bluuebunny/crossref_metadata_2025_split huggingface dataset:
P02.06.B CROSSTALK BETWEEN GLIOMA AND MYELOID SHAPES DISTINCT TUMOR MICROENVIRONMENT IN SPINAL CORD, BRAIN STEM AND CEREBRUM
Authors: Wang Y 
Published: October 2024

Abstract

BACKGROUND
Occurring in the cerebrum, brainstem, and spinal cord, glioma are the most common primary malignant tumors in the central nervous system. Currently, there is a increasing understanding of the microenvironment of cerebral gliomas and brainstem gliomas, and clinical trials of immunotherapy for them are also ongoing. However, research on the microenvironment of spinal cord glioma is still lacking, Their immunotherapy potential deserve further exploration.

MATERIAL AND METHODS
We performed single-cell sequencing of fresh tissues from 8 cases of spinal cord DMG. Through integrating public scRNA data from 19 brain glioblastoma cases and 9 cases of DIPG samples, we did an integrated analysis of 199,696 human glioma, immune, and other stromal cells at the single cell level. Further analysis of cell communication revealed the distinct interaction between glioma cells and different cells in the microenvironment, especially tumor infiltrating macrophages.

RESULTS
Single cell analysis indicates that the main participants in the glioma microenvironment are tumor cells and tumor infiltrating macrophages; In addition, compared to midline gliomas, brain gliomas contain a higher proportion of lymphocytes. Interaction analysis revealed that spinal cord gliomas can regulate the infiltration of macrophages in spinal cord gliomas through the THY1-ADGR5 axis and higher expression of IGF1 by macrophages, promoting the proliferation and invasion of gliomas with IGF1R.

CONCLUSION
This study provides insights into molecular, spatial, and functional heterogeneity of glioma and glioma-associated immune cells in GBM, DIPG and spinal cord DMG, suggesting that selectively modulating tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating glioma.
P02.14.B INCREASED PRE-OPERATIVE MEAN PLATELET VOLUME (MPV) IS ASSOCIATED WITH GLIOBLASTOMA IDH-WTOVERALL SURVIVAL, PRELIMINARY DATA FROM 167 PATIENTS
Authors: Snider S , De Domenico P , Roncelli F , Bisoglio A , Braga M , Ghelfi A , Barzaghi L R , Mura C , Mortini P , Gagliardi F 
Published: October 2024

Abstract

BACKGROUND
In recent years, there has been a growing interest in exploring the potential contribution of hemostasis and platelet activation in GBM biology. This study aims to address the association between pre-operative coagulation profile (PT ratio, aPTT ratio), overall platelets’ count (PC), and the mean platelet volume (MPV) with tumoral characteristics and overall survival in GBM IDH-wt patients.

MATERIAL AND METHODS
A total of 167 adult patients undergoing maximal safe resection of newly diagnosed glioblastoma WHO grade 4 IDH-wt were included. The variables of interest (MPV, PT ratio, and aPTT ratio) were dichotomized at the median, while the overall PC was split up using the central distribution (10th to 90th percentile). Analyses were conducted to explore the single contributions of these parameters in building a predictive model of overall survival (OS) in these patients. Results: The mean baseline MPV correlated to increasing age (r=0.18, p=0.01), the overall FLAIR tumoral volume (r=0.17, p=0.02), and lesional contrast-enhanced (T1-CE) volume (r=0.19, p=0.01). The median OS in the whole cohort of GBM patients was 14.4 months (95% CI: 12.9-17.6). Patients with MPV &gt; 10.3 10-15L had a median OS of 13.4 months (95% CI: 10.6-17.6) compared to 14.5 months (95% CI: 13.4-20.6) in patients with MPV &lt;= 10.3 10-15L, p = 0.028. Similarly, shorter OS was recorded in patients with PT ratio &gt; 1.01 (p=0.006), and PC out-of-range 165-300 109/L (p=0.026). A subgroup analysis of patients &gt; 65 years confirmed baseline MPV &gt; 10.3 10-15L was associated with shorter OS (9.4 months, 95% CI: 8.1-13.4) compared to 13.3 months (95% CI: 11.3-32.3, p = 0.026). Baseline increased MPV showed an independent predictive role for poor survival (HR: 1.29, 95% CI 1.01-1.66, p=0.04) in multivariate analysis accounting for age, gender, pre-operative performance status, and tumoral molecular and radiological characteristics, whereas PC within central range had a protective role (HR: 0.47, 95% CI 0.26-0.88, p=0.01).

