bluuebunny/crossref_metadata_2025_split huggingface dataset:
PL01.5.A ASSOCIATION BETWEEN RESTING-STATE-NETWORK FUNCTIONAL CONNECTIVITY AND SURVIVAL IN RECURRENT GLIOMAS DIAGNOSED USING FET PET
Authors: Friedrich M , Werner J M , Steinbach J P , Sabel M , Herrlinger U , Piroth M , Stoffels G , Filss C P , Lohmann P , Shah N J , Ruge M I , Mottaghy F M , Goldbrunner R , Langen K J , Fink G R , Kocher M , Galldiks N 
Published: October 2024

Abstract

BACKGROUND
Functional connectivity between glioma-infiltrated brain tissue and remote cortical regions has been linked to overall survival (OS) in patients with newly diagnosed glioblastoma. Here, we studied the association of functional connectivity between tumor and resting-state networks and OS in patients with recurrent gliomas.

PATIENTS AND METHODS
The study included 82 patients (age range, 26-81 years; median ECOG performance score, 0) with recurrent gliomas (CNS WHO grade 4 glioblastoma, n=57; CNS WHO grade 3 and 4 astrocytoma, n=12; CNS WHO grade 2 and 3 oligodendroglioma, n=13) who had undergone first-line therapy by current guidelines. In addition to the RANO criteria for anatomical MRI, diagnosis of glioma recurrence was confirmed by amino acid PET using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). FET PET and resting-state functional MRI were simultaneously acquired on a 3T hybrid PET/MR scanner. A seed-based dual regression analysis was performed to determine the functional connectivity between metabolically active recurrent tumors and a set of seven canonical resting state networks.

RESULTS
Average functional connectivity was significantly higher (p=0.028) in oligodendrogliomas (z-score, 6.9±1.9) and astrocytomas (z-score, 5.5±1.3) than in glioblastomas (z-score, 4.9±2.6) and was inversely related to the tumor grade (p=0.031). Univariate Cox regression analysis revealed a significant positive association between OS and tumor connectivity with the visual, somatomotor, and dorsal attention network (all p&lt;0.05). Subsequent stepwise multivariate Cox regression analysis refined this association to the dorsal attention network alone (HR, 0.88; 95% CI, 0.80-0.97; p=0.007). Patients with the highest functional connectivity (z-score &gt;8.3, n=21) had a median OS of 31.4 months, while those with the lowest functional connectivity (z-score &lt;4.3, n=21) had a median OS of 10.6 months. Functional connectivity between tumors and the dorsal attention network showed an independent association with OS (p=0.002) in a multivariate model, including the metabolic tumor volume (p=0.003).

CONCLUSION
Recurrent gliomas exhibit significant functional connectivity to most of the major known resting-state networks, which was generally higher in astrocytomas and oligodendrogliomas. The data suggest that high functional connectivity between the tumor and the dorsal attention network is an independent prognostic factor for improved OS.
PL02.1.A LOCOREGIONAL BI-SPECIFIC CAR-T CELLS TARGETING CD44 AND CD133 IN RECURRENT GLIOBLASTOMA: THE INTERIM RESULTS OF THE FIRST IN-HUMAN CLINICAL TRIAL
Authors: Zhai Y , Li G , Zhang W , Jiang T 
Published: October 2024

Abstract

BACKGROUND
Recurrent glioblastoma (rGBM) remains no standard of care exists, with a median overall survival of less than 1 year. Here, we report the pre-clinical data and the first four patients with rGBM in a phase I study of locoregionally administration of newly developed tandem CAR-T cell, targeting CD44 and CD133, armored with a truncated IL7Ra intracellular domain (Tris-CAR-T).

