Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC.

BACKGROUND: Mucopolysaccharidosis IIIC (MPSIIIC) is one of four Sanfilippo diseases sharing clinical symptoms of severe cognitive decline and shortened lifespan. The missing enzyme, heparan sulfate acetyl-CoA: α-glucosaminide-N-acetyltransferase (HGSNAT), is bound to the lysosomal membrane, therefore cannot cross the blood-brain barrier or diffuse between cells. We previously demonstrated disease correction in MPSIIIC mice using an Adeno-Associated Vector (AAV) delivering HGSNAT via intraparenchymal brain injections using an AAV2 derived AAV-truetype (AAV-TT) serotype with improved distribution over AAV9. METHODS: Here, intraparenchymal AAV was delivered in sheep using catheters or Hamilton syringes, placed using Brainlab cranial navigation for convection enhanced delivery, to reduce proximal vector expression and improve spread. RESULTS: Hamilton syringes gave improved AAV-GFP distribution, despite lower vector doses and titres. AAV-TT-GFP displayed moderately better transduction compared to AAV9-GFP but both serotypes almost exclusively transduced neurons. Functional HGSNAT enzyme was detected in 24-37% of a 140g gyrencephalic sheep brain using AAV9-HGSNAT with three injections in one hemisphere. CONCLUSIONS: Despite variabilities in volume and titre, catheter design may be critical for efficient brain delivery. These data help inform a clinical trial for MPSIIIC.

The role of artificial intelligence in paediatric neuroradiology.

Imaging plays a fundamental role in the managing childhood neurologic, neurosurgical and neuro-oncological disease. Employing multi-parametric MRI techniques, such as spectroscopy and diffusion- and perfusion-weighted imaging, to the radiophenotyping of neuroradiologic conditions is becoming increasingly prevalent, particularly with radiogenomic analyses correlating imaging characteristics with molecular biomarkers of disease. However, integration into routine clinical practice remains elusive. With modern multi-parametric MRI now providing additional data beyond anatomy, informing on histology, biology and physiology, such metric-rich information can present as information overload to the treating radiologist and, as such, information relevant to an individual case can become lost. Artificial intelligence techniques are capable of modelling the vast radiologic, biological and clinical datasets that accompany childhood neurologic disease, such that this information can become incorporated in upfront prognostic modelling systems, with artificial intelligence techniques providing a plausible approach to this solution. This review examines machine learning approaches than can be used to underpin such artificial intelligence applications, with exemplars for each machine learning approach from the world literature. Then, within the specific use case of paediatric neuro-oncology, we examine the potential future contribution for such artificial intelligence machine learning techniques to offer solutions for patient care in the form of decision support systems, potentially enabling personalised medicine within this domain of paediatric radiologic practice.

Manchester Arena Attack: management of paediatric penetrating brain injuries.

PURPOSE: The Manchester Arena bombing on 22 May 2017 resulted in 22 deaths and over 160 casualties requiring medical attention. Given the threat of modern- era terrorist attacks in civilian environments, it is important that we are able to anticipate and appropriately manage neurological injuries associated with these events. This article describes our experience of managing paediatric neurosurgical blast injuries, from initial triage and operative management to longer-term considerations. MATERIALS AND METHODS: Case study and literature review. RESULTS: Paediatric traumatic and penetrating brain injury patients often make a good neurological recovery despite low GCS at time of injury; this should be accounted for during triage and operative decision making in major trauma, mass casualty events. Conservative management of retained shrapnel is advocated in view of low long-term infection rates with retained shrapnel and worsened neurological outcome with shrapnel retrieval. All penetrating brain injuries should receive a prolonged course of broad-spectrum antibiotics and undergo long term follow-up imaging to monitor for the development of cerebral abscesses. MRI should never be utilised in penetrating brain injury cases, even in the absence of macroscopically visible fragments, due to the effect of MRI ferromagnetic field torque on shrapnel fragments. Anti-epileptic drugs should only be prescribed for the initial seven days after injury, as continuing beyond this does not incur any benefit in the reduction of long term post-traumatic epilepsy. CONCLUSION: All receiving neurosurgical units should become familiar with optimum management of these thankfully rare, but complex injuries from their initial presentation to long term follow up considerations. All neurosurgical units should have well-rehearsed local plans to follow in the event of such incidents, ensuring timely deliverance of appropriate neurosurgical care in such extreme settings.

