bluuebunny/crossref_metadata_2025_split huggingface dataset:
JS08.5.A VEGFR2-SPECIFIC CAR T CELLS WITH ANTI-GLIOMA AND ANTI-ANGIOGENIC ACTIVITY AGAINST GLIOBLASTOMA
Authors: Mastall M , Villars D , Silginer M , Rössig C , Weiss T , Weller M , Roth P 
Published: September 2023

Abstract

BACKGROUND
Chimeric antigen receptor (CAR) T cell therapy has emerged as a potent immunotherapy against hematological malignancies. In glioblastoma, however, limited infiltration of the tumor by CAR T cells, tumor heterogeneity, antigen escape and an immunosuppressive tumor microenvironment remain significant obstacles. Vessel-targeting CAR T cells have been shown to infiltrate solid tumors more efficiently and have the additional benefit of co-targeting the tumor vasculature with genomic stability. Therefore, vascular endothelial growth factor receptor 2 (VEGFR2)-CAR T cells may represent a promising strategy by targeting the tumor vasculature as well as VEGFR2-expressing tumor cells. Here, we explored the efficacy of VEGFR2-specific CAR T cells against experimental gliomas as well as the contribution of anti-tumor and anti-vasculature-dependent effects of this strategy.

METHODS
Tissue microarrays of glioblastoma patients (n=113) were stained for VEGFR2 expression. Human CAR T cells were generated by lentiviral transduction to express a second generation CAR construct against either mouse or human VEGFR2 (mVEGFR2 or hVEGFR2). Their activity was assessed in co-culture assays in vitro against murine endothelial and human glioma cells, respectively. Several orthotopic xenograft mouse glioma models were used to test the in vivo activity of the newly generated CAR T cells.

RESULTS
We confirmed high VEGFR2 expression on endothelial cells in glioblastoma tissue of stained tissue microarrays as well as in 20.3% of tissue samples also on tumor cells. In co-culture assays, hVEGFR2-CAR T cells were exclusively active against human glioma cells and mVEGFR2-CAR T cells against mouse endothelial cells, respectively. The specificity of hVEGFR2-CAR T cells was confirmed by a CRISPR/Cas9-mediated knockout of hVEGFR2 in a human glioma cell line. In all three in vivo glioma models, intratumoral treatment of hVEGFR2-CAR T cells significantly prolonged the survival of glioma-bearing mice and cured a substantial fraction of these animals in one model. Additionally, we found that survival was prolonged after mVEGFR2-CAR T cell treatment in one glioma model, which correlated with high vascularization of these tumors.

CONCLUSION
Our dataset demonstrates that VEGFR2-CAR T cells prolong the survival of glioma-bearing mice through anti-glioma and anti-glioma vasculature activity. The results suggest that the magnitude of the vasculature-targeting activity depends on vessel-density within the tumor. VEGFR2 might be a relevant target that could be exploited for a novel CAR T cell-based immunotherapeutic approach against glioblastoma.
JS09.7.A COMBINATION OF APPARENT DIFFUSION COEFFICIENT AND FET PET COMPARED WITH STANDARD IMAGING FOR QUANTITATIVE TUMOR PRESENCE IN DIFFUSE GLIOMAS
Authors: Tjong Tjin Joe K , Wesseling P , Barkhof F , Beliën J , Yaqub M M , Pouwels P J W , Verhaak R , Reijneveld J C , Rozemuller A J M , Vandertop W P , Boellaard R , Barthel F , de Witt Hamer P C , van de Giessen E , Verburg N 
Published: September 2023

Abstract

BACKGROUND
Diffuse glioma local treatment is currently guided by standard MRI sequences. Yet, the combination of apparent diffusion coefficient (ADC) and O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (FET PET) (ADC/FET) detects histopathological qualitative assessed tumor presence more accurately than standard imaging. It is unknown whether this is similar for quantitative assessed tumor presence. This study compares the diagnostic accuracy of standard imaging and ADC/FET for the detection of quantitative assessed tumor presence in diffuse glioma.

MATERIAL AND METHODS
Fifteen patients with newly diagnosed diffuse glioma were retrospectively included. Pre-operative standard imaging, ADC and FET PET were available. Multiregional image-guided stereotactic biopsies were acquired before craniotomy. Quantitative imaging data from regions-of-interests (ROIs) centered at the biopsy locations was obtained. For each biopsy, sample semi-automatic cellularity and proliferation index, as well as DNA methylation-based tumor purity was determined. Linear mixed models were used to evaluate which modalities were significant independent predictors for each tumor presence marker and fitness was assessed using Bayesian Information Criterium.

