tbuckley/cabot-search huggingface dataset:
JS03.7.A COMBINATION OF CDK4/6 AND MEK INHIBITION INCREASES ANTITUMOR EFFECTS IN PEDIATRIC HIGH-GRADE GLIOMA HARBORING BRAF MUTATION AND CDKN2A/B LOSS
Authors: L Mayr, L Mager, A Lang, S Madlener, L Gabler, K Bruckner, S Machreich, C Jaunecker, D Senfter, D Kirchhofer, A Lämmerer, G Zeitler, C Dorfer, C Haberler, K Schwark, B Lau, L Müllauer, C Koschmann, W Berger, J Gojo, D Lötsch-Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade gliomas (pHGG) comprise a heterogenous group of tumors characterized by rapid growth and dismal overall survival. Besides maximum safe resection, irradiation and chemotherapy, molecularly-defined therapeutic interventions are still missing. BRAFV600E mutations are detected in 5-10% of pHGG and this subgroup frequently harbors a concurrent homozygous CDKN2A/B loss. Taking advantage of those molecular alterations is of utmost importance to improve overall survival in these patients. Thus, we hypothesize that a combination of MEK and CDK4/6 inhibition lead to prolonged anti-tumor effects in this patient subgroup when compared to monotherapy. MATERIAL AND METHODS Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the efficacy of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combined with the MEK inhibitor trametinib. Drug response, induction of apoptosis, cell cycle alterations and senescence were evaluated upon short- and long-term exposure using cell-based assays. Effects on intracellular signaling cascades were determined by western blot and immunostainings in cell and patient-derived xenograft (subcutaneous and orthotopic) models. Clinical efficacy of combined treatment was further investigated in one patient suffering from progressive metastatic BRAF-altered anaplastic pleomorphic xanthoastrocytoma (aPXA). RESULTS Besides trametinib, the investigated cell models showed the highest sensitivity to abemaciclib, thus we assumed that combination of these two inhibitors would be most suitable in vitro. The simultaneous application of both drugs induced apoptosis and the effect on tumor cell senescence was even superior with the combined treatment. Regarding signal transduction, solely the combination of MEK and CDK4/6 inhibitors reduced PI3K activation at the level of S6. To confirm our findings, in vivo experiments in PDX models were conducted. Significantly increased overall survival and antitumor effects were observed with the combination of both inhibitors when compared to single-agent treatment. Corroboratively, one patient suffering from progressive metastatic aPXA with BRAF mutation and CDKN2A/B loss was successfully treated with trametinib and ribociclib showing stable diseases for two years. CONCLUSION Summarizing, our results suggest that combined treatment with MEK and CDK4/6 inhibitors represent a promising treatment strategy in pHGG harboring simultaneous BRAF mutation and CDKN2A/B loss.
P22.15.B THE DEVELOPMENT OF C-SMART: A NOVEL COGNITIVE REHABILITATION AND MINDFULNESS INTERVENTION FOR PATIENTS WITH BRAIN TUMORS
Authors: S E Braun, G Zarrella, A Fox, A Loughan, A Lanoye, M Parsons, W Beach, O Palesh, F Moeller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients diagnosed with brain tumors experience significant cognitive sequelae, yet they remain underrepresented in behavioral intervention research. We present the development and initial results from the pilot study of C-SMART (Cognitive Strategies, Mindfulness, and Rehabilitation Therapy), an integrated cognitive rehabilitation and mindfulness intervention for patients with brain tumor and mild cognitive decline. We incorporated key stakeholders and content experts’ opinions as a critical first step in developing empirically supported treatments for these underserved patients. We also present preliminary feasibility and acceptability data from an ongoing single-arm pilot study. METHODS Following the NIH Stage Model for Behavioral Intervention Development, a Stage Ia study convened two expert advisory boards (EABs), one comprised of brain tumor patients and their caregivers (n=4) and another of neuro-oncology professionals (n=5), to review evidence-based cognitive rehabilitation and mindfulness intervention manuals in other medical populations, identify topic applicability, determine medical relevance, and discuss necessary adaptations for patients with brain tumor. Then, a Stage 1a pilot trial was opened to investigate feasibility (rates of screening, eligibility, enrollment) and acceptability (satisfaction and intervention recommendations) of the resultant, newly developed C-SMART manual and research procedures. RESULTS Both EABs recommended adaptations to existing cognitive rehabilitation and mindfulness manuals to meet the distinct needs of patients with brain tumor. As a result, C-SMART’s key components include: 1) neurocognitive evaluation to inform the chosen cognitive rehabilitation strategies, 2) tailored goal-setting to each individual, 3) self-compassion training in the face of cognitive slips, 4) neuropsychological education and strategy training with consideration of disease and treatment characteristics, 5) mindfulness practice prior to strategy use, and 6) caregiver participation. To date, 69% of 16 interested individuals were screened (n=11), 82% were eligible (n=9), and, of those, 89% enrolled (n=8), with 75% also enrolling a caregiver (n=6). Currently, 50% are off trial with a completion rate of 80%. Those who have completed C-SMART have found it beneficial (100%) and would recommend to others (100%). CONCLUSION C-SMART is the first consensus-supported, individualized, mindfulness-based, cognitive rehabilitation intervention in neuro-oncology. Initial results support feasibility and acceptability of C-SMART for those diagnosed with brain tumors. The current preliminary results encourage the continued optimization and investigation of C-SMART.