Outcomes with respect to extent of surgical resection for pediatric atypical teratoid rhabdoid tumors.

PURPOSE: To evaluate overall survival for atypical teratoid rhabdoid tumors (ATRTs) in relation to extent of surgical resection. METHODS: The neurosurgical tumor databases from three UK Pediatric centers (University Hospital of Wales, Alder Hey and Royal Manchester Children's Hospital) were analyzed. Patients with a diagnosis of ATRT were identified between 2000 and 2018. Data was collected regarding demographics, extent of resection, complications, and overall survival. RESULTS: Twenty-four patients diagnosed with ATRT underwent thirty-eight operations. The age range was 20 days to 147 months (median 17.5 months). The most common location for the tumor was the posterior fossa (nine patients; 38%). Six patients (25%) underwent a complete total resection (CTR), seven (29%) underwent a near total resection (NTR), eight (33.3%) underwent a subtotal resection (STR), and three patients (12.5%) had biopsy only. Two-thirds of patients who underwent a CTR are still alive, as of March 2019, compared to 29% in the NTR and 12.5% in the STR groups. Out of the thirty-eight operations, there were a total of twenty-two complications, of which the most common was pseudomeningocele (27%). The extent of surgical resection (p = 0.021), age at surgery (p = 0.00015), and the presence of metastases at diagnosis (0.015) significantly affected overall survival. CONCLUSIONS: Although these patients are a highly vulnerable group, maximal resection is recommended where possible, for the best chance of long-term survival. However, near total resections are likely beneficial when compared with subtotal resections and biopsy alone. Maximal surgical resection should be combined with adjuvant therapies for the best long-term outcomes.

Non-myeloablative busulfan chimeric mouse models are less pro-inflammatory than head-shielded irradiation for studying immune cell interactions in brain tumours.

BACKGROUND: Chimeric mouse models generated via adoptive bone marrow transfer are the foundation for immune cell tracking in neuroinflammation. Chimeras that exhibit low chimerism levels, blood-brain barrier disruption and pro-inflammatory effects prior to the progression of the pathological phenotype, make it difficult to distinguish the role of immune cells in neuroinflammatory conditions. Head-shielded irradiation overcomes many of the issues described and replaces the recipient bone marrow system with donor haematopoietic cells expressing a reporter gene or different pan-leukocyte antigen, whilst leaving the blood-brain barrier intact. However, our previous work with full body irradiation suggests that this may generate a pro-inflammatory peripheral environment which could impact on the brain's immune microenvironment. Our aim was to compare non-myeloablative busulfan conditioning against head-shielded irradiation bone marrow chimeras prior to implantation of glioblastoma, a malignant brain tumour with a pro-inflammatory phenotype. METHODS: Recipient wild-type/CD45.1 mice received non-myeloablative busulfan conditioning (25 mg/kg), full intensity head-shielded irradiation, full intensity busulfan conditioning (125 mg/kg) prior to transplant with whole bone marrow from CD45.2 donors and were compared against untransplanted controls. Half the mice from each group were orthotopically implanted with syngeneic GL-261 glioblastoma cells. We assessed peripheral blood, bone marrow and spleen chimerism, multi-organ pro-inflammatory cytokine profiles at 12 weeks and brain chimerism and immune cell infiltration by whole brain flow cytometry before and after implantation of glioblastoma at 12 and 14 weeks respectively. RESULTS: Both non-myeloablative conditioning and head-shielded irradiation achieve equivalent blood and spleen chimerism of approximately 80%, although bone marrow engraftment is higher in the head-shielded irradiation group and highest in the fully conditioned group. Head-shielded irradiation stimulated pro-inflammatory cytokines in the blood and spleen but not in the brain, suggesting a systemic response to irradiation, whilst non-myeloablative conditioning showed no cytokine elevation. Non-myeloablative conditioning achieved higher donor chimerism in the brain after glioblastoma implantation than head-shielded irradiation with an altered immune cell profile. CONCLUSION: Our data suggest that non-myeloablative conditioning generates a more homeostatic peripheral inflammatory environment than head-shielded irradiation to allow a more consistent evaluation of immune cells in glioblastoma and can be used to investigate the roles of peripheral immune cells and bone marrow-derived subsets in other neurological diseases.