RESULTS
125 biopsies were analyzed (75 from eight high grade and 50 from seven low grade gliomas). Cellularity was predicted by T1 weighted MRI (p = 0.033), ADC (p = 0.016) and ADC/FET (p &lt;.001), with ADC/FET as best fit. Both proliferation index (p = 0.003) and tumor purity (p &lt;.001) were only predicted by ADC/FET.

CONCLUSION
Combining ADC and FET PET predicts cellularity, proliferation index and tumor purity better than standard imaging. Further investigation into ADC/FET-guided local treatment of diffuse glioma is therefore needed.
JS09.8.A COMPARATIVE PROGNOSTIC VALUE OF O-(2-[18F]-FLUOROETHYL)-L-TYROSINE PET IMAGING AND DCE MRI BLOOD VOLUME IMAGING IN PATIENTS WITH SUSPECTED RECURRENT IDH-WILDTYPE HIGH-GRADE GLIOMA
Authors: Henriksen O M , Muhic A , Lundemann M J , Larsson H B W , Lindberg U , Andersen T L , Hasselbalch B , Møller S , Marner L , Larsen V A , Poulsen H S , Hansen A E , Law I 
Published: September 2023

Abstract

BACKGROUND
Quantitative blood volume (BV) imaging using dynamic T1-weighted contrast enhanced (DCE) perfusion MRI may be of diagnostic value in patients with suspected recurrent high-grade glioma, but the association of DCE BV measurements with survival is not known. The aim of the study was to compare the prognostic information of DCE BV measurements with that of O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET imaging in treated IDH wildtype high-grade astrocytoma and glioblastoma (2016 WHO classification).

MATERIAL AND METHODS
A total of 94 hybrid [18F]FET PET/MRI scans with DCE from unique adult patients were retrospectively analysed. Scans were obtained after surgery/biopsy (n=94) and radiotherapy (n=93) due to variable suspicion of residual or progressive disease. In each scan the visually BV positive (VOLBV), the [18F]FET PET avid (VOLFET) and the contrast-enhancing (VOLCE) volumes were delineated, and fractional tumour volumes (fVOL) within VOLCE, as well as maximal BV (BVmax) and maximal [18F]FET tumour-to-background ratio (TBRmax) were determined. Accuracy for prediction of 6-month progression free survival and 1 year overall survival were assessed by logistics regression. Associations with overall survival were assessed for each parameter by Cox proportional hazard analysis.

RESULTS
In a univariate analysis, adjusted for age and MGMT, both VOLCE, and all [18F]FET and DCE BV derived metrics were predictive of both 6 month progression free survival, 1 year survival and overall survival. ROC AUC for prediction of 6 month progression free survival and 1 year overall survival tended to be higher for [18F]FET derived metrics, but ROC AUC values were not significantly different between any [18F]FET and DCE BV derived metrics. In Cox models for overall survival (adjusting for age, MGMT and VOLCE) only TBRmax and VOLBV had independent prognostic value among [18F]FET PET and DCE BV derived metrics, respectively. In a final model including both TBRmax and VOLBV, only TBRmax remained significant..

CONCLUSION
DCE BV and [18F]FET PET derived metrics provides prognostic information independent of age, MGMT status and contrast enhancing tumour volume in treated glioblastoma, with volume of increased BV and [18F]FET TBRmax providing strongest associations with overall survival. Accounting for functional imaging biomarkers may be important in balancing future randomized clinical trials.
OS01.4.A A DETECTABLE ANTITUMOR IMMUNE RESPONSE IS PRESENT IN GLIOMAS, BUT IS PROFOUNDLY DAMPED BY CHEMOTHERAPY
Authors: Picca A , Baron M , Labrèche K , Bouzidi A , Rousseau A , Morin V , Bielle F , Touat M , Sanson M , Autran B ,   IDEATION study group
Published: September 2023

Abstract

BACKGROUND
Until now, immunotherapy has been disappointing in gliomas. Promising results in cancer neoantigen (NeoAg)-directed vaccines have been seen, but final outcomes remain poor. We need a better comprehension of the factors associated with effectively immunogenic NeoAgs along with clinical features that correlate with detectable immune responses.

