bluuebunny/crossref_metadata_2025_split huggingface dataset:
P06.03.A EXPLORING THE THERAPEUTIC EFFICACY OF CHLOROQUINE AND HYDROXYCHLOROQUINE IN IDH-WILDTYPE AND IDH-MUTANT GLIOMA
Authors: Eisele A , Mastall M , Weller M , Roth P 
Published: October 2024

Abstract

BACKGROUND
Within the treatment of the most common and aggressive brain tumors - gliomas - the last decades have been characterized by an enormously high rate of failed and cost-intensive drug trials. Repurposing established medications for the treatment of cancer has the advantage of faster availability as well as cost-effectiveness. Chloroquine (CQ) and hydroxychloroquine (HCQ) are approved medications for the treatment of rheumatologic diseases and malaria and have gained attention in recent years due to evidence of potential anti-tumor efficacy in various cancer types. The data available to date on the use of (H)CQ for the treatment of gliomas are limited and remain controversial. Here, we study (H)CQ as a therapeutic option in IDH-wildtype and IDH-mutant glioma models in vitro.

MATERIAL AND METHODS
The effects of (H)CQ alone and in combination with other clinically relevant treatment modalities are characterized on several key biological properties of glioma cells.

RESULTS
Both CQ and HCQ show in vitro activity against IDH-wildtype (LN-229, LN-308, ZH-161, GL-261, SMA-560) and IDH-mutant (GS-827) glioma cells, with most cell lines being more sensitive to CQ than to HCQ. This effect is potentiated by a combination of (H)CQ with temozolomide or radiotherapy. Cell death is mediated by apoptosis and is associated with an upregulation of caspase 3 activity. (H)CQ induce autophagy inhibition and reduce TGF-beta 2 and 3 mRNA expression in glioma cells.

CONCLUSION
CQ and HCQ show promising effects against IDH-wildtype and IDH-mutant glioma cells in vitro. (H)CQ inhibits autophagy and is associated with a down-regulation of TGF-beta expression. Whether the anti-glioma activity of (H)CQ can be translated into in vivo models will be investigated in further studies.
P07.01.B ANDROGEN RECEPTOR SIGNALING MODULATES BOTH TUMOR AND IMMUNE CELLS IN GLIOBLASTOMA AND IMPACTS GLIOBLASTOMA GROWTH
Authors: Birzu C , Scherer L , Chaskis E , Boussier J , Belin L , Quissac E , Da Costa Perreira T , Daddi K , Scuderi S , Laurenge A , Castro Vega L , Mokhtari K , Tran S , Mathon B , Verreault M , Idbaih A 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is more frequent (sex ratio M:F=1.6) and exhibits worse prognosis in males compared to females suggesting a role of the hormonal macroenvironment including androgen signaling in biology of GBM. In the current study, we studied the impacts of androgen signaling in GBM cells and their immune tissue microenvironment (iTME).

MATERIAL AND METHODS
In vitro, we have investigated the impacts of androgen receptor (AR) modulation on: (i)the transcriptional programs of GBM-PDCLs and GBM associated myeloid cells -GAM-, (ii)the secretome of human GAM (hGAM) and murine GAM (mGAM) and, (iii)the metabolism of myeloid cells using co-culture systems with normal human monocyte-derived macrophages -nhMDMs- and Dihydrotestosterone -DHT- producing AR+ GBM patient derived cell lines (GBM-PDCLAR+). We investigated the impact of AR signalling in GBM in GBMAR+ from TCGA RNAseq data. In vivo, the impacts of AR stimulation was explored using DHT implants and castration in male immunocompetent murine GBM models. The iTME was characterized using multiplex immunohistochemistry (mIHC).

RESULTS
value is more pronounced in young patients (HR of 1.75 for males &lt;45 years). In addition, we showed that both GBM tumor cells and GAM express AR. Human GBMAR+, from TCGA cohort, exhibit upregulation of type I interferon pathway but downregulation chemokine and cytokine production and receptor binding. In vitro, exposure of GBM-PDCLAR+ to DHT modulates genes involved in response to growth factors, cell differentiation, migration, metabolism (protein and glycosaminoglycan) and secretome (genes involved in macrophages differentiation). Pharmacological modulation of AR in hGAM identified (i) an AR-responsive cytokine signature including CCL2, CXCL10, IL-1ra, MIF, and IL-10, and of (ii) AR-associated mitochondrial respiration changes. Exposure of mGAM, from adult immunocompetent GBM-bearing mouse (Nfpp10), to DHT, is associated with a similar pro-inflammatory but dysfunctional cytokines profiles in males. In immunocompetent GBM-bearing mice, neither DHT exposure nor the androgen deprivation (i.e. castration) modulated significantly tumor growth or mice survival. However, DHT exposure is associated with more undifferentiated GBM tumor cells in castrated males. The castration doesn’t impact significatively the myeloid cell infiltration but lowers the T-cells count (p= 0.03). DHT appears to reverse this phenotype back to intact male level. In addition, the DHT exposure increased AR expression on myeloid and GBM cells but not on T-cells.