The evolution of British neurosurgical selection and training over the past decade.

Selection of junior doctors into the British neurosurgical training program and subsequent speciality training have undergone several key changes over the past decade. Shift patterns in the era of the European Working Time Directive (EWTD) have had a major impact on surgical training. We discuss the national selection process, formalization of surgical simulation training and the need to encompass generic professional capabilities within the neurosurgical curriculum in order to create the "well-rounded surgeon". Future directions including hybrid cerebrovascular training, training in stereotactic radiosurgery, and dedicated training opportunities in spinal surgery.

Operative planning aid for optimal endoscopic third ventriculostomy entry points in pediatric cases.

OBJECT: Endoscopic third ventriculostomy (ETV) uses anatomical spaces of the ventricular system to reach the third ventricle floor and create an alternative pathway for cerebrospinal fluid flow. Optimal ETV trajectories have been previously proposed in the literature, designed to grant access to the third ventricle floor without a displacement of eloquent periventricular structures. However, in hydrocephalus, there is a significant variability to the configuration of the ventricular system, implying that the optimal ETV trajectory and cranial entry point needs to be planned on a case-by-case basis. In the current study, we created a mathematical model, which tailors the optimal ETV entry point to the individual case by incorporating the ventricle dimensions. METHODS: We retrospectively reviewed the imaging of 30 consecutive pediatric patients with varying degrees of ventriculomegaly. Three dimensional radioanatomical models were created using preoperative MRI scans to simulate the optimal ETV trajectory and entry point for each case. The surface location of cranial entry points for individual ETV trajectories was recorded as Cartesian coordinates centered at Bregma. The distance from the Bregma in the coronal plane represented as "x", and the distance from the coronal suture in the sagittal plane represented as "y". The correlation between the ventricle dimensions and the x, y coordinates were tested using linear regression models. RESULTS: The distance of the optimal ETV entry point from the Bregma in the coronal plane ("x") and from the coronal suture in the sagittal plane ("y") correlated well with the frontal horn ratio (FHR). The coordinates for x and y were fitted along the following linear equations: x = 85.8 FHR-13.3 (r 2 = 0.84, p < 0.001) and y = -69.6 FHR + 16.7 (r 2 = 0.83, p < 0.001). CONCLUSION: The surface location of the optimal cranial ETV entry point correlates well with the ventricle size. We provide the first model that can be used as a surgical planning aid for a case specific ETV entry site with the incorporation of the ventricle size.

Ventricular metastatic dissemination of a paediatric craniopharyngioma: case report and literature review.

Distant intraventricular metastasis is extremely rare in childhood craniopharyngioma. Here, we report the isolated posterior ventricular recurrence of an adamantinomatous craniopharyngioma, in a child previously treated with surgery and proton beam therapy for local progression. The importance of surveillance imaging is highlighted, while specific surgical approaches and techniques are considered.

Telemetric intra-cranial pressure monitoring: clinical and financial considerations.

Intracranial pressure (ICP) measurement is an important diagnostic tool in Neurosurgery. Until relatively recently, conventional monitoring has required that subjects be admitted to a hospital bed and the device is only able to be left in-situ for limited periods of time. We have evaluated a Telemetric ICP monitoring system that has been proven, by several other groups worldwide, to permit rapid, repeated and prolonged ICP measurement, in multiple environments. In our unit, 4 patients have been implanted to-date, between the ages of 4 and 16, manifesting a wide range of complex neurosurgical conditions. The sensors have been left in-situ for between 460 and 632 days. There have been no clinical complications and the system has been universally well tolerated. Clinical events, costs and patient experience were all assessed prior to and following implantation. Overall, there was a significant reduction in associated admissions (44.3%), imaging requirements (72.5%) and costs (50.0%). Subjective feedback from both the patients (where possible) and their families was overwhelmingly positive, partly due to (a) the system's ease of use, (b) its ability to reduce the number of admissions/tests required and (c) the facility for rapid measurement of ICP that permitted on-the-spot reassurance of concerns. Additionally, the ability to monitor ICP at home and/or whilst ambulant, has provided measurements that were hitherto inaccessible to our team, facilitating all the potential benefits that analysis of such information would provide. Indeed, we have seen the resultant management in each case has been completely altered by the availability of this data, reaffirming that the importance of being able to obtain it should not be underestimated. The combination of both this and the ability to markedly improve patient experience, along with generating significant cost-savings, lead the authors to suggest that the implantation of this system should be strongly considered in selected individuals.

