bluuebunny/crossref_metadata_2025_split huggingface dataset:
JS04.6.A EVOLUTION OF GLIOBLASTOMA THERAPY IN TWO DECADES: COMPARISON OF TWO PROSPECTIVE, CONTROLLED TRIALS ON THE RESECTION OF GLIOBLASTOMA: THE 5-ALA AND IMRI VS. 5-ALA-TRIALS
Authors: Roder C , Study group i , Study group A , Haas P , Tatagiba M , Stummer W 
Published: October 2024

Abstract

BACKGROUND
Two prospective, controlled multicenter trials on the resection of glioblastomas are published to date spanning almost 2 decades of medical evolution. The 5-ALA (ALA) trial, published 2006, comparing the extent of resection (EOR) and overall survival (OS) of patients after 5-ALA fluorescence-guided and white-light surgery, and the iMRI vs. 5-ALA (iMRI/ALA) published 2023, comparing 5-ALA fluorescence-guided and iMRI-guided surgery. Both studies had comparable inclusion criteria, therefore this analysis aims to compare surgical and survival results of both studies.

MATERIAL AND METHODS
We analyzed the data of both trials in terms of baseline, peri- and postoperative clinical data, as well as EOR and OS.

RESULTS
Data of 243 patients of the ALA and 277 patients of the iMRI/ALA trial were analyzed. Median age and preoperative NIHSS were comparable between cohorts. Tumors were rated “eloquent” in 56% in the ALA and 51% in the iMRI/ALA trial. Total resection of contrast enhancement was achieved in 36.1% (white-light), 64.5% (ALA in ALA trial), 78% (ALA in iMRI/ALA trial) and 81% (iMRI). 19.5% (ALA trial) compared to 8% (iMRI/ALA trial) of patients deteriorated neurologically postoperatively. OS differed significantly between both studies, especially depending on the EOR: Patients with incomplete resections had a median OS of 11.8 (ALA-trial) and 19.4 (iMRI/ALA trial), in contrast to 16.9 and 25.4 months for completely resected tumors, respectively. Incomplete resections led to worse OS in both studies, regardless of residual tumor size. Patients with the prognostically “worst” tumors (MGMT non-methylated, subtotal resection) in the iMRI/ALA trial had a comparable median OS (16.1 months) to patients with the prognostically “best” tumors (total resection) have from the ALA-trial (16.9 months). First-line adjuvant treatment was radiotherapy in 92.6% of patients in the ALA trial and a combined radiochemotherapy with temozolomide in 84% of patients in the iMRI/ALA trial.

CONCLUSION
Most likely due to increasing experience with5-ALA fluorescence guidance, the numbers of complete resections using this technology increased from 64.5 to 78% within the last two decades. Further, the role of complete resections without any residual contrast enhancing tumor remains a highly significant prognostic factor. OS has significantly improved throughout the last years, most likely caused by the routine use of combined radiochemotherapy in combination with better surgical results.
JS05.6.A THE PROGNOSTIC IMPACT OF CDKN2A/B HETEROZYGOUS DELETIONS IN MENINGIOMA- INSIGHTS OF A MULTICENTER ANALYSIS
Authors: Ippen F M , Hielscher T , Patel A , Göbel K , Friedel D , Maas S L N , von Deimling A , Wick W , Suwala A K , Sahm F 
Published: October 2024

Abstract

BACKGROUND
Meningiomas are one of the most common primary brain tumors. Homozygous deletions of CDKN2A/B have reliably been shown to confer an increased risk of progression. However, the role of heterozygous CDKN2A/B deletions remains less clear.

MATERIAL AND METHODS
DNA methylation data, copy-number information and mutation data were generated on a multicenter cohort of meningiomas for a total of 970 samples. The CDKN2A/B locus was determined manually for each individual case in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan-Meier method.

