tbuckley/cabot-search huggingface dataset:
P02.21.A PROGNOSTIC ROLE OF CD68 AND CD163 IN GLIOMAS
Authors: G E D Petrescu, M P Dragomir, F M Brehar, R M Gorgan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor-associated macrophages (TAMs) have been demonstrated to play an important role in the growth and progression of multiple types of cancer, including glioblastoma. The aim of this study is to evaluate the distribution of CD68 and CD163 markers for TAMs in glioma samples and to determine their impact on survival. MATERIAL AND METHODS A tissue micro-array was performed using glioma samples from patients who underwent surgery at our institution. Diagnosis was established based on the WHO 2021 CNS classification. Thirty-six glioblastoma IDH-wt (GBM) and 15 oligodendroglioma, IDH mutant and astrocytoma, IDH mutant (CNS WHO grade 2 or 3) were included in the study. For comparison CNS WHO grade 2 or 3 samples were grouped. Immunohistochemical staining was performed for the detection of CD68 and CD163. CD68+ and CD163+ stainings were evaluated by counting the number of positive cells using QuPath (ver 0.4.4). For survival analysis the optimal cut-off method was used. RESULTS There was a statistically significant difference between the median CD68+ count in GBM vs. gr.2-3 (8.51 vs. 3.27, p =0.0009), and between the median CD163+ count (20.52 vs. 1.38, p&amp;lt;0.0001). By using the Spearman test, we observed a positive correlation (0.595) across all glioma samples between CD68 and CD163 (p &amp;lt; 0.0001). The Log-rank test showed increased survival in samples with low vs. high CD163+ count (median OS: 42 months vs 12 months, p = 0.0004) across all glioma samples. Similarly, there was a difference between the low (median OS: 34 months) and high (median OS: 17 months) CD68+ count, but without statistical significance (p = 0.11). A significant difference was also noted between samples with low count of CD68+ and CD163+ or one of the markers with high count compared to samples where both markers had a high count (median OS: 34 vs. 11.5 months, p = 0.0012). CONCLUSION Our findings reinforce the carcinogenic role of TAMs in glioblastoma, as well as their prognostic value, highlighting the possibility of targeted therapy against these targets.
P16.09.A TGFB1 INDUCED TET3 DEPENDENT REGULATION OF OTX2 SUPER ENHANCER HYPOMETHYLATION PROMOTES GROUP3 MEDULLOBLASTOMA PROGRESSION
Authors: C Xuan, L Jiankang, J Tao, L Hailong
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND DNA methylation patterns have been extensively utilized for medulloblastoma (MB) classification. However, the functional implications of enhancer methylation in MB remain poorly understood. METHODS We conducted bisulfite-based genome-wide sequencing on 189 human MB cases. Upon molecular classification, 80 cases was compared against 8 normal cerebellums, revealing differentially methylated regions (DMRs). Integration with gene expression data facilitated the identification of DMR target genes, subsequently validated in the 109 cases. Further, leveraging sn-ATACseq, we evaluated the association between DMRs in chromatin accessibility regions and tumorigenesis. Finally, we investigatedd the impact of upstream epigenetic events involving aberrant methylation on tumor development. RESULTS We observed a negative correlation between the methylation levels of DMR overlapping super enhancers (seDMRs) and the expression of targeted genes, particularly in Group_3 MB (G3-MB), the most aggressive subgroup. Genes targeted by hypomethylated seDMRs were significantly enriched in early-stage cerebellum development hallmarks, specifically the rhombic lip subventricular zone (RLSVZ), but not in the late stage. Hypomethylated seDMRs of OTX2 were associated with elevated chromatin accessibility and oncogenic activation of progenitor-like MB tumor cells, leading to worse prognosis. Integrative epigenetic analysis revealed highly active OTX2 binding sites within its own hypomethylated seDMRs, indicating feedback auto-regulation. Deletion of motif at this enhancer region reduced OTX2 expression and attenuated tumor progression. Further, we found that ten-eleven translocation 3 (TET3), a DNA methylation eraser, was recruited by OTX2 to catalyze active DNA demethylation at binding motifs, thereby organizing chromatin and stimulating gene expression. TET3 was upregulated by TGF-β1/Smad2 signaling. Based on these findings, nanoparticle-coated small interfering RNAs (siRNA) targeting TET3 were designed, effectively suppressing xenograft progression. CONCLUSION Our study highlights the increased transcriptional activity of OTX2 through cell-type-specific super enhancer demethylation, which is dependent on TGF-β1/Smad-induced TET3. This identifies a potential therapeutic strategy for G3-MB.
