tbuckley/cabot-search huggingface dataset:
JS08.7.A SURGERY TRANSIENTLY DISRUPTS THE BLOOD BRAIN BARRIER OF THE GLIOBLASTOMA RESECTION MARGIN: OPPORTUNITIES FOR EARLY AND SELECTIVE POSTOPERATIVE TREATMENT
Authors: L F Fernandes, N Lozano, C Peeyatu, Y Ho, L Thompson, K Kostarelos, T Kisby
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Resection surgery is the first line therapy for glioblastoma (GBM) that is performed in &amp;gt;70% of patients typically within days of suspected, MRI-based diagnosis. Current standard protocols for follow-on chemo/radiotherapy have shown only modest efficacy in eliminating residual disease, with inevitable tumour recurrence. There remains a need to develop new approaches to swiftly and effectively treat post-operative residual disease to prevent the rapid progression of recurrent GBM. MATERIAL AND METHODS Using two syngeneic preclinical models of glioblastoma resection/recurrence (GL261 and IDH-WT glioma neurospheres), we identified a spatially and temporally restricted window of resection margin-localized blood brain barrier (BBB) disruption during the immediate and early postoperative periods. This was mapped overtime by intravenous administration of fluorescently labelled lipid nanoparticles (LNPs) and using a combination of in vivo and ex vivo imaging modalities. RESULTS LNPs showed a selective accumulation at the postoperative resection margin site while largely being excluded from areas of the brain with an intact BBB. From longitudinal assessment of this phenomenon, we identified a biphasic increase in LNP accumulation whereby initial BBB disruption appeared to be mediated by the surgical procedure itself (minutes post-surgery), whereas a second temporary period of disruption (2-3 days after surgery) presumably driven by a post-operative inflammatory tissue response and remodelling. Confocal analysis confirmed the presence of extravasated LNPs in the parenchyma which largely interacted with glial populations that closely associated with residual tumour tissue. Exploiting this, we performed early intravenous administration of doxorubicin chemotherapy loaded LNPs coinciding with the peak of postoperative BBB disruption and demonstrated complete inhibition of tumour recurrence from a single administration. In contrast, late administration of doxorubicin LNPs (in line with the typical clinical post-operative treatment schedule) did not achieve such profound efficacy. Notably, administration of doxorubicin alone (not encapsulated in LNP) also did not show significant efficacy highlighting the importance of this selective nanocarrier in combination with BBB disruption. CONCLUSION Overall, this work underscores the importance of this early post-operative timeframe for margin/residual disease selective treatments that may have been overlooked in most trials of experimental GBM medicines. Furthermore, this demonstrates that clinically approved nanomedicines could be readily repurposed for early post-operative therapy in aggressive brain tumours. Further work is warranted to develop novel nanoparticle enabled approaches for the early treatment of residual GBM toward overcoming this longstanding clinical need.
PL01.4.A COMPUTATIONAL HISTOPATHOLOGY ENABLES HIGH-GRANULARITY DIAGNOSTICS IN CNS TUMOURS
Authors: A Shmatko, D Jin, A Patel, R Rahmanzade, W Wick, S Krieg, S M Pfister, D T W Jones, A von Deimling, M Gerstung, F Sahm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The recent WHO classification of CNS tumours has increased the number of molecular markers recommended for making a WHO-compatible diagnosis. Particularly, DNA methylation-based classification pioneered by the Heidelberg MNP classifier has emerged as a powerful tool for CNS tumour diagnostics. However, high costs, both in terms of time and resources, along with the need for skilled personnel and expensive equipment, have limited the adoption of such techniques to larger centres. Computational methods like deep learning have proven useful in tasks such as tumour subtyping, identifying genetic alterations and predicting treatment responses. The recent advent of self-supervised learning and multiple-instance learning (MIL) has enhanced the accuracy and generalisation of these models, simultaneously reducing the dataset size requirements, thus bringing computational histopathology closer to clinical applications. MATERIAL AND METHODS To enable broader accessibility of precision diagnostics for CNS tumours and alleviate the need for molecular profiling, we introduce Paiean (Precision AI-enabled Neuropathology) - a computational histopathology pipeline that predicts the diagnostically relevant classes in line with the Heidelberg MNP classifier using only H&amp;E stained whole-slide images (WSI). We designed a neural network architecture implemented in a MIL paradigm. Paiean employs a CTransPath pretrained feature extractor to identify and analyse relevant histological patterns and was fine-tuned on an in-house dataset of CNS tissue WSIs using the MoCo v3 contrastive objective. We trained the model on a dataset of 8,000 H&amp;E stained FFPE WSIs with matched methylation data from the Dept. of Neuropathology, University Hospital Heidelberg. We validated the model on 5 independent external datasets. Additionally, we compared the model to evaluations by 9 board-certified pathologists from across the world. RESULTS Paiean could reliably predict 108 classes of CNS tumours in 72.19% cases. Moreover, for high-confidence predictions (confidence &amp;gt; 0.5), the accuracy increased to 87.52%. We achieved an accuracy of 65.12% on the multi-center external datasets. The model outperformed the human evaluators by an average of 30.17%. CONCLUSION Our work demonstrates that deep learning can supplement conventional methods for molecular diagnostics in CNS tumours. Paiean requires only H&amp;E WSI, covers 108 diagnostically relevant tumour types and has a turnaround time of under an hour from sample to result. We provide an interface that can be easily run on consumer-grade hardware without extensive bioinformatics expertise. Since H&amp;E slides are readily used in routine tumour diagnostics worldwide, Paiean presents a rapid and cost-effective tool to incorporate molecular information into diagnostic decisions, thereby making precision medicine accessible worldwide.
