bluuebunny/crossref_metadata_2025_split huggingface dataset:
KS02.7.A LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA
Authors: Johnson K C , Spitzer A , Varn F S , Nomura M , Garofano L , Chowdhury T , Anderson K J , D’Angelo F , Bussema L , Gritsch S , Oh Y , Moon H , Paek S , Bielle F , Laurenge A , Di Stefano A , Mathon B , Picca A , Sanson M , Lipsa A , Hertel F , Zhao Z , Wang Q , Jiang T , Hermes B , Sanai N , Golebiewska A , Niclou S P , Huse J , Yung W , Lasorella A , Suvà M L , Iavarone A , Tirosh I , Verhaak R G 
Published: October 2024

Abstract

BACKGROUND
Hotspot mutations in the IDH genes serve as tumor-initiating events that define a subset of adult diffuse glioma that can further be divided into either oligodendroglioma or astrocytoma subtypes. Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood.

MATERIAL AND METHODS
To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing.

RESULTS
Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles.

CONCLUSION
Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.
KS03.4.A PATTERNS OF CARE AND CLINICAL OUTCOMES OF PATIENTS WITH GLIOBLASTOMA IN THE UNITED STATES FROM 2005-2020: A REAL-WORLD ANALYSIS
Authors: Jayram D , Bellur S , Ozair A , Ahmad S , Hodgson L , Frias Perez N , Podder V , Ganiyani M , Ahluwalia M 
Published: October 2024

Abstract

BACKGROUND
Survival for glioblastoma (GBM) remains low, with disparities affecting outcomes. Standard of care (SoC) includes surgery and adjuvant chemoradiation. This study explores the demographics, treatment patterns, and outcomes of GBM pts in the United States (US).

MATERIAL AND METHODS
We conducted a retrospective study with the US National Cancer Database (NCDB), capturing more than 70% of newly diagnosed patients in US, for GBM pts diagnosed in 2005-2020 according to ESMO Guidance for Reporting Oncology Real-World (GROW). Trends were analyzed with descriptive statistics and X2-test between time periods: 2005-08, 2009-12, 2013-16, and 2017-20. Predictors of SoC receipt were analyzed with multivariate logistic regression. Kaplan-Meier method and log-rank test were used to estimate and compare median overall survival (mOS) for univariate association and Cox proportional-hazards analysis for multivariate modelling. Adjustment was made using demographic, socioeconomic, and clinical factors. Associations were reported as (Odds Ratio [OR]/Hazard Ratio [HR] 95% CI) per STROBE guidelines.

RESULTS
Of 104,697 GBM pts, 42.5% were female. 91.2% White, 5.7% Black, and 2.0% were Asian. 5.3% were Hispanic. Median age was 65 (IQR 57-73). Percentage of pts ≥ 65 years increased from 48.8% in 2005-08 to 54.0% in 2017-20. 56.5% of pts received SoC. SoC receipt rose over time: 2009-12 (OR 1.26, CI 1.21-1.31, P&lt;0.001) vs 2013-16 (OR 1.36, CI 1.31-1.42, P&lt;0.001) vs 2017-20 (1.51, CI 1.45-1.57, P&lt;0.001). Older pts were less likely to receive SoC compared to pts aged &lt;50: 50-64: (OR 0.81, CI 0.77-0.86, p&lt;0.001), 65-74: (OR 0.59, CI 0.55-0.62, p&lt;0.001) vs &gt;74: (OR 0.23, CI 0.22-0.25, p&lt;0.001). Females (OR 0.91, CI 0.89-0.93 P&lt;0.001), Black (OR 0.81, CI 0.77-0.86, P&lt;0.001), and Hispanics (OR 0.91, CI 0.86-0.97, P=0.004) were less likely to receive SoC than males, White, and non-Hispanics. Privately insured were more likely to receive SoC than with Medicare (OR 0.83, CI 0.80-0.87, P&lt;0.001), Medicaid (OR 0.67, CI 0.64-0.71, P&lt;0.001), and uninsured pts (OR 0.60, CI 0.55-0.64, P&lt;0.001). SoC recipients had mOS of 14.6 months (CI 14.5-14.8) vs 4.8 (CI 4.7-4.9) for non-recipients (P&lt;0.001). Compared to 2005-08, pts were more likely to survive in 2017-20 (HR 0.84, CI 0.82-0.85, P&lt;0.001) followed by 2013-16 (HR 0.88, CI 0.86-0.89, P&lt;0.001) and 2009-12 (HR: 0.93, CI 0.91-0.94, P&lt;0.001).

