bluuebunny/crossref_metadata_2025 huggingface dataset:
P14.12.A IMMUNOTHERAPEUTIC ADVANCES IN GLIOMA MANAGEMENT: THE RISE OF VACCINE-BASED APPROACHES
Authors: Shah M , Awuah W , Tan J , Ranganathan S , Darko K , Ohenewaa Tenkorang P , Adageba B , Ahluwalia A , Shet V , Kundu M , Aderinto N , Abdul-Rahman T , Atallah O
Published: October 2024

BACKGROUND

Gliomas, originating from glial cells in the central nervous system, present formidable therapeutic challenges, especially the aggressive glioblastoma multiforme (GBM). Traditional treatments often fall short due to tumour heterogeneity and the protective CNS microenvironment. Glioma vaccines have emerged as promising immunotherapeutic strategies to combat these challenges. This review critically assesses the scientific rationale and clinical outcomes of glioma vaccines, aiming to elucidate their evolving role in glioma therapy.

MATERIAL AND METHODS

A systematic review of papers published between 2000 and 2024 that met the inclusion criteria was undertaken using several databases, including PubMed, EMBASE, Google Scholar, the Cochrane Library, and Scopus.

RESULTS

Glioma vaccines, including peptide-based, DNA/RNA-based, whole-cell, and dendritic cell vaccines, have shown promising outcomes in clinical trials. For example, the IMA950 peptide vaccine resulted in progression-free survival rates of 74% at 6 months and 31% at 9 months in newly diagnosed GBM patients. Similarly, the SurVaxM peptide vaccine led to 95.2% of patients remaining progression-free at 6 months, with an average progression-free survival of 11.4 months and an overall survival of 25.9 months. DNA/RNA-based vaccines targeting tumour-specific mutations have also shown efficacy. Trials integrating personalised vaccinations targeting unmutated antigens and neoepitopes yielded sustained responses in patients with newly diagnosed GBM. Additionally, whole-cell vaccines, when combined with adjuvants like GM-CSF, induced delayed-type hypersensitivity responses in 89% of patients and resulted in radiological evidence of response in 42% of cases, with clinical improvement observed in 26% of patients. Dendritic cell vaccines, such as DCVax-L and α-type-1 DC vaccines, demonstrated improvements in overall survival in GBM patients, with long-term benefits observed in patients with a methylated MGMT promoter. However, some trials reported adverse events such as allergic reactions and transient hepatotoxicity.

CONCLUSION

Glioma vaccines show promise in stimulating immune responses against tumours, offering potential benefits alongside standard treatments. Challenges in assessing vaccine efficacy and addressing treatment-related adverse effects emphasise the need for further research and clinical trials. Challenges like tumour heterogeneity and immune evasion persist, but advances in genetic engineering and immunotherapy offer hope for enhancing vaccine efficacy. Collaboration across disciplines is essential for translating these advances into effective glioma treatments.
P14.21.B ROLE OF 11C-METHIONINE POSITRON EMISSION TOMOGRAPHY EMPLOY BEYOND THAT ADVANCED MAGNETIC RESONANCE IMAGING FOR TARGET VOLUME DELINEATION IN PATIENTS UNDERWENT RE-IRRADIATION FOR RECURRENT GLIOBLASTOMA
Authors: Navarria P , Pessina F , Bellu L , Clerici E , Vernier V , Politi L , Raspagliesi L , Di Cristina L , Simonelli M , Di Pasquale A , Bono B , Franzini A , Evangelista L , Scorsetti M
Published: October 2024

BACKGROUND

Reirradiation for recurrent glioblastoma patients is a challenging and important topic under investigation. No clear evidences exists regarding indications, sequences with other therapeutic approach, optimal dose to delivered, and fractionation to use. But even more, the critical point is reaching correct tumor delineation based on imaging. The contrast enhancement T1-weighted-MRI usually outlines the most aggressive tumor area, and T2-weighted FLAIR-MRI allows a more accurate definition of the infiltrating microscopic disease growing outside the enhanced area on T1 MRI. More recently, different reports suggest that the use of carbon-11-methionine positron emission tomography ([11C]-methionine PET ([11C]METPET) improves diagnostic accuracy for treatment planning allowing more precise viable tumor cell identification. Evidence regarding the predictive, and prognostic value is still lacking, and its use in planning radiation therapy, is debated. For this reason, we investigated the role of [11C]-Methionine PET (PET-MET) in a cohort of adults patients with recurrent GBM treated with adiation therapy aiming to evaluate how it could modify target volume delineation, and if it could detect eventually tumor cells not otherwise visible.

MATERIAL AND METHODS

Patients with recurrent GBM, and an interval time (IT) from previous RT > 6 months were included. Simulation CT scan, MRI with different sequences and a 11CMETPET were performed in all patients, and images were co-registrated one with each other to define the target volume. Two different target volume were defined: Biological Target Volume (BTV) corresponded to the pathological uptake on METPET, and Clinical Target Volume (CTV) defined as the abnormalities volume on postcontrast T1 MRI. Correlation between BTV and CTV were recorded.

RESULTS

From September 2013 to January 2024, 121 patients received reirradiation for recurrent GBM. The median age was 52 years, and majority had KPS 90-100. In all cases, the whole BTV was inside the CTV, and in 10 (11%) patients, part of the BTV was outside the CTV into the FLAIR abnormalities area. The overlap between BTV and CTV showed low correlation between the two volumes, with CTV not always fully included in BTV. According to the 11CMETPET uptake, CTV was modified.

