Publications by authors named "Sebastian Brandner"

255 Publications

Glucocorticoid modulation of synaptic plasticity in the human temporal cortex of epilepsy patients: Does chronic stress contribute to memory impairment?

Epilepsia 2021 Oct 23. Epub 2021 Oct 23.

Department of Neurosurgery, Erlangen University Hospital, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Objective: Memory impairment is common in patients with temporal lobe epilepsy and seriously affects life quality. Chronic stress is a recognized cofactor in epilepsy and can also impair memory function. Furthermore, increased cortisol levels have been reported in epilepsy patients. Animal models have suggested that aggravating effects of stress on memory and synaptic plasticity were mediated via glucocorticoids. The aim of this study was, therefore, to investigate the effect of glucocorticoid receptor (GR) modulation on synaptic plasticity in the human cortex of epilepsy patients.

Methods: We performed field potential recordings in acute slices from the temporal neocortex of patients who underwent surgery for drug-resistant temporal lobe epilepsy. Synaptic plasticity was investigated by a theta-burst stimulation (TBS) protocol for induction of long-term potentiation (LTP) in the presence of GR modulators.

Results: LTP was impaired in temporal cortex from epilepsy patients. Pretreatment of the slices with the GR antagonist mifepristone (RU486) improved LTP induction, suggesting that LTP impairment was due to baseline GR activation in the human cortex. The highly potent GR agonist dexamethasone additionally weakened synaptic strength in an activity-dependent manner when applied after TBS.

Significance: Our results show a direct negative glucocorticoid effect on synaptic potentiation in the human cortex and imply chronic activation of GRs. Chronic stress may therefore contribute to memory impairment in patients with temporal lobe epilepsy. Furthermore, the activity-dependent acute inhibitory effect of dexamethasone suggests a mechanism of synaptic downscaling by which postictally increased cortisol levels may prevent pathologic plasticity upon seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.17107DOI Listing
October 2021

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated.

J Clin Oncol 2021 Oct 7:JCO2100784. Epub 2021 Oct 7.

Department of Neurosurgery, NYU Langone Hospital, New York, NY.

Purpose: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established ( and ), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma.

Methods: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases.

Results: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively).

Conclusion: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00784DOI Listing
October 2021

Filtration-Histogram Based Magnetic Resonance Texture Analysis (MRTA) for the Distinction of Primary Central Nervous System Lymphoma and Glioblastoma.

J Pers Med 2021 Aug 31;11(9). Epub 2021 Aug 31.

Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London WC1N 3BG, UK.

Primary central nervous system lymphoma (PCNSL) has variable imaging appearances, which overlap with those of glioblastoma (GBM), thereby necessitating invasive tissue diagnosis. We aimed to investigate whether a rapid filtration histogram analysis of clinical MRI data supports the distinction of PCNSL from GBM. Ninety tumours (PCNSL = 48, GBM = 42) were analysed using pre-treatment MRI sequences (T-weighted contrast-enhanced (TCE), T-weighted (T), and apparent diffusion coefficient maps (ADC)). The segmentations were completed with proprietary texture analysis software (TexRAD version 3.3). Filtered (five filter sizes SSF = 2-6 mm) and unfiltered (SSF = 0) histogram parameters were compared using Mann-Whitney U non-parametric testing, with receiver operating characteristic (ROC) derived area under the curve (AUC) analysis for significant results. Across all ( = 90) tumours, the optimal algorithm performance was achieved using an unfiltered ADC mean and the mean of positive pixels (MPP), with a sensitivity of 83.8%, specificity of 8.9%, and AUC of 0.88. For subgroup analysis with >1/3 necrosis masses, ADC permitted the identification of PCNSL with a sensitivity of 96.9% and specificity of 100%. For TCE-derived regions, the distinction was less accurate, with a sensitivity of 71.4%, specificity of 77.1%, and AUC of 0.779. A role may exist for cross-sectional texture analysis without complex machine learning models to differentiate PCNSL from GBM. ADC appears the most suitable sequence, especially for necrotic lesion distinction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11090876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472730PMC
August 2021

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.