CONCLUSION
Receipt of SoC has increased with significant improvement in OS. However, female, Black and Hispanic pts were less likely to receive SoC. Targeted efforts are warranted to mitigate disparities and increase receipt of SoC.
KS04.5.A DIFFERENCES IN COGNITIVE FUNCTIONING BETWEEN PATIENTS WITH IDH1-MUTANT OLIGODENDROGLIOMA AND ASTROCYTOMA BEFORE AND AFTER SURGERY
Authors: Landers-Wouters M , Butterbrod E , Brouwers B , Rutten G 
Published: October 2024

Abstract

BACKGROUND
Alongside differences in growth rate, IDH1-mutant oligodendroglioma and astrocytoma exhibit differences in growth pattern. Whereas oligodendroglioma seem to infiltrate subcortical tracts, astrocytoma tend to displace them. Tracts traversing a tumor are more likely to be damaged during surgical resection than displaced tracts, possibly resulting in a (temporary) worse cognitive outcome. This study explored differences in cognitive functioning before and after surgery between patients with IDH1-mutant astrocytoma and oligodendroglioma.

MATERIAL AND METHODS
Patients who underwent surgery for confirmed IDH1-mutant, WHO grade 2 or 3 oligodendroglioma (1p19-codeleted) or astrocytoma were included. Cognition was assessed with computerized and paper-and-pencil tests before surgery, and 3 and 12 months after. Test scores were standardized. Diagnostic groups were compared on sociodemographics, tumor location, awake vs. asleep surgery, type of mapping, extent of resection (EOR), adjuvant treatment and baseline cognition. We performed longitudinal mixed models (LMM) to investigate differences in performances over time in the total sample and stratified according to surgical modality (awake or asleep), α=.05. We first examined the effect of diagnosis only, and subsequently with correction for group differences.

RESULTS
Compared to astrocytoma patients (n=95), those with oligodendroglioma (n=67) were significantly older, more often harbored a tumor located in the frontal lobe, and less often in the temporal lobe. Gross total resection (vs. subtotal) was more frequently achieved in oligodendroglioma surgery. Diagnosis was not related to any baseline test performance, but WHO grade (3 vs 2) was. In univariable LMM, oligodendroglioma patients performed worse than astrocytoma patients on cognitive flexibility over time. This effect was most apparent in the first time interval (astrocytoma: B= -0.45, oligodendroglioma: B=-0.84), after which both groups improved (B=0.23, B=0.24). Stratification showed no effect of diagnosis on longitudinal performances in the awake surgery group, but there was a difference between diagnoses on cognitive flexibility in the asleep surgery group, where astrocytoma patients remained stable (B=-0.01) while oligodendroglioma declined significantly (B=-0.55). Differences were not significant after correcting for baseline differences and EOR. Age and EOR were associated with multiple performances.

CONCLUSION
Differences in cognitive trajectories between patients with IDH1-mutant oligodendroglioma and astrocytoma seem explained by other patient and tumor characteristics or surgical factors rather than tumor type. Studies directly linking pre- and postoperative tract integrity to test performances can enhance understanding of the interplay between tumor growth pattern, surgical resection and cognitive outcome.
JS07.5.A CORRELATION BETWEEN TUMOR-INFILTRATING LYMPHOCYTE DISTRIBUTION AND CLINICAL OUTCOME IN PHASE I/II CLINICAL TRIAL OF DENDRITIC-CELL BASED IMMUNOTHERAPY IN GLIOBLASTOMA PATIENTS
Authors: Pellegatta S , Di Ianni N , Anghileri E , Facciolla M , Cuccarini V , Milani M , Patane M , Acquino D , Pollo B , DiMeco F , Silvani A , Eoli M 
Published: October 2024

Abstract

BACKGROUND
Despite the first classification of glioblastoma as an immunologically “cold” tumor, accumulating evidence suggests that this cancer type is susceptible to T cell infiltration, providing a glimmer of hope for the development of effective immunotherapy approaches that until now had limited success in brain tumors. To explore the contribution of biomarkers that could identify groups of patients showing durable response to immunotherapy, we examined several clinical and biological finding in 69 newly-diagnosed glioblastoma patients treated with dendritic cell (DC) immunotherapy added to standard treatment (DENDR1 NCT04801147).