Multiple synchronous sites of origin of vestibular schwannomas in neurofibromatosis Type 2.

BACKGROUND: Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. METHODS: High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. RESULTS: Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. DISCUSSION: This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.

Primary cerebral histiocytic sarcoma in childhood: a case report of protracted survival and review of the literature.

INTRODUCTION: Histiocytic sarcoma (HS) of the central nervous system (CNS) is exceptionally rare in pediatric patients, historically associated with an exceptionally poor prognosis. Here, the authors present a novel case of protracted progression-free survival following surgical excision, radiotherapy and temozolomide. CASE REPORT: A 15-year-old Caucasian girl presented with a two-month history of headache, diplopia, vomiting, lethargy, weight loss and neurocognitive deterioration without gross neurological deficit on physical examination. Magnetic resonance imaging (MRI) of the brain identified a 5.8 × 4.7 × 4.0 cm lesion in the right frontal lobe with associated mass effect and no dissemination. Following two surgical procedures, gross total resection was achieved. Histology and immunohistochemistry confirmed HS, with strong CD163 staining. After focal radiotherapy with concomitant temozolomide, and a further seven cycles of temozolomide, the patient made an excellent recovery and is recurrence free without neurological deficit, 23 months following presentation. CONCLUSION: To the authors' knowledge, this is the first incidence of a prolonged, functionally preserved and recurrence-free outcome following a diagnosis of HS within the CNS of a pediatric patient. We suggest early diagnosis prior to dissemination and complete surgical resection as an essential treatment goal in this rare disease.

The role of CT body scans in the investigation of patients with newly diagnosed brain tumours.

OBJECTIVE: In the UK approximately 4000 patients are diagnosed with brain tumours each year. Many patients undergo CT scans of the chest, abdomen and pelvis as part of the investigation of such tumours. We aimed to determine the value of CT body scans in patients with newly diagnosed brain tumours. METHODS: We retrospectively reviewed the minutes of our neuro-oncology multidisciplinary team (MDT) meetings over a 12-month period to identify patients with a new radiological diagnosis of a brain tumour. Patients were divided into groups based on radiological diagnosis. Histology results were obtained for patients who underwent surgery. Results of CT body scans were obtained. RESULTS: A total of 261 patients were identified. Sixty percent had radiological primary brain tumours and 40% had secondary brain tumours. Concordance between radiological and histological diagnoses was high (97% for radiological primary brain tumours, and 83% for radiological secondary brain tumours). CT body scans demonstrated primary lesions in 90% of radiological secondary brain tumours. Thirty-four percent of patients with a radiological diagnosis of primary brain tumour underwent CT body scans. The majority of these scans were normal (78%). CONCLUSION: The ability of a specialist neuro-oncology MDT to correctly identify primary and secondary brain tumours on initial imaging is high. If the radiological diagnosis is of a secondary brain tumour, then CT body scans are essential. If the radiological diagnosis is of a primary brain tumour, then CT scans of the body are likely to add little to patient management.

Ventriculoperitoneal shunt survival in children who require additional abdominal surgery--are our estimations of the additional risk accurate?