Neuro Oncol 2021 09;23(9):1457-1469

Bristol Medical School, Brain Tumour Research Centre, Population Health Sciences, University of Bristol, Bristol, UK.

Background: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.

Methods: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.

Results: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.

Conclusions: We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noab105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408882PMC
September 2021

Assessment of conformity of actual thoraco-lumbar pedicle screw dimensions to manufacturers' specifications.

Sci Prog 2021 Jul-Sep;104(3):368504211035035

Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany.

Although correct selection of pedicle screw dimensions is indispensable to achieving optimum results, manufacturer-specified or intended dimensions may differ from actual dimensions. Here we analyzed the reliability of specifications made by various manufacturers by comparing them to the actual lengths and diameters of pedicle screws in a standardized experimental setup. We analyzed the actual length and diameter of pedicle screws of five different manufacturers. Four different screw lengths and for each length two different diameters were measured. Measurements were performed with the pedicle screws attached to a rod, with the length determined from the bottom of the tulip to the tip of the screw and the diameters determined at the proximal and distal threads. Differences in length of > 1 mm were found between the manufacturers' specifications and our actual measurements in 24 different pedicle screws. The highest deviation of the measured length from the manufacturers' specification was 3.2 mm. The difference in length between the shortest and longest screw with identical specifications was 3.4 mm. The highest deviation of the measured proximal thread diameters and the manufacturer's specifications was 0.5 mm. The diameter of the distal thread depends on the shape of the pedicle screw and hence varies between manufacturers in conical screws. We found clear differences in the length of pedicle screws with identical manufacturer specifications. Since differences between the actual dimensions and the dimensions indicated by the manufacturer may vary, this needs to be taken into account during the planning of spine instrumentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/00368504211035035DOI Listing
August 2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Acta Neuropathol 2021 Nov 5;142(5):827-839. Epub 2021 Aug 5.

Institute of Neuropathology, University of Giessen, Giessen, Germany.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02356-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500895PMC
November 2021

Microcystic Cerebral Neoplasm in a Nilgai Antelope (Boselaphus tragocamelus): Putative Microcystic Meningioma.

J Comp Pathol 2021 Jul 27;186:69-72. Epub 2021 Jun 27.

Bavarian Health and Food Safety Authority, Section of Veterinary Pathology, Oberschleißheim, Germany.

Tumours of the nervous system are rare in wild and captive mammals. In this report, we describe an intracranial, solid, space-occupying lesion originating from the meninges in a Nilgai antelope (Boselaphus tragocamelus). Histologically, the tumour had a conspicuous microcystic appearance with features similar to the histological subtype of microcystic meningioma described in humans. This is the first such tumour reported in this species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcpa.2021.05.007DOI Listing
July 2021

Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage.

Cerebrovasc Dis 2021 Jul 20:1-9. Epub 2021 Jul 20.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far.

Objective: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors.

Methods: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months.

Results: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health.

Conclusion: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000517242DOI Listing
July 2021

Operative variations in temporal lobe epilepsy surgery and seizure and memory outcome in 226 patients suffering from hippocampal sclerosis.

Neurol Res 2021 Nov 22;43(11):884-893. Epub 2021 Jun 22.

Department of Neurosurgery, Medical University Vienna, Vienna, Austria.