CONCLUSION

11CPET-MET allowed to detect areas at higher risk of recurrent. A challenging issue is represented by integration of morphological, and functional imaging to define CTV in the setting of reirradiation. This results are promising and could permit to better define the tumor volume, to reduce the dose at organs at risk, and potentially to allow a dose escalation for a better local control improving patients outcome in recurrent glioblastoma patients.
P16.06.B PROTEOMIC ANALYSIS OF PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS
Authors: Ferreyra Vega S , Carén H
Published: October 2024

BACKGROUND

Pediatric-type diffuse high-grade gliomas (pHGGs) are among the most lethal primary brain tumors in children, which lacks effective treatment. Glioma stem cells are thought to play a key role in tumor initiation, regrowth, and treatment resistance. We therefore profiled the proteomic landscape of pHGG stem cells to identify novel molecular drivers and therapeutic targets in this disease.

MATERIAL AND METHODS

Large-scale proteomic data was acquired from patient-derived pHGGs stem cell lines and neural stem cell lines (NSCs) using Tandem mass tag mass spectrometry. Differentially expressed proteins between pHGGs and NSCs were examined. Selected relevant proteins were validated by western blot and immunocytochemistry.

RESULTS

A total of 8499 proteins were identified and quantified by mass spectrometry, of which 557 were significant differentially expressed proteins between pHGGs and NSCs. We found 240 proteins to be upregulated in pHGGs compared to NSCs, while 317 proteins were downregulated in the tumor group. Enrichment analysis of differentially expressed proteins revealed significant alterations in biological processes related to RNA processing, ribosome biogenesis and cell division.

CONCLUSION

The study provides insights into important pathological mechanisms implicated in pHGGs and highlights novel therapeutic targets of potential clinical significance.
P17.26.A THE ROLE OF DENDRITIC CELLS IN THE IMMUNE RESPONSE TO BRAIN METASTASES
Authors: James F , Williams J , Fife C , Mallett G , Ingram N , MacDonald A , Lorger M
Published: October 2024

BACKGROUND

Brain metastases (BrM) are an unmet clinical need with poor prognosis and associated poor quality of life. They are found in 10-30% of patients with systemic malignancies and remain an important limiting factor in patient survival. Importantly, immune-biology and response to therapies differs in the brain from the rest of the body. It is hence critical to explore how immune responses work in the context of BrM. Our work focusses on dendritic cells as the major antigen-presenter.

MATERIAL AND METHODS

This work utilises unique in vivo models of BrM with both intracranial and extracranial tumor, best mimicking the clinical situation in most cases of BrM, and BATF3 knock-out mice which lack a subpopulation of dendritic cells - conventional dendritic cells subtype 1 (cDC1s). We use a combination of; tumour growth and survival analysis, immunofluorescence, ELISA, flow cytometry and bulk mRNAseq to explore the role of the cDC1 population in intracranial and extracranial tumours.

RESULTS

We have shown that cDC1-dependent regulation of anti-tumor immune responses differs between the intracranial and extracranial tumors. While the requirement for cDC1 population in controlling extracranial tumor growth varied in a cancer model dependent manner, cDC1s were consistently required for the control of intracranial tumour growth. cDC1s isolated from intracranial tumours differed in their molecular profile from those isolated from extracranial tumours. In addition, immune cell infiltration into tumours, including the infiltration of CD8+ T cells, CD4+ T cells, and NK cells, was dependent on cDC1s to a higher degree in intracranial as compared to extracranial tumours. cDC1s also regulated the activation of CD8+ T cells, leading to a lower transitory effector-to-exhausted T cell ratio in cDC1 absence, with a stronger effect observed in intracranial versus extracranial tumours.

CONCLUSION

These results show that dendritic cell biology in response to tumours differs in the brain compared to extracranial tumors and suggest promising avenues for dendritic cell related therapies that may be specific to intracranial tumours.
P17.28.A TUMORAL INTERFERON BETA INDUCES AN IMMUNE-STIMULATORY PHENOTYPE IN TUMOR-ASSOCIATED MACROPHAGES IN MELANOMA BRAIN METASTASES
Authors: Gellert J , Agardy D A , Kumar S , Jähne K , Bunse L , Davies M A , Platten M , Bunse T
Published: October 2024

BACKGROUND

Type I interferons (IFN) such as IFNβ are pro-inflammatory cytokines involved in antiviral immune responses. Increasing evidence indicates that the success of several anticancer therapies, including radiotherapy, relies on the immune-stimulatory effects of type I IFNs on innate and adaptive immune cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are one of the most abundant innate immune cells in the TME of melanoma brain metastases (MBMs) and can exert potent immune-suppressive functions compromising effective antitumor immune responses. Here, we investigate the potential of tumoral type I IFNs to re-educate TAMs towards an antitumor M1-like phenotype to enhance the efficacy of immunogenic anticancer therapies in MBMs.

MATERIAL AND METHODS

In order to minimize confounding effects of immunogenic cell death associated with type I IFN-dependent anticancer therapies, we generated an inducible IFNβ-overexpressing MBM mouse model. Tumor growth was measured by magnetic resonance imaging (MRI) and changes in the TME were analyzed by flow cytometry. We confirmed our in vivo findings by mixed-leukocyte reaction assay and RNA sequencing of IFNβ-treated bone marrow-derived macrophages (BMDMs) and validated our myeloid type I IFN-response signature gene set in a recently published RNA sequencing dataset of treatment-naïve and previously irradiated MBM patient samples.

RESULTS

In this murine MBM model, tumoral IFNβ markedly impaired tumor growth and TAMs from IFNβ-expressing tumors exhibited a decreased expression of CD206, a widely used marker for immune-regulatory M2-like macrophages. Functional and transcriptomic analyses of IFNβ-treated BMDMs revealed an immune-stimulatory M1-like phenotype. Following radiotherapy, the myeloid type I IFN-response signature was upregulated in over 40 percent of MBM patient samples which was associated with a higher M1/M2-like TAM ratio and increased overall survival.

