bluuebunny/crossref_metadata_2025_split huggingface dataset:
P06.08.B OF TRAVELING HOMEOPROTEINS AND MEDULLOBLASTOMAS
Authors: Vigneul E , Clotman F 
Published: October 2024

Abstract

BACKGROUND
Medulloblastomas (MB) are the most common pediatric malignancies. These WHO grade IV neoplasms are divided into four main subgroups called SHH-activated, WNT-activated, group 3 and group 4. These subgroups are governed by different molecular patterns involving transcription factors (TFs), in particular (TF) Orthodenticle homeobox 2 (OTX2) which, when overexpressed, is a key factor in group 3 and 4 medulloblastoma formations. In addition to being a transcription factor crucial for the proper cerebral and cerebellar embryogenesis, OTX2 is a homeoprotein with intercellular travelling properties. Indeed, via secretion and penetration sequences, OTX2 can travel between cells and influence the tumor neighborhood in a paracrine manner. The objective of this study is to establish the list of traveling homeoproteins associated with the development of MB.

MATERIALS AND METHODS
We found 57 homeoproteins with demonstrated intercellular transfer capabilities in vivo. We then systematically reviewed the literature and found 89 articles eligible for full-text analysis.

RESULTS
Ten traveling homeoproteins (CUX1, EN1, ISL1, LHX1, NKX2.2, OTX2, PAX5, PAX6, PAX8 and POU5F1) are involved in medulloblastoma formation. Apart from PAX8, which is underexpressed, all other homeoproteins are overexpressed in medulloblastoma.

CONCLUSION
This study highlights the role of several traveling homeoproteins in the formation of medulloblastoma. Most of these proteins are overexpressed in MB and have the ability to enter and modify the transcriptional and non-transcriptional mechanisms of surrounding cells. Antibodies targeting these transcription factors, as used in animal models, could become a promising tool to circumscribe the potential chain reaction of deregulation associated with these roaming homeoproteins.
P06.09.B RATIONAL DRUG COMBINATIONS TARGETING FAK AND MEK OVERCOMES TUMOUR HETEROGENEITY IN GLIOBLASTOMA
Authors: Furqan M , Elliott R , Nagle P , Loftus A , Masalmeh R , Munro A , Drake C , Dawson J , Brunton V , Frame M , Carragher N 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) presents a formidable clinical challenge with limited treatment options and poor outcomes. Despite efforts, the standard therapy has not improved for almost two decades. The heterogeneity of GBM, driven by multiple intracellular signalling pathways, complicates treatment response and contributes to drug resistance. Recent advancements in targeted combination therapy, such as dabrafenib and trametinib, offer promise for specific GBM subgroups, but identifying effective drug combinations remains challenging. Integrin mediated signalling, particularly through Focal Adhesion Kinase (FAK), plays a crucial role in GBM pathogenesis and invasion. While targeting FAK shows promise, identifying synergistic combinations is essential. Our study employs a chemogenomic screening approach to identify FAK targeted drug combinations in glioblastoma.

MATERIAL AND METHODS
Glioblastoma cells were cultured and subjected to chemogenomic screening to identify synergistic drug combinations with FAK depletion. Cell viability was assessed using the Alamar Blue assay, while morphological changes were observed using high content imaging. Synergies in drug combinations were determined using the SynergyFinder online tool. Molecular mechanism was elucidated through Reverse Phase Protein Array and western blots, with statistical analysis determining significance. Finally, in vivo efficacy was evaluated in an orthotopic transplantation model.

RESULTS
Using a CRISPR engineered model, we identified synergistic drug combinations with FAK loss, notably MEK inhibitors. Combining FAK inhibitors with MEK inhibitors showed potent synergy, validated by target engagement assays. Across a diverse panel of patient derived GBM stem cells, this combination inhibited spheroid growth and invasion. RPPA profiling elucidated their molecular effects. In vivo, the combination significantly reduced tumour volume. These results highlight a promising therapeutic strategy for glioblastoma.

