bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract

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

Abstract

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, &lt;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

Abstract

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

Abstract

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 &lt; 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

Abstract

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

Abstract

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

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

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

CONCLUSION
Glioma vaccines show promise in stimulating immune responses against tumours, offering potential benefits alongside standard treatments. Challenges in assessing vaccine efficacy and addressing treatment-related adverse effects emphasise the need for further research and clinical trials. Challenges like tumour heterogeneity and immune evasion persist, but advances in genetic engineering and immunotherapy offer hope for enhancing vaccine efficacy. Collaboration across disciplines is essential for translating these advances into effective glioma treatments.
P16.06.B PROTEOMIC ANALYSIS OF PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS
Authors: Ferreyra Vega S , Carén H 
Published: October 2024

Abstract

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

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

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

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

Abstract

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

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

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

CONCLUSION
These results show that dendritic cell biology in response to tumours differs in the brain compared to extracranial tumors and suggest promising avenues for dendritic cell related therapies that may be specific to intracranial tumours.