OBJECTIVE: Ventriculoperitoneal shunt (VPS)-dependent children require abdominal surgery for many reasons. Our objective was to quantify the risk of abdominal surgery on VPS survival and to determine whether timing of abdominal intervention impacts on shunt outcome. METHODS: Retrospective data collection was performed on all children undergoing primary VPS insertion or revision over 2 years (1/1/08-31/12/10). All shunt interventions were categorised into two groups: those undergoing additional "Abdominal surgery" (AS) versus those undergoing "Shunt-only" (SO). Kaplan-Meier survival curves were devised and analysed using log-rank. In the AS group, we compared shunt survival for shunts inserted at various "Time from abdominal surgery" (TAS). We conducted a control analysis to compare shunt survival in AS, SO and a control "clean general surgery" (SG) group. Chi-squared test was used to determine the cause of shunt failure in these three groups. RESULTS: Three hundred and forty two shunts from 109 patients were included. Twenty patients contributed 118 shunts to the AS group. Median shunt survival was 3.68 months (95% CI = 1.01-6.47) and 22.6 months (95% CI = 8.76-36.4) in the AS and SO groups, respectively (log-rank = 16.6, p < 0.001). For each additional abdominal intervention, the risk of shunt failure increased by 55.4% (p < 0.001). Median shunt survival was 1.48 months (95% CI = 0.00-3.09, p < 0.001), if shunt insertion occurred within 1 year of abdominal surgery. Beyond 1 year, median shunt survival increased five-fold to 7.65 months (95% CI = 0.00-20.1, log-rank = 23.2, p < 0.001). There was a 29% reduction in risk of shunt failure per year interval between a shunt and an abdominal surgery (95% CI = 0.11-0.44, p < 0.005). Our control analysis confirmed that shunts in the AS group had worst survival and infection (p < 0.001). CONCLUSION: Additional abdominal surgery shortens VPS lifetime and increases risk of infection. Delaying abdominal surgery from a shunt intervention or vice versa by at least 1 year may prolong shunt survival.

Management of children and young people with idiopathic pituitary stalk thickening, central diabetes insipidus, or both: a national clinical practice consensus guideline.

Unexplained or idiopathic pituitary stalk thickening or central diabetes insipidus not only harbours rare occult malignancies in 40% of cases but can also reflect benign congenital defects. Between 2014 and 2019, a multidisciplinary, expert national guideline development group in the UK systematically developed a management flowchart and clinical practice guideline to inform specialist care and improve outcomes in children and young people (aged <19 years) with idiopathic pituitary stalk thickening, central diabetes insipidus, or both. All such cases of idiopathic pituitary stalk thickening and central diabetes insipidus require dynamic pituitary function testing, specialist pituitary imaging, measurement of serum ß-human chorionic gonadotropin and alpha-fetoprotein concentrations, chest x-ray, abdominal ultrasonography, optometry, and skeletal survey for occult disease. Stalk thickening of 4 mm or more at the optic chiasm, 3 mm or more at pituitary insertion, or both, is potentially pathological, particularly if an endocrinopathy or visual impairment coexists. In this guideline, we define the role of surveillance, cerebrospinal fluid tumour markers, whole-body imaging, indications, timing and risks of stalk biopsy, and criteria for discharge. We encourage a registry of outcomes to validate the systematic approach described in this guideline and research to establish typical paediatric stalk sizes and the possible role of novel biomarkers, imaging techniques, or both, in diagnosis.

Use of tissue glue to prevent collapse of the cortical mantle during and after cranial surgery in children: a technical note.

INTRODUCTION: Young children with significant ventricular dilatation or large intracranial fluid spaces often have a very thin cortical mantle as a result of persistently raised intracranial pressure. This rim of cortex has a tendency to fall away from the dura into the cavity during and after intracranial surgery, due to the lack of support, once the pressure in the fluid cavity has been reduced. This can lead to tearing of cortical bridging veins and the formation of post-operative subdural haematomas. METHODS: We describe a simple technique that attempts to prevent this phenomenon occurring using tissue glue. Once the craniotomy has been performed and the dura has been formally opened, tissue glue is applied to the underside of the dura around the edge of the wound, prior to corticotomy. RESULTS AND CONCLUSION: This results in the cortical mantle adhering to the undersurface of the dura and prevents the mantle from falling into the cavity either during the procedure or post-operatively.

A retrospective regional study of aqueduct stenosis and fourth ventricle outflow obstruction in the paediatric complex neurofibromatosis type 1 population; Aetiology, clinical presentation and management.