CONCLUSION
In conclusion, our study reveals promising synergies with MEK inhibitors, notably trametinib, across diverse GBM models. This approach also highlights the potential of combination therapy to address the complex challenges of GBM treatment.
P06.10.A THE MIRNA 216B-5P ACTS AS A PROMISING TUMOR-SUPPRESSOR BY MANIPULATING CELL CYCLE PROGRESSION IN HIGH-GRADE GLIOMA CELLS
Authors: Lang A , Bürger S , Mager L , Kiesel B , Madlener S , Ricken G , Lämmerer A , Spiegl-Kreinecker S , Hackl M , Pultar M , Reisecker J , Kirchhofer D , Mischkulnig M , Berghoff A S , Woehrer A , Rössler K , Roetzer-Pejrimovsky T , Berger W , Jaunecker C N , Hainfellner J A , Hoeftberger R , Widhalm G , Erhart F , Loetsch-Gojo D 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma is the most common brain tumor in adults and with an approximate survival rate of 15 months, new treatment strategies are of utmost urgency. In our previous phase II clinical trial, applying immunotherapy with dendritic cells to glioblastoma patients, no differences in overall survival were observed. However, distinct miRNAs and in particular miR-216b, harbored a predictive power and were associated with therapy susceptibility. Thus, we hypothesize that amongst others, miR-216b is involved in glioblastoma aggressiveness and thereby impacting therapeutic success.

MATERIAL AND METHODS
First, we screened glioblastoma tissue samples (n=39) and several cell models for the expression of five different miRNAs. As miR-216b was generally low expressed compared to others, we investigated whether transfection with miR-216b “mimic” (upregulation) or “inhibitor” (blocking) had an impact on clonogenic survival, sphere-forming and migratory capacity in three patient-derived and two immortalized glioblastoma cell models. To gain deeper knowledge about miR-216b targets, miRNA sequencing was performed. Subsequently, predicted targets were confirmed by Western Blot, FACS analysis and drug sensitivity assays.

RESULTS
MiR-216b upregulation resulted in reduced cell proliferation and migration as well as in decreased stemness characteristics in the majority of the investigated high-grad glioma (HGG) models. RNA sequencing predicted target genes of miR-216b that are involved in cell division (e.g. CDK4). Accordingly, upon transfection with “miR-216b mimics”, protein levels of CDK4 and subsequently phosphorylation of RB were reduced, accompanied by an increase of cells in G0/G1 phase. When miR-216b was blocked, the sensitivity towards CDK4/6 inhibitors was distinctly increased, pointing towards a drug-targeting engagement.

CONCLUSION
Our data indicates that miR-216b acts as a tumor suppressor via the inhibition of CDK4 in glioblastoma cells. The prognostic and predictive value of this miRNA in glioblastoma is currently under investigation and harbors the potential to manipulate glioma cells into cell cycle arrest.
P06.12.B Microbiota-gut-brain axis in glioblastoma development and therapeutic resistance
Authors: Lavielle S , Delrot G , Lemaitre M , Pateras I S , Nikolski M , Daubon T , Martin O C B 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GB) is the most common subtype of glioma in adults. Despite treatment through tumor resection associated with chemo and radiotherapies, this cancer still has a very poor prognosis. Factors contributing to etiology, pathogenesis, or treatment resistance are not well known. The significance of understanding the microbiome-gut-brain axis (MGBA) in GB, a topic that has been recently shown to be crucial in several neurodegenerative diseases, cannot be overstated. Therefore, our project aims to understand how modulation of gut physiopathology (i.e., gut inflammation or microbiota dysbiosis) affects GB development and therapeutic resistance.

MATERIAL AND METHODS
We have examined the relationship between gut inflammation, microbiome modulation, GB development, and therapeutic resistance. Mice received dextran-sulfate sodium (DSS), a gut pro-inflammatory agent, and were orthotopically injected with mGB2 GB cells. Some mice were then resected and treated by radio and chemotherapy using Temozolomide (TMZ). To understand the role of the gut microbiota in GB, we performed gut bacterial microbiota depletion using antibiotics.

RESULTS
Our results showed that DSS-treated mice had a higher GB growth than non-treated mice. Moreover, the recurrence after treatment was higher in mice bearing gut inflammation. Interestingly, we also observed on DSS-treated mice that the GB-bearing mice had lower intestinal inflammation than the control. GB growth was also associated with microbiota modifications, which were restored by the treatment. Gut microbiota alteration leads to increased tumoral growth, suggesting an implication of the microbiota in GB development.

CONCLUSION
Altogether, our results support the bidirectional communication between the gut and the brain in the context of GB. Alteration of gut physiopathology strongly impacts GB development and therapeutic resistance. This connection suggests that targeting the gut microbiome could slow down GB progression and/or improve treatment efficacy.
P07.02.A SEX-SPECIFIC EVALUATION OF EMOTIONAL PROBLEMS, UNMET NEEDS AND PSYCHIATRIC COMORBIDITY IN PATIENTS WITH HIGH-GRADE GLIOMAS - A MULTI-CENTER STUDY
Authors: Renovanz M , Hippler M , Kuchen R , Doerner L , Rieger D , Steinbach J , Ronellenfitsch M , Kessler A , Misch M , Onken J , Rapp M , Nadji-Ohl M , Mehlitz M , Meixensberger J , Fehrenbach M , Keric N , Ringel F , Coburger J , Weiss Lucas C , Wehinger J , Schmidt-Graf F , Gempt J , Tatagiba M , Tabatabai G , Schranz M , Singer S 
Published: October 2024

Abstract

BACKGROUND
Patients diagnosed with high-grade gliomas (HGG) often experience considerable emotional distress. However, not all of them actively seek professional psychosocial support even when clearly needed and so far, gender aspects are not considered in clinical routine. We evaluated differences between female and non-female patients regarding emotional functioning and psychiatric comorbidity.

