tbuckley/cabot-search huggingface dataset:
P27.21.A RE-RESECTION FOR RECURRENT GLIOBLASTOMA - DOES TIMING MATTER?
Authors: O Alhalabi, P Dao Trong, K Mironov, K Nabiev, A N Gareib, M Jordan, S Joser, S M Krieg, A W Unterberg, C Jungk
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Surgery for recurrent glioblastoma (GBM) has the potential of prolonging patient survival. However, the impact of the timepoint of re-resection after tumor suspicion on post-surgical survival and neurological deterioration remains unclear. MATERIAL AND METHODS Patients undergoing first re-resection for recurrent WHO grade 4 IDH-wildtype GBM were analyzed retrospectively. Post-surgical neurological deterioration and post-surgical survival of patients undergoing early surgery (within 3 weeks) after suspected recurrence were compared to those receiving surgery later than 3 weeks. In addition, volumetric analyses were used to determine tumor burden and location. RESULTS 103 consecutive patients (mean age: 59 years; 64 males and 39 females) undergoing first re-resection for recurrent GBM from 2018 to 2022 were included. Gross total resection (GTR) had been achieved in 93 patients (91%) at first diagnosis and was achieved in 96 patients (93%) at repeat surgery. Intraoperative MRI-guided resection was performed in 84 (82%) cases and 5-ALA was applied in 8 (8%) cases, with neuromonitoring utilized in 14 (14%) cases. The median time interval between first and second resection was 341 days (IQR 343 days) while the median time interval between suspected tumor recurrence and re-resection was 20 days (IQR 23 days). Surgery was delayed beyond 3 weeks after suspected recurrence in 49 cases (mean interval 11 in the ‘early’ vs 187 days in the ‘late’ group, p&amp;lt;0.001) due to salvage chemotherapy/targeted therapy in 18 cases, suspicion of pseudo-progression in 7 cases and patient preference in 24 cases. Compared to patients receiving ‘early’ repeat surgery, this delay was not associated with a higher rate of immediate (14/54 vs 10/49 patients, p=0.508) or permanent (3/54 vs 4/49 patients, p=0.600) post-operative neurological deterioration. Median survival after repeat surgery was 220 days and did not significantly differ between early and late surgery (212 in the late vs 243 days in the early group, p=0.682). Volumetric analyses revealed no significant differences in tumor volume or localization pertaining to eloquence. CONCLUSION Timing of surgery for suspected first recurrence of GBM did not impact on functional outcomes and post-surgical survival. In general, satisfactory rates of postoperative neurological deficits and post-surgical survival in this contemporary cohort of patients with repeat surgery for recurrent GBM could be achieved.
P20.06.B CHOROID PLEXUS TUMORS IN ADULT: RETROSPECTIVE MONO-INSTITUTIONAL STUDY
Authors: E Anghileri, P Gaviani, A Amato, B Pollo, M Marchetti, F M Doniselli, M Eoli, V Redaelli, A G L Botturi, F Di Meco, P Ferroli, M Farinotti, L de Oliveira Muniz Koch, R Paterra, A Silvani
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid plexus tumors (CPT) are rare entities, mainly affecting childhood, including three grade subtypes. MATERIAL AND METHODS A mono-institutional retrospective series of adult CPT patients was collected. The database contains demographic and clinical details, diagnostic (radiological and histological/molecular), therapeutic, recurrence information, and survival data. RESULTS We described twenty-four adult CPT, with a median age of 43.29 years [Interquartile range (IR) 37.31-53.30]. Clinical onset (n=20/24) included cerebellar signs (n=11), intracranial hypertension signs (n=8), cranial nerves impairment (n=5), seizures (n=1), spinal signs (n=1) (multiple symptoms in some patients). Remarkably, in 17% the radiological detection was occasional.The tumors were mostly located in the ventricular system at first diagnosis: 79.2% were infratentorial, but any other locations can occur, including the spine (one case); meningeal involvement was present in one case. Only one case presented a pre-surgical hydrocephalus. CPT histological grade ranged from grade 1 (n=17), grade 2 (n=6), and grade 3 (n=1). TERTp mutations were detected in 17.6% (n=3/17). TP53 mutation in 5.9% (n=1/17). Complete resection was achieved in n=16/24 (66.7%), gross-total resection in n=3/24 (12.5%), partial resection in n=3/24 (12.5%), biopsy in one case, and no information on surgery extension in one case. 76% of the cases (n=16/21) experienced clinical worsening suddenly after surgery for different reasons, and mostly gradually recovered. Adjuvant therapy was performed only for grade 2 and 3 tumors, and included conformational radiotherapy (RT) in one disseminated grade 2 and in one grade 3 case. At recurrence, surgery, RT, and chemotherapy had been considered. The median Overall Survival from surgery was 108.1 months [IR 62.5-143.4]. CONCLUSION We could confirm that CPT can occur in adults, and are mostly grade 1 tumors and located in the ventricular system. The surgical approach is the gold standard, although a substantial number of clinical worsening occurred, but often transient. Adjuvant treatment is limited to higher grade CPT; however, no consensus has already been achieved about adjuvant therapy. FUNDING RRC Italian Ministry of Health
