the infrequency of the diagnosis, clinical presentation, and its unique neurovascular anatomy, the management of this case is discussed in corroboration with current literature. In addition, highlighting this unusual case in an individual adds to the growing body of literature for better disease understanding, especially in the pediatric population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Purpose: Diffuse leptomeningeal glioneuronal tumour (DLGNT) is an extremely rare tumour involving the neuroaxis. At present, its exact pathogenesis and associated factors remain incompletely characterised. Recent molecular investigations in a small cohort have offered some insights into this disease. However, the role of germline findings has not yet been fully explored in affected patients. The authors present a case of DLGNT, focusing on the clinical and molecular features with reference to current disease knowledge., Methods: A 4-year-old male presented with raised intracranial pressure symptoms secondary to extensive leptomeningeal disease of the brain and spine. Preliminary impression was that of an inflammatory lesion., Results: A lumbar biopsy of the lesion confirmed DLGNT on routine diagnostic examination. Further molecular analysis of his tumour and blood demonstrated a previously unreported TP53 exon 5 (c.147V > I) germline variant. Based on the latest DLGNT molecular subtyping classification, his tumour falls into the group with better clinical outcome. However, his germline findings may add an extra layer of uncertainty to his overall prognosis., Conclusion: Given that much remains unknown in many rare paediatric tumours at this stage, isolated findings found in an individual may be of significance. Supplementary genetic information, together with tumour molecular analysis, add to our current understanding of this uncommon disease. This case highlights the benefit of combined clinical and molecular efforts, including germline testing, especially for children affected by such challenging neoplasms.

Background: Primary paediatric epidural sarcomas are extremely rare. Overall, there remains a paucity of knowledge in paediatric epidural sarcomas owing to the infrequent number of cases. The Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) is a next-generation sequencing assay that has been reported to be a useful technique to detect recurrent fusion in sarcomas. We report the molecular exploration of 3 primary paediatric epidural sarcomas-one in the cranium (mesenchymal chondrosarcoma) and 2 in the spine (mesenchymal chondrosarcoma and Ewing sarcoma respectively)., Case Presentation: This is a study approved by the hospital ethics board. Clinico-pathological information from 3 consenting patients with primary epidural sarcomas was collected. These selected tumours are interrogated via Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) for genomic aberrations. Results were validated with RT-PCR and Sanger sequencing. All findings are corroborated and discussed in concordance with current literature. Our findings show 2 variants of the HEY1-NCOA2 gene fusion: HEY1 (exon 4)-NCOA2 (exon 13) and HEY1 (exon 4)-NCOA2 (exon 14), in both mesenchymal chondrosarcoma patients. Next, the Ewing sarcoma tumour is found to have EWSR1 (exon 10)-FLI1 (exon 8) translocation based on NGS. This result is not detected via conventional fluorescence in situ testing., Conclusions: This is a molecularly-centered study based on 3 unique primary paediatric epidural sarcomas. Our findings to add to the growing body of literature for these exceptionally rare and malignant neoplasms. The authors advocate global collaborative efforts and in-depth studies for targeted therapy to benefit affected children.

Introduction: Brain abscesses affect all age groups and are not peculiar to a particular country, race, or geographical location. It is a disease that, in the past, carried a high morbidity and mortality. With improvements in medical technology and expertise, outcomes have improved tremendously. The causative organisms vary vastly and have evolved with time. Treatment of brain abscesses is primarily with antimicrobial therapy but surgery plays a vital role in achieving better outcomes., Content: In this article, we review the literature to find out how the epidemiology of this disease has changed through the years and re-visit the basic pathological process of abscess evolution and highlight the new research in the biochemical pathways that initiate and regulate this process. We also highlight how magnetic resonance imaging and its various modalities have improved diagnostic accuracy. Finally, we discuss the pros and cons of traditional open surgery versus newer minimally invasive methods.