CONCLUSION
This study highlights an intriguing association between tumoral burden and systemic hemostasis activation in GBM IDH-wt patients. Increased MPV and deranged PC outside the central range were independent in predicting shorter OS, which was even more prominent among older patients.
P02.19.B NEW MURINE MODEL OF GLIOBLASTOMA SHOWS SUPPRESSIVE IMMUNE INFILTRATION
Authors: Forsythe D R , Burn O K , Small S J , Hermans I F , McConnell M J 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) research urgently requires a new murine model for preclinical research. The highly used cell line, GL261, reliably forms glioma-like tumours when transplanted intracranially, yet these tumours do not recapitulate human GBM, particularly when applied as a model for immune therapy. The tumour immune microenvironment (TIME) of a GL261 tumour consistently responds to immune checkpoint inhibitors, such as αPD-1 and αCTLA-4, which have shown no significance in multiple clinical trials.

MATERIAL AND METHODS
We have developed a novel murine model of GBM which has been designed to address the shortcomings of GL261. Into an immortalised eGFP astrocyte C57BL/6 cell line mutations were introduced to create genetic profile similar to human GBM cells. One version of these astrocytes models a classical GBM cell, with a Pten knockdown and RAS V12 stable transfection. Pten/RAS V12 and GL261 cells were separately transplanted intracranially into C57BL/6 mice and developed for either two weeks (spectral flowcytometry) or until ethical endpoint (survival and histological analysis).

RESULTS
Intracranial tumours reliably formed in both GL261 and Pten/RAS V12 models, with median survivals of 19.50 and 20.00 days, respectively. However, key histological differences were seen in H&E sections. The GL261 tumours were highly vascularised and showed clear borders with the healthy tissue. The Pten/RAS V12 tumours had very densely packed cell mass with more invasion into the surrounding tissue. Spectral flow cytometry indicated that macrophages and monocytes contributed predominately to the tumour immune infiltration of both models. Despite similar abundance of these cells, key inflammatory markers showed significant differences. The GL261 tumours myeloid compartment was largely comprised of classical monocytes (cMo). While the populations were heterogeneous, these cMo cells were characterised by high expression of Ly6C and MHCII, both markers associated with a proinflammatory, anti-tumour responses. Conversely, Pten/RAS V12 tumours showed significantly less of Ly6C+ MHCII+ cells, indicative of an immune suppressive environment comprised of anti-inflammatory TAMs and non-classical monocytes (ncMo). Additionally, GL261 tumours contained higher numbers of dendritic cells suggesting increased antigen presentation and greater potential for anti-tumour immune responses. Higher PDL1 expression was seen on infiltrating leukocytes in GL261 tumours, consistent with literature on GL261 demonstrating response to PD1 inhibitors. However, Pten/RAS V12 tumours showed minimal expression of PDL1, consistent with poor responses in GBM patients to immune checkpoint inhibitors.

CONCLUSION
Together, these data indicate that this novel model will be a more appropriate tool for GBM research to help understand how to better implement immune therapy.
P02.22.A REARRANGEMENTS OF PERITUMORAL TISSUE THAT OCCUR ALONG WITH GLIOMA PROGRESSION
Authors: Mori E , Spalletti C , Scalera M , Haddad S , Cangi D , Pillai V , Parmigiani E , Mainardi M , Landi S , Caleo M , Vannini E 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma Multiforme (GBM) is a high-grade glioma known to infiltrate the surrounding brain parenchyma inducing a direct neuronal damage. Indeed, GBM mass is not an isolated and self-sustained entity but rather participates and interacts with the surrounding neuronal tissue. Specifically, tumoral cells induce neuron hyper-excitability while peritumoral cells seem to regulate tumor proliferation and progression. GBM affects 3 in 100,000 people and has a median survival of 15 months; it remains poorly understood and lethal. Therefore, gaining a deeper understanding of the alterations occurring in peritumoral tissues during GBM progression is of paramount importance.