: The aim of this retrospective cohort study was to assess seizure and memory outcomes following temporal lobe surgery in patients suffering from medically refractory temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS).: A retrospective monocentric data analysis was performed in consecutive patients who were operated on during 2002-2018. In the first decennium, standard temporal lobe resections (TLR) were predominately performed, and later, antero-temporal lobe resections (ATLR) were mainly performed. Seizure and memory outcomes over time were assessed according to ILAE/Engel classification and the Berlin Amnesia Test (BTA), respectively.: Altogether, 231 surgeries were performed on 226 patients (mean age, 40 years [range, 10-68 years]; male: female, 1:1.4; mean seizure duration, 25 years; and mean follow-up duration, 4.75 years [range, 1-16]). Recently, outcomes of 78.3% of the patients in the total cohort were classified as Engel class I, with 54.9% of patients being completely seizure free. The recent cohort of ATLR since 2012 showed significant more completely seizure-free patients than before 2012 (Engel IA 46.6% versus 67.7%, p < 0.0025, ), although the Kaplan Meier analysis of all patients favors TLR for better seizure outcome (61% ATLR vs 73% TLR seizure free after 5 yrs, log rank p < 0.001). Verbal memory improved significantly in non-dominant patients. Minor neurological complications were noted (permanent severe complications, 0.4%; temporary severe complications, 4.8%).: Significant improvements in seizure and memory outcomes were observed over time, with surgical technique and seizure duration as important prognostic factors. Early admittance for surgery may favor an excellent seizure outcome in patients undergoing temporal lobe resection for HS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01616412.2021.1942407DOI Listing
November 2021

Molecular Diagnostics of Adult Gliomas in Neuropathological Practice.

Acta Med Acad 2021 Apr;50(1):29-46

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, the National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, United Kingdom.

This review focuses on adult gliomas, highlighting the most relevant biomarkers in the diagnosis of these tumours and the use of DNA methylation arrays to complement conventional molecular diagnostic techniques. The discovery and characterisation of diagnostic and prognostic biomarkers in brain tumours has significantly changed the neuropathological landscape over the last decade. These include mutations in the IDH1 and IDH2 genes in astrocytomas and oligodendrogliomas, histone H3 K27M mutations in midline gliomas, or BRAF mutations in a range of low-grade and high-grade glial and glioneuronal tumours. Other biomarkers of relevance are mutations in the TERT promoter, the ATRX gene, and genomic alterations such as 1p/19q codeletion, EGFR amplification, and chromosome 7 gain and 10 loss. The development of DNA methylation profiling and algorithmic classification of brain tumours has further enhanced the diagnostic abilities of neuropathologists. Methylation profiling is particularly useful for the diagnostic workup of biopsies with an inconclusive molecular test results, small samples, or samples with indistinctive low-grade or high-grade histology. This technology has become indispensable for the risk stratification of ependymal tumours, medulloblastomas and meningiomas. CONCLUSION: This review highlights the importance of an integrated approach to brain tumour diagnostics and gives a balanced view of the relevance and choice of conventional and molecular techniques in the workup of adult gliomas in diagnostic neuropathology practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5644/ama2006-124.324DOI Listing
April 2021

Alzheimer's disease neuropathological change three decades after iatrogenic amyloid-β transmission.

Acta Neuropathol 2021 07 28;142(1):211-215. Epub 2021 May 28.

Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, WC1N 3BG, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02326-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217014PMC
July 2021

Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas.

Cancer Discov 2021 Sep 20;11(9):2230-2247. Epub 2021 Apr 20.

Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Molecular groups of supratentorial ependymomas comprise tumors with or -involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared as a partner gene. Somatic overexpression of -associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation , and cross-species comparative analyses identified as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. SIGNIFICANCE: fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by fusion-positive tumors, such as GLI2..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-0963DOI Listing
September 2021

Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1.

Acta Neuropathol 2021 07 19;142(1):179-189. Epub 2021 Apr 19.

Division of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.

Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02302-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217054PMC
July 2021

Genomic Prognosticators and Extent of Resection in Molecularly Subtyped World Health Organization Grade II and III Gliomas-A Single-Institution, Nine-Year Data.

World Neurosurg 2021 07 15;151:e217-e233. Epub 2021 Apr 15.

Victor Horsley Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, Queen Square, University College London Hospitals NHS Foundation Trust, London, United Kingdom; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom.

Background: World Health Organization (WHO) grade II and III isocitrate dehydrogenase wild-type (IDH-wt) gliomas are often treated as WHO grade IV glioblastomas. However, cumulative evidence indicates that IDH mutation status alone is insufficient in predicting survival. The current study examines molecular and clinical markers to further prognostically stratify WHO grade II and III gliomas, in particular, IDH-wt.