RESULTS
A total of 970 meningioma cases were identified with 30 homozygous and 114 heterozygous CDKN2A/B deletion cases, 826 cases had balanced CDKN2A/B. Heterozygous CDKN2A/B deletions in general did not confer an increased risk of progression compared to CDKN2A/B balanced cases (p= 0.074). However, segmental heterozygous losses of 9p, encompassing CDKN2A/B, yielded a significantly worse prognosis when compared to meningiomas CDKN2A/B-balanced (p= 0.002) and in contrast to focal heterozygous deletions (p= 0.523). Segmental heterozygous 9p deletions encompassing CDKN2A/B were significantly more frequently associated with a higher amount of copy number variations (CNVs) than focal losses.

CONCLUSION
Segmental heterozygous CDKN2A/B deletions do confer an increased risk of progression, but focal heterozygous CDKN2A/B deletions do not. The signal for segmental deletions may not be locus-specific but just one representation of the generally instable genome of aggressive meningiomas.
OS04.7.A PRESERVATION OF FERTILITY AND FAMILY PLANNING IN PATIENTS WITH LOW-GRADE GLIOMA
Authors: Brüning A R , Reischl M , Jungk C , Onken J , Mielke D , Kniese K , Nadji-Ohl M , Krieg S , Vajkoczy P , Rohde V , Nabavi A , Ganslandt O , Wirtz R , Gerlach R , Czabanka M , Coburger J , Forster M 
Published: October 2024

Abstract

BACKGROUND
Patients suffering from a Low-grade glioma (LGG) will require adjuvant treatment at some stage of their course of disease which is a mayor impact for fertility and family planning. Given the predominantly young age of patients at the time of LGG diagnosis and the high 5-year survival rate of up to 95%, we aimed at analyzing fertility preservation measures and the influence of glioma diagnosis on family planning in LGG patients.

MATERIAL AND METHODS
Adult LGG patients having been enrolled prospectively in the German LoG-Glio registry since 2015 underwent semi-structured interviews to retrospectively evaluate repercussions of glioma on their family life.

RESULTS
199 LGG patients were contacted by phone, and 76 patients (38%), with 38 (50%) being females, completed the questionnaire. At the time of glioma diagnosis, 18 (47%) women and 14 (39%) men already were parents, and 13 (34%) women and 16 (42%) men desired to have (further) children. However, glioma diagnosis influenced family planning in 10 of each male and female patients, with most of them resigning their wish. Thus, fertility-preserving measures were initiated by 9 (24%) men but only 3 (8%) women by using sperm cryopreservation or egg freezing. In men, a total of 7 children were born after the diagnosis, with all pregnancies occurring naturally and all children been born healthy. Among female patients, 7 (18%) women became pregnant during the course of their illness; all pregnancies were uncomplicated and all children were born healthy and via vaginal delivery. Regarding relationship, at the time of the survey, 21 (55%) men and 26 (68%) women were still with the same partner as they had been at the time of diagnosis. However, 19 (50%) male and 24 (63%) female patients declared that tumor diagnosis had an impact on their relationship, with only 4 (20%) male and 10 (45%) female patients reporting on a positive influence.

CONCLUSION
Diagnosis of glioma has a major impact on family planning and on relationship in both, female and male patients. However, according to our data, fertility-preserving measures are only rarely taken, predominantly by male patients. Most importantly, pregnancies occurring after glioma diagnosis and treatment were uneventful and all children were born healthy. Further research in larger cohorts is necessary for better counseling patients and individual patient-centered therapy planning.
P01.10.A INVESTIGATING GLIOBLASTOMA BIOMARKERS IN THE INFILTRATION ZONE: TOPOGRAPHIC LINKS TO AN EARLY RELAPSE
Authors: Barak M , Brychta J , Hendrych M , Holecek T , Holikova K , Kazda T , Hermanova M , Sana J , Jancalek R 
Published: October 2024

