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Supplementary Data from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.Significance:We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic.This article is highlighted in the In This Issue feature, p. 587

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Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence–based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood–brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies.Significance:Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275

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© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Traumatic brain injury (TBI) is increasingly recognised as being responsible for a substantial proportion of the global burden of disease. Neurosurgical interventions are an important aspect of care for patients with TBI, but there is little epidemiological data available on this patient population. We aimed to characterise differences in casemix, management, and mortality of patients receiving emergency neurosurgery for TBI across different levels of human development. Methods: We did a prospective observational cohort study of consecutive patients with TBI undergoing emergency neurosurgery, in a convenience sample of hospitals identified by open invitation, through international and regional scientific societies and meetings, individual contacts, and social media. Patients receiving emergency neurosurgery for TBI in each hospital's 30-day study period were all eligible for inclusion, with the exception of patients undergoing insertion of an intracranial pressure monitor only, ventriculostomy placement only, or a procedure for drainage of a chronic subdural haematoma. The primary outcome was mortality at 14 days postoperatively (or last point of observation if the patient was discharged before this time point). Countries were stratified according to their Human Development Index (HDI)—a composite of life expectancy, education, and income measures—into very high HDI, high HDI, medium HDI, and low HDI tiers. Mixed effects logistic regression was used to examine the effect of HDI on mortality while accounting for and quantifying between-hospital and between-country variation. Findings: Our study included 1635 records from 159 hospitals in 57 countries, collected between Nov 1, 2018, and Jan 31, 2020. 328 (20%) records were from countries in the very high HDI tier, 539 (33%) from countries in the high HDI tier, 614 (38%) from countries in the medium HDI tier, and 154 (9%) from countries in the low HDI tier. The median age was 35 years (IQR 24–51), with the oldest patients in the very high HDI tier (median 54 years, IQR 34–69) and the youngest in the low HDI tier (median 28 years, IQR 20–38). The most common procedures were elevation of a depressed skull fracture in the low HDI tier (69 [45%]), evacuation of a supratentorial extradural haematoma in the medium HDI tier (189 [31%]) and high HDI tier (173 [32%]), and evacuation of a supratentorial acute subdural haematoma in the very high HDI tier (155 [47%]). Median time from injury to surgery was 13 h (IQR 6–32). Overall mortality was 18% (299 of 1635). After adjustment for casemix, the odds of mortality were greater in the medium HDI tier (odds ratio [OR] 2·84, 95% CI 1·55–5·2) and high HDI tier (2·26, 1·23–4·15), but not the low HDI tier (1·66, 0·61–4·46), relative to the very high HDI tier. There was significant between-hospital variation in mortality (median OR 2·04, 95% CI 1·17–2·49). Interpretation: Patients receiving emergency neurosurgery for TBI differed considerably in their admission characteristics and management across human development settings. Level of human development was associated with mortality. Substantial opportunities to improve care globally were identified, including reducing delays to surgery. Between-hospital variation in mortality suggests changes at an institutional level could influence outcome and comparative effectiveness research could identify best practices. Funding: National Institute for Health Research Global Health Research Group.

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence–based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood–brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. Significance: Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies. This article is highlighted in the In This Issue feature, p. 275

Objectives IgG4-related hypophysitis is a novel clinical disease entity, which is typically seen in the sixth decade of life and is typically complicated by hypopituitarism. We describe an adolescent female with IgG4-related hypophysitis with normal pituitary function and summarize the relevant literature. Case presentation A 11.8-year-old girl presented with headache and left VI cranial nerve palsy. MRI brain identified an enlarged pituitary gland. Endocrine investigations revealed normal pituitary function. She underwent a transsphenoidal biopsy of the pituitary gland, and histological examination confirmed the diagnosis of IgG4-related hypophysitis. Serum IgG4 concentrations were normal and no evidence of other organ involvement was found. Although the patient tested strongly positive for TB on an interferon gamma release assay, pituitary biopsy was negative for granuloma formation and acid-fast bacilli (Ziehl-Neelson staining). IgG4-related hypophysitis was treated with oral prednisolone and mycophenolate-mofetil with a good response. Conclusions We describe to the best of our knowledge, the youngest patient in the published literature with IgG4-related hypophysitis presenting without pituitary insufficiency. A literature review identified only five cases of IgG4-related hypophysitis in adolescence. Serum IgG4 concentrations were normal in all, except one of the adolescent patients reported so far, and appear unhelpful in diagnosis in this age group.