P19.16.A THE EFFECT OF TARGETING CCNB1 ON THE RADIOSENSITIVITY OF MALIGNANT MENINGIOMA
Authors: Z Gong, P Ma, D Zhou, T Xu, Y Fang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND While most meningiomas are benign with favorable outcomes, malignant meningiomas are challenging due to high recurrence rates. The standard treatment involves surgical resection followed by radiotherapy. However, radiotherapy resistance is common, underscoring the need for novel targets to improve radiotherapy outcomes. Cyclin B1 (CCNB1) serves as a key regulator at the G2/M checkpoint of the cell cycle. It plays a significant role in DNA damage repair pathways, intimately linked to various cancers’ development and radiosensitivity. MATERIAL AND METHODS 87 meningiomas (15 WHO Grade I, 63 WHO Grade II, 9 WHO Grade III) and 9 normal dural tissue microarrays were constructed for immunohistochemical and subsequent survival analyses. The malignant meningioma cell line IOMM-Lee was used to develop CCNB1 knockdown and overexpression models. In vitro assays included cell migration, proliferation, clonogenicity, apoptosis, cell cycle analysis, and DNA damage repair pathway assessments. In vivo, CCNB1’s impact on radiosensitivity was evaluated using an orthotopic meningioma model in nude mice, assessing post-irradiation tumor growth through bioluminescence imaging, and survival rates were analyzed. RESULTS Immunohistochemical analysis on tissue microarrays revealed that CCNB1 expression was minimal in normal dural tissues but significantly elevated in meningioma tissues, with higher expression particularly noted in high-grade tumors compared to low-grades. Survival analysis indicated that high CCNB1 expression correlates with a shorter progression-free survival (PFS) in patients. In vitro, CCNB1 knockdown in IOMM-Lee cells markedly reduced migration and proliferation compared to controls. Conversely, CCNB1 overexpression led to increased migration and proliferation compared to controls. The apoptotic rate in knockdown cells increased significantly post-irradiation to 11.43±0.40% from 6.27±0.34% in controls (p &amp;lt; 0.01). Additionally, a pronounced increase in G2/M phase arrest was observed, with cells exhibiting 66% in G2/M phase at 8 hours post-irradiation, compared to 48% in controls, indicating enhanced radiosensitivity. In vivo studies further confirmed these findings, demonstrating significant tumor growth suppression and prolonged survival in xenografted nude mice with CCNB1 knockdown tumors. These comprehensive results underline the significant role of CCNB1 in modulating DNA damage response pathways, particularly the ATR-Chk1 pathway, and its potential as a prognostic marker and therapeutic target in high-grade meningiomas. CONCLUSION CCNB1 is a pivotal factor in the radiosensitivity of malignant meningiomas. Targeting CCNB1 may improve the efficacy of radiotherapy, providing a potential therapeutic avenue to combat the high recurrence and mortality rates of these tumors.