CONCLUSION

Our findings demonstrate the immune-stimulatory capacity of tumoral IFNβ in the context of type I IFN-inducing anticancer therapies in MBM by re-polarizing TAMs towards a pro-inflammatory M1-like phenotype.
P18.01.A ADAPTER FITC CAR T-CELLS PLUS OCTOFLUO FOR THE TREATMENT OF GLIOMAS VIA SSTR2
Authors: Chen J , Pellegrino C , Roth P , Neri D , Manz M G , Weller M , Wirsching H
Published: October 2024

BACKGROUND

Somatostatin receptor (SSTR) 2 has been proposed as a target to deliver therapeutic agents to gliomas. The SSTR2 antagonist peptide octofluo was developed to redirect fluorescein-5-isothiocyanate (FITC)-specific adapter chimeric antigen receptor (AdCAR)-T cells towards SSTR2-expressing tumor cells.

MATERIAL AND METHODS

A tissue microarray of glioblastoma patient samples (N=161) was stained for SSTR2. Octofluo was used as an adapter to direct FITC-specific human CAR-T cells against glioma cells. The SSTR2- glioma cell line LN229 was lentivirally transduced to express SSTR2 and Luciferase. Flow cytometry-based killing assays were conducted in vitro. Tumor growth assessed by bioluminescence imaging and symptom-free survival were assessed in the orthotopic LN229 xenograft model. Mice harboring SSTR2+ or SSTR2- LN229 tumors were treated with two intratumor (i.t.) injections of CAR-T cells and every other day intravenous (i.v.) octofluo.

RESULTS

SSTR2 was highly expressed in a subset of glioblastomas (13%). In vitro, 10 nM was determined as the optimal concentration of octofluo, yielding tumor cell killing of SSTR2+ LN229 cells within 72 hours at effector-to-target cell (E:T) ratios as low as 1:10 in (CAR vs untransduced T cells 22 % vs 4 %, p < 0.001) and almost complete killing of tumor cells at an E:T ratio of 1:1 (CAR vs untransduced T cells 88 % vs 4 %, p < 0.001). In vivo, tumor growth inhibition by this AdCAR-T cell system was likewise confined to SSTR2+ LN229 tumors and was paralleled by prolonged survival compared with SSTR2+ LN229 tumors treated with untransduced T cells i.t. plus metronomic octofluo i.v. (hazard ratio [95% confidence interval], 0.24 [0.07 - 0.84], p=0.0002).

CONCLUSION

Targeting SSTR2+ gliomas with FITC-specific AdCAR-T cells plus octofluo is feasible. More in vivo and ex vivo translational experiments will be required prior to proceeding to early phase clinical trials in glioma patients, including careful evaluation of the octofluo tumor residence time and optimal injection frequency.
P18.07.B BEVACIZUMAB ALONE VERSUS BEVACIZUMAB PLUS IRINOTECAN IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A NATION-WIDE POPULATION-BASED STUDY
Authors: Kim S , Lee Y , Lee E , Roh T
Published: October 2024

BACKGROUND

This study was aimed to compare the survival of patients with recurrent glioblastoma who received bevacizumab monotherapy (BEV) and those received bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset.

MATERIAL AND METHODS

We screened patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database, and selected patients who underwent surgery or biopsy from January 2008 to November 2021 and subsequent standard concurrent chemoradiation with temozolomide. Among them, those who received BEV or B+I were included in this study. Demographic characteristics, in-patient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups.

RESULTS

Out of a total of 846 patients, 450 and 396 received BEV and B+I, respectively. The BEV group had a higher percentage of women (50.22%) than in the B+I group (42.68%). The mean age of the BEV group (54.50 years) was higher than that of the B+I group (51.98 years). However, there were no significant intergroup differences in the numbers of radiation and adjuvant temozolomide therapy cycles. The median overall survival from the initial surgery was 22.60 months (95 % CI: 20.50-24.21) and 20.44 months (95 % CI: 18.55-22.60), and there was no significant difference in survival outcomes between the groups (P = 0.5079, log-rank test).

CONCLUSION

There was no significant difference in overall survival between the BEV and B+I groups in this study. Considering the additional potential toxicities associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for patients with recurrent glioblastoma. To further substantiate these findings, additional prospective randomized trials are necessary.
P18.20.B GENETIC AND EPIGENETIC ALTERATIONS OF EPITHELIOID GLIOBLASTOMA
Authors: Adachi J , Shirahata M , Suzuki T , Mishima K , Nishikawa R
Published: October 2024

BACKGROUND

Epithelioid Glioblastoma (E-GBM) has been identified as a rare subtype of Glioblastoma. It is mainly known as in case reports. The details of its genetic, much less epigenetic profiles are not clear. Here, we retrospecivly studied the results of genetic and epigenetic features of E-GBM.

MATERIAL AND METHODS

Four patients who underwent surgery at our institution and were diagnosed with E-GBM, were included in this study. Histological diagnosis was obtained by surgical excision in all cases. We extracted DNA from the resected tissues and analyzed glioma-related genes using various methods such as high resolution melting (HRM), MGMT methylation-specific HRM, digital PCR, and Multiple ligation-dependent probe amplification (MLPA) analysis. Furthermore, comprehensive methylation array analysis was performed using Infinium Methylation EPIC ver2.0.