MATERIAL AND METHODS
We investigate the plastic rearrangements of motor cortical areas in two different glioma-bearing mouse models using optogenetic stimulation, two photon imaging and immunohistochemical analyses. Specifically, we took advantage of Thy1-ChR2 transgenic mice, injected with two syngeneic lines of murine glioma cells (i.e. GL261 and PDGF+ Trp53-/- cells) into the motor cortex. Mice were optogenetically stimulated in 120 points per session (covering the entire extent of forelimb motor representation) at 3 different time points: baseline (before glioma cells injection), 14 and 21 days after tumor implantation.

RESULTS
We show that both models of glioma-bearing mice underwent a strong remapping of forelimb motor territory. Namely, an increased threshold required for eliciting a forelimb movement was coupled with a decrease of forelimb specificity in the peritumoral area with respect to naïve mice. In addition, glioma-bearing mice showed a decrease in the number of dendritic spines, along with reduced density of perineuronal nets (PNNs) and inhibitory interneuron markers in the peritumoral cortex.

CONCLUSION
We provide important insight into the interaction between GBM and surrounding tissue that can be used for developing more effective treatments to improve patients’ quality of life and survival.
P03.01.A ANDROGEN MODULATION OF TEMOZOLOMIDE SENSITIVITY IN GLIOBLASTOMA
Authors: Plata-Bello J , Fariña-Jerónimo H , Martín-Ramírez R , Martín-Abreu C , Hagemeyer H , Medina L , González-Fernández R , Martín-Vasallo P 
Published: October 2024

Abstract

BACKGROUND
Androgen receptor (AR) activation appears to play a pathogenic role in glioblastoma. However, the impact of testosterone on sensitivity to temozolomide action has not been explored. The aim of the present work is to analyze the effect of testosterone on temozolomide action sensitivity on cell viability in glioblastoma.

METHODS
Three glioblastoma cell lines (U87-MG, U118-MG, and A172) cultured in DMEM/F12 were utilized. Various experimental conditions were applied: testosterone 100nM, bicalutamide 100uM (an AR inhibitor), and temozolomide 60ug/mL, as well as their combinations. Two control conditions were included. Cell viability was determined using the Cell Counting Kit-8 (Dojindo) at 24, 48, and 72 hours, with all experimental conditions performed in triplicate. Analysis of variance was employed to identify differences in cell viability, with Tukey correction for multiple comparisons.

RESULTS
Cell viability significantly increased with testosterone exposure and decreased with temozolomide treatment, as expected. The combination of temozolomide with testosterone attenuated the impact of the former on cell viability, indicating increased resistance in testosterone-exposed cells. This effect was more pronounced in U118-MG (p&lt;0.001) and A172 cells (p=0.019), with a similar trend observed in U87-MG cells (p=0.312). The attenuating effect of testosterone disappeared upon adding bicalutamide in U118-MG (p&lt;0.001) and A172 (p=0.015) cells, albeit to a lesser extent in U87-MG cells (p=0.085). The combination of bicalutamide and temozolomide showed a synergistic effect in reducing cell viability in all three cell lines.

CONCLUSION
The androgenic pathway modulates sensitivity to temozolomide action in glioblastoma, revealing potential implications for therapeutic strategies in this aggressive brain tumor.
P06.06.A HOXA1, A TRANSCRIPTION FACTOR UPREGULATED IN GLIOBLASTOMA, IS ABLE TO TRAVEL BETWEEN CELLS WITH THEIR NUCLEI AS TARGET
Authors: Vigneul E , Finet M , Bridoux L , Renaux E , Rezsohazy R , Clotman F 
Published: October 2024

Abstract

BACKGROUND
Homeobox A1 (HOXA1) is a transcription factor overexpressed in glioblastoma and an independent prognostic marker. As a transcription factor crucial for proper neural proliferation and differentiation, dysregulated expression of HOXA1 can potentially accelerate glioblastoma growth and invasion. Furthermore, recent publications highlight HOX homeoprotein ability to travel between cells and to potentially alter neighboring cell transcriptional or non-transcriptional mechanisms.