Infected cephalhaematomas are rare and can lead to complications such as sepsis, meningitis and osteomyelitis. We present an infected cephalhaematoma in a neonate with resultant underlying osteomyelitis and a review of the literature. Our patient presented 6 days following birth with a fever and a swelling consistent with cephalhaematoma. He was managed with intravenous antibiotics and early surgical intervention. Imaging demonstrated underlying osteomyelitis. The patient made a full recovery and was discharged home on completing his antibiotic course. On reviewing the literature, it is clear that early diagnosis and treatment with surgical intervention and antibiotic therapy are associated with improved outcome and can reduce the possibility of osteomyelitis developing.

Introduction and objectivesThe novel severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic has had drastic effects on global healthcare with the UK amongst the countries most severely impacted. The aim of this study was to examine how COVID-19 challenged the neurosurgical delivery of care in a busy tertiary unit serving a socio-economically diverse population.MethodsA prospective single-centre cohort study including all patients referred to the acute neurosurgical service or the subspecialty multidisciplinary teams (MDT) as well as all emergency and elective admissions during COVID-19 (18th March 2020–15th May 2020) compared to pre-COVID-19 (18th of January 2020–17th March 2020). Data on demographics, diagnosis, operation, and treatment recommendation/outcome were collected and analysed.ResultsOverall, there was a reduction in neurosurgical emergency referrals by 33.6% and operations by 55.6% during the course of COVID-19. There was a significant increase in the proportion of emergency operations performed during COVID-19 (75.2% of total,n=155) when compared to pre-COVID-19 (n= 198, 43.7% of total,p< 0.00001). In contrast to other published series, the 30-day perioperative mortality remained low (2.0%) with the majority of post-operative COVID-19-infected patients (n= 13) having underlying medical co-morbidities and/or suffering from post-operative complications.ConclusionThe capacity to safely treat patients requiring urgent or emergency neurosurgical care was maintained at all times. Strategies adopted to enable this included proactively approaching the referrers to maintain lines of communications, incorporating modern technology to run clinics and MDTs, restructuring patient pathways/facilities, and initiating the delivery of NHS care within private sector hospitals. Through this multi-modal approach we were able to minimize service disruptions, the complications, and mortality.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. Significance: We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587

High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derivedin vitroprimary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These includedMYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs withPPM1Dactivating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations inPDGFRAwere found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.

Background Neurocysticercosis is a helminthic infestation of the brain by the encysted larval form of the human tape worm Taenia Solium. It is a common cause of focal epilepsy in countries with inadequate sanitation following oro-faecal transmission and ingestion of food contaminated with TaeniaSolium eggs. The larvae can lodge in different parts of the human body including the brain parenchyma resulting invariable neurological clinical manifestations depending on the affected site. Onset of symptoms depends on the host immune response and on parasite defence mechanism. Over 90% patients present with focal seizures. Localised oedema surrounding the lesion can result in headaches from raised intracranial pressure, obstructive hydrocephalus. Other forms include spinal cysticercosis and ophthalmic cysticercosis. The diagnosis is usually made on clinical grounds, confirmed by imaging and immunodiagnostic tests. Case Report We report a previously well 13 year old girl who presented with a single episode of generalised tonic clonic seizure. She gave a 4 month history of altered sensation in her right upper limb and 1 month history of focal sensorimotor seizures. Examination showed subtle weakness of the right side of her face and upper arm. MRI brain scan showed a well defined left parietal lesion in the grey white matter junction with surrounding oedema and was referred to neurosurgery with suspicion of tumour. On review the images were suggestive of atypical infection - Cysticercosis or Tuberculoma. She was given Dexamethasone and Levetiracetam with good effect. At surgery she had a well encapsulated cystic lesion that was excised. Histopathology showed chronic cerebral lesion with parasitic cyst. Microscopy confirmed presence of a tapeworm larva. Following surgery she was started on Albendazole. Further history revealed regular camping trips at farms and woodland areas. She also swam in ponds and rivers. She did not report tic bites. Her diet included pork. She had been abroad. Conclusions Unifocal Neurocysticercosis in non-endemic countries is in the list space occupying lesions mistaken for a brain tumour. It presents with focal epilepsy and its diagnosis can be challenging.