P14.07.A BLOOD-BRAIN BARRIER DISRUPTION FOLLOWING MR-GUIDED LASER INTERSTITIAL THERMAL THERAPY
Authors: S H Nielsen, J Skjøth-Rasmussen, V A Larsen, J F Carlsen, R Rasmussen, A E Hansen
Journal: Neuro-Oncology (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 &amp;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.
P18.48.B THE TRANSFORMATION AND RECURRENCE PATTERN OF TARGET VOLUME FOR GLIOMA ON THE MR-LINAC
Authors: Y Chen, X Yin, L Guo, S Ding, Y Wang, M Deng, Z Liu, Y Mu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioma, which carries a poor prognosis, stands as the most prevalent primary tumor of the central nervous system. The magnetic resonance (MR) linear accelerator (Linac) was increasingly used in the treatment of glioma, allowing for the collection of MRI images before each radiotherapy session, facilitating real-time adjustments to target volume. MATERIAL AND METHODS The authors retrospectively reviewed the patients with newly diagnosed glioma who underwent adaptive radiotherapy by means of 1.5 T MR-linac between August 2021 and December 2022 at Sun Yat-sen University Cancer Center, and analyzed changes in target volume (GTV), Dice Similarity Coefficient, Hausdorff distance (HD), relative GTV volume, and recurrence pattern. RESULTS A total of 20 patients were treated, including 18 with high-grade glioma and 2 with low-grade glioma. In 18 high-grade gloma patients, 10 had a recurrence, with 50% (5/10) exhibiting in-field recurrence, 40% (4/10) ex-field, and 10% (1/10) in/ex-field recurrence. The median progression-free survival (PFS) was 6 months (range, 2-13 months). Among 3 patients with initial GTV HD greater than first radiation therapy session for 15mm, all had ex-field recurrence. Of 9 patients who underwent complete resection, 44.4% (4/9) experienced recurrence (3 in-field, 1 ex-field), while 66.7% (6/9) experienced recurrence (2 in-field, 4 in/ex-field) in the other 9 patients. In 17 patients, MGMT methylation IDH1/2 mutation status was evaluated. 50% (4/8) of the MGMT methylated population occurred recurrence (3 in-field, 1 ex-field); 66.7% (6/9) of the MGMT unmethylated population occurred recurrence (2 in-field, 3 ex-field, 1 in/ex-field). 75% (9/12) IDH1/2wt patients developed recurrence (4 in-field, 4 ex-field, 1 in/ex-field), whereas only 20% (1/5) IDH1/2mut patients developed in-field recurrence. All patients tolerated MR-linac radiotherapy well, with minimal complications or toxicity. Notably, while preparing for radiotherapy of one patient, whose radiotherapy was scheduled after reoperation due to recurrence. During the radiotherapy, 3 patients occurred recurrence, then received prompting adjustments to target volume and drug treatments, resulting in successful recovery. CONCLUSION The implementation of MR-linac offers a novel approach for precise radiotherapy to glioma. Among patients who received adaptive radiotherapy on the MR-linac, the incidence of in-field recurrence decreased compared to previous research, likely attributable to precise irradiation of GTV. Nevertheless, longer follow-up is necessary to determine survival benefits. Future research should focus on increasing sample sizes to explore the relationship between target volume deformation and recurrence pattern in radiotherapy, as well as developing new modes of target volume delineation and optimizing target volume dosages.