MATERIAL AND METHODS
Patients with post-surgery volume ≤10 cc underwent leukapheresis before radiotherapy and chemotherapy with temozolomide (TMZ). Three intradermal injections of mature DC loaded with whole tumor lysate were administrated before and four after adjuvant TMZ. In all patients peripheral immune effector subsets were assessed including T and NK cells,, In all tumor samples MGMT methylation status was evaluated, and in 36 cases an immunohistochemistry (IHC) analysis was performed on tumor specimen collected before DC immunotherapy.

RESULTS
After a median follow-up of 23months (mo) median progression-free survival (PFS) was 12 mo (CI 95%10.34-13.6) and median overall
survival (OS) was 22.6 mo (CI 95%18.7-24.5) comparing favorably with OS expected from the literature. MGMT status and expansion of NK cells positively impacted PFS and OS. Furthermore, our preliminary results suggest an association between the density and localization of specific Tumor Infiltrating Lymphocytes (TILs) and patients’ response to immunotherapy. TIL spatial patterns revealed either an immune-excluded, or an immune-infiltrated scenario with either scattered, clustered, or widespread T cell infiltration. Notably, an abundant widespread infiltration of CD8 TILs was correlated with prolonged survival of DENDR1 patients (PFS 18.0 vs. 8.9; OS 33.6 vs. 11.0; p&lt; 0.005 compared with excluded CD8+ TIL distribution), supporting that distribution can be predictive of immunotherapy responsiveness.

CONCLUSION
These findings suggest that in DENDR-1 improved clinical outcomes correlate with an increase in the number of active NK cells, MGMT status, and abundant widespread infiltration of CD8+ TILs.
OS03.4.A REPEATED INTRACRANIAL ADMINISTRATION OF ANTI-PD-1 ALONE OR IN COMBINATION WITH ANTI-CTLA-4 IMMUNE CHECKPOINT-BLOCKING MONOCLONAL ANTIBODIES IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA
Authors: Lescrauwaet L , Dirven I , Del’haye J , Geens W , Geeraerts X , Stevens L , Brock S , Kockx M , Seynaeve L , Everaert H , Vanbinst a , Tuyaerts S , Neyns B , Duerinck J 
Published: October 2024

Abstract

BACKGROUND
Recurrent high-grade glioma (rHGG) is an invariably fatal malignancy, currently lacking life-prolonging treatment options. Systemic administration of PD-1 and CTLA-4 immune checkpoint blocking monoclonal antibodies has shown limited efficacy. In the Glitipni multi-cohort dose finding phase I clinical trial, the primary aim is to establish safety and feasibility of intra- followed by postoperative intracranial (iCran) administration of nivolumab (NIVO), with or without ipilimumab (IPI), in patients with rHGG amenable for a maximal safe resection (MSR) or stereotactic core needle biopsy (SCNB).

MATERIAL AND METHODS
Sixty-one patients were enrolled (across 3 cohorts), receiving 10 mg NIVO IV within 24h prior to MSR or SCNB. Forty-three patients underwent MSR, followed by intracerebral (iCer) injection of NIVO (10 mg) and IPI (5 mg) in the brain tissue lining the resection cavity. Among them, 27 received an additional intracavitary injection of NIVO (10 mg) and IPI (1-, 5-, or 10 mg) (iCav, via an Ommaya reservoir) at the end of the neurosurgical procedure. Sixteen patients underwent SCNB followed by the intratumoral (iTum) injection of NIVO (10 mg) and IPI (5 mg). Postoperative iCav administrations were repeated bi-weekly for a maximum of 11 cycles, concurrently with 10 mg NIVO IV. Postoperatively, 1-, 5-, or 10 mg NIVO iCav was administered as a single agent in 28 patients. In the third cohort, postoperative administration of 10 mg NIVO iCav was combined with 1-, 5- or 10 mg IPI iCav in 22 patients.