Methods: A single institution's records were retrospectively reviewed for molecularly stratified WHO grade II and grade III gliomas over a 9-year period (2010-2019). Clinical data, IDH1/IDH2 status, EGFR amplification, and other molecular markers were recorded and correlated to the study outcomes. These outcomes were defined as progression-free survival (PFS), overall survival (OS), and time to malignant progression (TtMP).

Results: A total of 167 and 42 WHO grade II and III gliomas, respectively, were identified, totaling 209 cases with 157 IDH1/2 mutated and 52 IDH-wt tumors. The presence of IDH1/2 mutation was associated with longer OS (P < 0.0001) and PFS (P < 0.0001) but not with TtMP (P = 0.314). Lack of EGFR amplification, younger age, and greater extent of resection (EOR) (≥80%) were identified as independent, favorable OS prognostic factors. In the IDH-wt cohort, multivariate analysis indicated that older age (P = 0.003) and lesser EOR (<80%) (P = 0.007) are associated with worse OS. In addition, EGFR amplification showed a trend toward shorter OS in the IDH-wt cohort (P = 0.073).

Conclusions: IDH1/2 mutation favors longer OS and PFS but does not protect from malignant progression. Lack of EGFR amplification, younger age and greater EOR are favorable OS prognosticators. In the IDH-wt cohort, older age and lesser EOR were linked to worse OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2021.04.026DOI Listing
July 2021

Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion.

Cell 2021 04 14;184(9):2454-2470.e26. Epub 2021 Apr 14.

Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK; CRUK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, University of Edinburgh, Edinburgh EH42XR, UK. Electronic address:

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099351PMC
April 2021

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Nat Commun 2021 04 12;12(1):2148. Epub 2021 Apr 12.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1;CHD7 signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1;CHD7 xenograft model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22379-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042111PMC
April 2021

The white matter is a pro-differentiative niche for glioblastoma.

Nat Commun 2021 04 12;12(1):2184. Epub 2021 Apr 12.

Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK.

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22225-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042097PMC
April 2021

Potential of Magnetic Hyperthermia to Stimulate Localized Immune Activation.

Small 2021 04 18;17(14):e2005241. Epub 2021 Mar 18.

UCL Cancer Institute, University College London (UCL), Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK.

Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.202005241DOI Listing
April 2021

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

Cochrane Database Syst Rev 2021 03 12;3:CD013316. Epub 2021 Mar 12.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide.

Objectives: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide.

Search Methods: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014.

Selection Criteria: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis.

Data Collection And Analysis: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals.

Main Results: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status.

Authors' Conclusions: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD013316.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078495PMC
March 2021

Pedicle Screw Instrumentation of the Cervicothoracic Junction in the Sitting Position using CT-guided Navigation: Application and Technical Aspects.

J Neurol Surg A Cent Eur Neurosurg 2021 Mar 4;82(2):176-181. Epub 2021 Feb 4.

Department of Neurosurgery, University of Erlangen, Erlangen, Germany.

Background:  We evaluate the feasibility and potential advantages of spinal CT navigation in the placement of pedicle screws at the cervicothoracic junction in the sitting position to counteract the anatomy-related limitations of 2D fluoroscopy.

Methods:  We retrospectively analyze the data from 15 patients who underwent CT-based navigation-guided placement of a total of 36 pedicle screws at the cervicothoracic junction in the sitting position.

Results:  CT-based spinal navigation is a useful method in increasing accuracy of pedicle screw instrumentation in the sitting position, successfully counteracting the anatomy-related limitations of 2D fluoroscopy at the cervicothoracic junction.

Conclusion:  CT-based navigation-guided placement of pedicle screws at the cervicothoracic junction in the sitting position proved to be an accurate, safe, and user-friendly method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1718409DOI Listing
March 2021

Humanised transgenic mice are resistant to chronic wasting disease prions from Norwegian reindeer and moose.

J Infect Dis 2021 Jan 27. Epub 2021 Jan 27.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom.

