bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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

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

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

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.
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

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

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 <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

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

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

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

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

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 <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

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<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

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.
P12.01.B ANTI-VEGF TREATMENT EFFECT AGAINST GLIOMA IS IMMUNE DEPENDENT AND MEDIATED BY ENHANCED T CELL ACTIVITY
Authors: Maire C , Mohme M , Fita K , Reetz M , Heinemann S , Tolosa E , Alawi M , Casar C , Spohn M , Gempt J , Westphal M , Lamszus K
Published: October 2024

BACKGROUND

The majority of glioblastoma patients receive corticosteroids at some point during the course of disease to treat brain edema. Since steroids are immunosuppressive, immunotherapy trials increasingly avoid the use of steroids and consider bevacizumab as alternative. Targeting VEGF in the context of immunotherapy may additionally have immune stimulatory effects, as VEGF is a potent immunosuppressive factor. We explored whether anti-VEGF treatment has immune-mediated components and which mechanisms are involved.

MATERIALS AND METHODS

Murine glioma cells were injected intracerebrally into C57BL/6 wild-type mice or immunodeficient Pfp/Rag2 knockout (KO) mice. Animals were treated with B20 (anti-murine VEGF) or dexamethasone. Tumor-infiltrating and peripheral immune cells were profiled by flow cytometry, and RNAseq analyses were performed on sorted tumor and immune cells at different timepoints. T cells and NK cells were depleted using specific antibodies.

RESULTS

B20 prolonged the survival of immunocompetent mice (p < 0.0001) but not of Pfp/Rag2 KO mice, indicating that the immune system is important for the effect of anti-VEGF treatment. At an early timepoint when controls became symptomatic, B20 “early” tumors (B20-ea) showed increased infiltration with T cells and myeloid cells, and decreased vessel density, while B20 tumors at the survival endpoint resembled IgG-controls. Gene expression in B20-ea tumor cells was dominated by hypoxia, neural development, invasion, TGF-β, Notch and Wnt signatures as well as concerted upregulation of Kmt2 H3K4 methyltransferases. In CD11b+ myeloid cells from B20-ea tumors, M1 hallmark genes and T cell activation genes were upregulated, while M2 genes were downregulated. Bioinformatic deconvolution revealed a transient shift towards pro-immune microglia/macrophages as well as increased NK cells and DCs. In CD8+ and CD4+ T cells, B20 increased the expression of S1pr1 and of α/β TCR genes, indicating oligoclonal expansion. Further, the proportion of progenitor-like exhausted CD8+ cells, which can be reinvigorated by PD-1 blockade, was increased in B20-ea. Among CD4+ T cells, B20 caused skewing towards the CD4+ TFH cell lineage, while dexamethasone increased expression of TH2 cytokines. Immune cell depletion in B20-treated animals demonstrated that CD8+ and CD4+ T cells but not NK cells were necessary for the survival-prolonging effect of anti-VEGF treatment.

CONCLUSION

Anti-VEGF therapy has significant immunostimulatory effects, mediated by CD8+ and CD4+ T cells as well as pro-immune modulation of the myeloid compartment. However, pro-immune effects are largely transient, so that an early treatment window of opportunity may exist during which anti-VEGF treatment in combination with an effective immunotherapy could have a substantial supportive effect, extending beyond its anti-edema activity.
P13.13.B RADIONECROSIS VERSUS SECOND MALIGNANCY: BRAINSTEM LESION 19 YEARS AFTER PAEDIATRIC MEDULLOBLASTOMA TREATMENT
Authors: Turcas A , Mihut E , Homorozeanu B , Avram G , Roman A , Fekete Z
Published: October 2024

BACKGROUND

Brain radionecrosis is a rare, but severe complication of radiotherapy. In children, the incidence ranges around 2-4% of patients and peaks around 5-7 years after conventional radiotherapy, wherease in adults treated with stereotactic radiotherapy it can occur more often and sooner, usually between 6 monts up to 2 years. Other important late side effects of radiotherapy in paediatric patients are second malignancies, which usually occur in the irradiated region, around 15-20 years after treatment.

CASE REPORT

We present the case of a 36-year old patient treated at the age of 16 (in 2005) with surgery, followed by standard chemotherapy and cranio-spinal irradiation (36Gy) with a boost up to 54 Gy to the entire posterior fossa for a non-metastatic medulloblastoma. Complete remission was obtained and maintained until October 2023, when the patient developed new symptoms in terms of headache, balance issues and accentuated motor deficits in the lower limbs. The MRI showed a new infiltrative, enhancing lesion in the pontine region, with diffusion restriction and heterogenous hyper-intense T2. We raised the suspicion of a second, radiation-induced malignancy or a late radionecrosis. MRI spectroscopy showed high Lactate, low NAA, Choline and Creatinine, being suggestive of radionecrosis, thus the patient was offered corticosteroids (16mg Dexamethasone for 1 week with progressive reduction of doses and cessation after 4 weeks). Monthly follow-up MRI’s showed a progressive volume and enhancement reduction of the lesion, with significant improvement of the symptoms. The last MRI (April 2024) shows a major reduction of the lesion, from 3/2cm at diagnosis to 0.6/1cm at 6 months, with good clinical status.

CONCLUSION

The presented case is impressive in terms of the timing of radionecrosis, given that with standard-fractionated radiotherapy this toxicity occurs very rare and usually much sooner. Also, the radiologic and clinical response to steroids was impressive. This report aims to raise awareness on the importance of long-term follow-up in paediatric brain tumour patients and underlies the importance of advanced imaging techniques for differentiating between tumour relapse, radio-necrosis and second malignancies.