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), however there are no ACVR1 inhibitors licensed for the disease. Using an Artificial Intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has limited ability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits ABCG2 (BCRP) and ABCB1 (P-gp) transporters, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies.

Little is known about pseudoprogression in brain tumours other than gliomas. A 9-year-old male child with a pineal teratoma/germinoma underwent surgical resection followed by adjuvant chemo-radiotherapy. The magnetic resonance imaging scan 4 months post-radiotherapy showed a contrast-enhancing lesion within the surgical cavity suspicious of recurrence. These radiological findings subsequently resolved without any specific intervention. The child continues in remission 2 years post-treatment. This case illustrates the occurrence of pseudoprogression post-radiotherapy in intracranial GCT and highlights an unmet need for greater implementation of functional imaging techniques in paediatric neuro-oncology to avoid undue discontinuation of effective treatments or inappropriate enrolment in clinical trials.

Background: The novel severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic has had a drastic effect on global healthcare with the UK amongst the countries most severely impacted. The aim of this study was to examine how COVID-19 challenged the neurosurgical delivery of care in a busy tertiary unit serving a socio-economically diverse population. We also describe the strategies we adopted to meet these challenges. Methods: A prospective single centre cohort study including all patients referred to the acute neurosurgical service or the subspecialty multi-disciplinary teams (MDT) as well as all emergency and elective admissions during COVID-19 (18th March 2020-15th May 2020) compared to pre-COVID-19 (18th of January 2020-17th March 2020). Data on demographics, diagnosis, operation, and treatment recommendation/outcome were collected and analysed. Findings: Overall, there was a reduction in neurosurgical emergency referrals by 33·6% and operations by 55·6% during the course of COVID-19. There was a significant increase in the proportion of emergency operations performed during COVID-19 (75·2% of total, n=155) when compared to pre-COVID-19 (n=198, 43·7% of total, p

Introduction Arachnoid cysts (ACs) account for a small proportion of all intracranial lesions. They are often incidental but can become symptomatic and even cause a threat to life. Symptoms are usually due to direct compression of neural elements and/or raised intracranial pressure. Case report We report the case of an infant with an enlarging posterior fossa arachnoid cyst (PFAC) causing torticollis and gastro-oesophageal reflux (GOR), the combination of which had been previously unreported in this context. Endoscopic fenestration and cyst decompression were followed by complete resolution of the symptoms. We discuss the possible mechanisms of torticollis and GOR in this context.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterised by premature ageing. We report a case of a 13-year-old girl with HGPS who presented with an extradural haematoma following head injury. A conservative approach was successfully employed in this case, avoiding the risks of general anaesthesia and surgery. Keywords: Hutchinson-Gilford progeria syndrome, Head injury, Extradural haematoma

BACKGROUND Invading glioma cells affect the physiological function of the peritumoural cortex. This may manifest clinically as seizures. Here, we investigate the effect the invading glioma cells on the electrophysiological signalling of the peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). MATERIAL AND METHODS The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. We observed 5-ALA induced fluorescence in both low-grade and high-grade gliomas. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. RESULTS We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II - III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the electrical discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. CONCLUSION We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. This electrophysiological signature will be compared to infiltration and grade of the glioma cells in the donated sample. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.

Undergraduate student conferences provide networking opportunities for students interested in exploring a speciality. The ability to meet with like-minded students, engage with senior clinicians and experience the practical side of a speciality are valuable in shaping the career trajectory of undergraduates. We report our experience of developing a national undergraduate neurosurgery conference - a combined project between the medical students of King's College London School of Medicine and the neurosurgery department at King's College Hospital NHS Foundation Trust.Evaluation of conference design and student feedback.The conference was organised by medical students with support from a neurosurgical unit. Senior clinicians and trainees helped design practical workshops and a focused programme. Questionnaires were distributed before and after the conference to assess the quality of content and impact of the conference on students.Prior to the conference, 80.7% of respondents stated they were interested in a career in neurosurgery. After the conference the figure rose to 88.9%. The percentage of students who felt they understood what a career in neurosurgery involves increased from 38.6% to 92.1% of respondents. 39.0% of participants had no neurosurgery exposure prior to the conference. 91.9% of participants agreed or strongly agreed they would be more confident engaging with a neurosurgical department following the conference. All participants agreed (29.0%) or strongly agreed (71.0%) that they would recommend this conference to a colleague.Student conferences are a valuable method of increasing exposure to a career in neurosurgery. They serve a great purpose in demystifying the specialty and guiding those with an interest through the steps required to enter and progress.