Chronic wasting disease (CWD) is the transmissible spongiform encephalopathy or prion disease affecting cervids. In 2016 the first cases of CWD were reported in Europe in Norwegian wild reindeer and moose. The origin and zoonotic potential of these new prion isolates remain unknown. In this study to investigate zoonotic potential we inoculated brain tissue from CWD-infected Norwegian reindeer and moose into transgenic mice overexpressing human prion protein. After prolonged post-inoculation survival periods no evidence for prion transmission was seen suggesting that the zoonotic potential of these isolates is low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiab033DOI Listing
January 2021

Sarcoma classification by DNA methylation profiling.

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Time to focus on circulating nucleic acids for diagnosis and monitoring of gliomas: A systematic review of their role as biomarkers.

Neuropathol Appl Neurobiol 2021 06 29;47(4):471-487. Epub 2021 Jan 29.

Department of Research, Advanced Diagnostics and Technological Innovation, Genomic and Epigenetic Unit, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Gliomas are diffusely growing tumours arising from progenitors within the central nervous system. They encompass a range of different molecular types and subtypes, many of which have a well-defined profile of driver mutations, copy number changes and DNA methylation patterns. A majority of gliomas will require surgical intervention to relieve raised intracranial pressure and reduce tumour burden. A proportion of tumours, however, are located in neurologically sensitive areas and a biopsy poses a significant risk of a deficit. A majority of gliomas recur after surgery, and monitoring tumour burden of the recurrence is currently achieved by imaging. However, most imaging modalities have limitations in assessing tumour burden and infiltration into adjacent brain, and sometimes imaging is unable to discriminate between tumour recurrence and pseudo-progression. Liquid biopsies, obtained from body fluids such as cerebrospinal fluid or blood, contain circulating nucleic acids or extracellular vesicles containing tumour-derived components. The studies for this systematic review were selected according to PRISMA criteria, and suggest that the detection of circulating tumour-derived nucleic acids holds great promises as biomarker to aid diagnosis and prognostication by monitoring tumour progression, and thus can be considered a pathway towards personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nan.12691DOI Listing
June 2021

Imaging characteristics of H3 K27M histone-mutant diffuse midline glioma in teenagers and adults.

Quant Imaging Med Surg 2021 Jan;11(1):43-56

Teenage and Young Persons' Cancer Unit, Department of Paediatric Oncology, University College London Hospitals NHS Foundation Trust, London, UK.

Background: To assess anatomical and quantitative diffusion-weighted MR imaging features in a recently classified lethal neoplasm, H3 K27M histone-mutant diffuse midline glioma [World Health Organization (WHO) IV].

Methods: Fifteen untreated gliomas in teenagers and adults (median age 19, range, 14-64) with confirmed H3 K27M histone-mutant genotype were analysed at a national referral centre. Morphological characteristics including tumour epicentre(s), T2/FLAIR and Gadolinium enhancement patterns, calcification, haemorrhage and cyst formation were recorded. Multiple apparent diffusion coefficient (ADC, ADC) regions of interest were sited in solid tumour and normal appearing white matter (ADC) using post-processing software (Olea Sphere v2.3, Olea Medical). ADC histogram data (2, 5, 10 percentile, median, mean, kurtosis, skewness) were calculated from volumetric tumour segmentations and tested against the regions of interest (ROI) data (Wilcoxon signed rank test).

Results: The median interval from imaging to tissue diagnosis was 9 (range, 0-74) days. The structural MR imaging findings varied between individuals and within tumours, often featuring signal heterogeneity on all MR sequences. All gliomas demonstrated contact with the brain midline, and 67% exhibited rim-enhancing necrosis. The mean ROI ADC value was 0.84 (±0.15 standard deviation, SD) ×10 mm/s. In the largest tumour cross-section (excluding necrosis), an average ADC value of 1.12 (±0.25)×10 mm/s was observed. The mean ADC ratio was 1.097 (±0.149), and the mean ADC ratio measured 1.466 (±0.299). With the exception of the 2 centile, no statistical difference was observed between the regional and histogram derived ADC results.

