tbuckley/cabot-search huggingface dataset:
P14.14.A INTRA-ARTERIAL CHEMOTHERAPY TREATMENT FOR RELAPSING GLIOBLASTOMA: RESULTS FROM A FIVE-YEAR SERIES
Authors: L Roy, M Roy, G Gahide, J Latulippe, D Fortin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour in adults. The GBM malignant phenotype depicts anarchic invasion of the brain parenchyma as well as radio-/chemoresistant properties. The complete surgical resection is unachievable and responses to standard therapy are invariably transient. In addition to the malignant GBM phenotype, the blood-brain barrier (BBB) is one of the prominent features that limits the efficacy of chemotherapy. Indeed, this facet of the brain’s blood vessels significantly blocks the passage of numerous therapeutic molecules from the blood stream to the brain. Tumour progression often occurs during or after standard first-line therapy which includes radiotherapy with concomitant and adjuvant temozolomide. The median overall survival (OS) is 14.6 months, but recurrence occurs on average only seven months after the initial diagnosis. At relapse, there is no consensus on the standard of care and the median OS ranges between three and nine months. At our institution, we use intra-arterial infusion to treat relapsing GBMs. This delivery strategy bypasses the first pass and significantly increases the local peak plasma concentration and area under the curve. This leads to a 3 to 5 fold increase of the chemotherapy concentration in the glioma-infiltrated brain parenchyma. Over the last 15 years, we have treated more than 722 patients for a total of 3600 intra-arterial chemotherapy (IAC) procedures. MATERIAL AND METHODS In this revision of the 2018-2023 series, we treated 59 relapsing GBM patients. Every IAC procedure was completed every four to six weeks. We reviewed the medical files to follow treatment evolution, tumour response and for grades 3 and 4 toxicity. RESULTS During this five-year period, a total of 406 arteriographic procedures were completed. The following chemotherapeutic agents were used: carboplatin, melphalan, methotrexate, Caelyx, carboplatin + melphalan, carboplatin + methotrexate, carboplatin + etoposide phosphate or melphalan + methotrexate. The median OS from diagnosis and relapse were 24 and 9 months respectively. A total of 28 patients suffered one or more grade 3 hematological toxicity events (17% of IAC cycles). Likewise, 24 grade 4 hematological toxicity events occurred in 16 patients (6% of IAC procedure). CONCLUSION In comparison with published clinical trials results, the data from our series suggest that IAC is a promising strategy for the treatment of relapsing GBM. We will gather more data and perform uni- and multivariate analyses. Moreover, we will soon begin a randomized clinical trial to test the combination of carboplatin + etoposide phosphate and carboplatin + Caelyx in the treatment of relapsing GBM. Furthermore, we are currently conducting preclinical experiment using topotecan, cytarabin and paclitaxel to determine their effectiveness in the IAC setting.
P26.13.A TUMOR TREATING FIELDS (TTFIELDS) AT A FREQUENCY OF 100 KHZ AND 170 KHZ OPEN THE BLOOD-BRAIN BARRIER (BBB) IN A 3D IN VITRO BBB-MODEL
Authors: A S Lysinger, E Salvador, L Vormwald, R Ernestus, M Löhr, C Hagemann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The highly restrictive properties of the blood-brain barrier (BBB) pose a critical hurdle in combatting brain cancer. Tumor Treating Fields (TTFields) are a non-invasive treatment modality comprised of alternating electric fields of intermediate frequency (100-500 kHz) and low intensity (1-3 V/cm) that are CE-approved for WHO grade 4 glioma, and FDA-approved for the treatment of glioblastoma. At 100 kHz, TTFields loosen the BBB by reversibly delocalizing various tight junction and associated proteins in vascular brain endothelial cells, allowing drug delivery to peripheral regions of the brain. We investigated the effects of TTFields at 100 kHz and 170 kHz on a 3D human cell-based BBB in vitro model with the goal of improving on the outcomes already demonstrated at 100 kHz. MATERIAL AND METHODS The in vitro BBB model combines human brain microvascular endothelial cells (HBMVEC) grown on glass coverslips and immortalized pericytes in transwell inserts, or vice versa, two crucial cell types responsible for BBB integrity. Cells were treated with TTFields at either 100 kHz or 170 kHz for 72 h, whereas untreated cells served as controls. Change in BBB permeability was assessed by fluorescein permeation assays with dextran molecular weights of 4 kDa, 40 kDa and 70 kDa immediately before and after 72 h of TTFields administration. Effects on a molecular level were investigated by immunofluorescence staining of junctional proteins ZO-1, PECAM-1 and Claudin-5 in HBMVEC after 72 h of treatment with either frequency and their expression was monitored by Western-blotting. RESULTS Permeability assay of various fluorescein molecules demonstrated consistent increase in HBMVEC permeability among all treated groups compared to untreated cells for molecular weights of 4 kDa and 40 kDa with a significant increase from 100 kHz to 170 kHz, as well as significant increase in permeability for 70 kDa after treatment at 170 kHz. Staining of junctional proteins ZO-1, PECAM-1 and Claudin-5 revealed delocalization from the cell membrane to the cytoplasm in all treated samples, while Western-blot proved that their expression did not change in relation to untreated controls. CONCLUSION TTFields with a frequency of 170 kHz showed consistent or improved effects on BBB permeabilization over 100 kHz by rearranging tight junction proteins in HBMVEC in vitro, without impairing tight junction protein expression.