P02.03.A BLOOD-BRAIN BARRIER AFFECTING THE METABOLOMICS PROFILES IN THE TUMOR MICROENVIRONMENT, CSF AND BLOOD OF IN VIVO HUMAN GLIOBLASTOMA XENOGRAFT
Authors: T Altendorfer-Kroath, D Schimek, F Monedeiro, E Zügner, E Prugger, C Magnes, T Birngruber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Detection of glioblastoma (GBM) before clinical signs appear can significantly improve treatment outcome and patients’ quality of life. To date, there are various biomarker candidates for early detection of GBM but most of them can only be detected in cerebrospinal fluid (CSF) and in brain tissue biopsies. Brain tissue biopsies are very rarely taken in routine hospital practice while CSF or blood samples are part of the standard clinical routine in hospitals. However, no reliable biomarker has yet been identified for the early detection of most central nervous system (CNS) tumors in liquid biopsies, probably due to the limited ability of the biomarkers to cross the blood-brain barrier (BBB). In contrast to blood, CSF provides good access to the CNS. However, previous studies on pharmacokinetics of CSF and the interstitial fluid in the brain tissue (ISF) have shown that the equilibrium between the CSF and the ISF is slow and substance concentrations in the CSF do not reflect the concentrations that are locally present in brain tissue. We aimed to assess the metabolome from ISF collected with Open Flow Microperfusion (cOFM) from the tumor microenvironment (TME), CSF and blood from human GBM-bearing animals and compare it to respective samples collected from non-GBM-bearing animals (non-GBM controls) in order to identify potential metabolic biomarker or biomarker profiles that reflect the local situation of the TME. MATERIAL AND METHODS We applied a recently established atraumatic access to human GBM xenograft with cOFM that allows sampling of metabolites inside the TME with functional BBB. Tumor growth was monitored with magnetic-resonance-imaging. On day 18 post-inoculation, ISF from TME was collected with cOFM and blood, CSF and brain tissue were collected from the same animals at terminal time point. The collected samples were analyzed using a UHPLC-HRMS/MS metabolomics platform. Metabolomics data from GBM-bearing animals were analyzed and compared with that from non-GBM controls. RESULTS The metabolome from the GBM-bearing animals showed distinct metabolic patterns when compared to that from the non-GBM controls. GBM-relevant metabolites such as Kynurenine, Carnosine or Guanidinoacetate exhibited different levels in ISF from GBM-bearing animals than in CSF or blood samples from these mice. CONCLUSION This suggests that the BBB plays an important role when obtaining biomarkers from CSF or blood as it might affect the assessment of the local condition in the TME.