RESULTS

E-GBM tended to develop at a slightly younger age than other general glioblastoma. Genetic analysis revealed both TERT promoter mutations and BRAFV600E mutation in all cases. In addition, IDH mutation was not found, and MGMT promoter methylation was unmethylated in all cases. EGFR amplification, CDKN2A/2B homozygous deletion and 1p/19q co-deletion were not found in any cases. Classifier prediction from methylation array analysis tended to match Pleomorphic Xanthoastrocytoma, and E-GBM was not listed as a candidate tumor.

CONCLUSION

The simultaneous mutations of TERT promoter with BRAFV600E could serve as diagnostic molecular markers for the diagnosis of E-GBM. It has been difficult to predict E-GBM using current methylation array analysis alone.
P18.21.A GLIOBLASTOMA AS A METASTATIC DISEASE: A POSSIBLE MOLECULAR PATHWAY OF METASTATIC SPREAD ACCORDING TO THE GENE MUTATION PROFILE
Authors: Jancalek R , Barak M , Brychta J , Hendrych M , Sana J , Pospisil P , Kazda T
Published: October 2024

BACKGROUND

Glioblastoma (GBM) is the most common glial brain tumor in adults. It accounts for nearly 50 % of malignant primary brain tumors and represents a disease with a dismal prognosis. GBM is characterized by rapid infiltrative spread within the central nervous system; however, its metastases are considered sporadic. The molecular background of primary and secondary GBM is yet to be discovered, making it difficult to describe the possible molecular pathway/s of metastatic spread. Due to increasing overall survival rates in GBM patients, extracranial metastasis is becoming more common, making this topic increasingly relevant.

MATERIAL AND METHODS

We screened a case of spinal GBM metastasis and its molecular background and searched for differences in gene mutation profile between the primary and metastatic disease to outline possible molecular pathways of metastatic spread.

RESULTS

In this study, we discovered that the alteration of NF1, NOTCH3, and ARID1A could explain, at least in part, the acquired invasiveness and metastatic potential in a GBM case.

CONCLUSION

This finding underscores the importance of genetic testing in understanding tumor progression and its potential impact on patient oncological management. The project was supported by the NU23-03-00100 grant from the Ministry of Health, Czech Republic.
P18.25.B IMPACT OF ONLINE EDUCATION ON CLINICIANS’ KNOWLEDGE AND CONFIDENCE IN THE UNDERSTANDING OF EMERGING TARGETED THERAPIES FOR IDH-MUTANT GLIOMAS
Authors: Fiske Z , Grainger D , Habib J , Touat M , Preusser M , Wen P Y
Published: October 2024

BACKGROUND

The discovery of the IDH mutations represents a hallmark in the field of neuro-oncology, leading to significant progress in terms of glioma classification and potential novel therapeutic approaches for these tumors. The objective of this study was to assess the effect of an online continuing medical education (CME) activity on clinicians’ understanding of the clinical implications of recent research advances and how emerging systemic therapies could benefit patients with IDH-mutant glioma.

MATERIAL AND METHODS

This CME activity consisted of a 90-minute video recording of a live symposium at the Society for Neuro-Oncology Annual Conference in 2023, together with synchronised slides. Educational effect was assessed using a repeated-pair design with pre-/post-assessment. 3 multiple choice questions assessed knowledge/competence, and 1 question rated on a Likert-type scale assessed confidence, with each individual serving as their own control. A McNemar’s test assessed significance of improvement in the percentage of correct responses to knowledge/competence questions from pre- to post-assessment. P values <.05 are statistically significant. The activity launched on 15th of December 2023, with data collected through 26th February 2024 being reported in the current study.

RESULTS

86 neurosurgeons and 47 oncologists who answered all the assessment questions were included in this analysis. Both physician groups demonstrated a statistically significant improvement in knowledge across all learning themes. Overall correct responses increased from 17% pre- to 27% post-CME for neurosurgeons, and 33% pre- to 50% post-CME for oncologists, respectively. Specific areas of improvement include: knowledge regarding the latest clinical trial data of targeted therapies for IDH-mutant gliomas (pre 17%, post 28%, P <.001 for neurosurgeons; pre 27%, post 47%, P <.001 for oncologists); knowledge regarding identifying patients with IDH-mutant glioma who may benefit from emerging targeted therapies (pre 16%, post 24%, P <.01 for neurosurgeons; pre 47%, post 55%, P <.05 for oncologists). Additionally, 28% of neurosurgeons and 34% of oncologists reported increased confidence in their understanding of the potential clinical practice implications of emerging targeted therapies for IDH-mutant glioma, and that increase was, on average, 75% and 67% among the two physician groups, respectively.

CONCLUSION

This analysis demonstrates a positive educational impact of an online CME activity on the latest developments in the management of IDH-mutant glioma for key physician learner groups. It also highlights the ongoing educational needs to further improve clinician’s knowledge and help them stay up to date with the latest developments in the field.
P18.27.B INTRAOPERATIVE PHOTODYNAMIC THERAPY IN COMPLEX TREATMENT OF MALIGNANT GLIOMAS
Authors: Rynda A , Rostovthev D , Olyushin V
Published: October 2024

BACKGROUND

Treatment of malignant gliomas is an extremely difficult objective associated with difficult choice of correct strategy. Photodynamic therapy is still not the treatment standard in these patients although this approach significantly improves treatment outcomes in surgery of gliomas. To demonstrate the possibilities of chlorin e6-mediated photodynamic therapy for malignant glial tumors.

MATERIAL AND METHODS

There were 161 patients with malignant supratentorial glial tumors who were treated at the Polenov Russian Neurosurgery Institute between 2009 and 2016. Eighty patients comprised the main group (photodynamic therapy), 81 ones — control group (without photodynamic therapy).

