Diagnosing adult primary brain tumours: can we do better?

Clarissa Penfold is supported by funding from the Brain Tumour Charity (grant no. GN-000316)

Incidence of chronic subdural haematoma: a single-centre exploration of the effects of an ageing population with a review of the literature

Abstract: Background: Chronic subdural haematoma (cSDH) is a common neurosurgical pathology frequently occurring in older patients. The impact of population ageing on cSDH caseload has not been examined, despite relevance for health system planning. Methods: This is a single-centre study from the UK. Operated cases of cSDH (n = 446) for 2015–2018 were identified. Crude and directly standardised incidence rates were calculated. Medline and EMBASE were systematically searched to identify studies reporting on the incidence of cSDH by year, so an estimate of rate of incidence change could be determined. Local incidence rates were then applied to population projections for local catchment area to estimate operated cSDH numbers at 5 yearly intervals due to shifting demographics. Results: We identified nine studies presenting incidence estimates. Crude estimates for operative cases ranged from 1.3/100,000/year (1.4–2.2) to 5.3/100,000/year (4.3–6.6). When non-operated cases were included, incidence was higher: 8.2/100,000/year (6.0–11.2) to 48/100,000/year (37.7–61.1). Four pairs of studies demonstrated incidence rate increases of 200–600% over the last 50 years, but data was deemed too heterogeneous to generate formal estimate of incidence change. Local crude incidence of operated cSDH was 3.50/100,000/year (3.19–3.85). Directly standardised incidence was 1.58/100,000/year (1.26–1.90). After applying local incidence rates to population projections, case numbers were predicted to increase by 53% over the next 20 years. Conclusions: The incidence of cSDH is increasing. We project a 53% increase in operative caseload within our region by 2040. These are important findings for guiding future healthcare planning

Molecular Pathogenesis of Secondary Acute Promyelocytic Leukemia

Balanced chromosomal translocations that generate chimeric oncoproteins are considered to be initiating lesions in the pathogenesis of acute myeloid leukemia. The most frequent is the t(15;17)(q22;q21), which fuses the PML and RARA genes, giving rise to acute promyelocytic leukemia (APL). An increasing proportion of APL cases are therapy-related (t-APL), which develop following exposure to radiotherapy and/or chemotherapeutic agents that target DNA topoisomerase II (topoII), particularly mitoxantrone and epirubicin. To gain insights into molecular mechanisms underlying the formation of the t(15;17) we mapped the translocation breakpoints in a series of t-APLs, which revealed significant clustering according to the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast cancer or multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp “hotspot” region in PML intron 6, which was confirmed to be a preferential site of topoII-mediated DNA cleavage induced by mitoxantrone. Chromosome 15 breakpoints falling outside the “hotspot”, and the corresponding RARA breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the PML and RARA loci are susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL

Co-transplantation of Human Embryonic Stem Cell-derived Neural Progenitors and Schwann Cells in a Rat Spinal Cord Contusion Injury Model Elicits a Distinct Neurogenesis and Functional Recovery

Co-transplantation of neural progenitors (NPs) with Schwann cells (SCs) might be a way to overcome low rate of neuronal differentiation of NPs following transplantation in spinal cord injury (SCI) and the improvement of locomotor recovery. In this study, we initially generated NPs from human embryonic stem cells (hESCs) and investigated their potential for neuronal differentiation and functional recovery when co-cultured with SCs in vitro and co-transplanted in a rat acute model of contused SCI. Co-cultivation results revealed that the presence of SCs provided a consistent status for hESC-NPs and recharged their neural differentiation toward a predominantly neuronal fate. Following transplantation, a significant functional recovery was observed in all engrafted groups (NPs, SCs, NPs+SCs) relative to the vehicle and control groups. We also observed that animals receiving co-transplants established a better state as assessed with the BBB functional test. Immunohistofluorescence evaluation five weeks after transplantation showed invigorated neuronal differentiation and limited proliferation in the co-transplanted group when compared to the individual hESC-NPs grafted group. These findings have demonstrated that the co-transplantation of SCs with hESC-NPs could offer a synergistic effect, promoting neuronal differentiation and functional recovery

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Physical Passaging of Embryoid Bodies Generated from Human Pluripotent Stem Cells