MATERIAL AND METHODS
The primary outcomes were safety and any adverse events associated with Tris-CAR-T administration. Secondary outcomes include the distribution and persistence of Tris-CAR-T cells, cytokine concentration, and the therapeutic effect according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. At present, six patients of newly diagnosed rGBM underwent different doses of Tris-CAR-T administration via Ommaya reservoir of intratumoral or ventricular implantation. The first two patients had single or multi-doses of 107 Tris-CAR-T cells, the third and fourth patients had multiple doses of 108 Tris-CAR-T cells, and the last 2 patients had weekly doses of 0.5x108 Tris-CAR-T cells administration. Cytokine release syndrome and other side effects were assessed via cytokine quantification (serum and cerebrospinal fluid), K-CRP, and body temperature. Specimens of peripheral blood, cerebrospinal fluid, CAR-T products were collected for further bioinformatics analysis.

RESULTS
No neurotoxicity or adverse event greater than grade 1 was observed until now. Radiographic response and improvement in symptoms and signs were observed within days after the first infusion, and continued in the follow-up. Some patients underwent a remarkable tumor regression.

CONCLUSION
The newly constructed Tris-CAR-T cells are capable of GBM suppression with limited side effects. Long-term tumor control is considered to be related to dosage, product quality, and intervention frequency. A weekly or biweekly administration might be considered. The inspiring clinical response needs to be strengthened by follow-up and investigations in biological specimens (ClinicalTrials.gov identifier: NCT05577091)
JS04.5.A THE ROLE OF SURGERY IN IDH WILDTYPE DIFFUSE ASTROCYTOMA
Authors: Krenzlin H , Lange F , Dauth A , Kalasauskas D , Freyschlag C , Schnell O , Misch M , von der Brelie C , Wagner A , Krigers A , Rohde V , Meyer B , Vajkoczy P , Beck J , Thomé C , Ringel F , Keric N 
Published: October 2024

Abstract

BACKGROUND
Isocitrate dehydrogenase (IDH)1/2 wildtype astrocytomas, classified as CNS WHO grade 4 tumors in the latest WHO classification of 2021, have high recurrence rates. The role of surgery in these tumors remains uncertain.. In this study the impact of the extent of resection (EOR) on progression free (PFS) and overall survival (OS) in astrocytomas IDH1/2 wt (CNS WHO Grad 4) is compared to glioblastoma IDH1/2 wt (CNS WHO Grad 4).

METHODS
Data acquisition was conducted as a multi-center retrospective analysis at 6 University Hospitals (2016-2020). Patients with IDH 1/2 wildtype diffuse astrocytoma (CNS WHO grade 2-4) were included in our study. Patients presenting with IDH wildtype glioblastoma from one institution served as controls. Primary outcome parameters were EOR (GTR; &lt;5% residual tumor (RT), subtotal resection (STR; 5-75% RT), and biopsy (&gt; 75% RT) and OS.

RESULTS
160 patients with IDH-wildtype glioblastoma (CNS WHO grade 4) (45.6 % females) and 138 patients with IDH-wildtype diffuse astrocytoma (CNS WHO grade 2-4), (37.7 % females) were enrolled. The median age was 68 years (37-86 years) in the classic glioblastoma cohort and 55 years (20-87 years) in those with astrocytomas. GTR was achieved more often in patients with classic glioblastoma: 58.8% compared to those with diffuse astrocytoma 39.1% (p = 0.0001); STR (32.6%, p = 0.0048) and biopsy (28.3%, p = 0.0032) were more often in astrocytomas. The overall survival was 12.7±10.4 months in classic glioblastoma compared to 27.3±2.9 months in astrocytoma. GTR significantly increased OS in both entities (glioblastoma: 15.3±10.4 months, 95% CI 13.13 - 17.40, p = &lt;0.0001; diffuse astrocytoma: 26.7±17.9 months, 95% CI 20.13 - 33.25, p = &lt;0.0001). Further, also STR significantly increased OS in glioblastoma (11.46±11.03 months, 95% CI 7.55 - 15.37, p = 0.0257) and astrocytoma (18.8±13.54 months, 95% CI 14.47- 23.13, p = 0.0035). ROC analysis identified a residual cut-off tumor volume of &gt;20% in the glioblastoma cohort and &gt;60% in the difuse astrocytoma cohort to be associated with impaired OS. Multivariate logistic regression analysis identified age and EOR, not radio-chemotherapy, as independent predictors of OS in diffuse astrocytoma. MGMT methylation had no impact on OS (p = 0.11).

