bluuebunny/crossref_metadata_2025 huggingface dataset:
OS09.6.A METHYLATION CLASSIFICATION AND MOLECULAR LANDSCAPE OF H3 WILDTYPE SPINAL CORD GLIOMA
Authors: Chai R , Chen H , Chang Q , Wang Y , Wang J
Published: October 2024

BACKGROUND

Spinal cord H3-K27M-wildtype gliomas (H3WT-SCG) are rare and heterogeneous tumors whose pathological classification remain challenging.

MATERIAL AND METHODS

We comprehensively characterized 55 H3WT-SCG patients through DNA methylation array, whole-exome/transcriptome sequencing, proteomics, and single-cell RNA sequencing.

RESULTS

Methylation-based classification revealed six molecular classes in the enrolled cohort, including spinal cord pilocytic astrocytomas (PA-SPINE, n=29), normal-like (high-immune, n=10), Diffuse leptomeningeal glioneuronal tumour (DLGNT, n=10), subependymaoma (SUBEPN-SPINE) (n=3), glioblastoma-like (GBM-like, n=2), and pleomorphic xanthoastrocytoma-like (PXA-like) (n=2). To our surprise, the molecular classification is inconsistent with traditional histologic diagnoses in 61.8% of cases, and the most traditional diffuse astrocytoma classified into PA-SPINE (14/24) or normal-like (5/24). We found that compared to traditional methods, methylation-based classification more accurately reflects the molecular features and patient prognosis in H3WT-SCGs, evidenced by the enrichment of BRAF fusions in PA-SPINE and DLGNT (p-value 0.04), and the enrichment of chromosomes 1p loss (p-value 6.5e-08) and 1q gain (p-value 3.6e-05) in DLGNT. The largest subclass, PA-SPINE, can be further divided into adult (older than 18 year old) and pediatric subtypes, with differences in DNA methylation profile. The adult case has lower BRAF fusion frequency (p-value = 1.4e-03), shorter tumor length (p-value = 3.7 e-04) and longer progress-free- survival (p-value = 0.062). Moreover, adult PA-SPINE neoplastic cells exhibited a less differentiated status, characterized by higher expression of EGFR and neuronal markers, as well as lower expression of cytokines and chemokines than pediatric cases. Single cell analysis showed that adult cases demonstrated reduced infiltration of monocyte-derived macrophages and proliferative myeloid cells compared to pediatric cases.

CONCLUSION

This study revealed molecular classes of H3WT-SCGs that precisely reflect the clinical and molecular characteristics of these tumors and further highlight the differences in clinical, molecular, biological, and cellular features between adult and pediatric PA-SPINE.
OS10.4.A CXCL1 MEDIATES LEPTOMENINGEAL METASTASIS GROWTH
Authors: Osman A , Remsik J , Wijetunga A , Snyder J , Manoranjan B , Nobre A , Freret M , Guber D , Chabot K , Piedrafita-Ortiz S , Tong X , Wang H , Li M , Yang J , Boire A
Published: October 2024

BACKGROUND

Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer characterized by the entry of metastatic cancer cells originated from solid or hematologic tumors into the cerebrospinal fluid (CSF)-filled leptomeningeal compartment encasing the brain and the spinal cord. LM occurs in 5-20% in patients with solid tumors, especially those with breast cancer, lung cancer, melanoma. Untreated LM patients succumb within 4-6 weeks after diagnosis, or 2-5 months when they are treated with the current available therapies. To date, the only efficacious life-prolonging intervention was the application of proton craniospinal irradiation (pCSI) as demonstrated in the recent clinical trial, NCT04343573, with an average overall survival of 9 months. While a cohort of pCSI-treated patients survived over 18 months (responders), another cohort did not respond to pCSI and succumbed to the disease within 3 months post-treatment (non-responders). In this project, we aimed to characterize the molecular basis of pCSI response to turn the non-responders into responders.

MATERIAL AND METHODS

We performed proteomic analyses on serially collected CSF from LM patients at baseline (before pCSI), and multiple time points post-treatment. We further established syngeneic mouse models of LM-CSI to define the molecular basis of pCSI resistance.