OS07.2.A INTEGRATED SPATIALLY RESOLVED TRANSCRIPTOMICS AND ELECTROPHYSIOLOGY UNRAVELED THE ARCHITECTURAL HETEROGENEITY OF NEURONAL-GLIOMA INTERFACES
Authors: E Grabis, L Hilfiger, J Kueckelhaus, N Neidert, J Zhang, G Villa, Y Yabo, J Benotmane, M Prinz, F Ricklefs, J Beck, O Schnell, A Vlachos, D Delev, D Heiland
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In recent years, spatially resolved, high-dimensional methodologies have elucidated substantial transcriptional heterogeneity within malignant brain tumors. However, the absence of functional readouts has impeded the linkage of emergent insights from cancer neuroscience to the structural heterogeneity observed. To address these challenges, we developed a novel methodology that combines spatially resolved electrophysiological recordings with array-based transcriptomics on surgical specimens. This approach enables an exploration of the transcriptional underpinnings of electrophysiological network communication in glioblastoma. MATERIAL AND METHODS We analyzed 12 surgical glioblastoma specimens, which were sectioned (350µm) and subjected to high-resolution multi-electrode array (HD-MEA) recordings (64 x 64 pillar electrodes at a 2µm resolution, 3Brain), followed by spatially resolved transcriptomics (at a 55µm resolution, Visium). Data co-registration was achieved through affine transformations and postprocessing using SPATA2 (github.com/theMILOlab/SPATA2). RESULTS Utilizing graph-based analysis, we identified prominent communication hubs and prevalent signaling pathways within tumor and peritumoral areas. Horizontal and vertical integration across these data modalities, combined with latent-space clustering, revealed spatial heterogeneity in electrophysiological communication and transcriptional responses. Notably, regions of infiltrative growth and tumor borders exhibited enhanced neuronal-glioma interactions, characterized by transcriptional up-regulation of synaptogenic signaling and a predominant presence of oligodendrocyte progenitor cell (OPC)- and neural progenitor cell (NPC)-like tumor cells. These regions displayed distinct, repetitive spatial signaling patterns. Conversely, areas with heightened inflammatory responses, marked by macrophage and T cell enrichment, as well as hypoxic alterations, demonstrated a lack of coherent communication patterns. Tumor peripheries with increased astrocytic presence or activated microglia exhibited diminished communication between tumor and neuronal systems compared to infiltrative areas with elevated oligodendrocytic abundance, underscoring the critical role of oligodendrocytes in facilitating neuronal-glioma communication. CONCLUSION Our investigations into the electrophysiological and transcriptomic architecture of gliomas provide novel insights into the intricate heterogeneity of the neuronal-glioma interface and identify key regulatory elements that drive the integration of glioma within neuronal circuits.
KS03.6.A TUMOR-SPECIFIC B CELL RESPONSE IN THE CEREBROSPINAL FLUID OF MELANOMA PATIENTS: RECOMBINANT ANTIBODIES SPECIFICALLY BIND TO THE TUMOR-ASSOCIATED ANTIGENS DDX53, AKR1A AND KIFC3
Authors: S Schembecker, N Vasilenko, C Ruschil, M C Kowarik
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningeosis carcinomatosa is a diffuse dissemination of tumor cells in the cerebrospinal fluid (CSF) and/or meninges and occurs in around 5% of patients with malignant melanoma. In previous studies on CSF immune cell subsets an elevated CSF B cell fraction was found in a subset of melanoma patients with leptomeningeal spread. Elevated CSF B cells are mostly associated with neuro-inflammatory diseases and are largely absent during physiological conditions. Hence this study aims to assess if these CSF B cells resemble an intrathecal tumor-specific immune reaction and to test CSF B cell derived recombinant antibodies for tumor specificity from these melanoma patients. METHODS Three melanoma patients with leptomeningeal spread and a presumable CSF B cell reaction were selected by analyzing CSF parameters including intrathecal immunoglobulin (Ig) synthesis. Single cell sorting of CSF B cells was performed followed by conventional sequencing of Ig heavy and light chain transcripts. 13 recombinant antibodies were generated from CSF B cells and were tested for antigen specificity using antigen microarrays, FACS, ELISA and immunocytochemistry as well as bioinformatic tools for binding predictions. RESULTS By applying single cell analysis on CSF B cells, representative Ig transcriptome repertoires were obtained. CSF Ig repertoires showed features of a clonal expansion and multiple mutations to germline. These mutations were specifically found in the complementary determining regions suggesting an antigen stimulated affinity maturation within the CSF compartment. By systematic microarrays, the number of potential antigen targets was narrowed down and further evaluated by binding properties of each individual antibody to a well characterized melanoma cell line. Using FACS and immunocytochemistry on the melanoma cell line, antibody binding was confirmed for a subset of antibodies. In custom made ELISA tests, the specific binding of three antibodies to the individual proteins AKR1A1, KIFC3 and DDX53, a known cancer-testis antigen, was detected. Furthermore, potential binding epitopes for these three antibodies were characterized. CONCLUSION In summary, this study shows evidence for a targeted intrathecal B cell reaction with features of a clonally expanded CSF B cell population in melanoma patients with meningeal carcinomatosis. Specific antibody binding against the targets AKR1A1, KIFC3 and DDX53 was confirmed for three antibodies indicating that these antibodies are indeed tumor-specific and might represent a B cell response against the tumor cells. These antibodies and their corresponding tumor antigens may be extremely useful as they appear to be sufficiently immunogenic to elicit an immune response and thus may be utilized for tumor treatments. GRANTS AND FELLOWSHIPS This study was funded by the DFG (GZ: KO 4367/5-1; AOBJ: 692835; Projektnummer: 517964704).