P09.08.B GADOPICLENOL CAN HELP WITH GAMMA KNIFE LOCALIZATION OF BRAIN METASTASIS OVER OTHER CLASS II GADOLINIUM BASED CONTRAST AGENTS
Authors: G H J Stevens, J Wu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases are common and affect up to 30% of adult cancer patients. An estimated 150,000 to 200,000 brain metastases are diagnosed annually and some form of stereotactic radiosurgery (SRS) is commonly employed as a treatment modality. The magnetic resonance imaging (MRI) localization exam for SRS typically involves a volumetric post contrast T1 3D Flash or T1 Space sequence with 1mm slices using either gadoterate meglumine or gadoteridol as the contrast agent. Acquisition time is approximately 7 minutes. A gadolinium-based contrast agent that has high stability (lower risk of nephrogenic systemic fibrosis by having a higher dissociation half-life), a high T1 relaxivity (greater signal to noise ratio to allow for a lower dose of gadolinium and hence reduce gadolinium exposure), and high tolerability (lower rate of adverse reaction) is most ideal for lesion localization. Imaging requires a high lesion to background contrast and contrast to noise to allow accurate lesion visualization. Gadopiclenol is a class II Gadolinium based contrast agent that provides these properties. MATERIAL AND METHODS We analyzed 50 consecutive brain metastases patients using two MRI localization exams (as defined above), performed within 10 days using the same MRI scanner and same imaging parameters. One scan was completed using the contrast agent gadoterate meglumine and the other gadopiclenol. The MRIs were interpreted by the same Neuroradiologist. RESULTS There were 30 females and 20 males with a mean age of 62.4 years. The most common pathology was lung (N=28). In 10% of patients, the brain metastases were more conspicuous on the gadopiclenol study and /or a greater number of metastases were seen resulting in a treatment change. No adverse reactions were noted. CONCLUSION Our institution has transitioned to using primarily gadopiclenol for MRI gamma knife localization exams as it appears to be more effective in lesion localization compared to other available agents, with similar safety profile. Multiple cases will be presented.
P27.23.A SKULL REMODELING SURGERY IN COMBINATION WITH TUMOR TREATING FIELDS THERAPY FOR FIRST RECURRENT GLIOBLASTOMA. FINAL RESULTS FROM OPTIMALTTF-2, A MULTI-CENTER, RANDOMIZED, CLINICAL TRIAL
Authors: N Mikic, J Skjøth-Rasmussen, F Rom Poulsen, R Johannes Laursen, S Lukacova, S Møller, C Aaquist Haslund, R Hedegaard Dahlrot, O Solheim, T S Solheim, J H Sørensen, E T Wong, A R Korshøj
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND There are no standardized treatments for first recurrent glioblastoma (rGBM) and the prognosis in the clinical trial population is approximately 6-9 months. Skull remodeling surgery (SR-surgery) aims to optimize Tumor Treating Fields therapy (TTFields) by surgically removing areas of the low conductive skull and thereby increasing the electric field intensity directly into the tumor. In silico work suggests SR-surgery increases the electric field intensity by ~30-100% and OptimalTTF-1 (pilot trial) suggests the intervention is safe with a median overall survival (mOS) of 15.5 months. MATERIAL AND METHODS OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional clinical phase 2 trial aiming to examine the efficacy and safety of TTFields and physicians’ best choice oncological therapy with or without SR-surgery for 84 rGBM patients. SR-surgery was standardized with in silico work to consist of five burr holes, each 15mm in diameter, directly over the tumor resection cavity with the transducer arrays overlapping. The trial was active nationwide in Denmark from 2020-2024. Major eligibility criteria include age ≥18 years, histopathological confirmed 1st recurrence of supratentorial glioblastoma, KPS ≥ 70, and focal tumor. The primary endpoint is overall survival after 12 months (OS12), while secondary endpoints include PFS, QoL, ORR, QoL, KPS, steroid dose, and toxicity. RESULTS 52 patients were included in the prespecified interim analysis. 26 randomized to intervention, and 26 to control. The median age of 60 years [31-80]. Baseline characteristics were balanced without statistical differences. Intent-to-treat analysis showed that the OS12 was 56% [35-73%, 95%CI] vs. 50% [29-68%, 95%CI], p =0.65, and mOS was 14.09 months [7.9 -,95%CI] vs. 10.97 months [6.5-17.3, 95%CI], p=0.41, for intervention and control, respectively. No statistically significant difference between the arms in toxicity or QoL. Conditional power calculation also suggested a low survival benefit for the planned cohort of 84 patients. CONCLUSION The interim analysis did not show an advantage from SR-surgery, and the trial was terminated early based on the low expected survival benefit for the entire cohort. Examination of potential negative outcome modifiers, that may attentuate the increased electric field intensity from SR-surgery are needed in the post hoc analysis.