RESULTS

Photodynamic therapy in complex treatment of malignant brain gliomas significantly increases overall survival in patients with Grade III gliomas up to 39.1±5.5 months (control group — 22.8±3.3 months) and Grade IV gliomas up to 20.7±4.7 months (control group — 13.5±2.3 months) (p=0.0002). This method also increases relapse-free period in patients with Grade III gliomas up to 21.7±3.4 months (control group — 15.8±3.1 months) (p=0.0002) and Grade IV gliomas up to 11.1±2.1 months (control group — 8.0±2.3 months) (p=0.0001).

CONCLUSION

Considering our own and literature data, we can conclude that PDT in complex therapy of malignant gliomas improves long-term outcomes. This is partly achieved through higher resection quality due to inclusion of pathogenetic mechanisms of PDT affecting residual tumor cells. Therapeutic effect of PDT on tumor tissue differs significantly from the mechanisms of radio- and chemotherapy. Moreover, PDT does not complicate radio- and chemotherapy, but only potentiates the overall therapeutic effect. PDT has no systemic negative effects unlike adjuvant methods such as radio- and chemotherapy.
P18.35.B RBFOX1 GENE INFLUENCES NEURONAL SUBTYPE PLASTICITY IN INVASIVE HIGH GRADE GLIOMA CELLS
Authors: Flick M , Stevens V , Sereduk C P , Plaisier C L , Barajas R F , Hu L , Kannan K , Tran N
Published: October 2024

BACKGROUND

High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer with poor prognosis. Standard of care surgery employs Magnetic Resonance Imaging (MRI) to identify the contrast enhancing (CE) core for resection, leaving behind an unresected non-enhancing (NE) invasive rim of tumor which borders healthy brain tissue and invariably contributes to recurrence. Recent multi-omic analyses identified predominant neuronal and immune signatures within NE tumor; understanding these signatures could provide key insights to combatting recurrence and improving patient outcomes. To this end, we utilized a novel graph database method to integrate multi-omic data from a unique dataset of multi-regional spatially-localized biopsies from the CE core and invasive NE rim from a large cohort of patients with HGG.

MATERIAL AND METHODS

159 IDH-wildtype tumor biopsy samples from the NE and CE regions of 74 glioma patients were profiled by bulk RNA sequencing. Differentially expressed genes (DEG) (n=1159) across NE and CE samples were selected using EdgeR. Samples were hierarchically clustered (method = median) for each DEG and represented as nodes in a Neo4j graph network. Edges were generated between nodes sharing ≥ 1 sample. Modularity optimization was used to identify communities of densely connected nodes. Genes occurring exclusively within NE communities were localized by cell type using external single-cell RNA sequencing datasets and selected as candidate source nodes for NE network random walks. RBFOX1 was selected as a source (walk length = 5; 10,000 walks/source node). Random walks traversing samples with significantly elevated RBFOX1 expression (one-tailed test) were kept for analysis. Genes occurring at significantly high frequency (one-tailed test) within random walks were ranked by correlation with RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis (GSEA) for biological processes using clusterProfiler.

RESULTS

RBFOX1, a neurodevelopmental regulator, was upregulated (logFC = 1.85) in NE samples and uniquely occurred in NE communities. We show RBFOX1 is differential expressed in the aggressive Neuronal glioma subtype and enriched in neuroepithelial/astrocyte subpopulations across single cell HGG datasets. NE network random walks identified 201 DEGs associated with RBFOX1. GSEA revealed upregulation of neurodevelopmental signatures and downregulation of proliferative pathways amongst RBFOX1’s network.

CONCLUSION

RBFOX1’s genetic network within NE tumor represents neurodevelopmental processes potentially underlying glioma invasiveness within the NE region. As such, understanding the mechanistic role of key genes within the RBFOX1 network may provide insight into novel strategies for targeting these invasive cells within an aggressive subtype of glioma in the NE rim.
P18.36.A REGIONAL CENTRE EXPERIENCE OF LARGE PTV VOLUME PATIENT OUTCOMES WITH 40GY/15# RADIOTHERAPY FOR GLIOBLASTOMA MULTIFORME (GBM)
Authors: Streatfield K , Glendenning J , Davies A , Forner S L
Published: October 2024

BACKGROUND

Glioblastoma Multiforme (GBM) are aggressive proliferative tumours, which are often large at diagnosis such that radiotherapy unavoidably treats a large percentage of brain. The required expansion margins to create the Planning Target Volume (PTV) for radiotherapy treatment, can often lead to high volumes of normal brain included. In the 40Gy/15# regimen indicated for the older patient population, and younger patients with larger treatment volumes, we sought to evaluate the effect that this had on both treatment outcomes and ability to offer further treatment at progression.

MATERIAL AND METHODS

A retrospective review of GBM patients of performance status 0-1, treated during 2018-2023, with 40Gy/15# ± chemotherapy at the Kent Oncology Centre. Patient demographics, histology and radiotherapy planning data, subsequent lines of treatment and survival outcomes from radiotherapy start date were extracted from the local oncology electronic system. Analysis was performed using Python and the Lifelines survival analysis library.