MATERIAL AND METHODS
To investigate HOXA1 intercellular travel and their targeted intracellular compartment, human embryonic kidney 293 cells (HEK 293) and mouse N2a cells (a fast-growing neuroblastoma cell line) were transfected with plasmids containing Flag/V5-HOXA1 and Enhanced Green Fluorescent Protein (EGFP) coding sequences (producing cells), or untransfected (recipient cells). EGFP was used as positive control for transfection and as negative control of intracellular travel. Cell nuclei were marked using 4′,6-diamidino-2-phenylindole (DAPI). Flag immunohistochemistry was performed between 24 and 48 hours after cellular transfection.

RESULTS
Intercellular travel was assessed by immunofluorescence. Since cells were either cotransfected with HOXA1 and EGFP plasmids or untransfected, HoxA1 positive and EGFP-negative cells were considered homeoprotein recipients. On the recipient coverslips, the presence of HoxA1 was detected while EGFP was not, confirming the ability of HoxA1 homeoproteins to travel between cells. Moreover, colocalization with DAPI was detected in the receiving cells, suggesting the ability of HoxA1 to enter the nucleus of the target cells and potentially impact transcriptional mechanisms.

CONCLUSION
These results underscore the possibility for oncogene HoxA1 to be secreted by different types of cells, and to potentially influence the transcriptional activity of the surrounding cells.
P12.10.B HYPOKINETIC MOVEMENT DISORDERS FOLLOWING ADOPTIVE IMMUNOTHERAPY WITH BCMA-DIRECTED CAR T-CELLS: A CONSECUTIVE CASE SERIES
Authors: Gudera J A , Baehring J M , Fulbright R K , Dietrich J , Karschnia P 
Published: October 2024

Abstract

BACKGROUND
Chimeric Antigen Receptor (CAR) T-cells targeting the B-cell maturation antigen (BCMA) represent an emerging immunotherapy for refractory multiple myeloma. While acute neurologic toxicities frequently occur and are well-described, hypokinetic movement disorders are rare and ill-defined. Clinical experience and therapeutic management therefore remain to be elucidated.

MATERIAL AND METHODS
We retrospectively searched the institutional databases from the Sections for Neuro-Oncology at the Yale School of Medicine (New Haven, Connecticut) and the Massachusetts General Hospital (Boston, Massachusetts) to identify patients that presented for evaluation of movement disorders following transfusion of BCMA-directed CAR T-cells.

RESULTS
We identified four patients (females: n = 3, males: n = 1) with complex movement symptoms following transfusion of BCMA-targeting CAR T-cells. At presentation, median age was 74.5 ± 4.3 years (range, 67-77 years). All patients received a single transfusion of a commercially available CAR T-cell product (ciltacabtagene-autoleucel: n = 3; idecabtagene-vicleucel: n = 1). Parkinsonism-like symptoms were generally preceded by mild (maximal ICANS: grade 3) and transient (median duration: 4 days) neurotoxicity.Following resolution of acute neurotoxicity, all patients developed parkinsonism-like symptoms after a median of 23 ± 7 days (range, 19-35 days). Predominant motor symptoms were bradykinesia, oppositional paratonia, postural instability, and hypomimia. Psychiatric involvement was noted in three patients. Consistent with the potential on-target/off-tumor toxicity of the CAR T-cells against BCMA-positive basal ganglia, MRI revealed bilateral hyperintensities in the head of the caudate nucleus on FLAIR/T2-weighted or diffusion-weighted sequences in two patients. [18F]-FDG-PET scans revealed basal ganglia hypometabolism in one patient, diffuse frontal hypometabolism in another, and diffuse hypometabolism in a third patient.As symptoms progressed, treatment for movement symptoms was administered in all patients and included systemic immunosuppression (corticosteroids), interleukin-antagonists, aimed to reduce the number of circulating CAR T-cells (cyclophosphamide, intrathecal methotrexate, cytarabine) or symptomatic treatment (levodopa/carbidopa). At a median follow-up of 115 days (range, 69-198 days), one patient died of sepsis despite aggressive therapy while symptoms stabilized in three patients.