P27.22.B SEMISITTING POSITION VS. STANDARD SUPINE POSITION IN REDUCING INTRACEREBRAL BLEEDINGS DURING STEREOTACTIC BRAIN BIOPSY
Authors: L Bonosi, G Carone, E Porto, A Barbotti, T Galbiati, M Del Bene, F Di Meco
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Stereotactic brain biopsy (SBB) represents a minimally invasive procedure to acquire tissue samples for histological diagnosis. Despite SBB’s many benefits, there is a chance of hemorrhagic complications. The incidence of hemorrhagic complications following SBB is not well established, but studies suggest that it may be higher than previously thought. In semi-sitting position (30° elevation of the head), the intracranial pressure is lower than in supine position due to decreased venous congestion. In our hypothesis, intraoperative bleeding may be reduced by exploiting semi-sitting position, potentially leading to decreased surgical morbidity. MATERIAL AND METHODS We conducted a retrospective monocentric 2-arms cohort study at our institution (Istituto “C. Besta” in Milan, Italy). We reviewed all patients who underwent stereotactic brain biopsy from the 1st of March 2023 to the 1st of April 2024. The primary endpoint is to demonstrate the improved safety of the semi-sitting position, as assessed by the absence of intracranial bleeding on postoperative CT scans compared to standard supine position. RESULTS Our analysis covered 78 patients, with 39 undergoing biopsy in the semi-sitting position and the remaining 39 in supine positions. Out of those in the semi-sitting position, 5 exhibited a hemorrhagic spot along the catheter’s edge or within the lesion as revealed by CT scans. This contrasts with the 14 instances found among patients not in the semi-sitting position, indicating a statistically significant difference (p-value: 0.028). However, no other significant correlations were observed in CT findings, such as bleeding, when compared to age (p-value: 0.352), biopsy site (p-value: 0.355), number of samples (p-value: 0.141), or histology (p-value: 0.251). CONCLUSION This study can potentially shed light on an innovative approach for patient positioning in stereotactic brain biopsy. The observed decrease in intraoperative bleeding may decrease procedure-related risks and surgical morbidity. As a result, patient safety and outcomes can be improved.