P23.07.B POSTOPERATIVE TRAJECTORIES OF SELF-PERCEIVED COGNITIVE FUNCTION AND ASSOCIATED FACTORS IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: E Butterbrod, G Rutten, M Sitskoorn, K Gehring
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cognitive dysfunction profoundly impacts daily lives of patients with brain tumors. Standardized tests are key to its objective assessment, but fail to fully capture patients’ experience of cognitive (dys-)function in day-to-day activities. The way in which this self-perceived cognitive function (SPCF) changes over the disease course is not clear, and limited insights into factors that contribute to SPCF trajectories hinder early risk identification and intervention. This study aimed to identify latent trajectories of SPCF and associated factors in patients with meningioma or glioma. MATERIAL AND METHODS Patients with meningioma or glioma reported SPCF through the Cognitive Failures Questionnaire (CFQ) as part of a neuropsychological screening within two weeks before surgery, three months post-surgery and one year post-surgery. A higher CFQ score indicated more severe complaints. An unsupervised latent class growth (LCG) model was used to identify classes of patients based on the longitudinal trajectory of their CFQ scores. For comparative purposes, a second LCG model was applied to longitudinal data with similar intervals from healthy controls (n=158). Diagnosis, sociodemographics, anxiety and depression symptomatology, general and activity-related fatigue, and the presence of cognitive impairment (Z-score &amp;lt;-1.5 on ≥ 1 cognitive test) before surgery were adopted as external predictors of patients’ trajectories, based on proportional classification. RESULTS In total, 159 patients (meningioma, n=103; glioma, n=56 [60% IDH-1 mutated]) were included based on availability of ≥2 consecutive CFQ assessments. A four-class LCG model, i.e., four distinct trajectories, showed the best fit among patients. Trajectories were interpreted as follows: a moderate complaint load showing a mild increase across each timepoint (62% of the sample), a low and stable complaint load (20%), a high load with a late increase between 3 and 12 month follow-up (11%) and a low load with a similarly late increase (8%). In controls, three trajectories with low (46%), low-moderate (31%) and moderate (23%) complaint loads existed, all of which showing a mild decrease over time. After false discovery rate correction, pre-surgical general and activity-related fatigue were related to patients’ CFQ trajectories, with stronger fatigue particularly distinguishing the two trajectories with late increases from the others. CONCLUSION Patients showed four distinct trajectories of SPCF up to one year after surgery. Trajectories were characterized by different, but mostly increasing, complaint loads. While similar across diagnoses, patients’ trajectories were seemingly different from those of controls. Among early factors, fatigue types seem particularly related to the course of SPCF. Potentially diverse trajectories of domain-specific complaints should be investigated.
P18.18.B EFFICACY AND FAILURE PATTERNS OF SIMULTANEOUS INTEGRATED BOOST INTENSITY- MODULATED RADIOTHERAPY FOR WHO GRADE IV GLIOMAS
Authors: X Du, L Huo, M Deng, Y Chen, S Wu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We analyzed the efficacy and failure patterns of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with WHO grade IV gliomas. MATERIAL AND METHODS From June 2016 to December 2020, 246 newly diagnosed patients with histologically-proven WHO grade IV gliomas were retrospectively analyzed. All patients were treated with post-operative SIB-IMRT at a total planned dose of 60 Gy for gross tumor volume (PGTV) and 50 Gy for clinical target volume (PCTV), to be given in 28-30 fractions. On progression, recurrent tumors were classified as in-field, marginal, or distant, relative to the 95% isodose line of PGTV. RESULTS Median OS and PFS was 23.5 (95% CI 19.9-27.1) and 13.4 (95%CI 11.6-15.2) months, respectively. One-year OS and PFS was 86.4% and 56.1%, respectively. Multivariate analysis identified female sex, gross tumor resection and MGMT promotor methylation as independent predictive factors for better PFS and OS. Of the 98 patients with documented recurrences, 83 patients (84.7%) had an in-field component of treatment failure, 7 (7.1%) had a marginal component, and 18 (18.4%) had a distant component. Seventy-four patients (75.5%) had in-field only recurrence. Of the 100 documented local recurrent lesions, 87% lesions were located within 2 cm-margins of the original GTVs. Patients with multifocal disease were more likely to experience marginal failures (P = 0.041). CONCLUSION Post-operative SIB-IMRT is a feasible and safe treatment option for WHO grade IV gliomas with a low rate of marginal recurrence and good survival outcomes.