RESULTS

58 patients fulfilled the selection criteria, with the average age of 68 (range 46-80). The Male/Female ratio was 1:1. The Median Overall Survival (mOS) for the entire population was 9.0 months and Progression Free Survival (PFS) 5.0 months. 43% of the patients received surgical intervention with biopsy only and 55% debulking. 33 (57%) of the patients were MGMT unmethylated. As a percentage of the total brain volume, mean PTV size was 27.0%, with the range of 5.1-50.4%. 20 (34%) of patients had a large PTV size, defined as ≥30% of the total brain volume. These patients had poorer mOS in comparison to smaller PTV patients, with mOS 5.0 vs 11.0 months. Similarly, PFS was 4.0 months vs 5.0 months. Within the cohort of larger PTV patients, MGMT methylation status did not influence mOS (5 months Methylated vs 4 months Unmethylated) and PFS (both groups 4 months). In the 3 patients with very large PTV sizes (>45%, compared to ≤45%) of total brain volume, mOS was 4.0 months vs 9.0 months, and PFS 3.0 months vs 5.0 months. Fitness to receive subsequent lines of treatment was used as a measure of functional status at progression following radiotherapy. Of the 31 patients in the entire cohort with progressive disease, 12 (39%) received 2nd line treatment. 28% of progressing patients with large PTV sizes went on to receive 2nd line treatment, compared to 38% of smaller PTV sizes. No patients with very large PTV sizes >45%, received 2nd line treatment.

CONCLUSION

Our study indicates that large volume radiotherapy treatments (≥30% of total brain volume) are associated with poorer disease control and survival outcomes. This includes a lower proportion in patients with the functional ability to receive 2nd line treatment. Evaluation in larger patient cohorts to verify these findings would assist to inform treatment discussions.
P18.49.B TOWARDS INTEGRATING IMAGING AND IMMUNOLOGY IN GLIOBLASTOMA: MAPPING BLOODIMMUNE SYSTEM METRICS TO TUMOR MAGNETIC RESONANCE IMAGE DATA
Authors: Heugenhauser J , Visus C , Buchroithner J , Marosi C , Rössler K , Felzmann T , Widhalm G , Nowosielski M , Erhart F
Published: October 2024

BACKGROUND

Glioblastoma is the most aggressive and most frequent primary brain tumor. Glioblastoma is highly immunology-driven because a large portion of its cell mass consists of immune cells. In addition to immunology, imaging is a second important scientific field when it comes to glioblastoma. Regarding imaging, the VASARI brain tumor morphology classification system has been gradually accepted as a valuable tool. Despite the importance of both, imaging and immunology, for glioblastoma characterization, these two disciplines have been kept surprisingly separate. Integrating them more seems worthwhile and valuable.

MATERIAL AND METHODS

76 patients from a previous glioblastoma immunotherapy study were assessed ex post with regard to the accessibility of tumor imaging data and peripheral blood immunology metrics at the start of the study, i.e. at baseline. For 41 patients both were acquirable. Magnetic resonance images were then studied via volumetric analysis as well as VASARI morphology assessment. The therewith generated 27 imaging variables were integrated with 67 peripheral blood immunology metrics that had been measured via FACS and PCR. Finally, a screening for associations between these variables was performed.

RESULTS

In a first comprehensive mapping, 94 imaging-immunology correlations were present. Importantly, the edema volume seemed associated with CD56+CD16- natural killer cells, characteristics of the contrast-enhancing margin were associated with various cytotoxic T cell species and the necrosis volume was associated with mRNAs in the blood that indicate specific immunopolarization (IFN-γ, GATA3, ROR-gt). Curiously, the location of the tumor location also apparantly had a role as e.g. some blood helper T cell species seemed more frequent in patients with central/bilateral tumors or with tumors in the Broca region.

CONCLUSION

We here contribute first data that tumor imaging features and peripheral blood immunology metrics can be associated in glioblastoma. Via exploring the intersection between imaging and immunology in glioblastoma science, we advance basic tumor biology aspects and pioneer novel directions for continuative research.
P18.50.A TUMOR VOLUMES AND FEASIBILITY OF EXTENSIVE RESECTION IN NON-CONTRAST ENHANCING GLIOBLASTOMAS THAT LACK HIGH GRADE HISTOLOGICAL FEATURES: A SINGLE CENTER STUDY
Authors: Lakerveld S , Wijnenga M M J , Maas S L N , van Dis V , Smits M , Tesileanu M , Dubbink H J , French P J , Vincent A J P E , van den Bent M J
Published: October 2024

BACKGROUND

The clinical course and management of non-contrast enhancing glioblastomas that also lack the classic high grade histological features (non-CE GBMs) is unclear. Data on survival, clinical management including surgical therapies are sparse and conflicting. In this study we therefore investigated tumor volumes, surgical and postsurgical therapies and survival outcome of a single center cohort from the Netherlands.

MATERIAL AND METHODS

We identified adult cases of non-CE GBM in the Brain Tumor Center at Erasmus MC Cancer Institute in Rotterdam, the Netherlands from 2003-2024. Cases with ring-like contrast enhancement and/or central necrosis at time of diagnosis were excluded. Patients were classified as glioblastoma using a glioma-tailored NGS panel. Pre-and postoperative tumor volumes were segmented manually using open source software ITK-SNAP. Pre- and postoperative volumes were set equal when only a biopsy was performed. Clinical information and postoperative therapies were retrospectively collected from patient records. Overall survival was calculated from time of diagnostic MR scan.

RESULTS

We identified 77 patients with available imaging data. Median age of patients was 59 years. The presenting symptom was an epileptic seizure in 66.2% of patients. Tumor localization in 60 out of 77 patients involved mainly the temporal lobe. As initial surgical strategy 59 patients underwent a biopsy (stereotactic or open), and only 18 patients a resection (of which 5 were awake). In most cases a clinically relevant resection was considered not feasible. Of the 18 resected patients, 4 patients underwent a second resection at progression. Of the 59 biopsied patients, 5 underwent a subsequent resection, and 5 a second biopsy as the first biopsy was inconclusive. Patients that underwent a resection had higher KPS scores (≥90 in 95.7% vs 55.6%, P= 0.003), and lower rates of gliomatosis cerebri (8.7% vs 53.7%, P <0.001). Median preoperative tumor volume was 65 cc. In only 3 of 18 resected patients the postoperative tumor volume was ≤5 cc. After diagnosis, 41 patients underwent radiotherapy with concurrent temozolomide, of which 12 with a hypofractionated scheme. 12 patients only received radiotherapy and 13 patients only chemotherapy. Median OS was 21.1 months, with no significant difference in OS observed between the resection and biopsy group.

