bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS10.6.A GLIOBLASTOMA CELLS IMITATE NEURON’S EXCITABILITY IN ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES
Authors: Tong T , Ozsvar A , Hou W , Capogna M , Korshøj A R 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is a highly lethal cancer with a low treatment success rate due to its inter- and intra-patient molecular and physiological heterogeneity, and its complex interaction with brain tissue. Neuron-to-brain tumor-synaptic-communications (NBTSCs) are believed to contribute to glioma progression and tumor-induced epilepsy. However, the physiology of these synaptic interactions in the tumor-infiltrated human neocortex remains largely uncharacterized. In this study, we investigated the intrinsic electrical properties of cells and NBTSCs in the tumor-infiltrated human cortex.

MATERIAL AND METHODS
We established a unique experimental workflow that enables us to investigate glioma cells in acute and cultured human tumor-infiltrated brain slices. We utilized an adeno-associated virus-assisted gene delivery technique to selectively express fluorescence proteins in a cell-type specific manner. By performing fluorescence-guided whole-cell patch clamp recording, we characterized the electrophysiological properties of glioma cells and neurons under the tumor microenvironment.

RESULTS
We observed that glioma cells from tumor-infiltrated human brain samples display relatively depolarized -32.59 + 3.16 mV resting membrane potential and high input resistance of 1.73 + 0.43 GΩ, with 44.44% of glioma cells exhibit spikelets or distorted-action potentials upon current injection. Consistent with previous studies, some glioma cells (11.8%) from both acute and cultured human brain slices exhibit spontaneous excitatory postsynaptic currents (sEPSC). In addition, the tumor-infiltrated microenvironment significantly influences the proximal neurons’ physiology and the neuronal microcircuitry. Neurons within the tumor region show abnormal intrinsic electrical properties, depolarized resting membrane potential (-37.66 + 4.32 mV), and a significant reduction in spontaneous synaptic input frequency.

CONCLUSION
Collectively, we consolidate the existence of NBTSCs in human cancer patients and unprecedentedly reveal that glioma cells exhibit neuron-like excitability, which is contrary to the common understanding that they are considered as non-excitable. Under the tumor microenvironment, neurons display hyperexcitability. Our newly established organotypic human brain slice culture platform provides potential grounds for exploring further the biological characteristics of gliomas.

SUPPORT/DISCLOSURE
This study is supported by grants to AK (DCCC Consortium grant number R295-A16770 funded by the Danish Comprehensive Cancer Center); to MC (Lundbeck-NIH grant number R325-2019 funded by the Lundbeck Foundation, DFF-1 project 37741 funded by the Independent Research Fund Denmark).
OS10.7.A TUMOR-ASSOCIATED ASTROCYTES PROMOTE TUMOR PROGRESSION OF SONIC HEDGEHOG MEDULLOBLASTOMA BY SECRETING LCN2
Authors: Chang Q , Li H 
Published: September 2023

Abstract

BACKGROUND
Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive.

MATERIAL AND METHODS
We explored the function of TAAs of SHH-MB in transgenic mouse model and co-culture system by a series of molecular biological techniques. To illuminate the TAAs distribution pattern during tumor progression of MB, we firstly detected MB transgenic mice bearing tumor at different time points by nuclear Magnetic resonance imaging (MRI). Histologic sections were then evaluated under microscope after H&E staining. The RNA-sequencing was also performed to evaluate differential expression between normal astrocytes (ASs) and tumor-associated astrocytes (TAAs). Bio-informatic analysis was followed to find the specific gene expressed in TAAs. Drug treatment of TAA inhibitor was finally applied in the animal model to clarify its effects on tumor progression.

RESULTS
We illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors and dissemination foci. We further demonstrated that LCN2 secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo.

CONCLUSION
We for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.
OS12.5.A HIGH-GRADE GLIOMAS OCCURRING IN TEENAGERS AND YOUNG ADULT PATIENTS COMPRISE NOVEL MOLECULAR SUBGROUPS
Authors: Clarke M T , Pereira R , Mackay A , Grabovska Y , Clarke A , Nicoll J , Procter J , Moore A , Schagen J , Walker L , Roncaroli F , Ogunbigi O , Jacques T , Marshall L , Carceller F , Reisz Z , Al-Sarraj S , Vinci M , Kurian K , Ng H , Brandner S , Jones C 
Published: September 2023

Abstract

BACKGROUND
High-grade gliomas (HGG) arise in any central nervous system location, in adults and children, with a poor prognosis. HGGs in teenagers and young adults (TYA) are understudied; this project aimed to characterise these tumours and identify potential therapeutic targets.