Introduction: Leptomeningeal disease is a feared sequelae of malignant paediatric brain tumours. Current methods for its detection is the combined use of cranio-spinal MRI, and CSF cytology from a post-operative lumbar puncture. In this study, the authors hypothesize that CSF taken at the start of surgery, either from an external ventricular drain or neuroendoscope will have equal sensitivity for positive tumour cells, in comparison to lumbar puncture. Secondary hypotheses include positive correlation between CSF cytology and MRI findings of LMD. From a clinical perspective, the key aim of the study was for affected paediatric patients to avoid an additional procedure of a lumbar puncture, often performed under anaesthesia after neurosurgical intervention., Methods: This is single-institution, retrospective study of paediatric patients diagnosed with malignant brain tumours. Its main aim was to compare cytological data from CSF collected at the time of surgery versus data from an interval lumbar puncture. In addition, MRI imaging of the same cohort of patients was examined for leptomeningeal disease and corroborated against CSF tumour cytology findings., Results: Thirty patients are recruited for this study. Data analysis demonstrates a statistically significant association between our intra-operative CSF and LP sampling. Furthermore, our results also show for significant correlation between evidence of leptomeningeal disease on MRI findings versus intra-operative CSF positivity for tumour cells., Conclusion: Although this is a retrospective study with a limited population, our data concurs with potential to avoid an additional procedure for the paediatric patient diagnosed with a malignant brain tumour.

Background: Cystic cerebral cavernomas belong to a rare subset of cavernous malformations in the brain. At present, there is limited information with regard to the demographics and etiology of this condition., Case Description: The authors present a case of a previously well 13-year-old male who presented with symptoms secondary to a cystic lesion of the fourth ventricle compressing on his brainstem. He underwent stereotactic aspiration of the cystic lesion and insertion of an Ommaya reservoir in the same setting. Postoperatively, his symptoms improved. The cyst fluid did not yield any positive cytology or culture results. A repeat MRI brain did not demonstrate evidence of any underlying lesion. However, the patient was readmitted for hemorrhage into the region of his previous fourth ventricular lesion. Surgical evacuation of the haematoma was performed and intraoperative tissue was sent for pathological interrogation. The final histology reported a cavernoma., Conclusions: This is an unusual presentation of an intracranial vascular anomaly in a pediatric patient. Key features of the case include the diagnostic dilemma and management challenges faced from a neurosurgical perspective., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Posterior fossa syndrome (PFS) is a serious complication faced by neurosurgeons and their patients, especially in paediatric medulloblastoma patients. The uncertain aetiology of PFS, myriad of cited risk factors and therapeutic challenges make this phenomenon an elusive entity. The primary objective of this study was to identify associative factors related to the development of PFS in medulloblastoma patient post-tumour resection., Methods: This is a retrospective study based at a single institution. Patient data and all related information were collected from the hospital records, in accordance to a list of possible risk factors associated with PFS. These included pre-operative tumour volume, hydrocephalus, age, gender, extent of resection, metastasis, ventriculoperitoneal shunt insertion, post-operative meningitis and radiological changes in MRI. Additional variables included molecular and histological subtypes of each patient's medulloblastoma tumour. Statistical analysis was employed to determine evidence of each variable's significance in PFS permanence., Results: A total of 19 patients with appropriately complete data was identified. Initial univariate analysis did not show any statistical significance. However, multivariate analysis for MRI-specific changes reported bilateral DWI restricted diffusion changes involving both right and left sides of the surgical cavity was of statistical significance for PFS permanence., Conclusion: The authors performed a clinical study that evaluated possible risk factors for permanent PFS in paediatric medulloblastoma patients. Analysis of collated results found that post-operative DWI restriction in bilateral regions within the surgical cavity demonstrated statistical significance as a predictor of PFS permanence-a novel finding in the current literature.

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner., Methods: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival., Findings: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084)., Interpretation: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection., Funding: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Medulloblastomas are the most common pediatric malignant primary brain tumor. To our knowledge, there are no known critical and druggable tyrosine kinases in medulloblastomas, precluding the use of established tyrosine kinase inhibitors that have shown efficacy in other tumor types. We studied the expression of anaplastic lymphoma kinase (ALK), a well-characterized tyrosine kinase and drug target, in a cohort of medulloblastomas by immunohistochemistry, and identified three ALK-positive cases. Mutational analyses did not reveal a definite underlying genetic mechanism for the ALK expression, although one of the cases showed increased ALK copy number. Our findings have clinical implications and warrant further pharmacological and functional studies, as well as evaluation in larger patient cohorts, to fully characterize the value of ALK as a prognostic and predictive therapeutic marker in medulloblastomas., (Copyright © 2015 Elsevier Ltd. All rights reserved.)