P18.42.B TAU AND AMYLOID BETA PATHOLOGY IN IDH-MUTANT GLIOMA
Authors: L Greutter, S Klotz, L Schnitzenlehner, B Kiesel, Y Miller-Michlits, J Makoli, E Krause, G Widhalm, B Baumann, A Woehrer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND With an aging population the incidence of brain tumors and neurodegenerative diseases is increasing. Although biological associations between glioma and Alzheimer’s disease (AD) have been suggested, the frequency of comorbidity is insufficiently defined. We here screen tumor-adjacent cortex of a representative cohort of patients with low grade glioma for AD neuropathological changes (ADNC) specifically for phosphorylated tau (pTau) and amyloid beta (Abeta) deposition, microglial activation, amyloid precursor protein (APP) expression, diffuse axonal injury, and cortical tumor cell infiltration. MATERIAL AND METHODS A total of 85 patients with astrocytoma, IDH mutant, CNS-WHO grade 2-3, (N=37, median age: 39) and oligodendroglioma, IDH mutant and 1p-19q co-deleted, CNS-WHO grades 2-3 (N=48 median age: 50) were included. 2µm sections were immunohistochemically stained for the markers b-A4, t-AT8, NeuN, APP and Iba1. Whole slide quantification was performed using Matlab and QuPath codes. For a subset of 15 patients, longitudinal samples were available for analysis of post-treatment effects. RESULTS The median cell density in the tumor-adjacent cortex was 1355/mm2 for astrocytoma and 1392/mm2 for oligodendroglioma, which was significantly higher than in non-tumor infiltrated cortex (median: 1030 cells/mm², p-value&amp;lt;0.0001). A total of 32 patients (38%) showed Abeta (14%, n=12/85) and/or pTau pathology (36%, n=31/85) in the tumor-adjacent cortex. No difference between astrocytoma and oligodendroglioma was reported. ADNC was mostly frequently observed in older patients but was also present in young individuals (median: 34 years, range: 17 to 77 years). pTau was significantly positively correlated with tumor cell infiltration (Kendall´s tau=0.13, p=0.002). Both Abeta and pTau deposits were frequently observed in the frontal cortex (30%, N=18/60). The tumor infiltration into the cortical regions was associated with neuronal loss (Kendall´s tau=-0.29, p&amp;lt;0.0001). Microglial activation depended on the degree of tumor infiltration (R=0.29), followed by increasing patient age (R=0.12). Diffuse axonal injury was associated with ADNC (Chi²=19.6, p&amp;lt;0.05). APP expression of tumor cells was highest in patients of old age (R=0.35). Longitudinal samples showed stable ANDC pathology in 15/15 subjects. CONCLUSION Our preliminary findings suggest presence of ADNC in roughly a third of patients with low-grade glioma, which increases with tumor cell infiltration into the cortex, microglial activation and patient age. Notably, isolated pTau pathology was more pronounced than Abeta pathology suggesting the acquisition of a secondary tauopathy.