MATERIAL AND METHODS
HGG samples (n=195, FFPE/FF, 13-30 years) were collected from national/international collaborators, excluding well-characterised entities (histone/IDH-mutant). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package), n=195) classified cases against a reference cohort. Calibrated scores guided workflows to characterise mutational landscapes including RNA-based ArcherDx fusion panel (n=112), whole exome sequencing (n=84), and histological reviews in parallel. Well-characterised entities (n=50, including IDH-mutant tumours (n=18), PXA (n=12)) were excluded.

RESULTS
Of the cases scoring &gt;0.6, 64% classified as paediatric-type subgroups (pedHGG_RTK1A/B/C (30%), pedHGG_MYCN (10%), pedHGG_A/B (7%), pedHGG_RTK2A (6%)). 29% classified as subgroups more frequently seen in adults (GBM_MES (12%), GBM_RTK1/2 (3%)). 54% classified with a score &lt;0.6. 38% cases were assigned to novel, recently identified, poorly-characterised subgroups with distinct methylation profiles and molecular features (HGG_B, HGG_E, ANTCON, GBM_CBM). Frequency comparisons to publicly available methylation data showed GBM_MES_ATYP tumours are TYA age-specific, in contrast to adult age-specific GBM_MES_TYP. Copy number profiling identified frequent changes across the cohort, including chromosomal gains (chr1q (54%), chr2 (22%), chr7 (41%)) and losses (chr10 (40%), chr13 (64%)). Focal amplifications included PDGFRA (12%), CDK4 (7%), MYCN/ID2 (3%), MYC (2%) and EGFR (0.7%) and the most common focal deletion was CDKN2A/p16 (12%). The most frequent glioma-associated somatic variants included TP53, PDGFRA, EGFR, and NF1. BCOR alterations were enriched compared to adult and paediatric reference cohorts. 10% cases showed a hypermutator phenotype, enriched in HGG_E. CDK4 amplifications were recurrent in GBM_RTK1 and GBM_CBM. Histology showed variable cytological and architectural features within novel subgroups.

CONCLUSION
TYA HGG comprise novel subgroups with distinct methylation profiles and molecular characteristics, representing opportunities to refine future treatment.
OS13.5.A MOLECULAR CHARACTERISTICS AND PROGNOSTIC BIOMARKERS OF CENTRAL NEUROCYTOMA
Authors: Krech M , Muench A , Teichmann D , Kuzman P , Münther M , Weber K , Wenger-Alakmeh K , Onken J , Vajkoczy P , Behling F , May S , Ntoulias G , Krauss J K , Atallah O , Esmaeilzadeh M , Mueller W C , Heppner F L , Koch A , Capper D , Kaul D , Paulus W , Plate K H , Beschorner R , Neumann J E , Hartmann C , Thomas C , Schweizer L 
Published: September 2023

Abstract

BACKGROUND
Central neurocytomas (CN) are intraventricular brain tumors predominantly arising in young adults. Long-term prognosis is favorable in the majority of cases, whereas a considerable proportion of patients experience disease progression. Progression risk is currently assessed morphologically based on the presence of histological signs of atypia and/or an elevated ki67 proliferation index (&gt;3%). The molecular profile and etiology of CN remains elusive and molecular biomarkers for risk stratification have not been identified yet.

MATERIAL AND METHODS
We analyzed a retrospective multi-institutional cohort of 108 CNs by genome-wide DNA methylation profiling. DNA whole exome sequencing was performed in 12 cases. Follow-up information was available for 45 patients.