Conclusions: H3 K27M-mutant gliomas demonstrate variable morphology and diffusivity, commonly featuring moderately low ADC values in solid tumour. Regional ADC measurements appeared representative of volumetric histogram data in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/qims-19-954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719951PMC
January 2021

Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1.

Acta Neuropathol 2021 02 14;141(2):281-290. Epub 2020 Dec 14.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-020-02247-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847462PMC
February 2021

The Diagnostic and Therapeutic Role of Leptin and Its Receptor ObR in Glioblastoma Multiforme.

Cancers (Basel) 2020 Dec 9;12(12). Epub 2020 Dec 9.

Department of Basic Medical Sciences, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad 44000, Pakistan.

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764087PMC
December 2020

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Cell 2020 12 30;183(6):1617-1633.e22. Epub 2020 Nov 30.

Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791404PMC
December 2020

Parenchymatous hematoma in patients with atraumatic subarachnoid hemorrhage: Characteristics, treatment, and clinical outcomes.

Int J Stroke 2021 08 19;16(6):648-659. Epub 2020 Nov 19.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Data regarding the influence of concomitant parenchymatous hematoma (PH) on long-term outcomes in patients with atraumatic subarachnoid hemorrhage (SAH) are scarce. Further, it is not established if these patients benefit from surgical intervention.

Aim: The aim of this study was to determine the influence of concomitant PH in SAH patients on functional long-term outcome, and whether these patients may benefit from surgical hematoma evacuation.

Methods: Over a 5-year period, all consecutive patients with SAH treated at the Departments of Neurology, Neuroradiology, and Neurosurgery, at the University Hospital Erlangen (Germany) were recorded. In addition to the clinical and imaging characteristics of SAH, we documented the presence, location, and volume of PH as well as treatment parameters. Outcome assessment at 12 months included functional outcome (modified Rankin scale (mRS), favorable = 0-2), health-related quality of life, and long-term complications. For outcome analysis, a propensity score matching (ratio 1:1, caliper 0.1) was performed to compare SAH patients with and without PH. Sub-analyses were performed regarding PH treatment (surgical evacuation vs. conservative).

Results: A total of 494 patients with atraumatic SAH were available. Eighty-five (17.2%) had PH on initial imaging. SAH patients with PH had a worse clinical condition on admission and had a greater extent of subarachnoid/intraventricular hemorrhage. Median PH volume was 11.0 ml (5.4-31.8) with largest volumes observed in patients with ruptured middle cerebral artery (MCA)-aneurysm (31.7 ml (16.3-43.2)). After propensity-score matching (PSM), patients with PH had worse functional outcomes at 12 months (modified Rankin scale (mRS) 0-2: PH 31.8% vs. ØPH57.7% p < 0.001), and a lower rate of self-reported health compared to patients without PH (EQ-5D VAS: PH 50(30-70) vs. ØPH 80(65-95); p < 0.001). In PH patients, surgical evacuation was associated with a higher rate of favorable outcome at 12 months compared to those treated conservatively (surgery 14/28 (50.0%) vs. conservative 14/57 (24.6%); adjusted odds-ratio (OR; 95%CI): 1.34 (1.08-1.66); p = 0.001), irrespective of aneurysm location. Subgroup-analysis revealed positive associations of surgical hematoma evacuation with outcome in subgroups with larger PH volumes (>10 ml; OR (95%CI): 1.39 (1.09-1.79)), frontal PH location (OR 1.59 (1.14-2.23)), and early surgery (within 600 min after onset; OR 1.42 (1.03-1.94)).

Conclusions: Concomitant PH occurs frequently in patients with SAH and is associated with functional impairment after 1 year. Surgical evacuation of PH may improve outcomes in these patients, irrespective of aneurysm-location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1747493020971878DOI Listing
August 2021

Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns.

J Neuropathol Exp Neurol 2020 11;79(11):1141-1146

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlaa109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577514PMC
November 2020
-->