Cardiovascular Events After Primary Malignant and Non-Malignant Brain Tumour Diagnosis: A Population Matched Cohort Study in Wales (United Kingdom)

alexandrossfakianakis shared this article with you from Inoreader Cardiovascular Events After Primary Malignant and Non-Malignant Brain Tumour Diagnosis: A Population Matched Cohort Study in Wales (United Kingdom) via # Neuro-Oncology Current Issue Abstract AIMS It is uncertain whether the elevated cardiovascular diseases (CVD) risks in patients with brain tumours is due to differences in the distribution of risk factors. We compared CVD risks among patients with a primary brain tumour to a matched general population cohort. METHOD Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales, we identified adults aged ≥18 years with a diagnosis of brain tumour identified in the cancer registry between 2000-2014, and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population. Outcomes included fatal and non-fatal major vascular events and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks. RESULTS There were 2,869 and 3,931 people diagnosed with malignant and non-malignant brain tumours, respectively, in Wales. They were matched to 33 ,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). People with malignant tumour surviving one year had higher risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) compared to their matched controls. Individuals with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls. CONCLUSION The elevated risks of CVD suggest risk reduction a potential strategy to improve life quality and survival in people with malignant and non-malignant brain tumour. View on Web

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Glioma Cell Invasion Is Dependent Upon the DNA Damage Response Kinase ATR

alexandrossfakianakis shared this article with you from Inoreader Glioma Cell Invasion Is Dependent Upon the DNA Damage Response Kinase ATR via # Neuro-Oncology Current Issue Abstract AIMS Gliomas have high levels of DNA replication stress and clinical trials of inhibitors of the key replication stress response protein ATR (ataxia telangiectasia and rad 3 related protein) as radiosensitisers are planned. We aimed to investigate the effect of ATR inhibition on the ability of glioma cells to infiltrate and invade the brain. METHOD Live cell imaging in a panel of primary glioma cultures following siRNA or pharmacological inhibition of ATR. Invasion following treatment of murine orthotopic gliomas was determined by immunohistochemistry. Intravital imaging of GFP expressing murine orthotopic xenografts via an intracranial window model of glioma was undertaken. RESULTS Invading margins of human glioma samples demonstrated increased pATR expression relative to core. Live cell imaging demonstrated reduced cell velocity following ATR inhibition (Berzosertib/BAY1895344) or siRNA. Cytoplasmic vacuolation occur red following ATRi or siRNA which were single walled structures which engulf high molecular weight dextran, compatible with blockade of macropinosome processing. Live cell imaging with GFP-integrin α5 and integrin recycling assays showed sequestration of integrins within macropinosomes and reduced integrin cycling. Intravital in vivo imaging of murine xenograft tumours confirmed vacuolation and dextran uptake following ATRi, whilst a further in vivo study demonstrated a reduction in invading tumour cells. CONCLUSION We demonstrate a novel role for ATR in facilitating macropinocytic vesicle trafficking and integrin recycling in GBM cells which results in a profound motility defect in vitro and in vivo. ATR inhibitors are entering early phase trials as radiation sensitisers and we propose that therapeutic benefit will extend beyond DNA damage potentiation. View on Web

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Identification of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients

alexandrossfakianakis shared this article with you from Inoreader Identification of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients via # Neuro-Oncology Current Issue Abstract AIMS Description of effective biomarkers present in biofluids could prove invaluable in GBM diagnosis. Extracellular vesicles (EVs) are essential to intercellular crosstalk in the tumour bulk and circulating EVs have been described as a potential reservoir of GBM biomarkers. Therefore, EV-based liquid biopsies have been suggested as a promising tool for GBM METHOD Ethical approval was obtained for a prospective study of healthy donors and consenting GBM patients at the University Hospitals Sussex (Brighton). To identify GBM specific proteins, small EVs (sEVs) were isolated from plasma samples using differential ultracentrifugation and validated through Nanoparticles tracking analysis, transmission electron microscopy and detection of known sEVs markers such as CD9, CD63, CD81 and HSP70. sEVs content was characterised through mass spectrometry and bioinformatic tools. RESULTS Our data indicate the presence of a GBM infl ammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation including VWF, FCGBP, C3, PROS1, and SERPINA1. Bioinformatic analysis highlighted that all potential markers exclusively identified in patient samples had already been linked with either GBM diagnosis, prognosis or associated signalling, suggesting that sEVs protein cargo could mirror the landscape of the original tumour and that selective circulating sEV-derived proteins might be used as hallmarks for GBM patients. CONCLUSION this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GBM diagnosis and, consequently, patients' prognosis and quality of life. View on Web