OBJECTIVES: Aqueduct stenosis (AS) and fourth ventricle outflow obstruction are rare associations of neurofibromatosis type 1 (NF1), resulting in ventriculomegaly and hydrocephalus requiring surgical treatment. This study aims to identify the prevalence of AS and its patterns of clinical presentation, aetiology and treatment in the paediatric complex NF1 population. PATIENTS AND METHODS: Patients with NF-1 aged 0-18 years were recruited from the Regional Genetic Family Register, following institutional review board approval. Magnetic resonance imaging data and clinical documents were reviewed with respect to clinical presentation, degree of ventriculomegaly, aetiological factors and management of AS and fourth ventricle outflow obstruction. RESULTS: 24 of the 233 paediatric patients seen within the NHS highly specialised service for complex NF1 were found to have AS or and fourth ventricle outflow obstruction. This included 13 males and 11 females with a mean age of 9 years 5 months (range 8 months - 17 years). The majority of patients with AS or fourth ventricle outflow obstruction presented with symptoms of raised intracranial pressure associated with ventriculomegaly and/or hydrocephalus (n = 18). However, in 25 % of patients, AS was an incidental finding on MRI and was observed both in the presence (n = 2) and absence (n = 4) of ventriculomegaly. In the majority of cases a single cause of AS was identified (n = 16), of which tectal plate thickening (n = 7) was most frequently observed. The remaining 8 patients had multiple causes of AS, in which tectal plate thickening (n = 7) and aqueductal webs (n = 5) were the most common observations. Surgery was performed on all patients with evidence of raised pressure (n = 8) by performing endoscopic third ventriculostomy (ETV) (n = 5) or ventriculoperitoneal (VP)-shunting (n = 3). Tectal plate thickening was most frequently observed in patients who underwent ETV (n = 3), followed by aqueductal web (n = 1) and T2-signal changes in the tectal plate (n = 1). Patients treated with VP-shunt had 4th ventricle outflow obstruction (n = 2) and a tectal plate tumour (n = 1). CONCLUSION: This study identifies that AS is more prevalent amongst the paediatric complex NF-1 population than previously reported, occurring in 10 % of cases. Our findings demonstrate that AS is most commonly symptomatic in presentation but can be asymptomatic in 25 % of paediatric complex NF1 patients. In this population, AS can occur both in the presence and absence of ventriculomegaly and therefore requires careful monitoring for development of hydrocephalus. In this study, over one third of patients (9 of 24 patients) with AS eventually required treatment.

High content screening of patient-derived cell lines highlights the potential of non-standard chemotherapeutic agents for the treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation. METHODS: Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis. RESULTS: Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines. CONCLUSION: The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells.

Nonsynostotic Posterior Brachycephaly with Hindbrain Herniation.

BACKGROUND: Positional plagiocephaly is the most common cause of cranial asymmetry. The underlying cause of Chiari-1 malformation has many possible theories, and anecdotally some pediatric neurosurgeons have had experience of severe cases of positional brachycephaly with Chiari-1. However, to date, there have been no published cases linking nonsynostotic plagiocephaly with Chiari-1 malformation. CASE DESCRIPTION: An 18-month-old boy presented with a head injury. On examination he had a Glasgow Coma Score of 15 with no focal neurologic deficits, but he was noted to have marked posterior brachycephaly. A computed tomography scan showed a slim left-sided hemispheric acute subdural hematoma with no mass effect, which was treated conservatively. Of note, all of his cranial vault sutures were open, and a diagnosis of incidental positional plagiocephaly was made. Subsequent magnetic resonance imaging as part of a work-up to exclude nonaccidental injury showed a small posterior fossa with a steep tentorium and herniation of the cerebellar tonsils to the level of the body of the second cervical vertebra. CONCLUSIONS: Chronic hindbrain herniation is well reported in cases of craniosynostosis, but to our knowledge this is the first published case associated with nonsynostotic deformational plagiocephaly. We hypothesize that severe posterior plagiocephaly can cause disproportion of the posterior fossa: hindbrain volume ratio and acquired chronic cerebellar herniation. Nevertheless, positional plagiocephaly and Chiari-1 are common entities, and it is possible that the dual diagnoses were coincidental in this case. This report serves to raise awareness of a putative causal relationship between positional plagiocephaly, reduced posterior fossa volume, and hindbrain herniation.

Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults.

Importance: Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome. Objective: To determine the frequency of the known heritable meningioma- or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma. Design, Setting, and Participants: Using the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU. Main Outcomes and Measures: The type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma- and meningioma-predisposing syndromes. Results: In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation. Conclusions and Relevance: A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres.

OBJECTIVES: The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS: Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS: Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION: The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.