P14.10.B DIGITAL AND AI TECHNOLOGY APPIED IN NEUROSURGERY PROMOTES THE FORMATION OF A NEW PARADIGM OF PREOPERATIVE PLANNING, VIRTUAL SURGERY &amp; INTRAOPERATIVE GUIDANCE FOR BRAIN TUMORS
Authors: X Yang, P Zhang, J Guo, W Shi, T Chen, T Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND: I n this study, we aims to establish a new paradigm of preoperative planning, virtual surgery, and intraoperative guidance for brain tumor surgery, based on a new preoperative planning and intraoperative guidance system for brain tumors. MATERIAL AND METHODS (1) Complete multimodal cranial imaging, functional mapping, and fiber tracing before surgery. Reconstruct the overall structure of the brain, including the cortical sulcus and gyrus, cortical vein, functional area adjacent to the brain tumors, and their connectivity fiber; (2) Analyze the topological pathways surrounding brain lesions and complete preoperative planning; (3) Applying virtual reality and augmented reality technology to surgical decision-making, preoperative training, and virtual surgery to enhance the realism of preoperative planning and the effectiveness of surgical training; (4) Introducing augmented reality technology in surgical positioning and scalp flap planning; (5) Based on the automatic partitioning and topological structure of the cortex, determine cortical approach to the tumor; (6) Real time fusion of surgical navigation and ultrasound imaging to guide the resection of deep tumors. RESULTS (1) Through virtual reality and augmented reality technology, preoperative topological structure analysis of tumors can be achieved, which can predict neural function remodeling and facilitate the maximum removal of brain parenchymal tumors; (2) Virtual reality technology and augmented reality technology, through visualization and three-dimensional presentation, promote young doctors to understand the relationship between the brain structure at the lesion site and the overall brain structure, as well as the relationship between the lesion and brain function and surrounding blood vessels. They are a new way of surgical training; (3) The guidance of digital technology can achieve optimal positioning and skin flap design, avoiding the mismatch between the skin flap designed solely based on the surgeon's experience and the surgical approach in a visual way, which can cause difficulties in surgical resection; (4) The automated partitioning technology and topological structure display of the cerebral cortex help to enhance understanding of cortical partitioning and indication of cortical pathways during surgery, which can replace electrophysiological techniques in judging the central sulcus; (5) The fusion technology of neuronavigation and intraoperative ultrasound can compensate for the non real-time nature of navigation and the limitation of ultrasound only indicating lesion sound and shadow, achieving real-time and good structural guidance during surgery. CONCLUSION We believe that the development of digital and intelligent technology will continue to help us establish a developing strategy for precision neurosurgery in the new era.
P14.09.A DIFFUSION MICROSTRUCTURE IMAGING AS A DIAGNOSTIC CORRELATE OF HISTOMORPHOLOGY: ASSESSMENT ACROSS THE MOST COMMON INTRACRANIAL TUMOR ENTITIES
Authors: U Würtemberger, D Erny, M Reisert, V G Kiselev, J Beck, D von Elverfeldt, M Prinz, H Urbach, T Demerath, M Diebold
Journal: Neuro-Oncology (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 &amp;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.
P09.13.A METABOLIC ACTIVITY OF PROTON RADIATION THERAPY RELATED EFFECTS IN GLIOMAS MEASURED WITH [18F]FET PET IMAGING
Authors: K Madsen, A Muhic, D Scheie, R Rasmussen, J Carlsen, A Vestergaard, O Henriksen, I Law
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Proton radiation therapy (PRT) has since 2019 become a treatment option alongside photon therapy in Denmark. PRT reduces doses to normal brain structures and for gliomas PRT has been considered in oligodendroglioma WHO grade 2-3 (O2-3) and astrocytoma IDH mutated WHO grade 2-4 (A2-4). Concerns have been raised regarding the frequency of treatment-related effects. The aim of this study is to investigate the association between pathology results and metabolic activity when progression is suspected on MRI after PRT in glioma. MATERIAL AND METHODS Forty-nine patients from Rigshospitalet, Copenhagen, Denmark suffering from glioma were treated with PRT until October 2022 (mean age 41 years, range 23-65), and followed for a minimum 1.5 years until April 2024. Progression was suspected in 20 patients clinically and/or at MRI, of which 13 patients fulfilled the criteria of the study: a [18F]FET PET scan followed by first subsequent pathology assessment after PRT (biopsy n=8 and resection n=5, mean delay after PET imaging 18 days (range 1-50 days), mean interval after PRT 1.6 years (range 0.3-3.3 years). The initial pathology of gliomas were O3 n=5, A2 n=1, A3 n=5, A4 n=2. PET scans were performed 20 min after injection of approximately 200 MBq [18F]FET. The maximal metabolic activity relatively to healthy appearing cortex (TBRmax) was calculated for the suspicious lesion. RESULTS Tumor relapse was found in four patients (subsequent pathology A3 n=1, A4 n=3) with corresponding TBRmax of mean 3.1 (range 2.3-4.3). Pathology showed only treatment related effects in eight patients (initial pathology O3 n=5, A3 n=2 A4 n=1), with corresponding TBRmax of mean 1.8 (range 1.6-2.3), though one of these patients died 2.3 years later from tumor relapse. Mixed reactive changes and A2 tumor were found in the resected tissue of one patient with corresponding TBRmax of 1.6. Thus, the metabolic activity was significantly higher in tumor tissue compared to treatment-related effects using Students t-test, p=0.02 when classifying mixed as relapse (p= 0.002 when excluding mixed), and ROC AUC was 0.80 providing sens/spec of 80%/88% at an optimal TBRmax cut-off at 2.2. CONCLUSION The prevalence of treatment-related effects verified by histopathology was 16% in the patients treated with PRT during at least 1.5 year follow-up. A significantly lower metabolic activity was found in the treatment-related effects compared to tumor relapse measured with [18F]FET PET imaging. Indicating that [18F]FET PET imaging may be a valuable diagnostic tool to discriminate between relapse and treatment-related effects at an early stage after PRT. However, in our experience, reactive changes often expand over time and the metabolic intensity might accordingly increase later in the progress after PRT. For investigating this, systematic repeated [18F]FET PET imaging is needed.
P27.01.A ANLOTINIB COMBINED WITH RADIOTHERAPY IN THE TREATMENT OF ADULT NEWLY MALIGNANT BRAINSTEM GLIOMA PATIENTS: A MULTICENTER, PHASE II STUDY
Authors: Y Chen, P Li
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Due to the challenging location, adult malignant brainstem glioma can not undergo aggressive surgery and is associated with a quite poor prognosis. Effective therapy regimens for this disease have not been developed. This study assessed the efficacy and safety of anlotinib, a multitarget tyrosine kinase inhibitor, combined with radiotherapy in treating this group of patients. MATERIAL AND METHODS This is an ongoing phase II, multicenter, single-arm trial investigating the safety, tolerability, and activity of anlotinib combined with radiotherapy in malignant brainstem glioma. Eligible participants include adults (18-70 years old) with newly diagnosed malignant (WHO III - IV) brainstem glioma based on histology or radiology who are radiotherapy (RT), chemotherapy, immunotherapy, or biotherapy naïve. Patients with Karnofsky score &amp;lt; 40 and a life expectancy &amp;lt; 3 months are excluded. All participants received 54-60 Gy radiotherapy (RT,1.8-2.0 Gy per fraction, five days per week). Anlotinib (10mg, orally, daily, d1-14/3 weeks) concurrently administered with radiotherapy, then consolidatedly used until disease progression or occurrence of intolerable adverse events. The primary objective includes disease control rate (DCR) and 6-month progression-free survival rate (6m-PFS). The secondary objective includes overall survival (OS), and toxicity profile (NCT04668508). RESULTS As of January 31, 2024, 19 participants have enrolled, all patients have completed radiotherapy. Sixteen patients who with a follow-up of 6 months or longer were included in the analysis for this report. The median age is 32 (range 18-68) years old. The median follow-up is 22.7 (range 6.0-38.3) months. Seven patients were pathologically diagnosed and nine patients were radiologically diagnosed with high-grade glioma. The DCR is 100% (Stable disease, SD: 16/16) at the end of radiotherapy and is 100% three months after radiotherapy (Partial response, PR: 2/16; SD: 14/16). The median PFS is 11.7 months, 95%CI 6.9-16.4, and the 6m-PFS and 1 year-PFS rates are 74.0% 11.2% and 36.3% 13.3%. The median OS is 18.7 months, 95%CI 10.7-34.7, the 6m-OS and 1 year-OS rates are 93.3% 6.4%and 58.3% 15.0%. No death occurred during the treatment. No ≥ grade 3 adverse events were observed up to the last follow-up (January 31, 2024) of this study. CONCLUSION Anlotinib combined with radiotherapy is efficacious and well-tolerated and might be a treatment option for newly diagnosed malignant brain stem glioma in adults.