MATERIAL AND METHODS
We prospectively enrolled glioma patients from our institution in the IDeATIon project (NCT03706625) exploring tumors occurring in immunosuppressed conditions or in immune-privileged sites such as the CNS. We performed whole exome and RNA sequencing of tumor samples along with patients HLA typing. Using state of the art algorithms and personalized filters, we predicted cancer NeoAg sequences and expression. Peripheral blood mononuclear cells (PBMC) were collected in a subset of patients, and their reactivity to NeoAg-derived peptides was assessed ex vivo using ELISpot assays to validate in silico-predicted immunogenicity.

RESULTS
We enrolled 36 prospective glioma patients (IDH mutant, n=10; IDH wildtype, n=26). To test the ability of our pipeline to identify the most immunologically relevant NeoAgs among others, we privileged the inclusion of mismatch-repair (MMR)-deficient (MMRd) gliomas (n=21, of which 12 post-temozolomide and 9 de novo), given their expected high NeoAg burden. The median number of predicted immunogenic NeoAgs from 21 patients with both WES and RNASeq data was 274 and was higher for MMRd gliomas (1540 vs. 58, p&lt;0.001). Tumor mutational burden and the number of predicted NeoAgs were correlated (ρ=0.81, p&lt;0.001). Ex vivo PBMC responses were assessed for best ranked peptides (median 48 peptides/patient, range 12-62) in 18 patients (10 MMRd). NeoAg-specific T-cell responses (&gt;50 spot forming units/10e6 PBMC) were detected in 72% (13/18) of patients, including MMRd cases (8/10). All non-responder patients (5/5) were under treatment with cytotoxic chemotherapies (CHT) at the time of blood sampling, compared to 15% (2/13) of responders (p=0.003). Conversely, NeoAg-specific responses were seen in 100% (11/11) of patients not under CHT.

CONCLUSION
We developed and validated in vitro a robust and reliable pipeline for the identification of effectively immunogenic neoantigens using validated algorithms and personalized filters. Our results suggest that in the absence of CHT, a specific antitumor immune response is present in the majority of gliomas and may represent a therapeutic lever.
OS03.5.A MULTI-ANCESTRY GENOME-WIDE ASSOCIATION STUDY OF 4,069 CHILDREN WITH GLIOMA IDENTIFIES 9P21.3 RISK LOCUS
Authors: Foss-Skiftesvik J , Li S , Rosenbaum A , Hagen C M , Stoltze U K , Ljungqvist S , Hjalmars U , Schmiegelow K , Morimoto L , De Smith A J , Mathiasen R , Metayer C , Hougaard D M , Melin B , Walsh K M , Bybjerg-Grauholm J , Dahlin A M , Wiemels J L 
Published: September 2023

Abstract

BACKGROUND
While recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric CNS tumors have been identified to date.

MATERIAL AND METHODS
Meta-analysis of three population-based genome-wide association studies (GWASs) comprising 4,069 children with glioma and 8,778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18,628 genes.

RESULTS
Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, p-value 6.974e-10, OR 1.273, CI95 1.179-1.374). The association was driven by low-grade astrocytoma (p-value 3.815e-9) and exhibited unidirectional effects across all six genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, p-value 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (p-value 8.090e-8).

CONCLUSION
In this population-based GWAS meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
OS07.6.A INVESTIGATING REGIONAL HETEROGENEITY AND PROGRESSION-ASSOCIATED MARKERS IN OLIGODENDROGLIOMAS
Authors: Millner T O , Mikaeili H , Shabbir A , Lowe A , Brandner S 
Published: September 2023

Abstract

BACKGROUND
Oligodendrogliomas are defined by IDH-mutation, 1p/19q-codeletion and TERT promoter mutation. Molecular stratification of oligodendrogliomas has so far proved difficult, despite recent progress in other brain tumours. Loss of H3K27 trimethylation (H3K27me3) is seen in many, but not all oligodendrogliomas, and we have observed that this trimethylation mark is lost predominantly in low-grade oligodendrogliomas, and more often retained in high-grade tumours. The key aims of this project are to establish the downstream effects of H3K27me3 regulation in oligodendrogliomas to identify progression-associated biomarkers.

MATERIAL AND METHODS
78 oligodendrogliomas (CNS WHO grade 2: n=38, and grade 3: n=40) were tested for H3K27me3 expression. These tumours showed either down-regulation (H3K27me3-), retention of expression (H3K27me3+) or intratumoural heterogeneity (H3K27me3Het). 65 regions across these three types were micro-dissected for DNA methylation profiling and RNA sequencing.