P18.39.A SEIZURE PROPHYLAXIS IN GLIOMA SURGERY (SPRING): A MULTI-CENTRE, UNBLINDED, RANDOMISED TRIAL
Authors: M D Jenkinson, H Bulbeck, A Rooney, G Thompson, J Burns, T Robinson, L Vale, S Erridge, C Watts, R Grant
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND 50-80% of all glioma patients will suffer from seizures during their lifetime. Over half of these patients will have drug resistant seizures. Seizure risk is increased peri-operatively, at tumour progression, and shortly before death. Current guidelines do not support routine use of prophylactic peri-operative anti-epileptic drugs (AED) in seizure naïve patients; despite this, levetiracetam is frequently prescribed for this indication. The aim of this trial was to determine the clinical and cost effectiveness of prophylactic levetiracetam in seizure naïve patients undergoing surgery for a glioma at reducing the risk of seizures. MATERIAL AND METHODS Seizure naïve patients with newly diagnosed glioma undergoing surgery (biopsy or resection) were randomised (1:1) to receive 12 months prophylactic levetiracetam or no prophylaxis at 14 neurosurgery and neuro-oncology units in the UK. Participants received standard of care neurosurgery and neuro-oncology treatment and were followed until death or for a maximum of one year. The primary outcome was one year risk of first seizure analyzed using a logistic regression model and intention to treat analysis. Outcomes were analyzed by intention-to-treat. The target accrual was 804 participants. This trial was registered with ISRCTN 49474281. RESULTS Between Oct 10, 2019 and Aug 30, 2022, we randomised 96 patients, from 24 to 79 years of age, to levetiracetam (n=49) or no prophylaxis (n=47). Due to slow accrual during the Covid-19 pandemic the trial closed early. In the levetiracetam group there were 43 high grade glioma (HGG) and 6 low grade glioma (LGG), and in the no prophylaxis group there were 43 HGG and 4 LGG. Seventeen (35%) of 49 patients randomised to levetiracetam had a seizure, compared to 15 (32%) of 47 patients randomised to no prophylaxis (OR 1.25, 95%CI 0.49-3.21, p=0.64). Median time to first seizure was 4.8 months in the levetiracetam group and 3.0 months in the no prophylaxis group. In the levetiracetam group 20 (41%) of 49 patients died within 12 months (median overall survival 6.8 months; range 0.2-11.9), and in the no prophylaxis group 15 (32%) of 47 patients died within 12 months (median 4.7 months; range 0.1-12.0). There were no serious adverse events or suspected unexpected serious adverse events related to levetiracetam. CONCLUSION Due to poor accrual caused by the Covid-19 pandemic the SPRING trial closed early and is therefore underpowered. Based on the limited data there was no difference in the 12 month seizure risk in the prophylaxis and no prophylaxis patients undergoing surgery for newly diagnosed glioma. The role of prophylactic anti-epileptic drugs remains undefined.
