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.

The Role of HMGB1 in Traumatic Brain Injury-Bridging the Gap Between the Laboratory and Clinical Studies.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is amongst the leading causes of mortality and morbidity worldwide. However, several pharmacological strategies in the clinical setting remain unsuccessful. Mounting evidence implicates High Mobility Group Box protein 1 (HMGB1) as a unique alternative target following brain injury. Herein, we discuss current understanding of HMGB1 in TBI and obstacles to clinical translation. RECENT FINDINGS: HMGB1 plays a pivotal role as a 'master-switch' of neuro-inflammation following injury and in the regulation of neurogenesis during normal development. Animal models point towards the involvement of HMGB1 signalling in prolonged activation of glial cells and widespread neuronal death. Early experimental studies demonstrate positive effects of HMGB1 antagonism on both immunohistochemical and neuro-behavioural parameters following injury. Raised serum/CSF HMGB1 in humans is associated with poor outcomes post-TBI. HMGB1 is a promising therapeutic target post-TBI. However, further studies elucidating receptor, cell, isoform, and temporal effects are required prior to clinical translation.

Endoscope-assisted techniques for evacuation of acute subdural haematoma in the elderly: The lesser of two evils? A scoping review of the literature.

INTRODUCTION: Surgical evacuation of acute subdural haematoma (ASDH) in the elderly remains a point of contention due to the significant associated mortality. Therefore, there is a dire need for alternative treatment options. Endoscope-assisted techniques (EAT) have been increasingly reported over the last decade with variable outcomes. In this scoping review, we identify studies reporting the use of EAT for ASDH evacuation in elderly patients. Outcomes and patient selection criteria are discussed to identify patients that may benefit from EAT. METHODS: A multi-database literature search was performed between January 1990 and January 2021. Studies including patients aged 60 years or above who underwent EAT for ASDH evacuation with reported outcomes were included. RESULTS: A total of 13 studies and 122 patients were eligible for inclusion. Patient age ranged from 65 to 101 years, and average age from 78.6 to 87.4 years. High comorbidity burden, advanced age, absence of adverse imaging features, and pre-operative neurological status were the most common eligibility criteria for EAT. 52% of all procedures were performed under local anaesthetic (LA). Mortality rates ranged between 0% and 40%, whilst favourable outcomes ranged between 26.7% and 96.4%. Re-bleed was the most commonly reported complication, ranging between 0% and 13%. CONCLUSIONS: EAT pose a viable compromise for elderly patients with ASDH that may be unfit for GA. Heterogeneity of patient selection criteria prevents meaningful comparison between EAT and other approaches, and there is a clear impact of patient selection on outcome among studies reporting EAT. Further studies are required to identify the patient cohort that may benefit from this approach.

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.

Neurogenesis after traumatic brain injury - The complex role of HMGB1 and neuroinflammation.

INTRODUCTION: Traumatic brain injury (TBI) is amongst the leading causes of morbidity and mortality worldwide. Despite evidence of neurogenesis post-TBI, survival and integration of newborn neurons remains impaired. High Mobility Group Box protein 1 (HMGB1) is an 'alarmin' released hyper-acutely following TBI and implicated in hosting the neuro-inflammatory response to injury. It is also instrumental in mediating neurogenesis under physiological conditions. Given its dual role in mediating neuro-inflammation and neurogenesis, it serves as a promising putative target for therapeutic modulation. In this review, we discuss neurogenesis post-TBI, neuro-pharmacological aspects of HMGB1, and its potential as a therapeutic target. METHODS: PubMed database was searched with varying combinations of the following search terms: HMGB1, isoforms, neurogenesis, traumatic brain injury, Toll-like receptor (TLR), receptor for advanced glycation end-products (RAGE). RESULTS: Several in vitro and in vivo studies demonstrate evidence of neurogenesis post-injury. The HMGB1-RAGE axis mediates neurogenesis throughout development, whilst interaction with TLR-4 promotes the innate immune response. Studies in the context of injury demonstrate that these receptor effects are not mutually exclusive. Despite recognition of different HMGB1 isoforms based on redox/acetylation status, effects on neurogenesis post-injury remain unexplored. Recent animal in vivo studies examining HMGB1 antagonism post-TBI demonstrate predominantly positive results, but specific effects on neurogenesis and longer-term outcomes remain unclear. CONCLUSION: HMGB1 is a promising therapeutic target but its effects on neurogenesis post-TBI remains unclear. Given the failure of several pharmacological strategies to improve outcomes following TBI, accurate delineation of HMGB1 signalling pathways and effects on post-injury neurogenesis are vital.