CONCLUSION
The presented data suggests that resection prolongs OS in patients with IDH-wildtype astrocytomas and is of higher value than radio-chemotherapy. Of note, STR also positively influences OS in these patients. These results underline the importance of surgical resection even if GTR is not achievable and thus mark a potential paradigm shift in clinical decision making.
OS02.4.A CAREGIVER PROGRAM IN NEURO-ONCOLOGY: UCSF EXPERIENCE CARING FOR MORE THAN 4,000 CAREGIVERS OVER THE LAST 10 YEARS
Authors: Taylor J W , Page M , Rodriguez Almaraz E , Angelo D , Velasco C , Chang S M 
Published: October 2024

Abstract

BACKGROUND
Caregivers of patients with primary brain tumors are at high risk for distress and as they navigate caring for their loved one with both a cancer diagnosis and neurologic disorder. The last decade has seen growth of caregiver research in the brain tumor community, with evidence that caregiver mastery may correlate with survival in patients with glioblastoma (GBM). The UCSF Gordon Murray Neuro-Oncology Program, the first of its kind, launched in 2014 with a mission to address their unique needs. Caregiver care is now fully integrated into the clinical care of patients with brain tumors at UCSF, providing personalized care across the disease trajectory and programming to address common challenges and foster resilience. The Program includes a nurse, administrator, and social worker. Referrals occur 1) at first clinic appointment; 2) from clinical staff; and 3) caregivers of patients with GBM receive proactive outreach over the first 6 months after diagnosis. Caregivers are also contacted for bereavement support. Dedicated programming provides educational materials focusing on common concerns and building community through monthly support groups, educational webinars, annual retreats and family camp. We report our practical experience of the Program serving over 4,000 caregivers since its inception.

MATERIAL AND METHODS
Total number of individual caregivers were included from 01/2014 - 12/2023. Detailed demographic information was extrapolated during clinical interviews from a subset. Information regarding caregiver concerns and interventions was extracted from the medical records between 01/2017 - 12/2023.

RESULTS
The UCSF Gordon Murray Caregiver serves an annual average of 400 caregivers and over 800 encounters. Demographic information obtained from a subset revealed 66% females; 77% between 41-64 years of age; 60% a spouse; 89% working full time; and 30% had children in the home. The most common concerns for caregivers were informational (42%), followed by emotional (25%), and practical (23%). Examples of informational concerns included desire for informational resources, understanding the treatment plan/side effects, and understanding patient behavioral changes. Emotionally, they feel overwhelmed, uncertain, and sad. Practical concerns included physically caring for patients and issues around medical insurance, disability, and finances. Caregivers also expressed frequent concerns around talking with children/family members and feelings of isolation.

CONCLUSION
Caregivers of patients with primary brain tumors are at high risk of distress and have unique needs based on the tumor location and symptoms from treatment. Our practical 10 year experience of a dedicated, fully integrated, caregiver program highlights real world concerns of caregivers and identifies opportunities to develop tailored interventions to address these needs.
OS06.7.A PLATFORM-AGNOSTIC METHYLATION CLASSIFICATION OF 184 CLASSES OF CNS TUMOURS
Authors: Patel A , Schrimpf D , Jäger N , Loose M , Wick W , Krieg S , Schlesner M , Pfister S M , von Deimling A , Jones D T W , Sill M , Sahm F 
Published: October 2024

Abstract

BACKGROUND
The 2021 WHO classification underscores the importance of methylation-based Central Nervous System (CNS) tumour diagnostics. The Heidelberg MNP classifier has been widely used for methylation classification. However, current approaches for methylation classification warrant the use of methylation arrays which suffer from technical complexity, considerable equipment and reagent cost, as well as lengthy turnaround times. Recent advances in nanopore sequencing have demonstrated the feasibility of methylation classification of broad classes of CNS tumours. Here we introduce and validate MNP-Flex- a platform agnostic methylation classifier that classifies 184 classes of CNS tumours and is compatible with the version v12.8 of the Heidelberg MNP classifier. MNP-Flex is made available as a web-based service.