METHODS
In this multi-center study involving 13 centers, emotional functioning was assessed in patients with high-grade glioma during their visits to the outpatient clinic with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), using thresholds of clinical importance following Giesinger to define increased problems. Unmet psychosocial care needs were ascertained with study specific questions and psychiatric comorbidity with the Structured Clinical Interview according to DSM (SCID). Analyses employed chi-square tests and multivariate binary logistic regression.

RESULTS
In total, 763 patients were enrolled of whom n=691 could be interviewed with the SCID. About half of them (57%, n= 396) were male, 294 (43%) female and 1 (0.1%) identified as diverse. For the following analyses, females were compared with non-females (male and diverse). Emotional functioning was poor in 67% of female and 57% of the non-female patients (unadjusted odds ratio (OR) 1.5, 95% CI 1.1-2.1, p=0.01; adjusted OR=1.4, 95% CI 0.9-2.1, p=0.11). About 22% of the women and 20% of men/diverse expressed the wish for support by a psychologist (p=0.54); additional support by social workers was wished for by 9% of all sexes (p=0.90), and additional emotional support by oncologists from 11% of the women and 6% of the men/diverse. According to the SCID interview, a total of 217 patients (31%, CI 28%-35%) were diagnosed with at least one common mental disorder (male: 115, 29%; female: 102, 35%). There was no evidence that gender was a predictor of comorbid mental disorders (adjusted OR=1.2; 95% CI 0.9-1.8, p=0.25).

CONCLUSION
Patients diagnosed with a high-grade glioma are at risk of comorbid mental disorders independently of gender though women might express their support needs and emotional problems more openly. Therefore, support should be offered to all genders low-threshold and equally.
P07.03.B THE EFFECT OF SEX HORMONES ON THE COURSE OF MENINGIOMAS IN DIFFERENT HORMONAL PHASES IN THE FEMALE LIFE
Authors: Taliansky A , Haisraely O , Atar N , Jan E , Modan-Moses D 
Published: October 2024

Abstract

BACKGROUND
The influence of gender on the incidence and the survival of patients with nervous system tumors (NST) is well known, but the mechanism is not fully understood yet. The effect of sex hormones on the course of NST in different hormonal phases in female life raises interest, but only the pregnancy condition has been discussed in detail, however, consensus has not been reached regarding clinical recommendations. Descriptions of the effect of fertility treatments (FT) on NST are in a few not recent reports. The importance of sex hormones replacement treatment (HRT) as a risk factor for radiation induced tumors in patients after radiotherapy for childhood NST has not been studied yet.

MATERIAL AND METHODS
We retrospectively evaluated the data of three cases of high-grade meningiomas in women of reproductive age treated in the Neuro-oncology unit at Sheba MC.

RESULTS
One case is a 41 years old woman, who received two cycles of FT in 2022 and was diagnosed with a Rt. Frontal WHO 2 meningioma on April 2023 that was treated by gross total resection (GTR). The second case is a 32 years old woman treated with radiotherapy and chemotherapy at age 10 years due to medulloblastoma, who on January 2023 was diagnosed and had GTR for a Lt. Frontal WHO 2 meningioma after 1 year of HRT. The last case is a 28 years old woman that had GTR for a Rt cerebellar WHO 2 meningioma in 2020. During 2023 the patient had FT for surrogate pregnancy and on February 2024 recurrent tumor was diagnosed and treated with radiosurgery.