OS06.8.A PROSPECTIVE STUDY ON THE IMPACT OF THE GUT MICROBIOME COMPOSITION TO PATIENT’S RESPONSE TO STANDARD TREATMENT IN PCNSL
Authors: I Hernández-Verdin, E Kirasic, K Mokhtari, N Barillot, L Rincón de la Rosa, E Sourdeau, Y Abada, M Le Tarff-Tavernier, S Choquet, C Houillier, K Hoang-Xuan, A Alentorn
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gut microbiota has gained attention as a potential modulator of occurrence, progression, and response to cancer therapy, with host immune regulation as one potential mechanism. Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma whose treatment relies on a high-dose methotrexate (HD-MTX) regimen with or without consolidation. However, whether there is a specific microbiota composition association with treatment response and clinical outcomes remains incompletely understood. MATERIAL AND METHODS To identify the relationship between gut microbiome composition and response standard treatment in patients with PCNSL, we conducted a prospective study of PCNSL patients, included in the clinical trial NCT02313389 and the ancillary study NCT04253496 from 2020 to 2023 (patients aged more than 60 years, HD-MTX based induction and randomized HD-MTX-based maintenance versus follow-up without consolidation). Stool and cerebrospinal fluid (CSF) samples (n=49) were collected before (n=35) or after (n=14) therapy initiation to perform metagenomic and flow cytometry analyses. Clinical data, including treatment response, progression-free survival (PFS), and overall survival (OS), were collected and correlated with microbiome composition and immune cell content in CSF. RESULTS Analysis of paired samples (before versus after HD-MTX), revealed slight changes in microbial composition, especially the loss of a bacteria belonging to the Verrucomicrobiota Phylum. Unsupervised clustering on microbial data revealed two microbial communities associated with significantly distinct PFS (33.65 vs 7.60 months, p=0.001) and OS (36.75 vs 23.95 months, p=0.005) in PCNSL patients. Linear discriminant analysis Effect Size and differential abundance analysis between these communities revealed a specific organism belonging to the Bacteroidota Phylum whose enrichment is associated with improved OS and PFS at both univariate and multivariate models. Further stratifying patients according to this bacteria content showed an association with CD8 T cell infiltration to the CSF, suggesting a link between host immune cell regulation and gut microbiome composition. CONCLUSION Our findings suggest that gut microbiome communities may influence responses to standard treatment and clinical outcomes in PCNSL patients. Moreover, the identification of this particular microorganism could potentially provide a basis for patient stratification and guide personalized therapeutic strategies. We are currently working in a validation cohort to reinforce our findings and to elucidate the mechanisms underlying the interaction between the gut microbiome, the host immune regulation, and the treatment response.
Piezo, Nephrocyte Function, and Slit Diaphragm Maintenance in Drosophila
Authors: Yunpo Zhao, Jianli Duan, Iden D. Han, Joyce van de Leemput, Patricio E. Ray, Zhe Han
Journal: Journal of the American Society of Nephrology (2024)

Background: The Piezo gene encodes a highly conserved cell membrane protein responsible for sensing pressure. The glomerular kidney and the slit diaphragm filtration structure depend on pressure for filtration. However, how Piezo is involved in kidney function and in maintaining the slit diaphragm filtration structure is not clear. Methods: We used Drosophila pericardial nephrocytes, filtration kidney cells with striking structural and functional similarities to human podocytes, in a loss-of-function model (mutant and knockdown) to study the roles of Piezo in nephrocyte filtration and function. Results: Piezo is highly expressed at the invaginated membranes (lacuna channels) of nephrocytes. A Piezo loss-of-function mutant showed significant nephrocyte functional decline. Nephrocyte-specific silencing of Piezo showed disruption of the slit diaphragm filtration structure and significant functional defects. Electron microscopy showed that silencing Piezo in nephrocytes leads to reduced slit diaphragm density and abnormal shape of lacuna channels. Moreover, the Piezo-deficient nephrocytes showed internalized slit diaphragm component proteins, reduced autophagy, increased ER stress, and reduced calcium influx. Conclusions: Together, our findings suggest that Piezo plays an important role in the calcium homeostasis of nephrocytes and is required for maintaining nephrocyte function and the slit diaphragm filtration structure.
P01.01.A CHARACTERIZATION OF GLIOBLASTOMA’S MIGRATION HETEROGENEITY THROUGH A PATIENT-DERIVED 3D MODEL
Authors: A Pujol-Castiblanque, T Savin, A E Markaki, R Mair
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GB) is an aggressive brain cancer with an average survival of 14.6 months. Effective treatment is hindered by GB’s plasticity and invasive phenotype. Little is known regarding the molecular mechanisms driving invasion heterogeneity. MATERIAL AND METHODS We developed a bioengineered model of brain-like matrix, which together with patient-derived spheroids, allows study of GB’s migration in vitro. Twenty patient-derived cell lines with different intrinsic (genomic, transcriptomic) characteristics in several extrinsic (extracellular matrix stiffness, hypoxia vs normoxia) conditions were tested. RESULTS Time-lapse video analysis identified recurrent migratory phenotypes across the cell lines. GB’s subtype- proneural, neural, classical, and mesenchymal- did not cluster cell lines with similar migratory phenotypes. An increase in matrix stiffness led to a switch in migratory phenotype in certain cell lines. CONCLUSION We have identified finite and periodic migration phenotypes of GB in different conditions.