bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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 &lt; 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 &lt; 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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 &lt;.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 &lt;.001 for neurosurgeons; pre 27%, post 47%, P &lt;.001 for oncologists); knowledge regarding identifying patients with IDH-mutant glioma who may benefit from emerging targeted therapies (pre 16%, post 24%, P &lt;.01 for neurosurgeons; pre 47%, post 55%, P &lt;.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

Abstract

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

Abstract

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

Abstract

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 (&gt;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 &gt;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

Abstract

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.