RESULTS
The histological diagnosis of neurocytoma was epigenetically confirmed in 96 cases. 12/108 cases (11%) were assigned to another methylation class based on the v12.5 Heidelberg Brain Tumor Classifier. Median age at diagnosis was 29 years, distribution among sexes was equal. Based on morphology and immunohistochemistry, tumors were diagnosed as classical CN (n = 71), CN with increased proliferation (n = 10) and atypical CN (n = 15). In 49/72 cases (68%, NA=24), an elevated Ki67 above 3% was reported. DNA whole exome sequencing revealed no recurrent genetic alterations. Most copy number profiles were balanced (n = 87), while some cases (n = 9) showed individual chromosomal alterations (e.g. chr. +5, n = 3). Tumor recurrence was observed in 16/45 (36%, NA = 51) of cases. Median progression-free survival (PFS) after the initial diagnosis was 72 months, none of the patients died (observation time: range 3 - 141 months). In 16 cases, surgery was followed by adjuvant radiotherapy, predominantly in patients with subtotal resection (STR: n = 11, 69%; GTR: n = 5). There was no significantly different outcome between classical and atypical CNs (n = 45; median PFS 73 months vs. 26 months, p-value = 0.067) and cases with low vs. elevated Ki67 (n = 45; median PFS NA vs. 72 months, p-value = 0.44).

CONCLUSION
Preliminary data of our study indicate that histological diagnosis and Ki67 proliferation rate were not associated with PFS in epigenetically defined neurocytomas. Further research using clinical and molecular covariates is necessary to identify novel biomarkers to predict recurrence risk and benefit from adjuvant radiotherapy.
OS13.7.A ONSET SYMPTOMS PREDICT SURVIVAL IN GLIOBLASTOMA PATIENTS -REAL WORLD DATA FROM 1719 PATIENTS IN THE SWEDISH BRAIN TUMOUR REGISTRY 2018-2021
Authors: Bruhn H , Rosenlund L , Tavelin B , Henriksson R 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma, the most common malignant brain tumour in adults, still has a poor long term survival. Non-invasive clinical prognostic markers are important to more accurately predict a patient’s survival. The aim of our register-based real-life study was to explore if onset symptoms have a prognostic value for survival.

MATERIAL AND METHODS
Data on onset symptoms and survival, as well as known prognostic factors, were retrieved for all glioblastoma patients registered in the Swedish Brain Tumour Registry between 2018 and 2021. The prognostic impact of different onset symptoms were calculated using the Cox proportional hazard model.

RESULTS
Data from 1719 adults with pathologically verified glioblastoma were analysed. The median survival was 347 days (330-364). The two-year survival was 21.9 %. The most common onset symptoms were focal neurological deficits, cognitive dysfunction, headache, epilepsy, and signs of raised intracranial pressure, with some patients having multiple symptoms. Patients with initial cognitive dysfunction had a significantly shorter survival compared to patients without cognitive dysfunction (p&lt;0.001). Patients with onset seizures had significantly longer survival compared to patients with no onset seizures (p&lt;0.001). The differences in survival remained after Cox regressions adjusting for known prognostic factors. When comparing tumors of the same size, there was still a difference in survival between patients having or not having cognitive dysfunction.

CONCLUSION
This large real-life study shows that initial cognitive impairment is a negative, and epileptic seizure at onset is a positive prognostic factor for survival in glioblastoma patients.
P01.02.A WHOLE-BRAIN STRUCTURAL CONNECTIVITY PREDICTS COGNITIVE OUTCOMES IN PRETREATED PATIENTS WITH WHO GRADE 3 OR 4 GLIOMAS
Authors: Friedrich M , Stoffels G , Filss C P , Lohmann P , Mottaghy F M , Weiss Lucas C , Ruge M I , Shah N J , Caspers S , Langen K J , Fink G R , Galldiks N , Kocher M 
Published: September 2023

Abstract

BACKGROUND
Glioma patients frequently suffer from cognitive dysfunction potentially related to brain damage caused by tumor invasion or therapeutic intervention. We hypothesized that, as in other neurological disorders, the long-term outcome of cognitive functions in glioma patients critically depends on maintaining the structural connectivity of multiple interconnected networks.

PATIENTS AND METHODS
One hundred and twenty-one glioma patients (median age, 52 years; median ECOG score, 1) with histomolecularly characterized CNS WHO grade 3 or 4 gliomas were investigated after a median time of 14 months (range, 1-214 months) following first-line therapy, including resection and chemoradiation with alkylating agents. Hybrid amino acid PET/MR imaging using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine, a brain-networks-based cortical parcellation into nodes, and advanced fiber tractography tools were used for constructing fiber-count-weighted connectivity matrices. Cognitive performance was measured by ten different tests concerning various cognitive domains. The connectivity matrices and the patients' test scores were applied to a machine learning-based model that identified critical fiber connections, cortical nodes, and involved networks for predicting cognitive performance in the assessed domains.