MATERIAL AND METHODS
We trained a gradient boosted model on a training set comprising 7,495 methylome profiles spanning 184 classes and covering multiple sparsity levels. We validated the model on a comprehensive multi-centric dataset comprising over 79,000 samples processed using diverse approaches like- methylation arrays, nanopore shallow and deep whole genome sequencing using cryopreserved or FFPE tissue, intraoperative and post-hoc nanopore adaptive sampling (Rapid-CNS2) data, whole genome bisulphite sequencing using tissue and liquid biopsy samples, as well as methylation panels.

RESULTS
We achieved an overall accuracy of 94% across a diverse, cross-platform, global cohort of 79,000 samples spanning 9 different sequencing conditions. MNP-Flex could also successfully classify 85% of samples with sparse profiles including those obtained using nanopore sequencing in an intraoperative setting and from liquid biopsies.

CONCLUSION
MNP-Flex addresses the crucial need for accessibility of methylation-based CNS tumour diagnostics. It offers a single platform-agnostic methylation classifier applicable across diverse sample types and sequencing conditions which is provided as a web-service. The ability to effectively classify samples with sparse profiles extends its clinical utility to low throughput conditions. MNP-Flex aims to streamline methylation-based classification, ultimately improving access to molecularly-informed patient care in neuro-oncology.
OS09.7.A GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB
Authors: Lassman A , Alexander B , Berry D , Buxton M , Cavenee W , Colman H , De Groot J , Ellingson B , Gordon G , Hyddmark E M V , Khasraw M , Lim M , Mellinghoff I , Mikkelsen T , Perry J , Powell A , Sulman E , Tanner K , Weller M , Yung W K A , Blondin N , Brenner A , Butt O , de la Fuente M I , Drappatz J , Iwamoto F , Kim L , Lee E , Mantica M , Nabors B , Newton H , Schiff D , Walbert T , Weathers S , Cloughesy T , Wen P Y 
Published: October 2024

Abstract

BACKGROUND
GBM AGILE (NCT03970447;https://www.gcaresearch.org/research/gbm-agile) is a phase 3 Bayesian adaptive platform trial that efficiently tests multiple arms against common control, with 6 arms included to date. Primary endpoint is overall survival (OS). Stage 1 experimental arms are adaptively randomized against other arms. Demonstrated efficacy in stage 1 leads to fixed randomization stage 2. Stages 1 and 2 are combined for registration. Control randomization is fixed. Regorafenib, a multikinase-inhibitor, entered into GBM AGILE as the first arm and therefore was equally randomized against control. Regorafenib showed OS benefit in recurrent disease (RD) in randomized phase 2 REGOMA trial.

MATERIAL AND METHODS
Patient subtypes in GBM AGILE are newly diagnosed unmethylated (NDU), RD, and—not considered for regorafenib—ND methylated (NDM). Arm indications (signatures) are combinations of subtypes. Control is temozolomide (ND) and lomustine (RD). Efficacy is assessed by OS hazard ratio(HR), arm/control. Efficacy is demonstrated when Bayesian probability of benefit (HR&lt; 1.00) ≥ 98% (roughly analogous P-value: 0.02). Futility occurs at any monthly analysis when Bayesian predictive power (PP) is &lt; 25% for all signatures. Follow-up continues for 12 months after arm’s accrual stops.

RESULTS
When PP for all 3 pre-defined signatures was &lt; 25%, regorafenib’s accrual was stopped for futility. Regorafenib/control sample sizes were 49/51, 127/128, 176/179 for signatures NDU, RD, and both. Respective PPs: 0.138, 0.030, 0.025—none close to 0.25. Respective mean HRs: 1.26, 1.25, 1.23. Probabilities of benefit (HR&lt; 1.00): 0.35, 0.18, 0.17. At final analysis, mean HRs were 1.07, 1.08, 1.08 with final probabilities of benefit (HR&lt; 1.00) equal to 0.421, 0.312, 0.296—none close to 0.98.