Abstract
Glioblastoma, IDH-wildtype WHO Grade 4 (GB), is the most common primary malignant brain tumor. Despite significant advancements in surgical techniques allowing for a greater extent of resection, the use of targeted radiotherapy along with the application of novel anticancer drugs, GB remains an incurable disease with a median survival of 16 months. One of the key factors contributing to the development of therapeutic resistance and recurrence is the intratumoral heterogeneity of GB. Although surgical therapy aims at maximal safe resection with the goal of gross total tumor resection (GTR) when feasible, a considerable heterogeneous residual tumor population remains at the resection margin. These residual tumor populations encompass various genomic, epigenetic, and microenvironmental variations, creating a pool from which treatment-resistant clones can emerge and subsequently become a source of GB recurrence. This pilot study aims to analyze the molecular characteristics of these high-risk cell populations in the peritumoral infiltration zone using next-generation sequencing (NGS), with the objective of identifying driving factors contributing to early relapse.
P02.05.A COMPREHENSIVE ANALYSIS OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Cai X , Beumer-Chuwonpad A , Westerman B , Garcia Vallejo J 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common and extremely aggressive primary tumor of the central nervous system. Tumor-associated macrophages (TAM) can take up around 50% of cells in the tumor microenvironment (TME) of GBM and are thought to play a role in therapy resistance by creating an immunosuppressive TME. Researchers have used the M1/M2 dichotomy to describe the pro- and anti-inflammatory states of TAM, respectively. However, an expanding number of studies have found that this classification strategy oversimplifies the nature of TAM as seen in patients. Therefore, a more comprehensive strategy to represent the continuous spectrum of cellular states of TAM is essential. In this study, we aim to identify the cellular states of TAM, and further explore their impact on clinical outcomes and the TME.

MATERIAL AND METHODS
A bioinformatic pipeline based on principal component analysis was developed to identify the cellular states of TAM, which addressed the high inter-tumoral heterogeneity of GBM. A public Image Mass Cytometry dataset is used to verify the existence of the TAM states. The correlation analysis and survival analysis were conducted to identify the clinical relevance of the TAM states. Three spatial transcriptomic datasets were used to explore the role of these TAM states in the TME. A vessel/neuron impact index was developed to describe the impact of vessel/neuron on the TME. An 8-color multiplex immunohistochemistry is currently being developed to explore the role of VIM-TAM in the TME with spatial analysis in our cohort with 74 GBM patients.

RESULTS
Four public GBM scRNA-seq datasets with 94 samples were input into our pipeline. Four TAM states together with a proliferating state were identified: HLA-TAM (HLA-DR, SPP1, APOE, TREM2, C3, CD74), VIM-TAM (VIM, S100A4/6/10, CD44), IL1B-TAM (IL1B, CCL3, CD83), and HSP-TAM (HSP90AA1, BAG3). By mapping TAMs into a 3D plot based on these state scores, we revealed a continuous spectrum of TAM. Prognosis analysis found that the mean IL1B-TAM score showed a protective effect for OS (P = 0.065), while the mean VIM-TAM score had a risk impact on PFS (P = 0.045). Spatial transcriptomic analysis showed that the VIM-TAM is negatively correlated with neural-progenitor-like cancer cells and the neuron impact index.

CONCLUSION
A continuous spectrum of TAM could be described by these 4 identified TAM states. The IL1B-TAM and the VIM-TAM are predictors for OS and PFS, respectively. Also, the VIM-TAM is related to NPC-like cancer cells and neurons in the TME.
P02.16.A IRF8-DRIVEN REPROGRAMMING OF THE IMMUNE MICROENVIRONMENT ENHANCES ANTI-TUMOR ADAPTIVE IMMUNITY AND REDUCES IMMUNOSUPPRESSION IN MURINE GLIOBLASTOMA
Authors: Montoya M , Collins S A , Chuntova P , Patel T S , Nejo T , Yamamichi A , Kasahara N , Okada H 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could “reprogram” intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore anti-tumor T-cell responses.

MATERIAL AND METHODS
Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture.

RESULTS
Mice with RRV-IRF8 pre-transduced intracerebral tumors had significantly longer survival and slower tumor growth compared to controls. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Further, intra-tumoral and cervical lymph node DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. To assess mechanism of action, mice were treated azidothymidine (AZT), a viral replication inhibitor. Untreated mice maintained a superior survival benefit, which demonstrated that viral replication through proliferating cells is necessary for tumor control. This showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME. Moreover, subset of mice with RRV-IRF8 treated tumors achieved complete tumor clearance and further rejected subcutaneous GBM tumors, indicating the presence of immunological memory.