P20.07.A CLINICAL OUTCOMES OF LOW-GRADE INTRACRANIAL GANGLIOGLIOMA IN ADULT POPULATION
Authors: J Kulkarni, D Hutton, K Syed, M D Cearns, S J Mills, M D Jenkinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gangliogliomas are rare, primary tumors of the central nervous system that occur more commonly in the paediatric and young adult demographic. While they are generally low-grade and have a favorable prognosis, tumor recurrence and progression to malignancy may occur. The aim of this study was to investigate risk factors for recurrence and the outcomes of intracranial ganglioglioma in the adult population. MATERIAL AND METHODS Thirteen adult patients with WHO grade 1 and 2 ganglioglioma were identified retrospectively from patient database at a tertiary neurosurgical center between 2010 and 2022. Patient characteristics, MRI features, tumor location, clinical and seizure outcomes were obtained. Surgical treatment strategies were categorized into subtotal (STR) or gross total resection (GTR). RESULTS Median patient age was of 29.0 years with 84.6% (n=11) temporal lobe tumors and the most common presentation (69.2%) being seizures. STR and GTR were achieved in five and nine patients, respectively. Adjuvant radiotherapy was not administered to any patient. Only one patient with STR had a recurrence at 65 months during the median follow up period of 6.5 years. Two patients had persisting seizures at last outpatient follow-up. There were no deaths. CONCLUSION Adult intracranial gangliogliomas WHO grade 1 or 2 have an extremely favorable prognosis with a recurrence rate of less than 10%. In cases where GTR is achieved, long term MRI surveillance is not required. Patients can be safely discharged after annual MRI for 3 years post surgical treatment. In patients where STR is achieved, annual MRI surveillance is required although the recurrence and progression rates remain low.
OS08.7.A STIMULATED RAMAN HISTOLOGY FOR INTRAOPERATIVE DIAGNOSIS IN PEDIATRIC BRAIN TUMORS
Authors: B Kiesel, L Körner, J Makolli, C Vogel, c Haberler, C Dorfer, G Widhalm
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Intraoperative frozen sections for neuropathological assessment is an essential tool in pediatric neurosurgical tumor resection. However, preparation as well as analysis of the tumor tissue can take as long as 45 minutes. Recently, stimulated Raman histology was introduced as a novel technique to provide a rapid high-resolution digital image of an unprocessed tissue sample directly in the operating room. The aim of this study was to evaluate the use of stimulated raman histology during pediatric brain tumor surgery. METHODS All patients aged 18 years or younger who underwent a biopsy or resection of a suspected tumor lesion were included in the current study. Intraoperatively, tissue samples of the suspected tumor lesion were collected. One sample was prepared and sent to the neuropathology department and a conventional frozen section was performed. Additionally, a sample was used for stimulated raman histology analysis directly in the operating room. In a further step, a tool was applied to provide a histopathological diagnoses using artificial intelligence. Conventional intraoperative frozen section and images obtained using stimulated raman histology were compared and analyzed. RESULTS In total 55 patients were included. The median age of our patient cohort was 9 years and included 25 female and 30 male patients. In all cases stimulated raman histology showed comparable images as the conventional frozen sections. The most common histopathological diagnosis was pilocytic astrocytoma followed by diffuse glioma, Medulloblastoma and Ependymoma. In 25 cases diagnosis using artificial intelligence was available and applied. In 50% the provided diagnosis was confirmed by histopathological assessment. In the other half of the cases AI diagnosis was not correct. CONCLUSION Stimulated raman histology represents a useful rapid intraoperative tool to obtain images comparable to conventional frozen sections and thus provide important information for the neurosurgeon to optimize surgical management. The AI tool may in future represent a helpful tool to provide a rapid intraoperative diagnosis.