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.

Patient advice regarding participation in sport in children with disorders of cerebrospinal fluid (CSF) circulation: a national survey of British paediatric neurosurgeons.

BACKGROUND: Management of children with disorders of cerebrospinal fluid (CSF) circulation is a common aspect of paediatric neurosurgical practice. Sport and physical activity play an integral role in the lives of patients in this age group. However, there is little evidence to support the dissemination of appropriate advice to children regarding such activities. The aim of this study was to evaluate the perspectives of clinicians across the UK regarding the participation of children with disorders of CSF circulation in sports. METHODS: Questionnaires were distributed to Consultant Paediatric Neurosurgeons practising across the UK via the Society of British Neurological Surgeons (SBNS). Five different patient scenarios were supplied, and participants were asked to choose whether they would advise participation in the following sports: Taekwondo, rugby, skiing, and football. RESULTS: An overall response rate of 66.7% (36 out of 54 paediatric neurosurgeons) was achieved. The following percentages of clinicians advocated football, rugby, Taekwondo, and skiing across all scenarios: 96%, 75%, 77%, and 97%, respectively. The majority of responders (91.2%) relied on personal experience when providing advice, whilst 50% used available literature and 19.4% used available guidelines. CONCLUSIONS: There is a paucity of evidence in the literature to support the dissemination of appropriate advice to children with disorders of CSF circulation regarding participation in sports. Our findings demonstrate that the majority of clinicians rely on personal experience to make such decisions, emphasizing the necessity of larger scale studies to inform evidence-based guidelines.

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.

GalR3 mediates galanin proliferative effects on postnatal hippocampal precursors.

Galanin, a neuropeptide co-released from noradrenergic and serotonergic projection neurons to the dentate gyrus, has recently emerged as an important mediator for signaling neuronal activity to the subgranular neurogenic stem cell niche supporting adult hippocampal neurogenesis. Galanin and its receptors appear to play key roles in depression-like behavior, and effects on hippocampal neurogenesis are relevant to pharmacological strategies for treating depression, which in part appear to rely on restoring altered neurogenesis. We previously demonstrated that the GalR2/3 receptor agonist Gal 2-11 is proliferative and proneurogenic for postnatal hippocampal progenitor cells; however, the specific receptor mediation remained to be identified. With the recent availability of M1145 (a specific GalR2 agonist), and SNAP 37889 (GalR3 specific antagonist), we extend our previous studies and show that while M1145 has no proliferative effect, the co-treatment of postnatal rat hippocampal progenitors with Gal 2-11 and SNAP 37889 completely abolished the Gal 2-11 proliferative effects. Taken together, these results clearly demonstrate that GalR3 and not GalR2 is the specific receptor subtype that mediates the proliferative effects of galanin on hippocampal progenitor cells. These results implicate GALR3 in the mediation of galanin neurogenic effects and, potentially, its neurogenic anti-depressant effects.

Reversible brainstem dysfunction from spinal arterio-venous fistula.

A 45-year-old man presented with subacute onset of ataxia, diplopia, urinary retention and paraparesis. MR scan of brain showed abnormal T2 hyperintense signal within the cervical cord, medulla and lower pons and vascular appearances suggesting an arterio-venous fistula. The fistula was surgically explored and successfully disconnected with good clinical outcome. Brainstem or cervical dural arterio-venous fistulae more typically present as a myelopathy; only a handful of cases have presented with brainstem dysfunction. This is a rare but reversible cause of subacute brainstem dysfunction.

Neuropeptides and hippocampal neurogenesis.

Hippocampal neurogenesis is important for modulating the behavioural responses to stress and for certain forms of learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Neuropeptides such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and galanin have emerged as important mediators for signalling local and extrinsic interneuronal activity to subgranular zone precursors. Here we review the distribution of these neuropeptides and their receptors in the neurogenic area of the hippocampus and their precise effects on hippocampal neurogenesis. We also discuss neuropeptides' potential involvement in functional aspects of hippocampal neurogenesis particularly their involvement in the modulation of learning and memory and behavior responses.