CONCLUSION
Our study brings preclinical evidence that androgens signaling modulates both tumor cells and iTME cells in GBM. Further explorations should establish the role of AR blockade in reprogramming the GAM towards a more anti-tumorigenic phenotype.
P09.09.A IMAGING CHALLENGES: IMMUNOTHERAPY’S INFLUENCE ON THE DIAGNOSTIC ACCURACY OF AMINO ACID PET IN SUSPECTED PROGRESSIVE BRAIN METASTASES
Authors: Baumgart L , Delbridge C , Meyer B , Weber W , Meyer H S , Gempt J , Yakushev I 
Published: October 2024

Abstract

BACKGROUND
Immunotherapy (IT) has gained increased significance as a systemic therapy option in the management of various types of metastatic cancer, including cases involving brain metastases (BMs). The differential diagnosis of progressive/relapsed BMs and treatment-related changes (TRC) is often based on imaging with amino acid (AA) PET, in addition to standard magnetic resonance imaging (MRI), as this has been established to provide higher diagnostic accuracy. However, diagnostic value of the AA-PET in the context of IT has not been studied so far. In this pilot study we quantified diagnostic accuracy of AA PET in patients with suspected progressive BMs under IT.

MATERIAL AND METHODS
This retrospective study included patients with suspected progressive/relapsed BMs on MRI after radiotherapy (RT) between 04/2007 - 01/2023. Only patients with AA PET ≤ 4 weeks prior to surgery/biopsy of BMs were selected. AA PET results were compared with histopathological findings and distinctive features were highlighted.

RESULTS
Out of 29 patients, 7 were treated with IT (IT+ group). Remaining patients (IT- group) were treated with chemotherapy, targeted therapy, a combination of both, or obtained no systemic therapy before PET. The groups did not differ regarding age, gender, initial number of BMs or time interval between PET and last RT. In the IT+ group, 6 patients had malignant melanoma and 1 patient urothelial carcinoma as primary tumor. The IT+ patients obtained ipilimumab, nivolumab, or pembrolizumab, sequentially, or in combination. In the IT+ and IT- group, 7 and 21 PET scans were read as suspicious for progressive/relapsed BMs, respectively. The rate of false-positive findings was 5/7 (71.4%) and 3/21 (14.3%), respectively (chi square test, p=0.008). Histopathological analyses revealed an inflammatory reaction with lymphocytic infiltrates in the examined tissue in the IT+ group.

CONCLUSION
There is a significantly higher rate of false-positive AA PET findings in patients with BMs who have been treated with IT. This observation may be explained by an immunologically mediated inflammatory reaction. Further immunological analyses of lymphocytic infiltrates could provide more information.In conclusion, until more data are available, caution should be exercised when diagnosing tumor recurrence using AA PET in patients who have previously received IT.
P09.12.B INFLUENCE OF PATIENT CHARACTERISTICS AND ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY ON FET UPTAKE IN THE REFERENCE REGION IN PATIENTS WITH GLIOMAS
Authors: Ceccon G S , Wollring M , Stetter I , Werner J , Lohmann P , Fink G R , Langen K , Galldiks N 
Published: October 2024

Abstract

BACKGROUND
In PET imaging, the uptake of radiolabeled amino acids in the reference region is frequently used to calculate tumor-to-brain ratios in patients with gliomas. Nevertheless, besides patient characteristics, our understanding of the alkylating chemotherapy’s influence on the uptake of radiolabeled amino acid in the reference region in patients with CNS WHO grade 3 or 4 gliomas is incomplete.