RESULTS
No unexpected adverse events (AE) occurred related to the perioperative treatment. Dose limiting toxicity consisted of transient symptomatic grade 3 aseptic neutrophilic pleocytosis in 1- and 3 patients receiving iCav administration of 5- and 10 mg iCav IPI, respectively. The most frequent reported treatment related AE was fatigue (n=49,80%); no grade 5 AE occurred. PFS did not differ between cohorts. OS was superior in patients who underwent a MSR versus SCNB; but was not improved by the addition of iCav IPI (median OS: 15- [95% CI 0-53] vs. 42- [26-57] vs. 35 [29-40] weeks; 1y OS-rate: 12% [95% CI 0-28] vs. 37% [14-60] vs. 29% [12-46]). OS of pts who underwent a MSR compared favorable against a pooled historical control cohort (n=469) treated with VEGF(R)-inhibitors (log rank p.015).

CONCLUSION
This first-in-human, multi-cohort, phase I clinical trial on intracranial CTLA-4/PD-1 blockade in patients with rHGG, demonstrates that intra- and postoperative iCran administration of NIVO with or without IPI up to a bi-weekly postop iCav dose of 1 mg IPI and 10 mg NIVO can be safely performed. Promising survival is documented in patients amenable for resection.
OS04.6.A ONE STEP CLOSER TO THE END OF LIFE - A QUALITATIVE STUDY ABOUT THE EXPERIENCES OF PATIENTS AND THEIR FAMILIES IN RELATION TO THE RECURRENCE OF A HIGH-GRADE GLIOMA
Authors: Sørensen von Essen H , Dahl Steffensen K , Rom Poulsen F , Piil K 
Published: October 2024

Abstract

BACKGROUND
High-grade gliomas (HGG) are the most aggressive and infiltrative sub-type of primary brain tumors. Despite intensive treatment, the average survival time from diagnosis is less than two years, and all patients experience recurrence after the initial resection and oncological treatment. However, our understanding of patients’ and their families’ experiences related to the inevitable recurrence remains limited. This qualitative study aimed to explore how patients and their close family members cope with their fear of recurrence, and to understand their experiences when faced with the reality of recurrence.

MATERIAL AND METHODS
The present study is part of a larger study exploring the experiences of patients and their families related to the recurrence of an HGG. Semi-structured individual interviews were conducted. The interviews were audio recorded and transcribed verbatim. Following an inductive phenomenological hermeneutical approach, the interviews were coded, and the findings were divided into themes.

RESULTS
The study included 15 patients and 14 family members between the ages of 22 and 79. The analysis identified three overall themes. Theme I: Navigating the fear of recurrence. Theme II: Facing recurrence and preparing for death. Theme III: Redefining hope in the era of recurrence. The three themes were interrelated and provided an overall insight into the complex experiences related to the diagnosis of an HGG recurrence, which will be further elaborated on in the presentation.

CONCLUSION
During the disease trajectory of living with an HGG, patients and their family members tried their best to live life to the fullest and cope with their fear of the inevitable recurrence and death. They expressed an overall awareness about the prognosis, but their hopes and coping mechanisms left them off guard, causing the recurrence diagnosis to strike them as a shock. The recurrence was experienced as taking one step closer to the end of life, leading them to redefine their hopes and goals for the future. This new knowledge can be used to tailor advance-care-planning consultations, emphasizing patients’ and family members’ readiness to discuss end-of-life issues.
OS07.2.A INTEGRATED SPATIALLY RESOLVED TRANSCRIPTOMICS AND ELECTROPHYSIOLOGY UNRAVELED THE ARCHITECTURAL HETEROGENEITY OF NEURONAL-GLIOMA INTERFACES
Authors: Grabis E , Hilfiger L , Kueckelhaus J , Neidert N , Zhang J , Villa G , Yabo Y , Benotmane J , Prinz M , Ricklefs F , Beck J , Schnell O , Vlachos A , Delev D , Heiland D 
Published: October 2024

Abstract

BACKGROUND
In recent years, spatially resolved, high-dimensional methodologies have elucidated substantial transcriptional heterogeneity within malignant brain tumors. However, the absence of functional readouts has impeded the linkage of emergent insights from cancer neuroscience to the structural heterogeneity observed. To address these challenges, we developed a novel methodology that combines spatially resolved electrophysiological recordings with array-based transcriptomics on surgical specimens. This approach enables an exploration of the transcriptional underpinnings of electrophysiological network communication in glioblastoma.