P10.17.B IMPACT OF INTENSITY STANDARDISATION AND COMBAT BATCH SIZE VARIATION ON COMBINED CLINICAL AND RADIOMICS PROGNOSTIC MODELS IN PATIENTS WITH UNIFOCAL GLIOBLASTOMA
Authors: K Fatania, R Frood, H Mistry, S C Short, J O’Connor, A F Scarsbrook, S Currie
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Prognostic models for patients with glioblastoma (GBM) may include quantitative image features extracted from MRI (‘radiomics’). Multicentre image acquisition poses a challenge to radiomic feature (RF) reproducibility and MRI intensity standardisation techniques (ISTs) and ComBat may help. Optimal IST and minimum batch size (MBS) for ComBat are uncertain - the latter especially with real-world datasets where few patients are scanned at each site. Our aim was to assess the effect of three popular ISTs in conjunction with varying MBS on prognostic model performance and stability in a real-world, multi-centre GBM patient cohort. MATERIAL AND METHODS Patients with IDH-wildtype unifocal WHO grade 4 GBM and pre-operative MRI acquired across multiple geographic locations in the region between 2014-2020 were retrospectively included. Tumours were segmented using deep-learning with manual correction. WhiteStripe (WS), Nyul histogram matching (HM) and Z-score (ZS) ISTs were applied before RF extraction. Post-extraction, RFs were realigned using ComBat using MBS of 5, 10 or 15. Cox proportional hazards models were produced using five strategies to select the four best performing RFs, and the impact of IST and MBS was evaluated with bootstrapping (1,000 repetitions), and measuring model calibration, discrimination, relative explained variation and model fit. Model instability was assessed using bootstrap resampling to produce 95% confidence intervals (95% CIs), feature instability tables and calibration instability plots. RESULTS 195 patients were included with median overall survival of 13 months (95% CI 12-14). Increasing the ComBat MBS reduced the sample size available for modelling (195, MBS=5; 159 MBS=10; 129 MBS = 15). HM and WS tended to produce the highest relative increase in model discrimination, explained variation and model fit but IST choice did not influence model stability or calibration. Increasing the ComBat MBS improved model discrimination, relative explained variance and model fit, however it degraded model stability and calibration accuracy. Calibration instability plots showed a greater spread of calibration curves across the bootstrap resamples as the ComBat MBS increased (and sample size reduced), indicating worse calibration accuracy and stability. CONCLUSION IST and ComBat MBS had varied effects. Increased ComBat MBS (and reduced sample size) improved most performance metrics but stability and calibration deteriorated. HM and WS tended to increase most model performance metrics and did not negatively influence stability. Our real-world, multi-centre data showed that while ComBat may improve multi-centre radiomics models, it requires data to be excluded, with negative results for sample size and stability and unknown consequences for patients imaged in smaller centres.