RESULTS
Of the H3K27me3- tumours 85% (35/41) were grade 2, of the H3K27me3+ tumours 100% (10/10) were grade 3, and of the H3K27me3Het tumours 87% (20/23) were grade 3. With DNA methylation arrays and derived copy number data we have shown a different breakpoint of the 1p chromosome in H3K27me3+ samples or areas, and in 15 paired samples, 6 gains and 12 losses in H3K27me3+ regions, and overall 24 copy number differences between H3K27me3+ and me3- areas within the same tumours, indicative of spatial genetic heterogeneity. RNA sequencing suggests distinct expression profiles between H3K27me3+ and H3K27me3- areas.

CONCLUSION
We have shown a close correlation between areas with high-grade features and H3K27me3 expression both between and within tumours. We have shown that H3K27me3+ and me3- areas within the same tumours show copy number changes and have differential gene expression. Using pathway analysis we have identified pathways and genes involved in tumour progression and mediation of histone modification. We are currently using these targets for functional studies and protein level validation with the overall aim of developing immunohistochemistry biomarkers.
OS07.7.A GLIOBLASTOMA HYBRID CELL STATE CONVEYS RESISTANCE TO CONVENTIONAL THERAPIES
Authors: Bourmeau G , Anezo O , Ballestin A , Pichol-Thievend C , Reveilles J , Seano G 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GB) is a deadly disease and no therapeutic improvements have been made in the last 20 years. High phenotypic plasticity has been recognized as a major obstacle to the efficient treatment of GB. Single-cell sequencing revealed the coexistence of four different cell states within the same tumor. The transition from one subtype (or state) to another, such as from proneural (PN) to mesenchymal (MES), has been suggested as a mechanism for resistance to therapies. However, there is no prognostic value of the current GB states for patients, meaning that mechanisms of resistance may not lie in hardwire identities but in the transition from one subtype to another. Therefore, we investigated the role of the hybrid cell states in GB resistance to therapy.

MATERIAL AND METHODS
To dynamically follow spatiotemporal changes in GB plasticity in real time, we transduced patient-derived GB cells (patient-derived cell lines with different mutational and phenotypic landscapes) using two specific GB-subtype fluorescent synthetic genetic tracing cassettes. To follow the hybrid cell state dynamics and features, we functionally and transcriptionally investigated GB cells labeled with activated reporters for both the PN and MES subtypes. Using a combination of cytofluorimetry, live imaging, preclinical models, bulk and single-cell RNA-sequencing, we visualized the single-cell GB plasticity and studied the changes in the hybrid state subpopulation proportion over time and under therapeutic stress.

RESULTS
We discovered that the PN/MES hybrid state (GB-hybrid) has a definite molecular and phenotypic identity and that it is strongly induced after conventional therapies. The GB-hybrid cell state is highly resistant to therapy and more proliferative. Importantly, when implanted in mice the GB-hybrid cells were more aggressive than the rest of the cells, which is consistent with the marked prognostic power for the GB-hybrid geneset signature when tested in the TCGA database. Mechanistically, we showed that GB-hybrid cells were characterized by broad chromatin remodeling, an important increase in overall mRNA quantity per cell and intensification of the nuclear import/export machinery.

CONCLUSION
Here, we present a novel GB transition cell state between PN and MES subtypes/states. The GB-hybrid is at the same time highly proliferative and resistant to therapy, making it an interesting target to slow down GB recurrence after therapy.
OS08.5.A UNDERSTANDING THE ASSOCIATION BETWEEN FATIGUE AND COGNITION IN GLIOMA PATIENTS: AN OBSERVATIONAL MULTINATIONAL STUDY
Authors: Röttgering J G , Taylor J W , Brie M , Luks T , Hervey-Jumper S L , Phan S , Bracci P M , Smith E , De Witt Hamer P C , Douw L , Weyer-Jamora C , Klein M 
Published: September 2023

Abstract

BACKGROUND
Both fatigue and cognitive impairment are highly prevalent in individuals with glioma and have been associated with diminished health-related quality of life. Although the two are thought to be related, evidence remains sparse, in part, due to the limited availability of data. Therefore, we aimed to investigate the relationship between fatigue and cognition in adult glioma patients.

MATERIAL AND METHODS
We analyzed cognitive data from adult patients with diffuse glioma at the University of California San Francisco (UCSF, n=100) and Amsterdam UMC (n=127). Comparable cognitive tests were combined by domain: attention, information processing, mental flexibility, semantic fluency, verbal learning, verbal memory, and visual search. Z-scores of ≤ -1.5 SD were considered impaired. Fatigue was assessed with the Fatigue Symptom Inventory (UCSF) and the Checklist Individual Strength (Amsterdam UMC). Linear mixed models were used to assess associations between cognitive domains and fatigue adjusted for site, grade, histology, sex, radiotherapy, and chemotherapy. Latent profile analysis was used to identify distinct fatigue-cognitive phenotypes.