CONCLUSION
GBM AGILE efficiently and compellingly addressed regorafenib’s role in GBM, in RD and NDU. These findings are germane as they fail to confirm the REGOMA results in RD. GBM AGILE continues to efficiently assess other therapies, including utilizing concurrent and previously accrued controls. This abstract was accepted and previously presented at the 2023 SNO Annual Meeting and published in Neuro-Oncology, Volume 25, Issue Supplement_5, November 2023, Pages v97-v98.
OS11.5.A MYELOID CELLS DRIVE IMMUNOSUPPRESSION OF CHIMERIC ANTIGEN RECEPTOR T CELLS IN THE NEURONAL MICROENVIRONMENT OF GLIOBLASTOMA
Authors: Zhang J , Ehr J v , Look T , Benotmane J K , Neidert N , Kueckelhaus J , Weiss T , Heiland D H , Yabo Y A 
Published: October 2024

Abstract

BACKGROUND
Chimeric antigen receptor (CAR)-T cell therapy has been successful in hematologic malignancies but demonstrated limited success in solid cancers including glioblastoma. The heterogeneous nature of central nervous system malignancies and immunosuppressive microenvironment are major impediments to the efficacy of CAR-T cell therapy in glioblastoma. Here, we aim to explore the transcriptional adaptation of CAR-T cells and cellular interactions that may explain the T cell dysfunction in the glioblastoma microenvironment.

MATERIAL AND METHODS
We performed physically interacting cells sequencing (PIC-seq) to explore the transcriptional diversity of NKG2D CAR-T cells and control T cells in the glioblastoma ecosystem leveraging a human neocortical slice model. We investigated cellular interactions and receptor-ligand interactions through CellChat and integration of spatially resolved T cell receptor sequencing. CellOracle was used to reconstruct gene regulatory networks and identify key transcription factors associated with CD8 CAR-T cell dysfunction. Further, we used in-silico perturbation to identify transcriptional drivers that have the potential to enhance cytotoxic response of CAR-Ts.

RESULTS
We inoculated primary patient-derived glioma cells into human neocortical slices from surgical access tissue specimens. After 3 days of tumor growth, slices were treated with NKG2D CAR-Ts or control T cells. We observed that after an initial phase (2 days) of anti-tumor T cell response in the CAR-T group, tumor growth did not differ between conditions. After 7 days of treatment, PIC-seq was used to profile CAR-Ts (tomato+) and tumor cells (GFP+) as well as cells which were physically connected (+/+). We identified a transcriptional shift towards T cell exhaustion in CAR-T cells compared to T cells lacking the NKG2D construct. This transcriptional phenotype was driven by CAR-T cell-myeloid cell interaction. Integrative analysis identified that tumor-associated macrophages with enhanced phagocytic function in proximity to mesenchymal-like tumor cells located within hypoxic niches are the main drivers of T cell dysfunction. Gene regulatory network analysis demonstrated that MAF and BACH2 are key transcriptional regulators of CAR-T cell function.

CONCLUSION
Both myeloid-tumor and myeloid-T cell interactions collectively promote an immunosuppressive microenvironment in glioblastoma. Our data has the potential to catalyze the re-engineering and optimization of CAR-T cell therapies with sustained cytotoxic effect against glioblastoma.
P01.08.A HYOXIA-INDUCED EXPRESSION OF ARHGAP FAMILY MEMBERS PROMOTES GLIOBLASTOMA DISSEMINATION
Authors: Vaughn-Beaucaire P , Muller L , Prior S , Lawler S , Bruning-Richardson A 
Published: October 2024