RESULTS

We found that pCSI resulted in a significant drop in the levels of the chemokine CXCL1, a CXC-motif chemokine with elevated baseline levels after the onset of LM. Patients with significantly higher CSF CXCL1 levels prior to pCSI had worse central nervous system (CNS) progression-free survival. Using our preclinical LM mouse models, we found that both the cancer and host cells, namely macrophages, choroid plexus epithelial cells, and leptomeningeal fibroblasts, were a source of CXCL1. Genetic manipulation of Cxcl1expression in cancer cells or host revealed that the CXCL1 produced by the cancer cells was an essential factor for their growth in the leptomeninges. Moreover, we found that a subset of cancer cells expressed a receptor for CXCL1 - CXCR2 - and transcriptomic profiling of this rare population revealed an enrichment in pathways associated with cell cycle progression. Finally, intrathecally delivered CXCR2 antagonist hampered the LM growth.

CONCLUSION

Our results indicate that CXCL1/CXCR2 signaling axis regulates LM growth and suggests interruption of this signaling axis as a possible actionable therapeutic intervention to halt LM progression.
OS10.6.A THE IMPACT OF PATIENT-REPORT OUTCOME QUESTIONNAIRE PARTICIPATION ON OVERALL SURVIVAL IN PATIENTS WITH BRAIN METASTASES
Authors: David S , Cialdella F , Nagtegaal S H J , van Grinsven E E , Philippens M E P , Verhoeff J J C
Published: October 2024

BACKGROUND

The COIMBRA (NCT05267158) is a prospective, observational study of patients with brain metastases (BMs) which collects extensive longitudinal clinical, radiological and patient-report outcome (PRO) data before and after radiotherapy (RT). After enrollment, patients can make decisions whether to participate in additional data collection, for example in providing Quality of Life (QoL) data. Validated questionnaires, such as the EORTC QLQ-C30 among others, are designed to measure different aspects of QoL of cancer patients and thus gain insights into their mental, physical, and social well-being. In this study, we investigate whether patient consent to filling out QoL-questionnaires has an effect on overall survival (OS).

MATERIAL AND METHODS

We included 377 patients with BMs who were referred for stereotactic radiosurgery (SRS) and enrolled in the COIMBRA study in the UMC Utrecht, between 2019 April to 2023 April. Among them, 276 patients consented to providing PROs, while 101 did not. OS was calculated from the start of RT and analyzed using Kaplan-Meier analysis and Cox regression.

RESULTS

The median OS for patients who consented to PROs was 17.7 months, significantly higher than the 12.3 months for those who did not consent (log-rank test p=0.008). The effect of PRO consent on OS was significant in both univariate (HR = 0.62; p <0.001) and multivariate Cox regression (HR=0.72; p=0.02), the latter correcting for age, KPS, primary cancer type, chemotherapy, surgery, and time from diagnosis to receiving radiotherapy. The 1-, 2- and 5-year survival rates for the PRO consented vs non-consented were: 68% vs 50%; 46% vs 33% and 34% vs 14%, respectively.

CONCLUSION

Our results show a significant relationship between patient consent to filling out PRO questionnaires and longer OS in patients with BMs undergoing SRS. This suggests that patient engagement, as measured by willingness to participate in PROs, may be indicative of broader health behaviors linked to improved survival. However, it is important to consider that the act of participation could itself be influenced by underlying factors we did not investigate, which may predispose patients to both decreased engagement and worse outcomes. For example, factors such as lower levels of overall health literacy, lower socioeconomic status, the distribution of the lesions might contribute to lower participation and independently affect survival outcomes. Therefore, while fostering patient engagement remains a promising approach to enhance study involvement, our understanding of the complex interplay between patient characteristics and their participation in care processes must be further studied. These results may indicate that any study for which active patient participation is required might thereby introduce a selection bias for patients with better overall health and expected survival.
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