RESULTS
UCSF patients were older (50.3 vs. 44.9 years, p=0.002), more likely to have grade 4 tumors (32% vs. 18%, p=0.025), and more years since diagnosis (2.72 vs 1.27, p&lt;0.001). Interestingly, though UCSF patients were more impaired across nearly all cognitive domains, there was no difference in fatigue between institutions (-0.0457 vs. -0.178, p=0.60). Attention and impaired semantic fluency were associated with fatigue severity in univariate models. Using backward selection, the best-fit model included only impaired semantic fluency (estimated effect = 0.35, p= 0.014, r2=0.03). We identified four distinct cognitive phenotypes in the pooled dataset, which validated across sites, though fatigue severity did not contribute to these phenotypes.

CONCLUSION
Although fatigue and cognitive symptoms can overlap, the association between cognitive impairment and fatigue severity is weak. Interestingly, this important finding was validated across institutions and glioma subtypes. Further study is needed to address questions regarding the longitudinal change of symptoms. Given the limited relational overlap, fatigue and cognitive impairments should both be explicitly assessed and treated with targeted therapies.

SUPPORT/DISCLOSURE
Stichting Anita Veldman Foundation CCA-2019-2-21; Amsterdam University Fund 4056-2022-7-8; CCA travel grant 2022-10-10; Prins Bernhard Cultuurfondsbeurs 40042576/NOD; R.A. Laan fonds 2022-10-24; The loglio Collective; Sheri Sobrato Brisson Brain Cancer Survivorship Program.
OS08.6.A QUALITY OF LIFE IN PATIENTS AND CAREGIVERS FOLLOWING RADIOTHERAPY FOR BRAIN METASTASES: LOWER HEALTH STATUS AND MORE SYMPTOMS OF ANXIETY
Authors: van Grinsven E , Cialdella F , Vrolijk T G G , Philippens M E P , Verhoeff J J C , van Zandvoort M J E 
Published: September 2023

Abstract

BACKGROUND
The incidence of brain metastases (BMs) has been rising due to improvements in cancer treatment. Although survival rates are typically 3-4 months, more and more long surviving patients and their families are confronted with physical, practical, emotional, and cognitive consequences of disease and more effective treatments. Therefore, we investigated quality of life (QoL) in both patients and caregivers in the six months following radiotherapy (RT).

METHODS
To understand the impact of BMs on QoL for both patients and caregivers, we implemented the prospective Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) to examine all patients with BMs who received RT. 94 adult patients with BMs and their informal caregivers completed the same QoL-questionnaires for themselves (including EQ-5D-3L, EQ-VAS and HADS) before RT, one month, three months and six months after RT. Individual changes in QoL were evaluated using minimal clinically important differences as reported in previous literature. Trajectories of changes in QoL were assessed using mixed linear models with a growth curve approach.

RESULTS
On the group-level, growth models indicated stable QoL for both patients and caregivers over the six months following RT. However, individual trends showed variability in baseline levels and rate of change. That is, patients with higher baseline QoL, tend to experience larger decreases in QoL over time. A comparison of the trajectories of QoL indicated no differences between patients and caregivers. A closer inspection of the data, showed patients reported a lower health status (EQ-5D and EQ-VAS), while caregivers reported more symptoms of anxiety (HADS-anxiety) at all investigated time points (all p &lt; .05). Over all time points considered, 37% of caregivers experienced clinically relevant symptoms of anxiety. Highest individual differentiated rates of change were seen in the first month following radiotherapy, with 34% of patients improving on the EQ-5D-3L whereas 42% of patients declined on the EQ-VAS.

CONCLUSION
Overall, in the six months following brain radiotherapy QoL remained stable in both patients and caregivers. Individual analyses highlights differentiated trajectories, with the majority of patients and caregivers showing the largest changes within the first month. Since a relatively large group of caregivers experienced symptoms of anxiety, this suggests a potential benefit for of offering psychological support to caregivers throughout the treatment process could potentially be beneficial.

GRANT INFORMATION
E.G was supported by research funding from the Dutch Cancer Society “Koningin Wilhelmina Fonds (KWF)” (#11110).