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Survival and Prognostic Factors in Melanoma Brain Metastasis (MBM) Treated With Stereotactic Radiosurgery (SRS)

alexandrossfakianakis shared this article with you from Inoreader Survival and Prognostic Factors in Melanoma Brain Metastasis (MBM) Treated With Stereotactic Radiosurgery (SRS) via # Neuro-Oncology Current Issue Abstract AIMS Brain metastasis is a frequent complication in melanoma, ultimately affecting 40–60% of patients with metastatic disease1. In the era of immune checkpoint and small molecule inhibitor therapy, there is a need to identify patient, tumour and treatment characteristics which may predict an improved prognosis in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM). METHOD Retrospective casenote review was carried out for all patients receiving SRS, including gammaknife and cyberknife, for MBM between 2014 – 2020 at Barts Cancer Centre. Overall survival (OS) was calculated using the Kaplan-Meier method. Differences between groups were assessed using the Log-rank (Mantel-Cox) test. RESULTS 93 patients were treated with SRS for MBM, with a median of 15 patients treated per year. The median age at treatment decision was 60 years (range 26 – 90): 59% were male; 41% female. Median num ber of lesions treated was 2 (range 1 – 15). Survival data was available for 74 patients: median overall survival for all patients was 9.5 months, with no significant survival difference by gender nor treatment year (pre-2017 vs. post-2017). However, treatment of 1-2 brain lesions carried a better prognosis compared to 3 or more lesions (median 12.2 vs. 5.7 months, p = 0.0292). CONCLUSION Initial analysis reveals an improved overall survival when fewer MBM are present. Further analyses will examine the impact of the following factors on patient survival: status of extracranial metastases, symptomatic vs. asymptomatic brain metastasis, intratumoral haemorrhage, systemic therapy pre- and post-SRS, and corticosteroid use during and after SRS. View on Web

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Stereotactic Radiosurgery for Brainstem Metastases

alexandrossfakianakis shared this article with you from Inoreader Stereotactic Radiosurgery for Brainstem Metastases via # Neuro-Oncology Current Issue Abstract AIMS Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes. METHOD Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist. RESULTS 41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had p revious WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06). CONCLUSION Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented. View on Web

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Exploring a Link Between Alzheimer’s and Glioma by Investigating SORL1 Network

alexandrossfakianakis shared this article with you from Inoreader Exploring a Link Between Alzheimer's and Glioma by Investigating SORL1 Network via # Neuro-Oncology Current Issue Abstract AIMS Use bioinformatics methods to identify and validate associated proteins and genes in the SORL1 network. Generate a bank of patient derived cells in association with the Royal Preston Hospital BTNW tissue bank. Explore identified targets from the bioinformatics in patient derived cells. METHOD Proteins and genes associated with SORL1 and SORLA were identified on GeneCards. Connectivity mapping of known and predicted interactions linked to SORL1 was explored in STRING. For clinical validation differential expression was investigated by comparing genomic data from GTEX and TCGA, available at Xenabrowser. For survival analysis Kaplan-Meier curves were generated on cBioPortal. The five most differently expressed novel targets are taken forward for laboratory experiments using western blots for protein quantification and immunocytochemistry to identify and visualise target proteins. RESULTS A total of 73 genes (30 from GeneCards and 43 from STRING) were obtained. 63 genes from the generated SORL1-related network were shown to be differentially expressed whilst 40 were significantly different between low-surviving patients and high-surviving patients. The top five associated proteins are CKAP4, CTNND1, FN1, HSPA12A and SORCS3. CKAP4, CTNND1 and FN1 are highly expressed in both glioma and glioblastoma, but low expressed in healthy tissue. HSPA12A is low expressed in cancerous brain tissue and highly expressed in healthy samples. SORCS3 is differentially expressed in healthy samples and glioma, but significantly low expressed glioblastoma. CONCLUSION This project provides insight into SORL1 molecular relationships and function in tissue, cultured cells and serum from a patient cohort including demographics, disease progression and site. View on Web