Abstract

BACKGROUND
The Rho GTPase activating proteins (ARHGAPs) perform vital roles in the regulation of the Rho GTPases with direct effect on cellular plasticity and cell migration/invasion. We recently reported on the role of five ARHGAPs, identified by a microarray screen, in morphological plasticity in established and patient-derived Glioblastoma (GBM) cell lines and associated clinical relevance in terms of tumour recurrence after treatment. We established that the ARHGAPs either promoted or targeted cell migration/invasion by allowing cells to undergo morphological changes in preparation for dissemination. We also showed that co-expression of two ARHGAPs, 12 and 29, is associated with reduced time to recurrence after initial treatment in patients. ARHGAP activity has been also reported in metastatic cancers including breast and colorectal cancer highlighting the biological relevance of these, as yet understudied, proteins.

MATERIAL AND METHODS
Here, we explored the GBM microenvironment and the effect of hypoxia on ARHGAP expression and localisation in glioma cell lines.

RESULTS
Using immunocytological and in vitro migration and invasion assays we were able to ascertain that ARHGAP4, 12, 22, 25 and 29 acquired subcellular distributions different to those recorded under normoxia and expression also decreased or increased under hypoxia. We also found that the effect of the migrastatic inhibitor 6-bromo-indirubin-3′-oxime (BIO) targeting GSK-3 signalling was potentiated when cells were challenged with the drug under hypoxic conditions.

CONCLUSION
Our results confirm our initial findings of biological relevance of the ARHGAPs in cellular activities and highlight important roles for the ARHGAPs for promoting migratory/invasive activity and behaviour in GBM cells. We also conclude that migrastatic inhibitors will exert enhanced activity on GBM cells under hypoxic conditions making them excellent candidates for complement treatment with cytotoxic drugs or radiotherapy for an improved management of GBM.
P01.15.A SURGICAL RESECTION-INDUCED ISCHEMIA DRIVES GLIOBLASTOMA CELL PLASTICITY AND TUMOR MICROENVIRONMENT ADAPTATION
Authors: Ballestín A , Reveilles J , Pichol-Thievend C , Bourmeau G , Anezo O , Ribecco V , Blanchard B , Pettiwala A , Leboucher S , Daubon T , van Rheenen J , Seano G 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma IDH-wildtype (GBM) treatment involves a combination of surgical resection, radiation therapy, and chemotherapy with temozolomide. Despite the aggressive standard of care, 90% of patients experience recurrence a few months after treatment, typically marked by the regrowth of highly invasive cells spreading from the peritumoral brain resection zone. The impact of chemoradiotherapy has been studied, but the impact of microsurgical resection on the tumor microenvironment (TME) and the plasticity of GBM cells remains unknown. Hence, the objective of this work was to study histopathological and transcriptomic changes induced by microsurgical resection on residual tumor cells and TME.

MATERIAL AND METHODS
Syngeneic GBM cell lines CT2A and GL261 were orthotopically implanted in C57Bl6j mice brains meanwhile P3 xenografts were injected in immunosuppressed nude mice. We developed an optimized microsurgical resection protocol for GBM in mice, mirroring the steps performed in patients. In a size-matched study, mice were randomly assigned to four groups: control (pre-surgery) and 1, 3, and 7 days post-surgery. Tumor tissues were studied with a multilevel strategy composed of time-resolved bulk and single-cell RNA sequencing, immunohistochemistry and intravital multiphoton microscopy (IVM).

RESULTS
Our analyses showed that microsurgical resection induced pronounced proneural-to-mesenchymal transition (PMT) and stimulation of hypoxia-driven pathways in residual GB cells. Further, we detected significant changes in the TME relative to the immune response and vascular function in line with ischemia exposure, which could humper the response to treatment by altering the adequate effect and distribution of the subsequent chemoradiotherapy.

CONCLUSION
Microsurgical resection consequences play a crucial role in shaping the phenotypic landscape of GBM tumor cells and the TME, marked by a transient ischemic TME triggering PMT in GBM cells and potentially preventing the effective response to chemoradiotherapy.