MATERIAL AND METHODS
We analyzed 12 surgical glioblastoma specimens, which were sectioned (350µm) and subjected to high-resolution multi-electrode array (HD-MEA) recordings (64 x 64 pillar electrodes at a 2µm resolution, 3Brain), followed by spatially resolved transcriptomics (at a 55µm resolution, Visium). Data co-registration was achieved through affine transformations and postprocessing using SPATA2 (github.com/theMILOlab/SPATA2).

RESULTS
Utilizing graph-based analysis, we identified prominent communication hubs and prevalent signaling pathways within tumor and peritumoral areas. Horizontal and vertical integration across these data modalities, combined with latent-space clustering, revealed spatial heterogeneity in electrophysiological communication and transcriptional responses. Notably, regions of infiltrative growth and tumor borders exhibited enhanced neuronal-glioma interactions, characterized by transcriptional up-regulation of synaptogenic signaling and a predominant presence of oligodendrocyte progenitor cell (OPC)- and neural progenitor cell (NPC)-like tumor cells. These regions displayed distinct, repetitive spatial signaling patterns. Conversely, areas with heightened inflammatory responses, marked by macrophage and T cell enrichment, as well as hypoxic alterations, demonstrated a lack of coherent communication patterns. Tumor peripheries with increased astrocytic presence or activated microglia exhibited diminished communication between tumor and neuronal systems compared to infiltrative areas with elevated oligodendrocytic abundance, underscoring the critical role of oligodendrocytes in facilitating neuronal-glioma communication.

CONCLUSION
Our investigations into the electrophysiological and transcriptomic architecture of gliomas provide novel insights into the intricate heterogeneity of the neuronal-glioma interface and identify key regulatory elements that drive the integration of glioma within neuronal circuits.
OS08.6.A MACHINE LEARNING BASED PREDICTIVE RADIOMICS FOR EVALUATION OF CANCER IMMUNE SIGNATURE IN GLIOBLASTOMA: THE PRECISE-GBM STUDY
Authors: Ghimire P , Modat M , Booth T 
Published: October 2024

Abstract

BACKGROUND
Immunotherapy is an effective personalized treatment for several cancers. Radiogenomics in glioblastoma patients may serve as pre-operative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The aim of the study is to identify machine learning based radiological biomarkers that can predict immune status within the tumor microenvironment of IDH wildtype glioblastoma.

MATERIAL AND METHODS
This is a retrospective multicentre machine learning based study utilizing open access anonymized matched radiogenomic data of TCGA-GBM, CPTAC, Ivy GAP and REMBRANDT datasets. REMBRANDT data acted as a hold out dataset for validation. Imaging data consisted of pre-operative MRI based radiomics features extracted from deep learning based segmented tumours. Transcriptomic data-based overall immune scores and cell-specific (T cells and tumour associated macrophages-TAMS) scores were extracted using CIBERSORTx. Outliers were identified and filtered using principal component analysis. Combat and neuroCombat were utilized for data harmonization of genomic and imaging data respectively. Radiomic feature selection was performed using LASSO technique with cross validation. Support vector machine (SVM) was trained and tested with 80:20 radiomic data split, and binary labels based on (1) overall immune scores, and (2) immune cell-specific scores. Data query and analysis was performed using python.

RESULTS
One hundred and one patients with 15 in the hold out dataset were included in the study. Trained SVM models predicted the labels for immune score and cell-specific scores (T cells -CD4, CD8; TAMS - M0, M1, M2) with AUC of 0.93, 0.79, 0.86, 0.81, 0.95, 0.76; balanced accuracy of 0.72, 0.82, 0.93, 0.80, 0.86, 0.71 respectively. In the holdout set, the models predicted the labels with robust prediction sensitivity for overall immune scores (100%) and M2 (M2 pro-tumour subtype macrophages) scores (75%) and with robust prediction specificity for T cell scores (CD4: 100%, CD8: 90%) along with M0 (M0 precursor pro-tumour macrophages) (62.5%) and M1 (M1 anti-tumour subtype macrophages) (83%) scores. The radiomic signature employed for prediction models were a group of first order and second order radiomic features obtained after feature selection.

CONCLUSION
A radiogenomic SVM model non-invasively predicted immune status in wildtype glioblastoma microenvironment with good accuracy. This model has the potential to be utilized in a prospective glioblastoma clinical trial for immunotherapy.