P22.12.B PREDICTION OF QOL IN PATIENTS WITH IDH-MUTATED GLIOMAS, BEFORE AND ONE YEAR AFTER TREATMENT
Authors: I Ryden, S Malmqvist, P Hellström, T Gomez Vecchio, A Smits, A Store Jakola
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND IDH-mutated gliomas are primary brain tumours that typically affect relatively young individuals. As survival rates have increased due to changes in treatment strategies, maintaining health-related quality of life (HRQoL) has become more significant. This study will investigate factors influencing HRQoL in patients with IDH-mutated gliomas. MATERIAL AND METHODS Patients undergoing surgery (biopsy/resection) for a presumed IDH-mutated glioma between January 2017 to August 2024 were asked to do a neuropsychological assessment and fill out HRQoL questionnaires. As to this date, inclusion is not finished, and analyses based on molecular subgroups are not yet available. Results presented at the conference will be update. This abstract presents preliminary results for patients included so far (n=96). Two overlapping groups were created based on data availability: a preoperative (preop) group (n=85) and a 12-month postoperative (postop) group (n=71). HRQoL was assessed using the EORTC QLQ-C30 global health status. Tumour-specific, treatment-specific, cognitive, and psychological factors were identified as potential predictors, and hierarchical regression analysis was used for each group. Further analyses were conducted to compare HRQoL with the general population and to explore the most significant predictors. RESULTS In the preop group, anxiety levels (Hospital Anxiety and Depression Scale) were significantly associated with HRQoL, explaining 34 % of the variance. In the postop group, radiation therapy was initially associated with lower HRQoL, explaining 7 % of the variance, but this association was not significant in subsequent analyses. Instead, cognitive impairment (no/mild vs. moderate/severe) and anxiety levels were significant predictors of lower HRQoL, accounting for 61% of the variance, with anxiety being the stronger predictor. Compared to the general population (M = 76.3, SD = 21.8), HRQoL was significantly lower in both preop (M = 56.81, SD = 23.47, t = -7.38, p&amp;lt;.001, d = 0.86) and postop groups (M = 64.81, SD = 24.68, t = -3.98, p&amp;lt;.001, d = 0.50). A significant proportion of patients scored above the lower cut-off for anxiety: 53 % in the preop group (27 % above the pathological cut-off) and 30 % in the postop group (18 % above the pathological cut-off). CONCLUSION Patients with LGG reported lower HRQoL compared to the general population. Anxiety and cognitive impairment are key factors affecting HRQoL, with anxiety being the strongest predictor. These findings underscore the need to screen for psychological symptoms and evaluate cognitive functioning. In addition, they suggest key areas for rehabilitation to help improve HRQoL in patients with IDH-mutated gliomas.
OS04.5.A SEXUALITY IN PATIENTS WITH LOW-GRADE GLIOMAS
Authors: A M Buunk, F F Siebenga, M H Bosma-Bleeker, J M Spikman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients diagnosed with a low-grade glioma (LGG) face various challenges that influence their daily functioning, such as mood disorders, cognitive decline and fatigue. However, little is known about problems concerning sexuality and intimacy in patients with LGG, although these can have a profound negative impact on quality of life and well-being. Also, related factors (disease characteristics, cognitive functions, emotional problems) are unknown. Therefore, the aim of the present study was twofold: 1) investigate changes in sexuality after diagnosis of and surgery for LGG, and 2) examine if sexuality changes are related to disease characteristics (tumor volume and localisation), cognitive impairments and mood problems. MATERIAL AND METHODS Patients with diffuse oligodendrogliomas and astrocytomas (WHO grades II and III) were included. After surgery, before the start of adjuvant therapy, cognitive functions and mood were investigated with neuropsychological tests and questionnaires respectively. At least 3 months after proton therapy, sexuality was investigated with the Brain Injury Questionnaire of Sexuality (BIQS), with lower scores indicative of decreases in sexual functioning compared to pre-diagnosis. The subscales Sexual Functioning (8 items, range 8-40, score between 8-23 = indicative for negative change) and Relationship Quality &amp; Self-Esteem (5 items, range 5-25, score between 5-14 = indicative for negative change) were used. Tumor volume and location were recorded. Descriptive statistics, between-group comparisons and correlational analyses were used. RESULTS 46 patients with LGG were included (mean age = 43.2 years, 32.6% female). Compared to pre-diagnosis, 71.7% of all patients reported decreased sexual functioning and 54.3% lower relationship quality and self-esteem. On item level, most frequent changes were decreased sex drive (41.3%), lower importance of sexuality (43.5%), decreased ability to give partner sexual satisfaction (47.8%), and lower frequency of sexual activities (67.4%). Correlational analyses and between-group comparisons yielded no significant associations between sexuality changes and tumor volume, localisation, cognitive impairments, and mood problems. CONCLUSION Changes in sexuality were found in over 70% of the patients with LGG, with most frequent changes being lower frequency and the decreased ability to give a partner sexual satisfaction. Decreases compared to pre-diagnosis did not appear to be closely connected to disease-related, psychological or cognitive factors. Consequently, our results emphasize the need to consider sexual health in all patients with LGG in clinical practice, as neglecting sexuality can lead to unnecessary sexual problems, feelings of loneliness and isolation. Future studies could examine the effect of adjuvant therapies, such as proton therapy, on sexuality more closely.