The outcome of patients with surgically treated meningioma in England: 1999-2013. A cancer registry data analysis.

Purpose: Meningiomas are the commonest predominantly non-malignant brain tumour in adults. The use of surgery appears to be increasing, and outcomes are thought to be good, but whole nation data for England is scarce. The aim of this report is to examine the epidemiology of patients operated for cranial and spinal meningioma in England, and to assess associations between outcomes and gender, age, meningioma site (cranial or spinal), and grade. Material and methods: A search strategy encompassing all patients coded with cranial and spinal meningioma treated between January 1999 and December 2013 was obtained from data linkage between the National Cancer Registration and Analysis Service and Hospital Episode Statistics for England. Results: 25,694 patients were diagnosed with meningioma in England between 1999 and 2013, in whom 24,302 were cranial and 1392 spinal. Of these patients, 14,229 (60%) cranial and 1188 (85%) spinal meningioma received surgery. Of those operated on 70.1% were women, and, where the tumour grade was recorded, 79.5% were WHO grade I, 18.4% grade II, and 2.1% grade III. Five and ten year net survival rates for surgically treated cranial meningiomas were respectively 90% and 81% for those with WHO grade I, 80% and 63% for grade II, and 30% and 15% for WHO grade III tumours. Overall survival after surgery is better in women, younger adults, and people with spinal or lower grade meningiomas. Outcomes have improved over the time period examined. Conclusion: The outcome for patients with meningioma is good and is improving. However, there remains a significant mortality related to the disease process

The role of the corpus callosum in seizure spread: MRI lesion mapping in oligodendrogliomas

Our data suggest that the genu of the corpus callosum may be a major pathway for seizure generalization in patients with oligodendrogliomas

Interval brain imaging for adults with cerebral glioma

© 2018 The Cochrane Collaboration. This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine whether interval brain imaging (performing brain imaging at regular intervals) compared with brain imaging upon clinical indication (performing brain imaging upon the development of new or worsening symptoms) improves outcomes associated with cerebral glioma. To appraise critically and summarise current evidence on the costs and cost-effectiveness of interval brain imaging compared with symptomatic imaging

The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial): study protocol

BACKGROUND: Insertion of a ventriculoperitoneal shunt (VPS) for the treatment of hydrocephalus is one of the most common neurosurgical procedures in the UK, but failures caused by infection occur in approximately 8% of primary cases. VPS infection is associated with considerable morbidity and mortality and its management results in substantial cost to the health service. Antibiotic-impregnated (rifampicin and clindamycin) and silver-impregnated VPS have been developed to reduce infection rates. Whilst there is some evidence showing that such devices may lead to a reduction in VPS infection, there are no randomised controlled trials (RCTs) to support their routine use. METHODS/DESIGN: Overall, 1,200 patients will be recruited from 17 regional neurosurgical units in the UK and Ireland. Patients of any age undergoing insertion of their first VPS are eligible. Patients with previous indwelling VPS, active and on-going cerebrospinal fluid (CSF) or peritoneal infection, multiloculated hydrocephalus requiring multiple VPS or neuroendoscopy, and ventriculoatrial or ventriculopleural shunt planned will be excluded. Patients will be randomised 1:1:1 to either standard silicone (comparator), antibiotic-impregnated, or silver-impregnated VPS. The primary outcome measure is time to VPS infection. Secondary outcome measures include time to VPS failure of any cause, reason for VPS failure (infection, mechanical failure, or patient failure), types of bacterial VPS infection (organism type and antibiotic resistance), and incremental cost per VPS failure averted. DISCUSSION: The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial) is the first multi-centre RCT designed to determine whether antibiotic or silver-impregnated VPS reduce early shunt infection compared to standard silicone VPS. The results of this study will be used to inform current neurosurgical practice and may potentially benefit patients undergoing shunt surgery in the future. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN49474281

Metastasis-inducing proteins are widely expressed in human brain metastases and associated with intracranial progression and radiation response

Background:Understanding the factors that drive recurrence and radiosensitivity in brain metastases would improve prediction of outcomes, treatment planning and development of therapeutics. We investigated the expression of known metastasis-inducing proteins in human brain metastases.Methods:Immunohistochemistry on metastases removed at neurosurgery from 138 patients to determine the degree and pattern of expression of the proteins S100A4, S100P, AGR2, osteopontin (OPN) and the DNA repair marker FANCD2. Validation of significant findings in a separate prospective series with the investigation of intra-tumoral heterogeneity using image-guided sampling. Assessment of S100A4 expression in brain metastatic and non-metastatic primary breast carcinomas.Results:There was widespread staining for OPN, S100A4, S100P and AGR2 in human brain metastases. Positive staining for S100A4 was independently associated with a shorter time to intracranial progression after resection in multivariate analysis (hazard ratio for negative over positive staining=0.17, 95% CI: 0.04-0.74, P=0.018). S100A4 was expressed at the leading edge of brain metastases in image guided sampling and overexpressed in brain metastatic vs non-brain metastatic primary breast carcinomas. Staining for OPN was associated with a significant increase in survival time after post-operative whole-brain radiotherapy in retrospective (OPN negative 3.43 months, 95% CI: 1.36-5.51 vs OPN positive, 11.20 months 95% CI: 7.68-14.72, Log rank test, P<0.001) and validation populations.Conclusions:Proteins known to be involved in cellular adhesion and migration in vitro, and metastasis in vivo are significantly expressed in human brain metastases and may be useful biomarkers of intracranial progression and radiosensitivity