CONCLUSION
Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation in situ, achieving improved tumor control and conferring a significant survival benefit.
P02.17.B MANIPULATING GABAERGIC MECHANISMS TO DELAY GLIOMA INVASION IN PERITUMORAL MICROENVIRONMENT
Authors: Scalera M , De Santis E , Sturlese Verduri A , Meneghetti N , Barsotti N , Novelli E , Mazzoni A , Pasqualetti M , Costa M , Caleo M , Vannini E 
Published: October 2024

Abstract

BACKGROUND
The interaction between tumor cells and the main components of the tumor microenvironment (TME) seems to guide the progression of glioma. Several recent studies have highlighted that the synaptic activity of pyramidal neurons potently drives Glioblastoma (GB) proliferation. However, the role played by other neuronal cell types is still poorly understood. Based on our previous findings showing that the optogenetic stimulation of parvalbuminergic (PV)-inhibitory interneurons negatively regulates glioma progression, here we tested whether a chemogenetic manipulation of peritumoral PV-interneurons could influence GB growth.

MATERIAL AND METHODS
To address this issue, AAV-hSyn-DIO-hM4D(Gi)-mCherry or AAV-hSyn-DIO-hM4D(Gq)-mCherry were injected in the motor cortex bilaterally with respect to the GL261 injection site in PV-Cre mice. In order to manipulate PV-interneurons activity, animals will be randomized to receive CNO or vehicle intraperitoneally twice a day from day 12 (i.e., the glioma symptomatic stage) to day 22 (i.e., the glioma late stage) post tumor induction. As readouts, we: i) evaluated the tumor volume using Magnetic Resonance Imaging (MRI), ii) performed a longitudinal monitoring of motor capabilities using specific motor tests (i.e., Grip Strength and Grid walk), iii) assessed the survival, iv) determined the GB proliferation index of glioma-bearing mice after different treatments.

RESULTS
We found that the PV-interneurons inactivation resulted in worsening motor performances with respect to the vehicle mice. Despite that, no difference was observed in animal median survival or tumor volume among the two groups. However, MRI data showed a very significative reduction in the tumor volume at 28 days after glioma induction in PV-activated glioma bearing mice (p=0,004). In addition, PV-activation exert a slight effect on the maximum survival of CNO-treated glioma bearing mice with respect to the vehicle mice (39 vs 32 days).

CONCLUSION
Since there is no cure for GB, it is essential to find new and effective therapeutic approaches to improve the quality of life and to extend the life expectancy in patients. These data suggest that the inhibitory circuitry in the tumor-adjacent zone could delay GB growth, protecting peritumoral tissue from GB proliferation.
P03.03.A GAMMAKNIFE RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Nogueira B V , Palavani L , Chen H , Vilardo M , Mitre L , Landeiro J 
Published: October 2024

Abstract

BACKGROUND
Vestibular Schwannomas (VS), benign CNS tumors originating from Schwann cells on the eighth cranial nerve, typically present with symptoms such as trigeminal and facial neuropathy, tinnitus, vertigo, dizziness, and progressive hearing loss. Due to their anatomical location, proximity to important structures, and size, treating VS poses a significant challenge. Treatment strategies must carefully consider the impact on the patient’s quality of life and neurological function, ranging from surgical resection to observational management with magnetic resonance imaging to radiosurgery. This systematic review and meta-analysis specifically aims to assess the safety and efficacy of Gamma Knife radiosurgery in treating VS.

MATERIAL AND METHODS
This systematic review and meta-analysis was conducted in accordance with the Cochrane Collaboration Handbook and PRISMA guidelines. A comprehensive literature search was performed across multiple databases, including Medline, Embase, Web of Science, and the Cochrane Library. Eligible studies included those reporting data from primary GK treatment or GK with prior surgery. The primary endpoints analyzed were new or worsened symptoms, tumor control, and complication rates. Statistical analyses were conducted using R Studio, utilizing a random effects model, with results presented as proportions accompanied by 95% confidence intervals.