P27.20.B RARE NEUROLOGICAL PRESENTATION OF BING NEEL SYNDROME AND TREATMENT PERSPECTIVES: A CASE SERIES
Authors: P Giglio, A Malvaso, P Bini, L Diamanti, E Marchioni
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Bing-Neel syndrome (BNS) is a rare complication of Waldenström macroglobulinemia (WM) stemming from direct invasion of the central nervous system by malignant lymphoma cells. BNS patients present with gradually progressive symptoms (e.g. headache, nausea, vomiting, cranial neuropathies), rarely accompanied by aphasia and cognitive decline resulting from involvement of brain parenchyma . MATERIAL AND METHODS Three cases (68 y, F; 69 y, F; 74 y, M) of patients affected by WM and diagnosed with BNS are illustrated here. Clinical data have been collected from medical records for all patients. RESULTS A 68 year old female, a 69 year old female and a 74 year old male presented with aphasia, limb ataxia, behavioral changes and memory loss. The second patient also developed anti-MAG polyneuropathy. Obstructive hydrocephalus due to CNS invasion by previously unknown lymphoplasmacytic lymphoma was the inaugural manifestation of disease in the third patient; furthermore, BNS represented the initial presentation of WM in the second patient, whereas CNS involvement became apparent 7 years after disease onset in the first patient. Brain and spinal magnetic resonance imaging revealed brain leptomeningeal contrast enhancement in all patients with associated spinal leptomeningeal enhancement in the first two patients. The cerebrospinal fluid (CSF) analysis showed an increased WBC count (14/mm^3 and 27/mm^3) and elevated CSF/serum albumin transfer index (1,8% and 0,7%) in the first and the third patients. Monotypic CD20+, CD19+, CD5-, CD23-, CD10- lymphocytes with kappa chain monoclonal restriction were observed in all patients. Hence, a definitive diagnosis of BNS was made in all cases and immunosuppressive therapy was started with poor clinical improvement. Lastly, Ibrutinib was administered obtaining clinical and radiological benefits in all patients after 12 months of follow-up. CONCLUSION We suggest that the occurrence of rare, but typical neurological presentations in patients with WM could be clinically relevant and life threatening. Furthermore, BNS might be the initial clinical manifestation of WM. According to our monocentric experience and recent literature, BNS patients treated with Ibrutinib may reach high rates of 2-year event-free survival. However, randomized controlled trials are required to define the role of Ibrutinib as an important therapeutic option in BNS.
P27.24.A SYSTEMIC AND LOCAL THERAPIES BEFORE AND AFTER DIAGNOSIS OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH BRAIN METASTASES: AN EXPLORATIVE, SINGLE-CENTER RETROSPECTIVE COHORT STUDY
Authors: D Wasilewski, C Eitner, S Murad, Z Shaked, J Steinle, A Sargut, A Wetzel-Yalelis, A Roethe, C Jelgersma, R Mertens, P Truckenmüller, A Früh, J Rösler, L Wessels, D Kroneberg, A Kowski, H Radbruch, F Ehret, D Kaul, N Frost, J Onken, U Keller, J Sehouli, P Vajkoczy, U Keilholz, M Misch
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Leptomeningeal metastasis (LMD), the dissemination of cancer cells into leptomeninges and/or cerebrospinal fluid, is believed to increase in incidence due to improved survival of oncological patients. Real-world data on therapies before and after diagnosis of LMD in brain metastasis patients are still limited. We aimed to characterize local and systemic therapies before and after diagnosis of LMD in these patients. MATERIAL AND METHODS We included 120 patients (treated from 2012 to 2023) with underlying solid malignancy, presence of brain metastasis together with leptomeningeal spread, either confirmed by MRI, cerebrospinal fluid sampling, or both modalities. Data on demographics, radiological, and therapy-related characteristics were collected. Kaplan-Meier estimates and Cox model regression analysis were performed to identify factors associated with survival. RESULTS Breast cancer (35.8%), NSCLC (20.8%), melanomas (16.7%), and gastric cancer (5.7%) were among the most common entities. In 56% of cases, the diagnosis was made by MRI, in 5% by cerebrospinal fluid puncture (LP) alone, and in 39% by both MRI and LP. The median overall survival (OS) of the cohort was 2.77 months [95% CI: 2.27 - 4.20]. Patients who received systemic after diagnosis of LMD, either chemotherapy (n=26), targeted therapies (n=21) or checkpoint inhibitors (n=9) showed increase survival as compared to respective control patients. The only independent prognostic factors at diagnosis of LMD were presence of lung cancer (HR: 2.36 [95% CI: 1.28 - 4.4], p=0.006) and melanoma (HR: 2.30 [95% CI: 1.27 - 4.2], p=0.006). Local or systemic treatment modalities before LMD diagnosis were not associated with survival. CONCLUSION This study provides insights into the complex treatment modalities for LMD patients, both in terms of prior therapies and therapies after diagnosis of LMD. These results underscore the need for large prospective multi-center registries and interventional studies to further improve interdisciplinary and personalized therapy for these patients.