CONCLUSION
There is not much information available regarding the effect of sex hormones on the course of meningiomas, possibly due to the low incidence of meningiomas during the reproductive years. In Israel, fertility treatments are included in the national healthcare and the number of treatment cycles is not limited. This allows the collection of information about the effect of fertility treatments on NST, especially meningiomas in women. This project initiated this year. A phenomenon of “ social” egg freezing that has been expanding in recent years caused an increase in the number of women applying for fertility treatments and the need for a large number of treatment cycles. Since the incidence of meningiomas increases with age, presumably, the use of fertility treatments at an older age may affect the incidence and the grade of meningiomas in women. We would like to raise the importance of this topic.
P08.01.A ANGIOGENESIS IN CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY (CIPN): EXPLORING CIRCULATING VEGF AS BIOMARKER OF CIPN DEVELOPMENT AND RECOVERY
Authors: Velasco R , Andrés-Benito P , Marco C , Roca-Pereira S , Pros-Marsal A , López-Sampere Y , Eva D , Santos C , Stradella A , Bruna J 
Published: October 2024

Abstract

BACKGROUND
Chemotherapy induced peripheral neuropathy may result from an antiangiogenic effect of these drugs, resulting in destruction of the vasa nervorum. Vascular integrity alterations may contribute to neuropathic pain pathogenesis. Vascular endothelial growth factor A (VEGF-A) is an angiogenic factor that enhances nerve blood flow and oxygen supply by inducing angiogenesis, in response to the nerve ischemia and hypoxia caused by these drugs. Besides, microvascular damage has been suggested as the basis for neuropathic pain due to chemotherapy. Whether VEGF-A plays a role in the pathogenesis and repairment of CIPN is unknown. The aim of this study was to (1) explore the evolution of plasma VEGF during and after chemotherapy treatment and its association with development and recovery of CIPN; (2) compare the VEGF among different neurotoxic chemotherapy agents; (3) investigate the potential role of VEGF as biomarker of CIPN severity and prognosis.

MATERIAL AND METHODS
This is a single-center prospective observational longitudinal study including three cohorts of patients with breast, lymphoma or colorectal cancer treated with paclitaxel, brentuximab and oxaliplatin, respectively. All patients were assessed using the Total Neuropathy Score- clinical, Common Terminology Criteria for Adverse Events, EORTC QLQ-CIPN20 and nerve conduction studies (NCS) before, and periodically up to 12 months after finishing treatment. Serial VEGF and light chain Neurofilaments (NfL), a biomarker of nerve axon damage, were collected at the same timepoints and quantified using ELISA and SIMOA techniques, respectively. The changes in VEGF identified will be compared between groups of agents (platinum or microtubule disruptors) alone or in combination, and correlated with clinical, NfL and NCS data, depending on the degree of neuropathy and the presence of neuropathic pain.

RESULTS
One-hundred patients are included, mostly women (60%). At baseline, mean VEGF plasma levels were for males (215,70 +/- 204,06 pg/mL) and females (204,60 +/- 224,97 pg/mL), with no differences according to type of chemotherapy agent received (p=0.148). No correlation between VEGF and NfL at baseline was identified (p=0.9). One-third of the whole patients developed clinically relevant (&gt; grade 2) CIPN) or painful CIPN. Analysis of VEGF is ongoing and will be reported as part of this abstract.

CONCLUSION
Mechanisms of CIPN are not fully elucidated and differences among agents must be investigated. Whether CIPN development and/or recovery is associated with a significant modulation of angiogenesis identified by changes in the levels of VEGF will be reported.
P08.04.B DECREASED PERIPHERAL BLOOD SEROTONIN AND KYNURENINE LEVELS ARE ASSOCIATED WITH POOR ONCOLOGICAL OUTCOMES IN GLIOBLASTOMA IDH-WT PATIENTS
Authors: De Domenico P , Snider S , Comai S , Bertazzo A , Nasini S , Roncelli F , Mortini P , Gagliardi F 
Published: October 2024

Abstract

BACKGROUND
The contribution of tryptophan (TRP) metabolism via the kynurenine (KP) and serotonin (SP) pathways in GBM biology has recently seen a growing interest. This study aims to address the association between pre-operative peripheral blood levels of TRP, kynurenine (KYN), 5-hydroxy-tryptophan (5-HTP), and serotonin (5-HT) and relevant oncological outcomes in GBM IDH-wt patients.

MATERIAL AND METHODS
A total of 62 adult patients undergoing maximal safe resection of newly diagnosed glioblastoma WHO grade 4 IDH-wt (GBM) were included. The variables were dichotomized and analyzed to explore their single contributions in building a predictive model of overall survival (OS) and progression-free survival (PFS) in GBM patients.