Spherical three-dimensional cell aggregates called embryoid bodies (EBs), have been widely used in in vitro differentiation protocols for human pluripotent stem cells including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Recent studies highlight the new devices and techniques for hEB formation and expansion, but are not involved in the passaging or subculture process. Here, we provide evidence that a simple periodic passaging markedly improved hEB culture condition and thus allowed the size-controlled, mass production of human embryoid bodies (hEBs) derived from both hESCs and hiPSCs. hEBs maintained in prolonged suspension culture without passaging (>2 weeks) showed a progressive decrease in the cell growth and proliferation and increase in the apoptosis compared to 7-day-old hEBs. However, when serially passaged in suspension, hEB cell populations were significantly increased in number while maintaining the normal rates of cell proliferation and apoptosis and the differentiation potential. Uniform-sized hEBs produced by manual passaging using a 1∶4 split ratio have been successfully maintained for over 20 continuous passages. The passaging culture method of hEBs, which is simple, readily expandable, and reproducible, could be a powerful tool for improving a robust and scalable in vitro differentiation system of human pluripotent stem cells

Challenges and opportunities in the care of chronic subdural haematoma: perspectives from a multi-disciplinary working group on the need for change.

INTRODUCTION: A chronic subdural haematoma (cSDH) is a collection of altered blood products between the dura and brain resulting in a slowly evolving neurological deficit. It is increasingly common and, in high income countries, affects an older, multimorbid population. With changing demographics improving the care of this cohort is of increasing importance. METHODS: We convened a cross-disciplinary working group (the 'Improving Care in Elderly Neurosurgery Initiative') in October 2020. This comprised experts in neurosurgical care and a range of perioperative stakeholders. An Implementation Science framework was used to structure discussions around the challenges of cSDH care within the United Kingdom. The outcomes of these discussions were recorded and summarised, before being circulated to all attendees for comment and refinement. RESULTS: The working group identified four key requirements for improving cSDH care: (1) data, audit, and natural history; (2) evidence-based guidelines and pathways; (3) shared decision-making; and (4) an overarching quality improvement strategy. Frequent transfers between care providers were identified as impacting on both perioperative care and presenting a barrier to effective data collection and teamworking. Improvement initiatives must be cognizant of the complex, system-wide nature of the problem, and may require a combination of targeted trials at points of clinical equipoise (such as anesthetic technique or anticoagulant management), evidence-based guideline development, and a cycle of knowledge acquisition and implementation. CONCLUSION: The care of cSDH is a growing clinical problem. Lessons may be learned from the standardised pathways of care such as those as used in hip fracture and stroke. A defined care pathway for cSDH, encompassing perioperative care and rehabilitation, could plausibly improve patient outcomes but work remains to tailor such a pathway to cSDH care. The development of such a pathway at a national level should be a priority, and the focus of future work

The management and outcome for patients with chronic subdural hematoma: a prospective, multicenter, observational cohort study in the United Kingdom

Symptomatic chronic subdural hematoma (CSDH) will become an increasingly common presentation in neurosurgical practice as the population ages, but quality evidence is still lacking to guide the optimal management for these patients. The British Neurosurgical Trainee Research Collaborative (BNTRC) was established by neurosurgical trainees in 2012 to improve research by combining the efforts of trainees in each of the United Kingdom (UK) and Ireland's neurosurgical units (NSUs). The authors present the first study by the BNTRC that describes current management and outcomes for patients with CSDH throughout the UK and Ireland. This provides a resource both for current clinical practice and future clinical research on CSDH

Activin/Nodal Inhibition Alone Accelerates Highly Efficient Neural Conversion from Human Embryonic Stem Cells and Imposes a Caudal Positional Identity

Background Neural conversion from human embryonic stem cells (hESCs) has been demonstrated in a variety of systems including chemically defined suspension culture, not requiring extrinsic signals, as well as in an adherent culture method that involves dual SMAD inhibition using Noggin and SB431542 (an inhibitor of activin/nodal signaling). Previous studies have also determined a role for activin/nodal signaling in development of the neural plate and anterior fate specification. We therefore sought to investigate the independent influence of SB431542 both on neural commitment of hESCs and positional identity of derived neural progenitors in chemically defined substrate-free conditions. Methodology/Principal Findings We show that in non-adherent culture conditions, treatment with SB431542 alone for 8 days is sufficient for highly efficient and accelerated neural conversion from hESCs with negligible mesendodermal, epidermal or trophectodermal contamination. In addition the resulting neural progenitor population has a predominantly caudal identity compared to the more anterior positional fate of non-SB431542 treated cultures. Finally we demonstrate that resulting neurons are electro-physiologically competent. Conclusions This study provides a platform for the efficient generation of caudal neural progenitors under defined conditions for experimental study

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease