tbuckley/cabot-search huggingface dataset:
P13.01.A 11C-METHIONIN PET FOR RADIOTHERAPY TREATMENT PLANNING IN PATIENTS WITH RAPID EARLY PROGRESSION AFTER GLIOBLASTOMA SURGERY: PROSPECTIVE PHASE II TRIAL
Authors: T Kazda, R Lakomy, L Hynkova, P Pospisil, J Vasina, R Belanova, T Prochazka, Z Rehak, J Adam, J Sana, P Burkon, M Slavik, I Selingerova, R Jancalek, P Fadrus, O Kalita, K Polachova, T Stepankova, M Lojova, P Slampa
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiotherapy (RT) is a standard treatment for nearly all glioblastoma patients following initial surgery. Few retrospective studies indicate negative prognostic instances of progression during the planning magnetic resonance (MR) (up to 1 week before initiating RT), termed Rapid Early Progression (REP). The optimal RT management for REP patients remains uncertain. The objective of this prospective phase II trial (NCT05608395) is to assess impact of 11C-Methionine PET used for RT planning in REP glioblastoma patients. It is one of the first prospective clinical interventional trials focused on this specific cohort of patients. MATERIAL AND METHODS We enrolled glioblastoma, IDHwt, or Astrocytoma, IDHmt, WHO grade IV patients, who developed REP characterized by 1) increase in postoperative residuum by ≥ 25%, 2) appearance of new contras enhancing lesion, 3) unequivocal progression of the unresected satelite. Patients received treatment based on the Stupp or Perry protocol. Treatment response was evaluated using RANO criteria. RT target volumes were delineated as follows: Gross tumor volume included tumor cavity, enhancing lesion and 11C-MET PET (1.3 tumor-to-background ratio). The clinical target volume was GTV plus a modified 2cm margin reflecting surrounding organs at risk. Volumetric analyses of different radiotherapy target volume were performed using EclipseTM software including patterns of failure. RESULTS During 12/2020 - 12/2023, total of 31 patients were enrolled (16 treated via abbreviated RT course); median age 60 years, ECOG 0-1 in 28 patients, median follow up 20 months. No effect of 11C-MET PET - based radiotherapy treatment planning of GBM patients with REP was observed on PFS (median 3.4 months comparing to 4.9 in historical control cohort) and OS (12.3 months comparing to 15.7 months). Median MET volume was 7.3cm3 (43% of MRI volume), MET avidity was presented in 7 patients et least 1cm beyond MRI volume. Central recurrence was presented in 87% patients. CONCLUSION The optimal treatment of patients with REP is unknown and needs to be studied in more details including dose escalation studies with reduced target margins potentialy directed also by aminoacid PET examination. Adjustment of target radiotherapy volumes using 11C-MET PET did not lead to improved PFS or OS. Supported by NU20-03-00148.
P02.12.B IMMUNOMODULATORY EFFECT OF MESENCHYMAL CELLS ON T-LYMPHOCYTES IN A 3D SPHEROID MODEL OF GLIOBLASTOMA
Authors: T Šváblová, N Ternerová, M Houdová Megová, B Vymolová, E Balážiová, P Bušek, A Šedo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) represents the most aggressive form of primary brain tumors, typically resulting in a median survival of less than two years. Immunosuppression characterized by macrophage polarization into a protumorigenic phenotype and T cell dysfunction belong to key features of glioblastoma microenvironment. Recently, mesenchymal cells were identified in GBM, but their immunomodulatory effect has not been elucidated yet. This study aimed to establish a 3D GBM spheroid model to investigate the influence of mesenchymal cells derived from GBM patients on the phenotype of human T cells. MATERIAL AND METHODS Glioma stem-like cells (GSCs) and paired mesenchymal cell cultures were derived from 3 human GBMs. CD4+ T-lymphocytes were isolated from buffy coats of healthy donors using Ficoll Paque gradient separation, followed by negative magnetic isolation. T-lymphocytes were activated using anti-CD2, anti-CD3, and anti-CD28 antibodies. 3D spheroids were generated by encapsulating the GSC and T-lymphocytes in extracellular matrix (Geltrex) with or without mesenchymal cells. After co-culture for 5-days, the spheroids were dissociated, and the expression of T-cell activation markers CD69 and CD25, along with immune checkpoint molecules LAG3, TIM-3, and PD-1 was analyzed by flow cytometry. Immunohistochemistry was performed on frozen sections of the spheroids to investigate the spatial distribution of the cell populations. RESULTS In spheroids with mesenchymal cells, CD4+ T-lymphocytes exhibited elevated expression of the activation marker CD69, whereas no significant changes were observed in CD25 expression. PD-1 expression was higher in spheroids containing mesenchymal cells, whereas no difference was noted in TIM3 and LAG3 expression levels. Uniform distribution of glioblastoma-derived cells was revealed in spheroids containing glioma stem-like cells with and without mesenchymal cells and T-lymphocytes did not exhibit any specific spatial distribution pattern. CONCLUSION We have successfully established a 3D spheroid model to investigate the impact of mesenchymal cells on the GBM microenvironment. Our findings suggest that mesenchymal cells can influence the phenotype of CD4+ T-lymphocytes in glioblastoma. This research was funded by project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) by the European Union - Next Generation EU, and Charles University Cooperatio Program,,Oncology and Haematology“.
P16.07.A STUDYING NEUROBLASTOMA TUMOR MICROENVIRONMENT THROUGH A NOVEL PRE-CLINICAL MODEL
Authors: C Buxbaum, A Deo, B Manobla, S Levin, S Ash, Y Shaked
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neuroblastoma is a pediatric cancer that develops from neural crest cells. It has a dramatically variable course, ranging from very aggressive disease to benign differentiation and even spontaneous regression. In neuroblastoma, a crucial prognostic marker is the distinct cutoff at 18 months of age. Thus, children older than 18 months have a significantly worse prognosis than younger children. This age cutoff was studied thoroughly, but no explanatory mechanism has been found. All current pre-clinical research encompasses models in adult subjects while the development of tumors is greatly impacted by its microenvironment, which varies between young and adult individuals, thus creating disparate biological conditions. Therefore, the development of age-relevant neuroblastoma models is of great interest, especially when age is a major prognostic factor. MATERIAL AND METHODS C57BL/6 mice aged 12-days (young) and 8-weeks (adults) were used to reflect the different age groups, where 12-day-old mice correspond to children younger than 18-month. Mice were orthotopically implanted into the adrenal gland with 0.5 million 9464D-luciferase tagged murine neuroblastoma cells. Tumor growth assessment was performed once a week using micro-ultrasound to estimate tumor volume. At the endpoint, tumors were harvested and prepared for histopathological and immune characterization using flow and mass cytometry. RESULTS Tumors exhibited divergent growth patterns when comparing young and adult mice. In the initial week following implantation, tumors in young mice showed inhibited growth in contrast to those in adult mice (0.65mm3 vs. 5.44mm3 p=0.005). Following this initial phase, tumors in young mice started to grow rapidly, eventually leading to an equal final tumor load in both groups. The tumor characteristics were notably different between the groups. For example, the tumor immune cell infiltration exhibited a significantly increased number of B cells (3.598 vs. 10.01 p=0.01), CD4 cells (31.2 vs. 41.24 p=0.32) in young mice. Conversely, adults exhibited a higher number of G-MDS’c (32.2 vs. 13.856 p=0.005). CONCLUSION Our study reveals a delayed development of neuroblastoma in young mice during the early post-implantation phase. This observation mimics the natural biological behavior of this disease and potentially emulates the spontaneous regression seen in children under 18 months-old. In our investigation of the tumor microenvironment, we analyzed immune cell populations, revealing notable differences between the age groups. Further and updated findings are forthcoming. This study proposes a new approach for neuroblastoma research and potentially for all preclinical studies of pediatric cancer.