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

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 > 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 <= 10.3 10-15L, p = 0.028. Similarly, shorter OS was recorded in patients with PT ratio > 1.01 (p=0.006), and PC out-of-range 165-300 109/L (p=0.026). A subgroup analysis of patients > 65 years confirmed baseline MPV > 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

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

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

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<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<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

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

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

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

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.
P12.16.A PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN A WOMEN TREATED BY DARATUMUMAB AND LENALIDOMIDE FOR A MULTIPLE MYELOMA: A CASE REPORT
Authors: Silva Gomes A , Perlot Q , D’Aout C
Published: October 2024

Progressive multifocal leukoencephalopathy (PML) is a potentially fatal demyelinating disease of the central nervous system caused by reactivation of the John Cunningham virus (JCV) and occurs mainly in immunocompromised patients with lymphoproliferative and myeloproliferative disorders, human immunodeficiency virus (HIV) infection or immunomodulatory therapy. The aim of this article is to present the atypical case of a 72-year-old woman with IgG-kappa multiple myeloma (MM) treated with DRD (D: daratumumab; R: lenalidomide; D: dexamethasone), who was admitted to our neurology department in August 2023 after developing left hemiparesis and gait disorder within a few weeks after 2 years of treatment. A preliminary brain magnetic resonance imaging (MRI) revealed the presence of multiple hyperintense white matter lesions on fluid attenuated inversion recovery (FLAIR), with a predilection for the cerebellum, brainstem bridge and right temporal lobe. Despite a comprehensive workup that included an initial lumbar puncture, the precise etiology of the lesions remained elusive. Clinical improvement enabled the patient to be discharged home, but she was subsequently readmitted to the hospital due to the onset of a major cerebellar syndrome. An increase in leukopathy was demonstrated on cerebral MRI, with a particular focus on the cerebellar region. Suspecting PML, a second lumbar puncture was performed and the polymerase chain reaction (PCR) was positive for JCV. Sadly, despite the administration of an experimental therapy, the patient died within weeks of diagnosis. The literature reports several cases of PML associated with therapies used in MM, including lenalidomide and daratumumab. However, to the best of our knowledge, only one case has been described under the DRD regimen by Seko et al. In conclusion, it is crucial to increase clinical surveillance in patients receiving DRD therapy in order to promptly identify any potential neurological deterioration. Furthermore, it is vital to screen for the possibility of PML, an extremely rare but serious complication of this treatment, and to promptly discontinue the therapy in the event of its occurrence.
P12.17.B SHAPING THE IMMUNE LANDSCAPE - ROLE OF NEO(ADJUVANT) CHECKPOINT INHIBITION IN RECURRENT GLIOBLASTOMA
Authors: Krenzlin H , Dauth A , Corr F , Wagner E , Ubbens H , Sommer C , Alessandri B , Ringel F , Keric N
Published: October 2024

BACKGROUND

In recurrent glioblastoma treatment options are limited. Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. Although ineffective as adjuvant monotherapy in glioblastoma, Pembrolizumab, an anti-PD-1 monoclonal antibody, might be valuable during a neo-adjuvant window of opportunity and in addition to alkylating chemotherapy in patients with recurrent glioblastoma.

METHODS

In this study, 10 patients with recurrent IDH wild-type glioblastoma (CNS WHO grade 4) scheduled for surgical debulking were treated with Pembrolizumab prior to resection. CPI was continued together with Lomustine/CCNU after surgery. Patients with resection and adjuvant CCNU alone served as controls. Eligibility criteria included Eastern Conference Cooperative Oncology Group (ECOG) Score ≤2, first line therapy with at chemo-radiotherapy, unequivocal evidence of tumor progression. Patients received pembrolizumab 200 mg intravenous infusions 14 ± 5 days prior to- and every three weeks after re-surgery additionally to CCNU (up to six-week cycles). NCI-CTCAE 5.0 was used to evaluate adverse events. To examine CPI induced changes, transcriptome sequencing (RNAseq), T-cell receptor sequencing in tumor samples and detection of inflammatory cytokines (Il-1a, Il-1b, Il-6, Il-8, TNF-a, IFN-y, MCAF, GM-CSF) in blood using ELISA and qPCR, was performed.