RESULTS
Compared to a matched cohort of healthy subjects, the cognitive scores of the patients were significantly lower in 9 of 10 cognitive tests. The most affected domains were executive function/concept-shifting (-72%), attention/processing speed (relative performance, -53%), followed by semantic word fluency (-25%), verbal working and semantic memory (-8 and -22%, respectively), and visual working memory (-11 to -20%). For each cognitive test, a subset of connections (median number, 254; range, 32-542) was identified whose fiber count sum showed a correlation with the actual scores in a linear model (median R2, 0.37; range, 0.16-0.44). Leave-one-out cross-validation confirmed the model's generalizability in 7 of 10 tests (median correlation coefficient for predicted compared to observed scores, 0.47; range 0.39-0.57). The distribution of critical cortical regions (node degree of ≥ 5 predictive edges), found in 90% of the cross-validation iterations, varied considerably between domains. These included predominantly left-sided cortical nodes of the visual, somatomotor, dorsal/ventral attention, and default mode networks. Highly critical nodes (degree of 15-20 predictive edges) included the default-mode network’s left temporal and bilateral posterior cingulate cortex.

CONCLUSION
These results suggest that the cognitive performance of pretreated glioma patients is strongly related to the structural connectivity within multiple brain networks and depends on the integrity of known network hubs.
P01.10.B EMOTION RECOGNITION IN PATIENTS WITH LOW-GRADE GLIOMA: THE RELATIONSHIP WITH TUMOR LOCATION AND TUMOR VOLUME
Authors: Siebenga F F , van der Weide H L , Gelmers F , Rakers S E , Kramer M C A , Enting R H , Bosma I , van der Hoorn A , Jeltema H , Wagemakers M , Groen R J M , Spikman J M , Buunk A M 
Published: September 2023

Abstract

BACKGROUND
Patients with low-grade gliomas (LGG), generally function well at the time of diagnosis and have a favourable prognosis. However, LGG can have impact on cognitive functioning of patients. To date, little is known about social cognition (SC) in patients with LGG. Social cognitive functions allow the processing of complex social information, with as important element the ability to recognize other people’s emotional expressions. Inaccurate recognition or misinterpretation of emotional facial expressions can lead to impairments in social functioning, which can have adverse effects on quality of life. Therefore, the aim of the present study was to investigate emotion recognition in patients with LGG and the relationship with tumor location and tumor volume.

MATERIAL AND METHODS
125 patients with IDH mutated astrocytoma and oligodendroglioma grade 2 and 3, were matched with 169 healthy controls (HC). Tumor location and volume were evaluated pre-radiotherapy based on MRI scans. As a parameter for LGG volume the clinical radiotherapy target volume was used. SC was measured with a test for emotion recognition, i.e. the Facial Expressions of Emotion Stimuli and Tests (FEEST), after surgery. Descriptive statistics and between-group comparisons were performed.

RESULTS
On a group level, patients with LGG performed significantly lower on the FEEST total score compared to HC. Also, compared to norm data used in clinical practice, 32.8% of the patients showed an impaired performance. Larger LGG volume was significantly associated (p &lt; 0.001) with poorer performance on emotion recognition. However, no direct association between LGG location (frontal, temporal, parietal) and emotion recognition was found.

CONCLUSION
In patients with LGG, impaired emotion recognition is often present before start of radiotherapy, and is related to larger LGG volume but not to location. Because of the relatively favourable prognosis of patients with LGG, maintaining quality of life is of high importance. Therefore, a thorough neuropsychological examination, including measurements for SC, is necessary to inform patients with LGG about possible changes in SC, and offer appropriate psychoeducation and care.
P02.01.A THE ONGOING WAY TO PROVIDE EVIDENCE OF THE ANCESTRAL FOUNDER CELL TO OVERCOME THERAPEUTIC RESISTANCE IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Brognaro E 
Published: September 2023

Abstract

BACKGROUND
Multiple clinical aspects and accumulating indirect and direct experimental data are providing evidence that the supratentorial brain parenchyma becomes entirely and quiescently micro-infiltrated long before primary tumor bulk growth. Two diffuse micro-infiltrations occur in IDH-wildtype glioblastoma, the first long before primary bulk growth (the only one effective in giving rise to distant relapses) and the second, well known but ineffective, during bulk growth and evolution. Furthermore, they clearly indicate that there are two causes of therapeutic resistance, the second never yet therapeutically challenged.