P02.07.B FIBROBLAST ACTIVATION PROTEIN EXPRESSING MESENCHYMAL CELLS INFLUENCE T CELL ABUNDANCE AND FUNCTION IN GLIOBLASTOMA
Authors: N Ternerova, M Houdova Megova, T Buna, T Svablova, B Vymolova, E Balaziova, Z Vanickova, E Krepela, P Hrabal, R Tomas, D Netuka, P Busek, A Sedo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastomas (GBMs) are aggressive brain tumors with strong immunosuppressive properties. In epithelial cancers, mesenchymal cells expressing fibroblast activation protein (FAP) play an important role in modulating the T cell response. We have recently shown that FAP+ mesenchymal cells are present in human GBMs. The aim of this study was to determine their effect on T cell abundance and function. MATERIAL AND METHODS GBM tumors (16 samples) were mechanically and enzymatically dissociated and analyzed for immune cell subpopulations by flow cytometry. Expression of T cell related genes was analyzed by qRT-PCR in GBMs selected based on FAP protein concentration determined by ELISA (14 FAP high [upper tercile], 16 FAP low [lower tercile]). Immunohistochemistry (IHC) was used to compare the number of CD3+, CD4+, and CD8+ T cells in GBMs with high (upper tercile, n=21) and low abundance of FAP+ stroma (lower tercile, n=20). Co-localization of FAP+ mesenchymal cells and CD3, PD-L1 and PD-L2 was evaluated by immunofluorescence in frozen sections. 8 FAP+ mesenchymal and 3 glioblastoma stem-like cell cultures were derived from human GBMs and PD-L1 and PD-L2 expression was determined using ELISA. Peripheral blood mononuclear cells were isolated from healthy donors´ buffy coats. Proliferation of stimulated T cells in conditioned media from FAP+ mesenchymal cells was analyzed by flow cytometry. RESULTS The percentage of T cells in CD45+ cells from GBMs positively correlated with FAP expression. Expression of the T cell inhibitory molecule PD-L2 was higher in FAP high GBMs. Immunohistochemisty revealed that the numbers of CD3+ and CD8+ T cells were higher in GMBs with a high abundance of FAP+ stroma and T cells were frequently in close proximity to FAP+ mesenchymal cells, which were often PD-L2 positive. In vitro, FAP+ mesenchymal cells expressed more PD-L2 than glioblastoma stem-like cells. T cell proliferation was decreased after exposure to conditioned media from FAP+ mesenchymal cells. CONCLUSION FAP+ mesenchymal cells influence T cell abundance in GBMs and may affect T cell functions by limiting their proliferation via soluble factors or cell-cell contact. Acknowledgment: This work was supported by the National Institute for Cancer Research (LX22NPO5102), the Center for Tumor Ecology (CZ.02.1.01/0.0/0.0/16_019/0000785), Charles University project GAUK 365022 and Cooperatio Program Oncology and Haematology“.
OS06.5.A ACCURATE AND COMPREHENSIVE EVALUATION OF MGMT PROMOTER METHYLATION BY NANOPORE SEQUENCING
Authors: S Halldorsson, R M Nagymihaly, H Leske, P Brandal, I Panagopoulos, M Lund-Iversen, A Patel, F Sahm, E O Vik-Mo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter region is essential in evaluating the prognosis and predicting the drug response in patients with glioblastoma (GBM). In this study, we evaluated the utility of using nanopore long-read sequencing as a method for assessing methylation levels throughout the MGMT CpG-island, compared its performance to established techniques, and demonstrated its clinical applicability. MATERIALS AND METHODS We analysed 165 samples from CNS tumours, focusing on the MGMT CpG-island using nanopore sequencing. Oxford Nanopore Technologies (ONT) MinION and PromethION flow cells were employed for single sample or barcoded assays, guided by a CRISPR/Cas9 protocol, adaptive sampling or as part of a whole genome sequencing assay. Methylation data obtained through nanopore sequencing were compared to results obtained via pyrosequencing and methylation bead arrays. Hierarchical clustering was applied to nanopore sequencing data for patient stratification. RESULTS Nanopore sequencing displayed a strong correlation (R² = 0.91) with pyrosequencing results for the four CpGs of MGMT analysed by both methods. The MGMT-STP27 algorithm’s classification was effectively reproduced using nanopore data. Unsupervised hierarchical clustering revealed distinct patterns in methylated and unmethylated samples, providing comparable survival prediction capabilities. Nanopore sequencing yielded high-confidence results in a rapid timeframe, typically within hours of sequencing, and extended the analysis to all 98 CpGs of the MGMT CpG-island. CONCLUSIONS This study presents nanopore sequencing as a valid and efficient method for determining MGMT promotor methylation status. It offers a comprehensive view of the MGMT promoter methylation landscape, which enables the identification of potentially clinically relevant subgroups of patients. Further exploration of the clinical implications of patient stratification using nanopore sequencing of MGMT is warranted.