Adult brain tumour research in 2024: Status, challenges and recommendations

In 2015, a groundswell of brain tumour patient, carer and charity activism compelled the UK Minister for Life Sciences to form a brain tumour research task and finish group. This resulted, in 2018, with the UK government pledging £20m of funding, to be paralleled with £25m from Cancer Research UK, specifically for neuro-oncology research over the subsequent 5 years. Herein, we review if and how the adult brain tumour research landscape in the United Kingdom has changed over that time and what challenges and bottlenecks remain. We have identified seven universal brain tumour research priorities and three cross-cutting themes, which span the research spectrum from bench to bedside and back again. We discuss the status, challenges and recommendations for each one, specific to the United Kingdom

External validation and recalibration of an incidental meningioma prognostic model – IMPACT: protocol for an international multicentre retrospective cohort study

Introduction: Due to the increased use of CT and MRI, the prevalence of incidental findings on brain scans is increasing. Meningioma, the most common primary brain tumour, is a frequently encountered incidental finding, with an estimated prevalence of 3/1000. The management of incidental meningioma varies widely with active clinical-radiological monitoring being the most accepted method by clinicians. Duration of monitoring and time intervals for assessment, however, are not well defined. To this end, we have recently developed a statistical model of progression risk based on single-centre retrospective data. The model Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and MRI Tests (IMPACT) employs baseline clinical and imaging features to categorise the patient with an incidental meningioma into one of three risk groups: low, medium and high risk with a proposed active monitoring strategy based on the risk and temporal trajectory of progression, accounting for actuarial life expectancy. The primary aim of this study is to assess the external validity of this model. Methods and analysis: IMPACT is a retrospective multicentre study which will aim to include 1500 patients with an incidental intracranial meningioma, powered to detect a 10% progression risk. Adult patients ≥16 years diagnosed with an incidental meningioma between 1 January 2009 and 31 December 2010 will be included. Clinical and radiological data will be collected longitudinally until the patient reaches one of the study endpoints: intervention (surgery, stereotactic radiosurgery or fractionated radiotherapy), mortality or last date of follow-up. Data will be uploaded to an online Research Electronic Data Capture database with no unique identifiers. External validity of IMPACT will be tested using established statistical methods. Ethics and dissemination: Local institutional approval at each participating centre will be required. Results of the study will be reported through peer-reviewed articles and conferences and disseminated to participating centres, patients and the public using social media

Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

Voxel-wise comparisons of cellular microstructure and diffusion-MRI in mouse hippocampus using 3D Bridging of Optically-clear histology with Neuroimaging Data (3D-BOND)

A key challenge in medical imaging is determining a precise correspondence between image properties and tissue microstructure. This comparison is hindered by disparate scales and resolutions between medical imaging and histology. We present a new technique, 3D Bridging of Optically-clear histology with Neuroimaging Data (3D-BOND), for registering medical images with 3D histology to overcome these limitations. Ex vivo 120 × 120 × 200 μm resolution diffusion-MRI (dMRI) data was acquired at 7 T from adult C57Bl/6 mouse hippocampus. Tissue was then optically cleared using CLARITY and stained with cellular markers and confocal microscopy used to produce high-resolution images of the 3D-tissue microstructure. For each sample, a dense array of hippocampal landmarks was used to drive registration between upsampled dMRI data and the corresponding confocal images. The cell population in each MRI voxel was determined within hippocampal subregions and compared to MRI-derived metrics. 3D-BOND provided robust voxel-wise, cellular correlates of dMRI data. CA1 pyramidal and dentate gyrus granular layers had significantly different mean diffusivity (p > 0.001), which was related to microstructural features. Overall, mean and radial diffusivity correlated with cell and axon density and fractional anisotropy with astrocyte density, while apparent fibre density correlated negatively with axon density. Astrocytes, axons and blood vessels correlated to tensor orientation

Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression

Background: Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined. Materials and methods: The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString™, nCounter™ Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined. Results: There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate 1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P Conclusion: This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome.</p