CONCLUSION

In this series on non-CE GBMs with low grade histological features, a clinically relevant resection was not feasible in most cases because of pre-operative size of the lesion and location, only in 3 patients a small postoperative volume of ≤5cc was achieved. This may contribute to the poor outcome of these patients compared to other series.
P18.51.A UNIQUE GENETIC AND EPIGENETIC ALTERATIONS IN GLIOBLASTOMA VERY LONG-TERM SURVIVORS (VLTS): INSIGHTS FROM TWO CLINICAL CASES
Authors: Anghileri E , Pollo B , Calatozzolo C , Lazzarini E , Patrizi S , Pedace L , Barresi S , Patanè M , Maddaloni L , Lamperti E , Indraccolo S , Paterra R , Miele E
Published: October 2024

BACKGROUND

Glioblastoma (GBM) 5-year survival (LTS) and a 10-year survival (VLTS) rate are extremely low, reaching 7% and 4.7% respectively (2020 CBTRUS Statistical Report). The biological mechanisms that drive the prolonged clinical outcomes remain significantly understudied.

MATERIAL AND METHODS

As part of a recent study on LTS (PMID: 38423245), here we detail two out of the 17 VLTS cases, addressed with extensive molecular analyses.

RESULTS

Patient AR 10-046 was a 31-year-old female with a left fronto-parietal giant cell GBM (gcGBM), treated with surgery, radiotherapy and chemotherapy. After 6 months from the diagnosis, she recurred and underwent tumor exeresis and adjuvant TMZ, maintaining disease stability for a total of 243 months. According to the v12.5 BTC the tumor was assigned to the methylation subclass pedHGG_RTK1a subtype (score >0.99), frequently associated with Lynch syndrome (LS). Indeed, we detected MSH6 mutation in tumor DNA as well as in peripheral lymphocyte. We detected high Tumor Mutational Burden. Interestingly, the Copy Number Variation (CNV) plots showed chromosome 1q gain and chromosome 13 loss with no other typical GBM alterations.Patient AR 10-037 was a 70-year-old male with left temporal lobe GBM treated with surgery, adjuvant radiotherapy and chemotherapy, achieving a survival of 73 months. Histology was classical GBM. The tumor was assigned to the pedHGG_MYCN subclass with a suboptimal score (0.5). At CNV examination, apart from the canonical chromosome 7 gain and chromosome 10q loss, we observed MDM2 gene amplification and possible rearrangements on chromosome 12 and 18 with the typical aspect of a chromothripsis (CT), confirmed by RNASeq analysis. Our case presented CT on chr12 harboring two putative gene fusions: CPSF6::CPM and PTPRR::RAB3IP never reported in the literature.

CONCLUSION

We described two cases of VLTS patients with peculiar molecular profile, widening the scenario of clinical and molecular variability that can be found in such patients. Further studies are still needed to identify the biological mechanisms causing such prognosis, with a fundamental contribution from molecular analyses, including DNAm profiling, NGS and RNAseq.

FUNDING

RRC Italian Ministry of Health
P18.53.A USING THE PATTERN OF 5-AMINOLEVULINIC ACID (5-ALA) POSITIVE RESIDUE TO PREDICT THE OUTCOME OF GLIOBLASTOMA PATIENTS
Authors: Manik V , Sim V , MacDonald M , Mannava A , Soumpasis C , Kalaitzoglou D , Ashkan K , Bhangoo R , Gullan R , Brazil L , Al-Salihi O , Vergani F , Chia K , Swampillai* A , Lavrador* J P
Published: October 2024

BACKGROUND

Glioblastoma multiforme (GBM) portends poor prognosis despite multiple attempts at finding newer therapies. The current standard of care remains maximal safe resection. 5-ALA guidance helps to maximise the resection extent but complete removal is not always possible. It is unclear, if the residual 5-ALA pattern can predict the outcome of patients with GBM.

MATERIALS & METHODS

Patients with GBM treated at our centre between January 2018 - July 2019 were included if they had 5-ALA based tumour excision & were planned for adjuvant treatment per Stupp. Patient, tumour & treatment related factors were collected. Operation notes were reviewed to determine the pattern of 5-ALA residual & classified as no residue if there was no visible 5-ALA left at the end of resection; focal residue if 5-ALA positive tissue left involved 1-2 walls; or diffuse residue if all walls were involved. Date of relapse & date of death were collected to compute progression free survival (PFS) & overall survival (OS) respectively. Data was analysed in SPSS™ v29, Kaplan Meier curves were used for survival analysis with log rank testing to compare between groups.

RESULTS

Total of 23 eligible patients were identified. Median age was 58 (32 - 70), majority were males (n=15). No residual 5-ALA was seen in 12, 8 had focal & 3 had diffuse residual. There was moderate correlation (f=0.453, p=0.03) between 5-ALA residual & the extent of resection however the positive (58.3%) & negative (63.6%) predictive values were low. The quantity of 5-ALA residual, no or focal residual vs diffuse residual, was predictive of overall survival 18.2 vs 9.3 months (p < 0.001) as well as progression free survival 10.9 vs 4.5 months (p = 0.006). The impact on overall survival was maintained even when the groups were stratified with age (65 and above or less than 65, p=0.006) or with their MGMT status (unmethylated or methylated, p=0.002). Cox proportional hazard showed that older age (p=0.004), unmethylated MGMT (p=0.031), intra-operative ventricular involvement (p=0.005) & diffuse 5-ALA residue (p=0.003) all had a negative impact on overall survival. A sub-group analysis, did not show any difference between the no residual and focal residual 5-ALA groups for OS (p = 0.548) or PFS (p = 0.498).