RESULTS

Median age was 58.7 years (43-74 years) in controls and 54.9 years (33-68 years) in those with neo(adjuvant) CPI. Female:male ratio was 4:1. Complete resection was achieved in 70.0%, gross total resection in 10.0%, partial resection in 10.0% and biopsy in 10.0%. A total of 10 neoadjuvant and 24 adjuvant cycles of CPI were given. PFS (12.9±3.6 months; p=0.001) and OS (32.4±6.5 months; p=0.028) was improved in patients with neoadjuvant CPI compared to controls. Fever associated with CPI occurred in 2 patients. No severe adverse occurred. Neo(adjuvant) CPI led to increased IFN-y serum levels (p=0.0057). Using NGS analysis, improved OS was associated with higher number of tumor infiltrating NK cells (p = 0.0264), M1 macrophages (p = 0.029) and TCR clonality (p = 0.0002). NK cell infiltration was higher in patients treated with neoadjuvant CPI (p=0.001). However, no longitudinal transcriptome changes occurred between primary and relapse regarding the immune contexture, TCR diversity (p=0.69) or clonality (p=0.85).

CONCLUSION

Neoadjuvant checkpoint inhibition is well tolerated and associated with distinct changes to tumor transcriptome and immune milieu leading to prolonged overall survival. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficient approach to the salvage treatment of this uniformly lethal tumor.
P13.14.A REPEATED TREATMENT-ASSOCIATED CHANGES IN PATIENTS WITH A DIFFUSE GLIOMA
Authors: Mechroubi A , Flies C M , Dankbaar J W , Verhoeff J J C , Robe P A , Snijders T J
Published: October 2024

BACKGROUND

Radiological and clinical progression after treatment of patients with a diffuse glioma can be caused by progressive disease (PD) or be an effect of treatment-associated changes/pseudoprogression. These changes may occur more than once in the same patient, but data on such repeated changes are scarce. The goal of this study is to investigate the incidence of repeated treatment-associated changes, as well as the associated clinical and radiological characteristics.

MATERIAL AND METHODS

In this retrospective mono-centre cohort study, patients with a diffuse glioma (WHO grade 2-4) who were treated with (chemo-)radiation and who developed treatment-associated changes afterwards were included. We reviewed the patient files to identify patients with more than 1 episode of treatment-associated changes. An episode of treatment-associated changes was defined either radiologically, as new or increasing contrast-enhancement (CE) on MRI that subsequently stabilised for ≥12 weeks or regressed for ≥1 month, or histologically, as treatment-associated changes without proliferating tumour. We searched for predictors for repeated treatment-associated changes with univariable odds ratios (OR) and compared the survival between patients with a single versus repeated episodes of treatment-associated changes.

RESULTS

Of 176 patients with treatment-associated changes, 58 patients (33%) developed 174 repeated episodes, of which 21% were confirmed by histopathology. Most patients (54%) had an IDH-wildtype glioblastoma. The first episode started one month after radiotherapy (median; interquartile range IQR, 0-11). The median duration of the radiological episodes was 32 weeks (IQR, 24.5-60). An oligodendroglioma grade 3 tumour type and an IDH-mutation compared to IDH-wildtype glioblastomas were positive predictors for repeated treatment-associated changes (OR, 8.8 and 5.0; both p, <0.001; 95%-CI, 2.1-37.1 and 2.2-11.6). Furthermore, a higher age was a protector against repeated treatment-associated changes (OR, 0.97; p, 0.018; 95%-CI, 0.94-0.99). MGMT promoter methylation or treatment characteristics (temozolomide, extent of resection, radiation dose) had no predictive value. Survival was longer in patients with repeated episodes compared to patients with one episode. Most of the patients had two to three episodes (N=48), but four to seven were also reported (N=10).

CONCLUSION

Repeated treatment-associated changes are common in patients with a diffuse glioma after a first confirmed episode, and are associated with prolonged survival. If there is a new or increasing CE lesion seen on the MRI of a patient after a previous episode of treatment-associated changes, physicians should consider the possibility of repeated treatment-associated changes.

