A high-density 3-dimensional culture model of human glioblastoma for rapid screening of therapeutic resistance.

Glioblastoma is among the most lethal cancers, with no known cure. A multitude of therapeutics are being developed or in clinical trials, but currently there are no ways to predict which patient may benefit the most from which drug. Assays that allow prediction of the tumor's response to anti-cancer drugs may improve clinical decision-making. Here, we present a high-density 3D primary cell culture model for short-term testing from resected glioblastoma tissue that is set up on the day of surgery, established within 7 days and viable for at least 3 weeks. High-density 3D cultures contain tumor and host cells, including microglia, and retain key histopathological characteristics of their parent tumors, including proliferative activity, expression of the marker GFAP, and presence of giant cells. This provides a proof-of-concept that 3D primary cultures may be useful to model tumor heterogeneity. Importantly, we show that high-density 3D cultures can be used to test chemotherapy response within a 2-3-week timeframe and are predictive of patient response to Temozolomide therapy. Thus, primary high-density 3D cultures could be a useful tool for brain cancer research and prediction of therapeutic resistance.

Management of neurotrauma during COVID-19: a single centre experience and lessons for the future.

INTRODUCTION: Traumatic brain injury (TBI) is amongst the leading causes of morbidity and mortality worldwide. The unprecedented emergence of COVID-19 has mandated neurosurgeons to limit viral spread and spare hospital resources whilst trying to adapt management plans for TBI. We aimed to characterize how this affects decision-making on TBI management and drive strategies to cope with future expected waves. METHODS: Retrospective TBI data collection from a single tertiary referral unit was performed between: 01/04/2019 - 30/06/2019 ('Pre-Epidemic') and 01/04/2020 - 30/06/20 ('Epidemic'). Demographics, mechanism of injury, TBI severity, radiological findings, alcohol/anticoagulants/antiplatelets use, and management decisions were extracted. RESULTS: 646 TBI referrals were received in 'Pre-Epidemic' (N = 317) and 'Epidemic' (N = 280) groups. There was reduction in RTA-associated TBI (14.8 vs 9.3%; p = .04) and increase in patients on anticoagulants (14.2 vs 23.6%; p = .003) in the 'Epidemic' group. Despite similarities between other TBI-associated variables, a significantly greater proportion of patients were managed conservatively in local referring units without neurosurgical services (39.1 vs 56.8%; p < .0001), predominantly constituted by mild TBI. CONCLUSION: Despite COVID-19 public health measures, the burden of TBI remains eminent. Increases in local TBI management warrant vigilance from primary healthcare services to meet post-TBI needs in the community.

Disulfide HMGB1 acts via TLR2/4 receptors to reduce the numbers of oligodendrocyte progenitor cells after traumatic injury in vitro.

Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons. Whilst high-mobility group box-1 (HMGB1) and its key receptors TLR2/4 are identified as key initiators of neuroinflammation post-TBI, they have been identified as attractive targets for development of novel therapeutic approaches to improve post-TBI clinical outcomes. In this report we establish unequivocal evidence that HMGB1 released in vitro impairs OPC response to mechanical injury; an effect that is pharmacologically reversible. We show that needle scratch injury hyper-acutely induced microglial HMGB1 nucleus-to-cytoplasm translocation and subsequent release into culture medium. Application of injury-conditioned media resulted in significant decreases in OPC number through anti-proliferative effects. This effect was reversed by co-treatment with the TLR2/4 receptor antagonist BoxA. Furthermore, whilst injury conditioned medium drove OPCs towards an activated reactive morphology, this was also abolished after BoxA co-treatment. We conclude that HMGB1, through TLR2/4 dependant mechanisms, may be detrimental to OPC proliferation following injury in vitro, negatively affecting the potential for restoring a mature oligodendrocyte population, and subsequent axonal remyelination. Further study is required to assess how HMGB1-TLR signalling influences OPC maturation and myelination capacity.

The efficacy of endoscopic third ventriculostomy in children 1 year of age or younger: A systematic review and meta-analysis.