Background Exposure to neurosurgery at the undergraduate level is an important factor in determining future interest in and applications to the specialty. Given the high competition for training posts, this exposure is also becoming an almost essential addition to an applicant’s portfolio. We organized a neurosurgical conference aimed at undergraduate medical students. The aim of this study was to determine factors attracting and deterring students from the specialty before and after the conference. Methods Responses were collected prospectively from students attending a national neurosurgical conference organized by medical students with support from the local neurosurgical unit. Questionnaires were distributed before and after the conference examining students’ perceptions of a career in neurosurgery using free-text responses. Results Poor lifestyle or work-life balance was the most important factor deterring students from a career in the specialty both before (29.7%) and after (60%) the conference. The most important factor attracting students to the specialty before the conference was the practical (surgical approaches and techniques) aspect (21.9%). After the conference, the most important attracting factor was the rewarding nature of the specialty (18.9%). Conclusions The most notable factor deterring students from a career in neurosurgery was work-life balance. Other deterring factors were much less prevalent following the conference. Understanding how exposure to neurosurgery influences students’ perceptions is important for developing future initiatives to prevent misconceptions and allow students to make informed choices as well as encourage the right candidates to apply.

INTRODUCTION: In patients presenting with obstructive hydrocephalus secondary to pineal region lesions, a combined endoscopic third ventriculostomy (ETV) and tumour biopsy is an increasingly common procedure. Performing it through a monoportal approach with a rigid scope is especially challenging given the anatomy of the third ventricle. Here we report our experience of the monoportal endoscopic combined approach made possible by splitting the choroid fissure (CF) and massa intermedia (MI). METHODS: A 13-year-old male was referred to our unit having presented with a 2-day history of headache, blurred vision, diplopia and vomiting. An MRI revealed a pineal region lesion causing obstructive hydrocephalus. RESULTS: An ETV was performed. Access to the pineal region was then gained by splitting of the CF and subsequent division of a small MI. A biopsy was taken and limited debulking performed (tumour was large and hard making complete resection difficult). Histopathology confirmed an immature teratoma. Post-operatively the patient made an excellent recovery. CONCLUSION: The endoscopic transchoroidal approach with splitting of the MI allows management of hydrocephalus and access to pineal tumours for biopsy/debulking via a single burr hole and using a solid scope. In the future complete resection of pineal lesions via this approach may become commonplace with improved instrumentation and equipment.

BACKGROUND. Molecular alterations: point mutations, amplifications and deletions give cells the ability to bypass therapeutic approaches. Molecular profiling facilitates access to personalised strategies to treat patients harbouring such alterations. METHODS. A Next Generation Sequencing (NGS) panel comprising 78 genes (version1) or 92 genes (version2) has been piloted in the UK since March 2016, using formalin-fixed paraffin embedded tissue of children and young adults with solid tumours, including central nervous system (CNS) tumours. RESULTS. Of 156 cases profiled, patients with primary CNS tumours constituted the largest subset (59 patients; 38%). Main diagnoses included high grade astrocytoma (22 patients; 37%), ependymoma (8 patients; 14%) and medulloblastoma (8 patients 14%). In 66% of sequenced samples the panel detected at least one genetic alteration and a total of 54 distinct genetic alterations were uncovered; most frequently in TP53 (16; 14%), H3F3A (8; 7%) and ATRX (7; 6%). In 2 cases (3%), identification of therapeutic targets (BRAF mutations) led to treatment with a combination of BRAF and MEK inhibitors via compassionate access programmes in young adults who had exhausted standard treatment options and were beyond the age eligibility cut-off for enrolment in the ongoing paediatric BRAF/MEK inhibitor studies. CONCLUSIONS. Molecular profiling is increasingly being integrated into standard of care for patients with CNS tumours. However, the finding of truly actionable mutations with available targeted therapies remains limited in clinical practice. More efficient approaches to implement personalised medicine strategies for CNS tumour patients are still needed as is currently illustrated by initiatives such as ESMART (NCT02813135).