SUPPORT

The foundations Stophersenkanker.nu and Vrienden UMC Utrecht supported this study.
P14.06.B ADVANCES IN INTRAOPERATIVE MAPPING AND VISUALIZATION TECHNIQUES FOR HIGH-GRADE GLIOMA RESECTION: AN UPDATE ON CONTRAST AGENTS AND EMERGING STRATEGIES
Authors: Dib C , Zaatar J , El Ghawi O , Khalil J , Saroufine K , Elias L , Alagha M , Sayegh M , El Khoury J , Moubayed I , Tout M
Published: October 2024

BACKGROUND

Brain tumor mapping is crucial for achieving optimal resection, particularly for deep-seated tumors near eloquent areas. Although preoperative contrast-enhanced imaging guides neurosurgeons, its reliability diminishes intraoperatively, necessitating real-time methods for delineating tumor margins. Numerous novel contrast agents and imaging modalities are being investigated for intraoperative visualization of high-grade gliomas (HGG).

MATERIAL AND METHODS

A narrative review was conducted using the PubMed database to gather review articles and clinical trials published within the past 10 years that focus on the intraoperative use of diverse contrast agents and imaging techniques that guide HGG resection. Search terms included “high-grade glioma”, “contrast agents”, “intraoperative mapping”, and “image-guided tumor resection”.

RESULTS

Fluorescein sodium (FNa), an affordable and safe fluorescent agent, can be intravenously administered during incision. When combined with preoperative imaging, it achieved an 81% gross total resection rate in HGG patients, surpassing the 74% rate associated with the more costly and specific oral fluorescent agent, 5-aminolevulinic acid (5-ALA). Indocyanine green (ICG), a near-infrared (NIR) fluorescent agent, accumulates in highly vascular tumors. Recent studies suggest its efficiency matches that of fluorescein and 5-ALA in tumor localization. However, ICG, particularly in the second near-infrared window (NIR-II), is better suited for identifying necrotic areas and residual tumor cells, especially in deep tumors. Furthermore, the application of methylene blue staining on resected gliomas has yielded promising outcomes, suggesting its potential utility in intraoperative tumor detection. Additionally, contrast-enhanced ultrasonography is a novel and highly specific approach that combines ultrasound with unique intravascular contrast agents to pinpoint tumor localization and vascularity.

CONCLUSION

Current evidence supports the intraoperative utilization of various contrast agents like FNa, 5-ALA, and ICG during resection of HGG, particularly when integrated with other pre and intraoperative imaging techniques. Nevertheless, their efficacy may be limited by factors such as potential adverse effects, variability in tissue uptake, and the need for specialized equipment and skills to ensure their optimal use. Also, novel approaches such as contrast-enhanced ultrasonography offered promising early results, but further research is needed to study its impact on surgical outcomes.
P14.07.A BLOOD-BRAIN BARRIER DISRUPTION FOLLOWING MR-GUIDED LASER INTERSTITIAL THERMAL THERAPY
Authors: Nielsen S H , Skjøth-Rasmussen J , Larsen V A , Carlsen J F , Rasmussen R , Hansen A E
Published: October 2024

BACKGROUND

MR-guided Laser Interstitial Thermal Therapy (MRgLITT) is a minimally invasive neurosurgical treatment that was recently introduced in Europe for managing newly diagnosed and recurrent gliomas, as well as drug-resistant epilepsy (DRE). Emerging research suggests that MRgLITT facilitates localized disruption of the blood-brain barrier (BBB) surrounding the lesion. In this study, we investigated the effects of MRgLITT on BBB permeability using perfusion MRI and biochemical markers.

MATERIAL AND METHODS

Twenty-five patients referred for MRgLITT were prospectively included: 12 with brain tumors and 13 with DRE. To assess the integrity of the BBB, we employed Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) one day preoperatively, and on days 1, 15, 30, and 45 postoperatively. Concurrently, we collected blood samples at these time points to evaluate biomarkers indicative of BBB integrity and circulating tumor DNA.