MATERIAL AND METHODS
The collection of separate multiregional samples in the tumor bulk enabled us to reconstruct the phylogenetic tree of the primary tumor mass. However, the therapeutic solution to IDH-wildtype glioblastoma lies in the micro-infiltrated brain where the ancestral founder CSCs reside quiescently (they are invariably extinct in the tumor bulk at the time of diagnosis). We are using the four ethical methods, as part of normal glioblastoma surgery, to sample the micro-infiltrated brain parenchyma to identify and deeply characterize the dormant ancestral founder CSCs.

RESULTS
In the bulk, multiple separated samples allowed us to infer the phylogenetic tree of the tumor as well as driver and passenger events and the CSC variants. The ethical methods to sample the micro-infiltrated brain parenchyma are enabling us to identify and characterize the ancestral founder CSCs, which hibernate in the perivascular parenchymal niches of the supratentorial brain (their activation being the only cause of distant recurrences).

CONCLUSION
The first cause of therapeutic resistance is due to intratumor heterogeneity and the second to the silent presence in the whole supratentorial brain of quiescent founder CSCs. The IDH-wildtype glioblastoma is the only brain tumor that arises from the III layer of the SVZ and it is able to disseminate widely across the supratentorial brain parenchyma before starting its growth. Only the identification and characterization of the ancestral founder CSC will enable us to simultaneously overcome both causes of resistance and provide a therapeutic solution to this dreadful malignancy. Indeed, the ancestral founder CSC is identical to the premalignant progenitor of the SVZ and to the cell that activated in one (or more) brain location, gave rise to the primary tumor bulk(s) and transmitted the ancestral driver genomic alterations to all subsequent evolutionary CSC variants.
P02.02.B LOSS OF ELAVL2 PROMOTES MAINTENANCE AND TUMORIGENIC COMPETENCE IN GLIOBLASTOMA
Authors: Argento C M , Modelska A , Zasso J , Soldano A , Dassi E , Destefanis E , Ricci G , Mione M C , Idilli A I , Longhi S , Rosatti E F , Sighel D , Broso F , Quattrone A 
Published: September 2023

Abstract

BACKGROUND
IDH1 wild type glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. It has been proven that it is driven by glioma stem cells (GSCs) that govern tumor growth and determine treatment resistance. GSCs transit between active and quiescent states, whose balance is likely dependent on both cell-autonomous and microenvironmental signals.

MATERIAL AND METHODS
transgenic cell lines were produced by retroviral infection following standard protocols, as well as zebrafish growths and orthotopic mouse brain transplants. Transgenic Drosophila lines were crossed with conventional procedures. Phenotypic evaluations, iClip protocol were conducted with standard methods as well.

RESULTS
in our study, we identified the gene ELAVL2, encoding the HuB protein, as commonly lost in GBM. We demonstrated that the ELAVL2 deletion occurs collaterally with the CDKN2A/B deletion, very close in the 9p21 region, but it is also present as an independent event. Rescue of HuB expression on a panel of ELAVL2-null GSCs affects their invasive ability and shifts their cell state toward differentiation, with loss of self-renewal and multipotency. A reduction in the proportion of quiescent cells determines an increased cytotoxicity of the drug temozolomide (TMZ).We validated these results in vivo, in two different animal models, showing that the tumorigenic potential of xenotransplanted ELAVL2-rescued GSCs is greatly reduced with respect to the ELAVL2-null GSCs in zebrafish and in the mice brain. We also analyzed the effects of ELAVL2 silencing, through RNAi, in a GBM genetic model in D. melanogaster, observing an increased brain volume when Rbp9, the ELAVL2 ortholog in Drosophila, is silenced. Profiling of HuB target mRNAs in GSCs highlighted genes associated with PTEN and stem cells related pathways. PTEN is upregulated in ELAVL2-rescued GSCs and mediates part of the effects of HuB, as PTEN knock-down in the same cells interferes with cell growth and TMZ-sensitivity. In our Rbp9-silenced Drosophila genetic model PTEN overexpression rescues the Rbp9 phenotype, reducing brain volume.

CONCLUSION
our results, both in vitro and in vivo, indicate that ELAVL2 acts as a tumor suppressor in GBM and its selective loss increases the fitness of GSCs, thus resulting in increased GBM aggressiveness. ELAVL2 promotes activation and neuronal commitment of quiescent GSCs and PTEN is one of the mediators of ELAVL2 in tumor development.