CONCLUSION
Given that parkinsonism-like movement disorders may develop weeks after transfusion of BCMA-directed CAR T cells, a high degree of suspicion is crucial to establish diagnosis. Since symptom stabilization may be achieved, early diagnosis may form the basis for more favorable outcomes. Thus, a multidisciplinary care team appears crucial to provide optimal care of affected patients.
P12.11.A IMMUNOTHERAPY WITH AUTOLOGOUS DENDRITIC CELLS IN THE TREATMENT OF GBM - RESULTS
Authors: Rynda A , Rostovthev D , Olyushin V 
Published: October 2024

Abstract

BACKGROUND
Malignant gliomas are the most common primary brain tumor. Despite the variety of modern treatments, it is still a fatal disease with an extremely poor prognosis. The use of immunotherapy as a technique for the treatment of malignant tumors has great promise, retraining and exploiting the patient’s immune response against tumors. Evaluation of the effectiveness of dendritic cell vaccine in patients with malignant brain gliomas in the structure of complex treatment in comparison with the control group of patients without immunotherapy in the structure of treatment.

MATERIAL AND METHODS
In a single-center, prospective, cohort study, taking place on the basis of the RNSI named after prof. A.L. Polenov, 91 patients with morphologically established malignant glial tumor (glioblastoma) took part. The main group of 41 patients who, in addition to standard treatment (surgical, radiation and chemotherapy), underwent specific antitumor immunotherapy. 50 patients received only standard treatment, without immunotherapy.

RESULTS
Median survival was 21.7 months in the immunotherapy group (95% CI 4-37 months) and 15.8 months (95% CI 3-22 months) in the non-immunotherapy group (p = 0.002). The median relapse-free period in the group with immunotherapy was 13.8 months (95% CI 1-20 months), and in the group without immunotherapy 7.9 months (95% CI 1-12 months) (p = 0.003).

CONCLUSION
In general, the use of immunotherapy in the structure of complex treatment of patients with malignant gliomas demonstrates a clear positive trend in terms of overall survival and median relapse-free period. But nevertheless, immunotherapy requires further development as a therapeutic tool, study and improvement, which will take into account immunosuppression in malignant gliomas and means of overcoming it, optimization in terms of target antigen selection, cell preparation and integration of dendritic vaccines into other treatment regimens.
P12.13.B LOCOREGIONAL BI-SPECIFIC CAR-T CELLS TARGETING CD44 AND CD133 IN RECURRENT GLIOBLASTOMA: THE FIRST IN-HUMAN CLINICAL TRIAL RESULTS
Authors: Zhai Y , Li G , Jiang T , Zhang W 
Published: October 2024

Abstract

BACKGROUND
Recurrent glioblastoma (rGBM) remains no standard of care exists, with a median overall survival of less than 1 year. Here, we report the pre-clinical data and the first four patients with rGBM in a phase I study of locoregionally administration of newly developed tandem CAR-T cell, targeting CD44 and CD133, armored with a modified IL7Ra intracellular domain (Tris-CAR-T).

MATERIAL AND METHODS
Target screening and verification were based on primary glioma stem cells, GBM patient samples, and corresponding sequencing datasets. The antitumor activity of Tris-CAR-T cells was verified in patient-derived tumor stem cells, intracranial xenograft models, GBM patient-derived xenograft models and glioblastoma organoids. Single-cell RNA sequencing and mass spectrometry were used to assess the immune phenotype of Tris-CAR-T cells. The study’s primary outcomes were safety and any adverse events associated with Tris-CAR-T administration. Secondary outcomes include the distribution and persistence of Tris-CAR-T cells, cytokine concentration, and the therapeutic effect according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.

RESULTS
CD44 and CD133 are two inverse-correlated targets. Locoregionally administered Tris-CAR-T cells in vivo induced long-term tumor control with preferable safety. Patient-derived autogenous CAR-T showed robust antitumor capacity in the matched glioblastoma organoid model. All four patients had progressive disease at the time of treatment. At present, the first patient had 1 dose of 107 Tris-CAR-T cells administration, the second patient had multiple doses of 107 Tris-CAR-T cells administration, and the third and fourth patient had multiple doses of 108 Tris-CAR-T cells administration. No neurotoxicity or adverse event greater than grade 2 was observed until now. Radiographic tumor regression or suppression was observed within days after the first dose infusion. The improvement of signs and symptoms were also recorded.

CONCLUSION
The newly constructed Tris-CAR-T cells are capable of GBM suppression with limited side effects. The inspiring early-stage efficacy requires confirmation with subsequent doses of administration, additional patients, biospecimen investigation, and follow-up. The therapeutic response may mainly correlated with tumor burden, product quality, and dose level. ClinicalTrials.gov identifier: NCT05577091.