MATERIAL AND METHODS
We evaluated the effects of sex, age, and adjuvant chemotherapy with temozolomide on the uptake of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in the reference region in newly diagnosed glioma patients who had undergone surgery and radiotherapy with concomitant temozolomide chemotherapy. FET PET was performed at baseline and after the second cycle of adjuvant temozolomide chemotherapy. Besides, we calculated standardized uptake values (SUV) of FET in the reference region located in the contralateral, unaffected hemisphere. Unpaired Student’s t-tests were used to test differences between independent groups (e.g., females and males). The paired Student’s t-test was used to compare background SUV at baseline and follow-up. The Pearson’s correlation coefficient determined correlations between clinical parameters and SUV in the background region.

RESULTS
Sixty-three patients with gliomas (females, n=32) were retrospectively evaluated (CNS WHO grade 4 glioblastoma, n=55; CNS WHO grade 4 H3K27-mutant diffuse midline glioma, n=2; CNS WHO grade 4 astrocytoma, n=4; CNS WHO grade 3 astrocytoma, n=1; CNS WHO grade 3 oligodendroglioma, n=1). SUV in the reference region did not significantly differ between female and male patients at baseline (P=0.259) and follow-up (P=0.384). Patients’ age at initial diagnosis was positively correlated with background SUV at baseline (r=0.384; P=0.002). After two cycles of adjuvant temozolomide chemotherapy, the SUV in the reference region at follow-up was not significantly different from baseline (P=0.485).

CONCLUSION
Our data suggest that the reference SUV was unaffected by adjuvant temozolomide chemotherapy. In contrast, age has a modest influence on the physiological FET uptake. Further studies to evaluate the impact of patient characteristics and treatment are warranted.
P10.01.B A GRADIENT-BOOSTING MACHINE LEARNING MODEL PREDICTS PRIMARY TUMOR ORIGIN IN PATIENTS TREATED WITH GAMMA-KNIFE FOR BRAIN METASTASES
Authors: Panchawagh S , Sanker V , Suresh V , Kirani Tan J 
Published: October 2024

Abstract

BACKGROUND
Brain metastasis is a devastating consequence of cancer. It can present as focal neurologic deficits, following which a search for the primary tumor is mounted. Usually, after such an initial presentation, computed tomography or magnetic resonance imaging scans of the brain are performed to visualize the underlying pathology. Radiomics leverages quantitative texture analysis to understand unique image signatures that are otherwise incomprehensible to the naked eye. We propose a predictive machine learning model that can identify the locus of origin of brain metastasis using radiomic image analysis.

MATERIAL AND METHODS
We used magnetic imaging and segmentation data from 47 patients and 244 lesions from the open-source gamma-knife registry at the University of Mississippi Medical Center. After image pre-processing, 1688 radiomic features were extracted using different filters. Ensemble feature selection techniques were applied, and we retained 34 features deemed most important by the model. We fitted logistic regression, support vector kernel, random forest, and extreme gradient boosting models to the selected features to predict a multi-class outcome for tumor origin (lung, breast, kidney, melanoma, bladder, esophagus, ovary, or uterus). Local interpretable model-agnostic explanations were used to explain model predictions.

RESULTS
The cohort’s median age at diagnosis was 60, with 21 males (45%). For the multi-class prediction, the logistic regression (accuracy = 77.4%), support vector kernel (accuracy = 84.9%), and random forest (accuracy = 88.7%) models performed worse than the extreme gradient boosting (accuracy = 90.1%, precision = 89.9%, recall = 90.1%, and Dice score = 0.895) model. Gray-level co-occurrence matrix and gray-level dependence matrix features explained model predictions the best.

CONCLUSION
Our results suggest that quantitative radiomic analysis is useful in predicting tumor origin in brain metastasis. Specifically, features measuring texture, structure, and heterogeneity best explain model predictions. Refining the model further and using multicentric data can help create a robust, clinically useful software to aid physicians and radiologists in detecting tumor origin, improving patient care, and potentially reducing healthcare costs.
P10.07.B AN INNOVATIVE CELL TYPE-PAIRED SINGLE-CELL RNA SEQUENCING APPROACH DECIPHERING GLIOBLASTOMA HETEROGENEITY FOR THE IDENTIFICATION OF NOVEL SUBGROUPS WITH THERAPEUTIC POTENTIAL
Authors: Grimaldi A , Esposito C , Ducret V , Lubrano M , Thiriez C , Maussion C , Fidon L , Hoffmann C 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GB) is an aggressive brain cancer with poor prognosis and limited effective treatment. Many challenges hinder the success of anti-cancer therapies such as drug resistance, low surgical and pharmacological accessibility, and migration of cancer cell to nearing brain tissue. The origin of the tumoral population is often evasive due to a high tumoral cell heterogeneity, impeding drug discovery strategies.