RESULTS

Quantitative analysis using DCE-MRI revealed a significant postoperative increase in regional BBB permeability on days 15, 30, and 45 (p < 0.005), as measured by the permeability constant (Ki) in both patient groups. However, no significant change in permeability was observed on the first postoperative day. Permeability reached its maximum between days 15 and 30 following MRgLITT and remained high on day 45, at 70% of the maximum.

CONCLUSIONS

Our findings confirm the existence of a therapeutic window lasting several weeks, during which the blood-brain barrier (BBB) opens in response to laser ablation. This temporal pattern lays a foundation for designing future clinical trials that aim to integrate MRgLITT with adjuvant antitumor therapies. Such trials could exploit the period of elevated BBB permeability to enhance the delivery and efficacy of therapeutic agents, thereby advancing treatment strategies for brain tumor patients.
P14.09.A DIFFUSION MICROSTRUCTURE IMAGING AS A DIAGNOSTIC CORRELATE OF HISTOMORPHOLOGY: ASSESSMENT ACROSS THE MOST COMMON INTRACRANIAL TUMOR ENTITIES
Authors: Würtemberger U , Erny D , Reisert M , Kiselev V G , Beck J , von Elverfeldt D , Prinz M , Urbach H , Demerath T , Diebold M
Published: October 2024

BACKGROUND

Distinct histomorphologic features differentiate the four most common intracranial neoplasms: meningioma, metastasis, glioblastoma, and primary CNS lymphoma. Utilizing advanced diffusion imaging, we explore how non-invasive assessment of microstructural tumor characteristics can provide insights into intratumoral morphology and may guide further diagnostic strategies.

MATERIAL AND METHODS

101 newly diagnosed intracranial tumors (35 metastases, 34 glioblastomas, 21 meningiomas, 11 primary CNS lymphomas) underwent advanced diffusion imaging including Diffusion Tensor Imaging (DTI), Neurite Orientation and Dispersion Imaging (NODDI), and Diffusion microstructure Imaging (DMI) at 3 Tesla. In addition to DTI-derived estimates about the directionality and extent of diffusion, the biophysically motivated diffusion NODDI and DMI allowed subdivision of voxels into an intra-axonal (NODDI ICVF, DMI V-intra), extra-axonal cellular (DMI V-extra) and a free water (NODDI ISO-VF, DMI V-CSF) fraction using a multi-compartment model. We evaluated segmented contrast-enhancing tumor areas in relation to confirmed definitive diagnoses and histomorphology based on correlated biopsy material. Ultrahigh resolution microstructure analysis of selected pre-fixated tumor tissue samples at 9.4 Tesla is used to test association of distinct diffusion parameters with histomorphological characteristics of tissue compartments, heterogeneity, directionality, axonal preservation and cell type.

RESULTS

Pairwise comparison of tumor entities identified distinct diffusion metrics encompassing the different diffusion techniques as ideal discriminators for each two tumor entities. Differentiation of glioblastoma and meningioma was best achieved by the intracellular compartment (DMI V-intra, p = 0.005) and NODDI-ICVF (p = 0.0008). Likewise, glioblastoma and metastasis were discriminated by the extracellular compartment (DMI V-extra, p = 0.002) and DTI-OD (p = 0.00008[DTD1] ), glioblastoma and primary CNS lymphoma by the CSF compartment (DMI V-CSF, p = 0.002) and DTI-aD (p = 0.00005), meningioma and metastasis by the CSF compartment (DMI V-CSF, p = 0.0002) and NODDI-ISOVF (p = 0.0007), and metastasis and primary CNS lymphoma by the CSF compartment (DMI V-CSF, 0.00004) and NODDI-ISOVF (p < 0.00001). Spatial distribution of the DMI discriminators within tissue blocks were correlated with histomorphological features at ultrahigh resolution.

CONCLUSION

Multiparametric diffusion imaging enables distinguishing between the four most common intracranial neoplasms. It could serve as a non-invasive approach for estimating histomorphological tumor features and intratumoral compartments during the initial diagnostic evaluation and thus potentially guide further diagnostic and therapeutic procedures.