P01.14.B SYNGN: A NOVEL EPIGENETIC PLATFORM TO DISCOVER PATIENT-SPECIFIC DISEASE MECHANISMS AND DRUGGABLE TARGETS IN GLIOBLASTOMA
Authors: S Marino, C Vinel, M Constantinou
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The alteration of the glioblastoma genome by epigenetic mechanisms that share functions with normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC), is a key piece of evidence that links brain cancer pathogenesis with dysregulated stem cell functions. A patient-specific comparison of glioblastoma stem cells (GSC) with NSC, a putative cell of origin of at least a proportion of these tumours, is not feasible as patient-matched endogenous NSC are not surgically accessible and all epigenetic studies in glioblastoma have so far compared epigenetic changes of different tumours with each other or to comparators obtained from foetal brains or an unrelated donor. We reasoned that availability of syngeneic GSC and NSC pairs would allow to identify crucial epigenetic differences on a patient-specific basis and would provide essential therapeutic contrast to define disease-and patient-intrinsic biomarkers of drug response that are less confounded by germline variation. MATERIALS AND METHODS We have derived GSC from IDH-wildtype glioblastoma and harnessed state-of-the-art stem cell technologies to generate patient-matched fibroblast-derived EPSC, which were induced to NSC (iNSC). We generated transcriptome, DNA methylome, ChIP-Seq (H3K4me3, H3K27ac, H3K3me3, H3K27me3) and ATACSeq datasets for 10 GIC/iNSC pairs. RESULTS Comparative integrated analysis has shown that redistribution of selected histone marks as well as shifts in chromatin states across the genome identifies differentially expressed genes, including novel druggable regulatory mechanisms in GSC, which are specific of the neoplastic context. In particular, we identified METTL7B as an essential regulator of lineage specification and plasticity in human glioblastoma, with impact on both tumour size and invasiveness in an in vivo xenograft model. Single cell transcriptomic analysis of these tumours and of cerebral organoids derived from expanded potential stem cells (EPSCs) overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cells-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks. CONCLUSION SYNGN is an epigenetic platform which can identify novel disease mechanisms and druggable targets in glioblastoma.
P06.12.B Microbiota-gut-brain axis in glioblastoma development and therapeutic resistance
Authors: S Lavielle, G Delrot, M Lemaitre, I S Pateras, M Nikolski, T Daubon, O C B Martin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GB) is the most common subtype of glioma in adults. Despite treatment through tumor resection associated with chemo and radiotherapies, this cancer still has a very poor prognosis. Factors contributing to etiology, pathogenesis, or treatment resistance are not well known. The significance of understanding the microbiome-gut-brain axis (MGBA) in GB, a topic that has been recently shown to be crucial in several neurodegenerative diseases, cannot be overstated. Therefore, our project aims to understand how modulation of gut physiopathology (i.e., gut inflammation or microbiota dysbiosis) affects GB development and therapeutic resistance. MATERIAL AND METHODS We have examined the relationship between gut inflammation, microbiome modulation, GB development, and therapeutic resistance. Mice received dextran-sulfate sodium (DSS), a gut pro-inflammatory agent, and were orthotopically injected with mGB2 GB cells. Some mice were then resected and treated by radio and chemotherapy using Temozolomide (TMZ). To understand the role of the gut microbiota in GB, we performed gut bacterial microbiota depletion using antibiotics. RESULTS Our results showed that DSS-treated mice had a higher GB growth than non-treated mice. Moreover, the recurrence after treatment was higher in mice bearing gut inflammation. Interestingly, we also observed on DSS-treated mice that the GB-bearing mice had lower intestinal inflammation than the control. GB growth was also associated with microbiota modifications, which were restored by the treatment. Gut microbiota alteration leads to increased tumoral growth, suggesting an implication of the microbiota in GB development. CONCLUSION Altogether, our results support the bidirectional communication between the gut and the brain in the context of GB. Alteration of gut physiopathology strongly impacts GB development and therapeutic resistance. This connection suggests that targeting the gut microbiome could slow down GB progression and/or improve treatment efficacy.
P17.26.A THE ROLE OF DENDRITIC CELLS IN THE IMMUNE RESPONSE TO BRAIN METASTASES
Authors: F James, J Williams, C Fife, G Mallett, N Ingram, A MacDonald, M Lorger
Journal: Neuro-Oncology (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.
P20.12.B INTEGRATED GENETIC ANALYSES OF IMMUNODEFICIENCY-ASSOCIATED EPSTEIN-BARR VIRUS- (EBV) POSITIVE PRIMARY CNS LYMPHOMAS
Authors: L D Kaulen, E Denisova, F Hinz, L Hai, D Friedel, O Henegariu, D Hoffmann, J Ito, A Kourtesakis, P Lehnert, S Doubrovinskaia, P Karschnia, L von Baumgarten, T Kessler, J Baehring, B Brors, F Sahm, W Wick
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. MATERIAL AND METHODS In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. Deconvolution of bulk RNA sequencing data was performed using CIBERSORTx to characterize the tumor microenvironment. RESULTS EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL. CONCLUSION In addition to novel insights into the pathobiology of EBV+PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.