PURPOSE: Hydrocephalus is a major cause of morbidity in the pediatric population, with potentially severe consequences if left untreated. Two viable strategies for management of non-communicating hydrocephalus are endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunting. However, there is uncertainty over the safety and efficacy of ETV in younger infants aged 1 year or below. In this systematic review, we aim to elucidate the success rate and procedural risks of ETV in this age group. METHODS: A multi-database (PubMed, Embase, Web of Science) literature search between January 1990 and April 2018 was performed in accordance with PRISMA guidelines. Eligible studies were included if they (i) examined non-communicating hydrocephalus; (ii) quantified the success/failure rates of ETV; and (iii) assessed outcomes in children 1 year of age or younger. RESULTS: A total of 19 articles with 399 patients were eligible for inclusion. Mean age at procedure was 4.2 months (range 34 weeks gestation to 12 months), with 116 females and 143 males. Commonest underlying aetiology was congenital aqueductal stenosis (AS) (60.4%). Remaining causes included post-haemorrhagic, post-infection, Chiari malformations, malignancies and others. Overall and AS mean success rates were 51.6% and 56.5% respectively. Overall complication rate was 10.0%, consisting mainly of CSF leak, infection, and haemorrhage. Younger age was significantly associated with poorer ETV success rate when divided into <6 months and 6-12 months of age (44.4 vs 66.7%; p = 0.0007). Underlying pathology had no significant association with ETV outcome when divided into AS and other pathologies (p = 0.53). CONCLUSIONS: Age is significantly associated with ETV success rates. Pathology-dependent effects were not found in this age group. Despite a lower ETV success rate at younger ages (44.4 vs 66.7%), it offers a comparable safety profile that is independent of age. ETV remains a viable treatment option for non-communicating hydrocephalus for infants aged 1 year or younger.

Demographics, presentation, and clinical outcomes after traumatic bifrontal contusions: a systematic review.

Traumatic bifrontal contusions (TBC) form a recognised clinical entity among patients with traumatic brain injury (TBI). This study aims to systematically review current literature on demographics, management, and predictors of outcomes of patients with TBC. A multi-database literature search (PubMed, Cochrane, OVID Medline/Embase) was performed using PRISMA as a search strategy. Studies were selected by predefined selection criteria (PROSPERO: CRD42018055390), and risk of bias was assessed using an adapted form of ROBINS-I tool. Of the 275 studies yielded by the literature search, seven articles met the criteria for inclusion, all of which were level III evidence. Total cohort consisted of 468 patients; predominantly male (n = 5; 303/417 patients) with average age 44.3 years (range, 7-81). Falls (44.9%) and road traffic accidents (46.6%) were the commonest mechanisms of injury with an average presentation GCS of 9.2 (n = 3, 119 patients). GCS on admission of ≤ 13.1 and contusion volume at day 2 post-injury of ≥ 62.9cm3 were associated with increased risk of deterioration needing surgical interventions (n = 1, 7 patients). The majority of patients underwent surgery; the average GOS was 4, at an average follow-up duration of 11.7 months (n = 6, 356 patients). The currently available evidence on the management of TBC is scarce. Larger multicentre well-designed studies are needed to further delineate the factors behind acute deterioration, the effectiveness of management options. Once in place, this can be used to develop and test an algorithmic approach to management of TBC resulting in consistently improved outcomes.

Neurocutaneous melanosis presenting with hydrocephalus and malignant transformation: case-based update.

INTRODUCTION: Neurocutaneous melanosis (NCM) is a sporadic condition characterised by congenital melanocytic nevi and melanocytic thickening of the leptomeninges. It is believed to result from congenital dysplasia of melanin-producing cells within the skin and leptomeninges. The management of cutaneous manifestations remains controversial; for neurological manifestations, outcome remains poor even with the use of radiotherapy and chemotherapy. PATIENTS AND METHODS: We describe the case of a 5-month-old boy who presented with giant congenital melanocytic nevus and hydrocephalus. MR imaging and CSF immunohistochemistry confirmed leptomeningeal melanosis. We discuss the diagnosis, treatment and prognosis of this rare disorder in the light of recent published literature. RESULTS: Patient required placement of right-sided ventriculoperitoneal shunt to control hydrocephalus. The patient tolerated the procedure well and was discharged home with normal neurological function. A presumptive diagnosis of NCM was made based on the MR characteristics, CSF cytology and clinical presentation. He received trametinib, a MAPK/Erk kinase inhibitor for 7 months. At 30 months of age, he developed left-sided weakness and status epilepticus requiring paediatric intensive care unit admission and ventilator support. The patient eventually succumbed to malignant transformation of leptomeningeal disease. CONCLUSION: Cutaneous manifestations of NCM are usually congenital, and neurological manifestations develop early in life. Patients with large or multiple congenital nevi should therefore be investigated early to facilitate treatment. MR imaging is the investigation of choice which can further assist in performing biopsy. Symptomatic NCM is refractory to radiotherapy and chemotherapy and has a poor prognosis. A multidisciplinary approach is necessary in the management of NCM patients.