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Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories

alexandrossfakianakis shared this article with you from Inoreader Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories via Brain Pathology Abstract Recurrence is a major complication of some meningiomas. Although there were many studies on biomarkers associated with higher grades or increased aggressiveness, few studies specifically examined longitudinal samples of primary meningiomas and recurrences from the same patients for molecular life history. We studied 99 primary and recurrent meningiomas from 42 patients by FISH for 22q, 1q, 1p, 3p, 5q, 6q, 10p, 10q, 14q, 18q, CDKN2A/B homozygous deletion, ALT (Alternative Lengthening of Telomere), TERT re-arrangement, targeted sequencing and TERTp sequencing. Although NF2 mutation and 22q were well known to be aetiological events in meningiomas, we found that in these paired meningiomas, combining the two events resulted in an NF2/22q group (57 tumors from 25 patients) which were almost mutually exclusive with those cases without these two changes (42 tumors from 17 patients) for NF2/22q. No other molecular changes were totally unique to NF2/22q or non-NF2/22q tumors. For molecular evolution, NF2/22q meningiomas had higher cytogenetic abnormalities than non-NF2/22q meningiomas (p = 0.003). Most of the cytogenetic changes in NF2/22q meningiomas were present from the outset whereas for non-NF2/22q meningiomas, cytogenetic events were uncommon in the primary tumors and most were acquired in recurrences. For non-NF2/22q tumors, CDKN2A/B homozygous deletion, 1q gain, 18p loss, 3p loss, and ALT were preferentially found in recurrences. Mutations were largely conserved between primary and recurrent tumors. Phylogenetic trees showed 11/11 patients with multiple recurrent tumors had a conserved evolutionary pattern. We conclude that for molecular life history, NF2 and 22q should be regarded as a group. NF2/22q recurring meningiomas showed more cytogenetic abnormalities in the primary tumors, whereas non-NF2/22q meningiomas showed C DKN2A/B deletion and other cytogenetic abnormalities and ALT at recurrences. Although chromosome 1p loss is a known poor prognostic marker in meningiomas, it was also associated with a shorter TBR (time between resection) in this cohort (p = 0.002). View on Web

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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

alexandrossfakianakis shared this article with you from Inoreader Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome via Brain Pathology The brains of 8-week-old wildtype (WT) mice (left) and mice carrying mutations (D1113H) in the ADAR1 gene (right) probed for expression of Interferon Stimulated Gene 15 (ISG-15) using In situ hybridization (red). WT mice show little to no expression of ISG-15 while ADAR1 mutant mouse brain shows a broad and chaotic distribution of expression throughout the brain (8 of many foci circled). Abstract Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi–Gutiérrez Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-c anonical pathways that may accentuate normal aging pathways. View on Web

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Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians

alexandrossfakianakis shared this article with you from Inoreader Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians via International Endodontic Journal Abstract Aim To investigate if there was an association between genetic polymorphisms in TNF-⍺ and its receptors TNFRSF1A and TNFRSF1B with persistent apical periodontitis (PAP) in Brazilian subjects. Methodology Patients who had pulpal necrosis and apical periodontitis installed at the time of treatment, with at least one-year of follow-up after non-surgical root canal treatment were recalled. 378 subjects were included, 150 subjects with signs/symptoms of PAP and 228 subjects with root canal–treated teeth exhibiting healthy perirradicular tissues (healed). Genomic DNA was extracted from saliva and used for TNF-⍺ (rs1800629), TNFRSF1A (rs1800693) and TNFRSF1B (rs1061622) genotyping by real-time PCR. Genotypes and alleles frequencies were evaluated by c2 or Fisher's exact tests and odds ratio were implemented (𝛂= 5%). Results The genetic polymorphism in TNF-α (rs1800629) was associated as a protective factor for the development of PAP (p<0.05), once subjects who presented at least one allele A (AA+AG X GG), had a higher chance to lesion repair (p<0.05). The polymorphisms rs1800693 and rs1061622 in TNF receptors (TNFRSF1A and TNFRSF1B respectively) were not associated with the development of PAP (p>0.05). Conclusions The observed results demonstrate that polymorphism in TNF-α but not in its receptors is associated with PAP. View on Web

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