RESULTS
The mean baseline serum levels of 5-HT, KYN, 5-HTP, and 5-HT/TRP were significantly lower (-76%, -87%, -76%, -75%, p&lt;0.001 respectively) in GBM patients when compared to n=27 healthy individuals. The median OS in the whole cohort of GBM patients was 16.3 months (95% CI:13.4-21.7). Patients with 5-HT &lt; 78 ng/mL had a median OS of 14.4 months (95% CI: 11.4-17.6) compared to 22.5 (95% CI:17.7-27) in patients with 5-HT &gt; 78 ng/mL (p = 0.01). Shorter OS was recorded in patients with KYN &lt; 18 ng/mL (9.8, 95% CI:11.4-17.6 vs 17.5 months, 95% CI:14.4-22.5, p=0.002), KYN/TRP &lt; 2.55 (13.4, 95% CI:11.4-15.6 vs 19.1 months, 95% CI:14.0-28.6, p=0.002), 5-HTP/TRP &lt; 0.89 (11.5, 95% CI:10.9-20.6 vs 17.6 months 95% CI:14.4-32.4, p=0.02), and 5-HT/TRP &lt; 5.78 (13.4, 95% CI: 11.4-15.6 vs 19.1 months, 95% CI: 14.0-28.6, p=0.002)The median PFS was 9.27 months (95% CI:7.77-13.9). Significantly shorter PFS was observed in patients with 5-HT &lt; 78 ng/mL (p=0.04), KYN &lt; 18 ng/mL (p=0.02), 5-HT/TRP &lt; 5.78 (p=0.001), KYN/TRP &lt; 2.55 (p=0.005). Multivariate Cox analysis (R2=67%) confirmed an independent predictive role for poor OS of decreased KYN (p=0.001), 5-HTP (p&lt;0.001) and 5-HT (p&lt;0.001). Similarly, decreased 5-HT (p=0.004), and decreased 5-HTP (p=0.01) were predictive of poorer PFS.

CONCLUSION
This study highlights an intriguing association between enhanced degradation of TRP into KYN at the expense of the amount of the amino acid for the SP and median survival times in GBM. Decreased levels of KYN, 5-HTP, and 5-HT were associated with shorter OS.
P08.05.A LIQUID BIOPSY FOR GLIOBLASTOMA: UTILIZING PLASMA EXTRACELLULAR VESICLES FOR TUMOR DIAGNOSIS AND MONITORING
Authors: Del Bene M , Zaccheroni E , Osti D , Faletti S , Cavallo S , Costanzi E , DiMeco F , Pelicci G 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM), the deadliest brain tumor in adults, is traditionally diagnosed and characterized using neuroimaging and brain biopsies. These methods, however, suffer from limited specificity and sensitivity. The surgical risks associated with tumor sampling further complicate the monitoring of GBM’s molecular progression. Consequently, the identification of circulating GBM biomarkers is crucial for non-invasive tracking of the disease from diagnosis to relapse. Extracellular vesicles (EVs) secreted by GBM cells, which cross the blood-brain barrier and carry tumor-derived molecules, present a promising avenue for the continuous evaluation of GBM presence and status.

MATERIAL AND METHODS
We isolated extracellular vesicles (EVs) using Size Exclusion Chromatography (SEC) from 2 mL of plasma and characterized them via immunoblotting, flow cytometry, and transmission electron microscopy. The concentration and size of EVs were measured using Tunable Resistive Pulse Sensing (TRPS). We compared EV levels in 50 glioblastoma (GBM) patients pre-surgery with those in non-GBM controls, which included 100 healthy individuals and 50 patients with brain malignancies that present similarly to GBM in neuroimaging studies. Longitudinal assessments of plasma EVs were performed in 44 GBM patients by comparing pre-operative and post-operative samples taken 72 hours after surgery. Additionally, we analyzed surface markers on GBM and non-GBM plasma EVs using MACSPlex and conducted proteomic analyses via mass spectrometry in 27 GBM patients and 38 healthy individuals.

RESULTS
We found higher concentrations and mean sizes of plasma EVs in GBM patients compared to controls, with a noticeable decrease post-operatively. Multiplex flow cytometry indicated universal expression of CD9, CD63, and CD81 across all samples, with significant enrichment of CD63 and CD81 in GBM plasma EVs. The expression profiles of the other 34 markers were similar across all samples, suggesting dilution of tumor-derived EVs among non-tumor EVs. However, T-cell markers CD8 and HLA-DRDPDQ were more prevalent on GBM-derived EVs. Proteomic analysis identified over 2,000 proteins in all samples, with 117 being upregulated in GBM samples, predominantly within the complement cascade pathways.

CONCLUSION
Our findings suggest that monitoring circulating EV levels provides a reliable, non-invasive method for the differential diagnosis and follow-up of GBM patients. The combined analysis of EV concentration, size, and proteome offers potential as promising biomarkers for longitudinal monitoring of GBM, supporting the implementation of liquid biopsy in GBM care.