INTRODUCTION: The use of the endoscopic ultrasonic aspirator for the management of intraventricular tumours is still in its infancy. We share our early experience using the aspirator in the management of intraventricular, paraventricular and suprasellar tumours. SUBJECTS: 19 patients (10 males, 9 females) underwent 22 operations with the endoscopic ultrasonic aspirator. Ages ranged from 6 months to 86 years. Tumour types included: a choroid plexus papilloma (grade II), an infiltrative glioma (grade II), an intraventricular meningioma (grade I-II), a diffuse glioma (grade II-III), three craniopharyngiomas, an anaplastic ependymoma (grade III), two glioblastomas (grade IV), an immature teratoma, 2 gangliogliomas (grade I), a choroid plexus cyst, a central neurocytoma (grade II), a pineocytoma (grade I), a metastasis (lung primary), a subependymoma (grade I) and a pilocytic astrocytoma with pilomyxoid features (grade I). RESULTS: A monoportal approach guided by neuronavigation was used in all patients. Of the 22 procedures, 18 were carried out in patients with hydrocephalus. In 6 procedures a total or near-total resection was achieved. Tumour resection was limited by tumour location, size and consistency as well as instrumentation. CONCLUSION: The endoscopic ultrasonic aspirator is a powerful addition to our neuro-endoscopic armamentarium and with further development, endoscopic total resections may become more commonplace.

Infant gliomas have been considered as early-onset examples of tumour types found throughout paediatric populations. Interestingly, infant high-grade gliomas (HGG) have a better overall survival compared to older children, indicating that grading may not accurately reflect the biology of these tumours. We have to-date collected 181 cases of diffuse glioma (WHO II-IV) occurring in children aged

INTRODUCTION: Citation number can be considered a measure of a publication’s academic influence. Previous studies have suggested a citation number greater than 50 and a citation rate higher than 5 per year constitute a high impact in neurosurgery. We set out to determine and categorise the most highly influential papers related to the neurosurgical management of paediatric central nervous system (CNS) tumours between 2005-2010. METHODS: Child’s Nervous System, Journal of Neurosurgery: Pediatrics and Pediatric Neurosurgery were previously identified as publishing the most influential papers in paediatric neurosurgery. All papers published by these journals between 2005-2010 were collected from Web of Science. Papers describing surgical management of paediatric CNS neoplasms were identified and the 50 most cited were determined. RESULTS: Of the most highly cited papers, 54% were published in Child’s Nervous System, 26% in Journal of Neurosurgery: Pediatrics and 20% in Pediatric Neurosurgery. The citation number ranged from 27-93 (mean = 43) and citations rate (per year) ranged from 2.31-8.25. Of the top 50 papers, 24% had more than 50 citations and 8 of these had a citation rate greater than 5 per year. 72% of papers were experiential studies and 24% were review articles. 42% described surgical management of craniopharyngiomas and 10% related to management of posterior fossa tumours. There were no randomised controlled trials. CONCLUSION: Between 2005-2010, 8 papers related to surgical management of paediatric CNS tumours can be considered as having high impact in the literature. The majority of papers focused on surgical management of craniopharyngiomas.

Spontaneous intracranial haemorrhage may present as a surgical emergency requiring rapid assessment of the patient and rapid access to diagnostic imaging. The site of the haemorrhage will determine whether there is global cerebral dysfunction or the development of a focal deficit. Hydrocephalus may complicate intracranial haemorrhage. Immediate decision making as to the timing and means of treatment of the patient and the appropriateness of any intervention may be necessary. In this chapter we discuss the common types of intracranial haemorrhage, the significant features of the assessment and how these are used to guide treatment. Recent multicentre clinical studies have influenced decision making for this group of patients.

Intracranial germinomas are rare primary central nervous system tumours that are highly sensitive to radiotherapy and chemotherapy. Recurrences are infrequent, with the majority occurring within 5 years. Although multidisciplinary treatments have resulted in good event-free survival, long-term outcomes, over decades, are relatively poorly reported. We present a rare case of a recurrence in the conus medullaris 12 years after complete remission of the primary pituitary germinoma. To the best of our knowledge, this represents the first case of a significantly delayed spinal recurrence, occurring at a very distant and uncommon site, from the primary tumour. This case highlights the importance of long-term follow-up, even after complete remission, in order to identify and limit disability from late spinal recurrences in a relatively young patient population. We consider the literature regarding identifying high risk patients, and the role of craniospinal irradiation in limiting late spinal recurrences.