RESULTS
The analysis included data from 43 studies comprising 6,634 patients with an approximate median age of 56.0 years. Primary GK reatment showed a tumor regression rate of 56%(95% CI: 0.46 to 0.65, I² = 86%), tumor stability rate of 37% (95% CI: 0.26 to 0.48, I² = 92%), and tumor progression rate of 6% (95% CI: 0.04 to 0.08, I² = 76%); new or worsened facil neuropathy rate of 3% (95% CI: 0.01 to 0.05, I² = 86%), post-GK serviceable hearing rate of 48% (95% CI: 0.38 to 0.58, I² = 97%), major complication rate of 3%(95% CI: 0.01 to 0.05, I² = 84%), minor complication rate of 11% (95% CI: 0.04 to 0.18, I² = 95%), and VS-related mortality of 0% (95% CI:0.00 to 0.00, I² = 0%). In comparison, GK with prior surgery had a tumor regression rate of 61% (95% CI: 0.53 to 0.68, I² = 0%), tumor stability rate of 20% (95% CI: 0.08 to 0.31, I² = 58%), tumor progression rate of 17% (95% CI: 0.7 to 0.27, I² = 53%); new or worsened facil neuropathy rate of 23%(95% CI: 0.04 to 0.43, I² = 90%).

CONCLUSION
Our findings indicate that Gamma Knife radiosurgery (GK) is a feasible and safe treatment option for Vestibular Schwannomas (VS). It demonstrates effective tumor control, low complication rates, and considerable symptom management.
P06.02.B DECODING THE DIVERSE SURFACEOME LANDSCAPE IN MALIGNANT BRAIN TUMORS IDENTIFIES TARGET CANDIDATES FOR PERSONALIZED IMMUNOTHERAPY
Authors: Boukredine A , Gonçalves de Oliveira K , Talbot H , Governa V , Bång-Rudenstam A , Forsberg-Nilsson K , Bengzon J , Malmström J , Welinder C , Belting M 
Published: October 2024

Abstract

BACKGROUND
Immunotherapies with antibodies, antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor cell-surface antigens (surfaceome), currently revolutionize clinical oncology. Target identification warrants a comprehensive understanding of the surfaceome in individual tumors, and how it is modulated by the tumor microenvironment and conventional treatments. The identification of surfaceome targets has historically focused on differential mRNA expression between tumor and healthy tissues. However, mRNA constitutes a poor surrogate for membrane protein availability. Hence, there is an increasing emphasis on proteomic approaches directed at the elusive plasma membrane proteome.

MATERIAL AND METHODS
We have developed a new strategy for comprehensive tumor surfaceome profiling (TS-MAP), to unravel the surfaceome makeup in GBM. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. TS-MAP, RNAseq, and WGS were applied on primary GBM cells, cultured in 2D and 3D, with or without tumor mimicking stress conditions (hypoxia, acidosis, irradiation, temozolomide), as well as on freshly resected GBM specimens with preserved tissue architecture and their matched primary cultures. In paralell, extracellular vesicles (EVs) were retrieved from patient plasma and matched cell culture media for EV-surfaceome profiling. Target candidates were validated by FACS, IF, as well as live antibody internalization and ADC cytotoxicity studies.

RESULTS
Our findings unveil a diverse selection of putative tumor antigen candidates in GBM that may be harnessed for targeted immunotherapies. Confronting potential targets with ADC constructs supported the validity our approach. Moreover, integrated proteotranscriptomics provides compelling evidence that mRNA levels poorly reflect surfaceome-endocytome protein abundance in patient tumors, underscoring the importance of refined proteomic strategies. Ongoing studies aim at the development of therapeutic modalities (ADC and CAR-T) against a lead candidate target, and to understand the utility of EV-surfaceome profiling for non-invasive, dynamic monitoring of the tumor surfaceome landscape.

CONCLUSION
Together, our results provide new layers of understanding fundamental to the future development of individualized immunotherapy strategies in GBM, and identify lead candidates for potential clinical development.