P25.01.B ASSOCIATION BETWEEN EXPOSURE TO AIR POLLUTION AND BRAIN TUMOR INCIDENCE IN THE UNITED STATES
Authors: M Price, C Neff, C Ballard, H Hsu, C Kruchko, J S Barnholtz-Sloan, Q T Ostrom
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Air pollution contains known human carcinogens. Prior studies evaluating an association between pollution exposure and central nervous system tumors (BT) are inconclusive. Using multiscale geographically-weighted linear regression (MGWR), we investigated the association between average county-level air pollution and geographic variation of glioblastoma and tumors of the meninges (ToM) incidence in the United States (US). MATERIAL AND METHODS Annual county-level air pollution from 2000-2016 was obtained from the Environmental Protection Agency’s Air Quality Index (AQI) which analyzes daily ambient air concentration for ozone and particulate pollution in participating US counties. County-level annual age-adjusted incidence rates (AAAIRs) of glioblastoma and ToM per 100,000 population (&amp;gt;20 years old) between 2004-2020 were estimated using data from the Central Brain Tumor Registry of the United States, which aggregates data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Counties with missing data were excluded. The 2016-2020 American Community Survey data were used to identify county sociodemographic and average exposure indoor/workplace pollution. Spatial patterns were visualized using Moran’s I measure and the global G-statistic analyses computed in R. Variables were mean normalized and regressed in a MGWR model using county centroids in the Spatial Analysis Research Center’s MGWR 2.2 program to assess geographically-varying effects of the independent variables. RESULTS Data was available from 1,109 counties. Significant spatial clusters and outlier counties were identified for both tumor types (glioblastoma Moran’s I=0.126, p &amp;lt;0.001, G-statistic=0.003; ToM Moran’s I=0.487, p &amp;lt;0.001, G-statistic=0.003). When restricted to significantly high/low counties (p &amp;lt;0.05), low-rate clustering for glioblastoma was observed in Alaska, Arizona, Virginia, and parts of the central mid-west. High-rate clustering was observed in parts of the north, mid-west, and northeast. ToM showed low-rate clustering in northwest, Virginia, Kansas, and parts of the north mid-west, with high-rate clustering in Washington, Utah, Colorado, and Wisconsin. MGWR model showed that in both tumor types, increased AQI (glioblastoma mean βMGWR 0.06; MoT mean βMGWR 0.12) was associated with increased tumor incidence. This association was present in 45% and 59% of counties, respectively. CONCLUSION This is the first study applying a MGWR model to assess geospatial associations between ambient air pollution and BT incidence, allowing for magnitude, direction, and significance of coefficients to change across geographic space. and allows for more accurate identification of geographic regions affected by potential BT health disparities.
P11.03.A BRAIN METASTATIC LESIONS IN THE FRONTAL LOBE NEGATIVELY IMPACT PATIENT ENGAGEMENT
Authors: S David, F Cialdella, S H J Nagtegaal, E E van Grinsven, M E P Philippens, J J C Verhoeff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) significantly affect patients’ cognition, which can alter their ability to make informed decisions regarding treatment or engagement in scientific studies. In the COIMBRA (NCT05267158) study, we prospectively collect data from patients with BMs, including clinical assessments, radiological data, and patient-reported outcomes (PROs) pre- and post-radiotherapy. After enrolling in the trial, patients can make a number of decisions to participate in data collection efforts, such as engaging in QoL questionnaires. Here, we explore how lesion distributions or the disconnected white matter, known as the disconnectome, correlates with patient consent to QoL questionnaires. MATERIAL AND METHODS Between April 2019 and April 2023, 377 patients with BMs gave consent for COIMBRA and were referred for stereotactic radiosurgery. Of them, 276 consented to provide PROs, while 101 chose not to participate. The T1 MRIs, along with the gross tumor volumes (GTVs) were nonlinearly registered the MNI brain template, using EasyReg from Freesurfer. We used the BCBtoolkit to calculate the disconnected white matter areas. Voxelwise statistical comparison between the PRO consented and non-consented groups was performed with PALM. Family-wise error rate correction was performed to adjust for multiple comparison correction, p-value &amp;lt;0.05 was applied for significance. RESULTS The lesion-based analyses revealed a cluster of 3098 mm3, which significantly associated with PRO non-consent, predominantly located in the frontal lobe, specifically within the Frontal Pole (FP) and Cingulate Gyrus (CG), as well as part of the right Middle FG and the Insular Cortex. The disconnectome analysis identified a cluster of 7718 mm3, with disconnections in both sides of the anterior division of the CG, extending to FP and Superior FG. White matter tracts in the Anterior Thalamic Radiation and Forceps Minor are disrupted on both sides. The prefrontal subthalamic regions on both sides also show disconnections. There are no regions identified by either analysis method that show more lesions in the PRO consented group. CONCLUSION BM lesions in specific frontal lobe regions and disruptions in related white matter tracts significantly lowered patients’ consent fill-in QoL questionnaires. Data collection in research studies, particularly concerning aspects of patients’ mental health, typically relies on voluntary acts such as neuropsychological assessments or the collection of PROs. However, when patients cannot or are unable to participate in such efforts, due to their condition influenced by for example the lesion location, the results are likely to be biased. Clinicians may consider these ‘neural barriers’ in the design of studies and data collection methods, potentially integrating more observational or caregiver-reported measures to obtain evaluation of the patient’s condition.
P01.09.B IDENTIFICATION OF TIME-DEPENDENT PHENOTYPIC SHIFTS IN PATIENT-DERIVED GLIOMA STEM-LIKE CELLS AFTER CHEMORADIOTHERAPY
Authors: L Van Eupen, Y De Visser, C Bravo Gonzalez-Blas, B Cole, J Loers, M Derweduwe, A Claeys, K Tabury, I Primac, V Vermeirssen, F De Smet, R Quintens
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma remains among the deadliest tumors without a suitable cure. The failure of virtually all clinical trials from the past 20 years can be attributed to the extensive (epi)genetic and phenotypic heterogeneity within and across GBM patients but also to the extensive plasticity of cancer stem-like cells that can easily adapt and drive resistance to treatment. A fundamental understanding of this plasticity and its underlying mechanisms is still largely missing, but it remains pivotal to identify suitable targets that can prevent cells from surviving treatment. METHODS In this project, we start by defining the landscape of standard-of-care-induced plasticity using multi-omic profiling of patient-derived glioma stem-like cells (PDGSCLs) after radiation therapy (RT, 2 Gy) and temozolomide (TMZ, 150 μM). In a pilot experiment, bulk RNA sequencing was performed on six PDGSCLs at different time points after RT+TMZ (16 hours, 3 days, 10 days). A single-cell RNA sequencing (scRNAseq) experiment has been set up in a similar fashion, including the 16-h and 3-d time points. RESULTS Analysis of the bulk transcriptomic data, including module scoring based on transcriptional cell states defined by Neftel et al. (2019), revealed a time-dependent shift in phenotype after treatment. Two of the six PDGSCLs did not show clear indications of plasticity, while two others showed minor shifts in phenotype and two PDGSCLs displayed clear shifts towards the mesenchymal (MES) phenotype, with one of them reverting back to its original state after 10 days. Pathway analysis additionally indicated an upregulation of MES-associated processes including ameboidal-type cell migration, cell-substrate adhesion and wound healing, with differentially upregulated pathways between sensitive and resistant PDGSCLs that both displayed MES-shifts. CONCLUSIONS Our results confirm that treatment can induce phenotypic changes in PDGSCLs in a cell line-specific manner, suggesting different mechanisms can lead to the enrichment of the same phenotype. Moreover, our time course data highlights that the timing of read-out is important as well, and comparing tumors at diagnosis vs. at recurrence might not suffice to fully understand this plastic behavior, for which these intermediate time points are more relevant. The scRNAseq experiment is currently ongoing and will inform on the gene regulatory networks responsible for the observed shifts while also highlighting the heterogeneity within these PDGSCLs with greater resolution, as seen in the patient population. This project is funded by FWO (11B2323N) and the Foundation against Cancer (F/2022/2026).