MATERIAL AND METHODS
This study uses the public scRNAseq atlas ExtendedGBMap (Ruiz-Moreno et al., 2022). The processed dataset was filtered to only keep 48 patient samples that contributed both tumor and normal cells, and only 8 cell types were selected, consisting of 4 tumor/healthy pairs: Astrocyte-like/Astrocyte cells, (50335/201 cells), Mesenchymal-like/Mural cells (32795/2528 cells), Neuron Progenitor-like/Neuron cells (8580/1091 cells) and Oligodendritic Progenitor-like/Oligodendritic Progenitor cells (38684/933 cells). All other cells were excluded. Patient-wise differential expression analysis was performed comparing tumor versus healthy cells, independently of cell-type, using scanpy.tl.rank_genes_groups default t-test, and patient were clustered based on their statistical test scores for each gene in the matrix using the k-means algorithm. Genes were ranked based on their statistical score, and gene set enrichment analysis was carried out using the WikiPathways, GO:MolecularFunction, Reactome, and Hallmark databases.

RESULTS
This novel scRNAseq and paired tumor-healthy comparison based approach unraveled 3 main GB groups with distinct transcriptomic profiles. Group1 was enriched in DNA replication, glycolytic metabolism, amino-acid production, and Hypoxia. Group2 exhibited known activities of epithelial-to-mesenchymal transition, miRNA in cancer, and chondroitin/dermatan sulfate biosynthesis. Group3 was comprised of patients that did not seem to belong to any of the 2 groups, but that did not share any specific gene signature.

CONCLUSION
We present a new approach to GB patient subgroup identification with a potential for target discovery, exploiting bystander normal cells in high-throughput scRNAseq. This method partially overcomes inter-patient and intra-patient tumor heterogeneity and may support new therapeutic avenues for GB patients. We aim at validating and enriching this approach with paired scRNAseq and Spatial Transcriptomic data from the MOSAIC consortium.
P10.21.A MODELLING GBM RECURRENCE - THE INFLUENCE OF PERI-LESIONAL OEDEMA AND THE DISCONNECTOME
Authors: Tariq M , Ruffle J , Mohinta S , Brothwell M R S , Brandner S , Nachev P , Hyare H 
Published: October 2024

Abstract

BACKGROUND
Residual tumour burden after surgery in GBM patients is a prognostic imaging biomarker, often involving the area of T2 signal elevation surrounding the tumour core, histopathologically representing infiltrative oedema with tumour cells. We present the first stage of a model to improve the prediction GBM recurrence by specifically investigating the perilesional oedema compartment.

MATERIAL AND METHODS
UK-wide sample of histologically proven IDHwt GBMs with MRIs at the time of diagnosis underwent state-of-the-art in-house tumour segmentation pipeline and radiomic feature extraction of whole-tumour, enhancing, non-enhancing and oedema components, and masked disconnectome map components. Of these, early GBM recurrence, within 6 months after completion of radiotherapy, was curated and distribution mapped across the brain.

RESULTS
1464 patients were identified: male = 901, median age 63 years, average overall survival 597 days. The radiomic features: Compactness 1 and 2, Surface Area, Spherical Disproportion, Sphericity, and Maximum 2D Diameter column of the disconnectome-related perilesional oedema compartment were most predictive of survival outcome (p value &lt;0.01). Of these, 47 patients with average overall survival 357 days and average time from end of radiotherapy to progression of 131 days were identified.

CONCLUSION
Our early results reveal the relationship between perilesional oedema, MRI features and survival, with disconnectome-related perilesional oedema features most predictive. This suggests that extended brain network aberrations caused by gliomas may also influence tumour recurrence. Further work will focus on the development of more robust predictive models of tumour recurrence that have potential for significant impact on surgical and radiotherapy planning.
P11.02.B ASSESSMENT OF PATIENT-REPORTED NEUROLOGICAL DEFICITS THROUGH BRAIN NETWORK DISRUPTIONS ON MRI IN PATIENTS WITH BRAIN METASTASES
Authors: David S , Cialdella F , Nagtegaal S H J , van Grinsven E E , Philippens M E P , Verhoeff J J C 
Published: October 2024

Abstract

BACKGROUND
Patients with brain metastases (BMs) experience a range of neurological deficits, including motor and vision problems. The EORTC BN20 is a validated questionnaire specifically designed to evaluate various aspects of patient-reported neurological health of patients with brain tumors. In the COIMBRA study (NCT05267158), data is prospectively collected pre- and post-radiotherapy (RT) including clinical assessments, imaging, and patient-reported outcomes. This study aims to explore the relationship between BM lesion location, the resulting white matter disruptions (i.e. the disconnectome), and the reported resultant neurological deficits in motor or visual functions.