CONCLUSION

Diffuse pattern of 5-ALA residual had a negative impact on the oncological outcome of patients treated with 5-ALA guided maximal safe resection followed by oncological treatment, even when adjusted for established risk factors like age & methylation status.

*-joint authors
P19.01.A A SYSTEMATIC REVIEW OF THE NEUROSURGICAL MANAGEMENT OUTCOMES OF POSTERIOR PETROUS MENINGIOMAS
Authors: Awuah W , Ali S , Tan J , Adebusoye F , Shah M , Boye A , Sanker V , Tenkorang P , Chidi-Ikeji S , Frimpong M , Abdul Rahman T , Attalah O
Published: October 2024

BACKGROUND

Posterior petrous meningiomas (PPMs) present challenges in neurosurgical practice due to their proximity to critical neurovascular structures. Surgical management necessitates consideration of tumour characteristics and adjacent structures to optimise outcomes and minimise complications. Despite advancements in techniques and imaging, determining the optimal surgical approach and outcomes for PPMs remains an area of ongoing investigation. Understanding surgical outcomes and factors influencing postoperative recovery is crucial for informing clinical decisions and enhancing patient care.

MATERIALS AND METHODS

Databases such as PubMed/Medline, Web of Science (WOS) and Cochrane Library were systematically searched from their inception to April 2024. Among the retrieved articles were 10 retrospective studies, 2 case series, and 9 case reports encompassing a cohort of 622 patients who had undergone various procedures for PPMs. A meticulous quantitative analysis was conducted on the individual patient data extracted from these sources, allowing for a comprehensive examination of the aggregated findings. Additionally, a qualitative analysis was performed on available individual patient data, utilising the Chi-Squared Test methodology to explore potential associations between preoperative symptoms, surgical approach, and postoperative outcomes. In this analysis, a significant threshold of p < 0.05 was employed to determine noteworthy correlations.

RESULTS

Our search revealed studies with 622 individuals (468 females and 154 males), with a mean age of 54.92 years. Quantitative analysis revealed some degree of hearing loss as the predominant symptom (32%). For treatment, the retrosigmoid approach was most common (63%), followed by the translabyrinthine approach (16%). Resections were mostly total, with the most common postoperative complications being neurological deficits of the 8th cranial nerve (21%). Postoperative facial nerve function was fully preserved in 71.5% of patients, and 36.5% retained unimpaired hearing. Qualitative analysis indicated significant associations between postoperative hearing status, surgical approach (p = 0.001), and neurological deficits (p = 0.003).

CONCLUSION

Preliminary evidence from this systematic review suggests that the surgical approach matters when it comes to avoiding sequelae arising from surgical treatment of PPM. Specifically, the widened retrolabyrinthine approach shows promise in reducing neurological deficits, while the retrosigmoid approach appears favourable for preserving postoperative auditory function. However, given the limited scope of the current literature, further research is warranted to corroborate these findings and enhance our understanding of optimal surgical strategies for PPM management.
P19.07.A INCREASED LOCAL TUMOR CONTROL AFTER POSTOPERATIVE RADIOTHERAPY IN RECURRENT MOLECULARLY HIGH-RISK WHO GRADE 1 MENINGIOMAS
Authors: Deng M Y , Maas S N , Debus J , Sahm F , König L
Published: October 2024

BACKGROUND

Despite an overall favorable prognosis, early recurrences occur in a significant proportion of WHO grade 1 meningiomas following surgical resection. Given a wide variety of institutional preferences, individualized patient circumstances, and a lack of level 1 evidence, there are no standardized guidelines for the treatment of recurrent WHO grade 1 meningiomas, in particular to the requisiteness of radiotherapy and its timing. Our study assessed the local tumor control after postoperative radiotherapy in recurrent molecularly high-risk WHO grade 1 meningiomas.

MATERIAL AND METHODS

Patients with primary WHO grade 1 meningioma and DNA methylation profiles (n=224) were retrospectively screened for recurrences (n=31). The local 3-year progression-free survival (PFS) after primary resection, as well as recurrence resection, was determined using Kaplan-Meier analysis. Integrated risk scores were calculated for primary and recurrent WHO grade 1 meningiomas.

RESULTS

Primary WHO grade 1 meningiomas were completely resected (GTR) in 81.3% (182/224). The 3-year PFS was 95.4% for molecularly prognostically favorable (IntS-low) versus 71.1% for prognostically unfavorable (Int-S-int/high) primary WHO grade 1 meningiomas. None of the patients received postop-RT after primary resection. After recurrence resection (n=31, Int-S-low: 14/31, Int-S-int/high: 17/31), 85% of subtotally resected meningioma recurrences received postop-RT. Notably, the local 3-year PFS for clinically-molecularly prognostically unfavorable recurrences (STR, Int-S-int/high) after postop-RT was 85.9%.

CONCLUSION

Postop-RT in molecularly prognostically unfavorable, recurrent WHO grade 1 meningiomas after STR may lead to improved local tumor control. Future matched-pair analyses with patients with recurrent WHO grade 1 meningiomas are warranted to further illustrate the benefit of postop-RT after recurrence resection.