OS10.6.A THE IMPACT OF PATIENT-REPORT OUTCOME QUESTIONNAIRE PARTICIPATION ON OVERALL SURVIVAL IN PATIENTS WITH BRAIN METASTASES
Authors: S David, F Cialdella, S H J Nagtegaal, E E van Grinsven, M E P Philippens, J J C Verhoeff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The COIMBRA (NCT05267158) is a prospective, observational study of patients with brain metastases (BMs) which collects extensive longitudinal clinical, radiological and patient-report outcome (PRO) data before and after radiotherapy (RT). After enrollment, patients can make decisions whether to participate in additional data collection, for example in providing Quality of Life (QoL) data. Validated questionnaires, such as the EORTC QLQ-C30 among others, are designed to measure different aspects of QoL of cancer patients and thus gain insights into their mental, physical, and social well-being. In this study, we investigate whether patient consent to filling out QoL-questionnaires has an effect on overall survival (OS). MATERIAL AND METHODS We included 377 patients with BMs who were referred for stereotactic radiosurgery (SRS) and enrolled in the COIMBRA study in the UMC Utrecht, between 2019 April to 2023 April. Among them, 276 patients consented to providing PROs, while 101 did not. OS was calculated from the start of RT and analyzed using Kaplan-Meier analysis and Cox regression. RESULTS The median OS for patients who consented to PROs was 17.7 months, significantly higher than the 12.3 months for those who did not consent (log-rank test p=0.008). The effect of PRO consent on OS was significant in both univariate (HR = 0.62; p &amp;lt;0.001) and multivariate Cox regression (HR=0.72; p=0.02), the latter correcting for age, KPS, primary cancer type, chemotherapy, surgery, and time from diagnosis to receiving radiotherapy. The 1-, 2- and 5-year survival rates for the PRO consented vs non-consented were: 68% vs 50%; 46% vs 33% and 34% vs 14%, respectively. CONCLUSION Our results show a significant relationship between patient consent to filling out PRO questionnaires and longer OS in patients with BMs undergoing SRS. This suggests that patient engagement, as measured by willingness to participate in PROs, may be indicative of broader health behaviors linked to improved survival. However, it is important to consider that the act of participation could itself be influenced by underlying factors we did not investigate, which may predispose patients to both decreased engagement and worse outcomes. For example, factors such as lower levels of overall health literacy, lower socioeconomic status, the distribution of the lesions might contribute to lower participation and independently affect survival outcomes. Therefore, while fostering patient engagement remains a promising approach to enhance study involvement, our understanding of the complex interplay between patient characteristics and their participation in care processes must be further studied. These results may indicate that any study for which active patient participation is required might thereby introduce a selection bias for patients with better overall health and expected survival.
OS01.5.A MEASURABLE DISEASE AS BASELINE CRITERION FOR RESPONSE ASSESSMENT IN GLIOBLASTOMA TRIALS - A COMPARISON OF THE MRI-BASED (RANO 2.0) VERSUS PET-BASED (PET RANO 1.0) ASSESSMENT
Authors: K J Müller, R Forbrig, J Reis, L Wiegand, E Barci, S Kunte, L Kaiser, S Schönecker, C Schichor, P Harter, N Thon, L von Baumgarten, M Preusser, N L Albert
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The baseline criterion for response assessment in IDH-wildtype glioblastoma relies on measuring contrast enhancement, known as ‘measurable disease’ on MRI. Recently, criteria based on amino acid PET have been proposed for response assessment in clinical glioblastoma trials (PET RANO 1.0 criteria). Here, we compare ‘measurable disease’ as defined by PET RANO 1.0 criteria with the standard MRI-based RANO 2.0 criteria in patients with newly diagnosed IDH-wildtype glioblastoma. MATERIAL AND METHODS In this retrospective single-center study, we identified patients with newly diagnosed IDH-wildtype glioblastoma who underwent [18F]FET PET and MRI after resection or biopsy (if non-operable) and before chemoradiotherapy. This timepoint aligns with the baseline recommended by PET RANO 1.0. Two independent investigators analyzed ‘measurable disease’ according to PET RANO 1.0 versus MRI-based RANO 2.0 criteria. Additionally, lesion size and uptake intensity, including maximal and mean target-to-background ratio (TBRmax, TBRmean) were assessed. RESULTS We evaluated 132 patients (median age 60.5 years, 40.2% females) with 87 cases after biopsy and 45 after resection. Using RANO 2.0, a total of 49/132 (37.1%) patients had measurable disease (median sum of maximum perpendicular diameters: 36.3mm). However, with PET RANO 1.0, a significantly higher proportion (117/132, 88.6%, p&amp;lt;0.001) had measurable disease (median TBRmax: 3.4; median TBRmean: 2.0; median PET volume: 17.6cm3). None of the 15 patients without measurable disease on PET had measurable disease on MRI, while 68/83 (81.9%) of patients without measurable disease on MRI exhibited measurable disease on PET. Conclusion: PET RANO 1.0 identifies a significantly higher number of patients with ‘ measurable disease’ compared to conventional MRI-based criteria in the perioperative period of newly diagnosed glioblastoma. PET-based assessment may thus serve as a novel baseline parameter for evaluating treatment response and outcome in glioblastoma trials, that may allow enrollment of larger patient populations. Further validation in prospective trials is warranted.