MATERIAL AND METHODS
Between April 2019 and April 2023, 216 patients with BMs undergoing stereotactic radiosurgery completed the baseline questionnaire. T1 MRI scans and gross tumor volumes (GTVs) were nonlinearly registered to the MNI152 template using the EasyReg tool. Patient-specific disconnectomes were calculated using BCBtoolkit. Voxelwise correlations between disconnectomes or lesion distributions (GTV) and patient scores on motor or visual deficits from the BN20 questionnaires were tested using robust permutation tests with the PALM toolbox. Multiple comparison related false positives were corrected with family-wise error rate adjustment with significance established at p-val&lt;0.05.

RESULTS
Significant correlations in an area of 593mm3 were found between reported motor deficits and the presence of lesions in the Precentral and Superior Frontal Gyri and Superior Thalamic Radiation, and broader dysconnectivity in areas including the Corticospinal Tracts (CST) and Precentral Gyrus (PCG), involving a volume of 14726 mm3. For reported visual deficits, significant correlations were identified in the occipital lobe, particularly affecting the Optic Radiations and the occipital cortex regions in both sides with a cluster size of 12876 mm3. No correlations were found between the mere presence of lesions and visual disorder scores.

CONCLUSION
Disconnectome-driven correlations with deficit scores show a good fit with the well-known anatomy for the motor- and the visual systems. Both motor and visual problems are measured with three simple questions with four rating options from the BN20 questionnaire, which appear sufficient to identify the critical role of network disruptions. White matter disruptions should be considered to fully appreciate the neurological or other impact of BMs, suggesting that further targeted investigations could enhance diagnostic precision and therapeutic interventions for these patients. While these findings are significant, further investigation is needed to determine if more distinct motor-related issues, such as trouble with coordination, or visual disorders like diplopia or field cuts, can be pinpointed to specific brain areas or networks.
P11.09.B STRUCTURAL REORGANIZATION IN MOTOR-ELOQUENT GLIOMA PATIENTS EXHIBITING MOTOR DEFICITS
Authors: Gong Z , Zhang H , Schwendner M , Schröder A , Meyer B , Ille S , Krieg S 
Published: October 2024

Abstract

BACKGROUND
Recent advancements in navigated transcranial magnetic stimulation (nTMS) have significantly improved the localization of motor functions in human subjects. Although previous studies have demonstrated the occurrence of tumor-induced motor plasticity, the detailed mechanisms of motor function plasticity and reorganization in patients with tumors affecting motor-eloquent regions are not fully elucidated. Our study aims to investigate the functional plasticity of motor functions in patients with gliomas located within motor-eloquent regions, providing deeper insights into the mechanisms of functional plasticity.

MATERIAL AND METHODS
In this research, we studied 60 glioma patients with tumors located in the motor-eloquent region. These patients were categorized into two groups depending on whether they experienced motor impairments in the upper extremities. We utilized nTMS, including Motor Evoked Potentials (MEP), to outline the control regions of motor function in terms of area, localization, and Center of Gravity (CoG). These identified regions also acted as seeds for tracing the Corticospinal Tract (CST).

RESULTS
The study unveiled significant variations in cortical and subcortical motor function localizations between the groups. Patients with motor impairments exhibited a broader cortical distribution connected to motor functions and increased volumes of CST, reflecting compensatory adaptations with different fractional anisotropy (FA) values (FA 0.15, p=0.02; FA 0.10, p=0.04). The analysis of the CST also showed overlapping regions, particularly within the hand-knob areas, which is indicative of these areas acting as critical motor output pathways. Despite varying degrees of functional impairment, all patients maintained some degree of motor output capability.

CONCLUSION
These findings suggest that motor-eloquent gliomas induce significant cortical and subcortical reorganization of motor functions. A persistent network of CST fibers, crucial for preserving motor function, highlights a complex interplay between cortical adaptation and subcortical reorganization. This study underscores the resilience of motor pathways and their pivotal role in functional recovery and plasticity, emphasizing the clinical relevance of nTMS in the therapeutic planning and monitoring of patients with motor-eloquent gliomas.