tbuckley/cabot-search huggingface dataset:
P09.17.B TUMOUR SIZE AND OVERALL SURVIVAL IN A COHORT OF PATIENTS WITH UNIFOCAL GLIOBLASTOMA. A UNI- AND MULTIVARIABLE PROGNOSTIC MODELLING AND RESAMPLING STUDY
Authors: K Fatania, R Frood, H Mistry, S C Short, J O’Connor, A F Scarsbrook, S Currie
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Identifying prognostic factors for patients with glioblastoma (GBM) may better stratify patients into different risk groups, and accelerate individualised treatment strategies. One potential prognostic factor is tumour size. This is routinely assessed clinically usually by measurement of the diameter of the enhancing core, but there are now more readily available segmentation algorithms that allow estimation of tumour volume. Published models typically vary in their selection of tumour size in the final model. We aimed to investigate the effect of tumour size on prognosis in an institutional cohort of patients with GBM, and investigate the effect of log-transform and different sample sizes with bootstrap resampling. MATERIAL AND METHODS 279 patients with unifocal IDH-wild type WHO grade 4 GBM (2014-2020) had their tumours segmented using deep-learning and manual correction and diameter measured manually. Institutional data was used to examine any prognostic effect between diameter, core, or whole tumour volume (CV, WV respectively) using Cox proportional hazards models. Data underwent bootstrap analysis (1,000,000 repetitions) to determine if log-transformation and/or changes in sample size had an impact on the chance of detecting a prognostic relationship of size. Multivariable models were adjusted for clinical predictors: age, gender, surgery (biopsy, gross-total, near-total or sub-total resection), MGMT promoter methylation and completion of adjuvant therapy (full Stupp, partial Stupp or none). P-value distribution across all resamples was assessed with a 2-sided Kolmogorov Smirnov (KS) test to ascertain the impact of log-transform and sample size on the chance of detecting a prognostic relationship. RESULTS All models adjusted for surgery were significant (p = 0.016, 0.013 and 0.018 respectively). Diameter adjusted for all clinical predictors was also significant (p=0.03). Log-transformation had a large effect on chances of detecting a prognostic effect of WV, by significantly decreasing the distribution of p-values towards 0.05 or below (KS test &amp;lt;0.05). Multivariable resampling experiments also demonstrated that with increased sample size, the chance of detecting a prognostic relationship of size (diameter, CV or WV) increased, which is the opposite of the expected behaviour for noise variables (i.e. predictors with random association to overall survival (OS)). CONCLUSION This study of a large single institutional cohort of patients with GBM,found: (1)diameter and WV are prognostic of OS in multivariable models, (2) log-transformation increases the chances of detecting a prognostic relationship of WTV with OS, and (3) greater sample sizes increase the chance of finding a prognostic role for tumour size.
P06.02.B DECODING THE DIVERSE SURFACEOME LANDSCAPE IN MALIGNANT BRAIN TUMORS IDENTIFIES TARGET CANDIDATES FOR PERSONALIZED IMMUNOTHERAPY
Authors: A Boukredine, K Gonçalves de Oliveira, H Talbot, V Governa, A Bång-Rudenstam, K Forsberg-Nilsson, J Bengzon, J Malmström, C Welinder, M Belting
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immunotherapies with antibodies, antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor cell-surface antigens (surfaceome), currently revolutionize clinical oncology. Target identification warrants a comprehensive understanding of the surfaceome in individual tumors, and how it is modulated by the tumor microenvironment and conventional treatments. The identification of surfaceome targets has historically focused on differential mRNA expression between tumor and healthy tissues. However, mRNA constitutes a poor surrogate for membrane protein availability. Hence, there is an increasing emphasis on proteomic approaches directed at the elusive plasma membrane proteome. MATERIAL AND METHODS We have developed a new strategy for comprehensive tumor surfaceome profiling (TS-MAP), to unravel the surfaceome makeup in GBM. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. TS-MAP, RNAseq, and WGS were applied on primary GBM cells, cultured in 2D and 3D, with or without tumor mimicking stress conditions (hypoxia, acidosis, irradiation, temozolomide), as well as on freshly resected GBM specimens with preserved tissue architecture and their matched primary cultures. In paralell, extracellular vesicles (EVs) were retrieved from patient plasma and matched cell culture media for EV-surfaceome profiling. Target candidates were validated by FACS, IF, as well as live antibody internalization and ADC cytotoxicity studies. RESULTS Our findings unveil a diverse selection of putative tumor antigen candidates in GBM that may be harnessed for targeted immunotherapies. Confronting potential targets with ADC constructs supported the validity our approach. Moreover, integrated proteotranscriptomics provides compelling evidence that mRNA levels poorly reflect surfaceome-endocytome protein abundance in patient tumors, underscoring the importance of refined proteomic strategies. Ongoing studies aim at the development of therapeutic modalities (ADC and CAR-T) against a lead candidate target, and to understand the utility of EV-surfaceome profiling for non-invasive, dynamic monitoring of the tumor surfaceome landscape. CONCLUSION Together, our results provide new layers of understanding fundamental to the future development of individualized immunotherapy strategies in GBM, and identify lead candidates for potential clinical development.
P11.11.B VALIDITY RELATED EVIDENCE FOR COGSTATE TASKS IN PATIENTS WITH BRAIN METASTASES
Authors: J S Wefel, H A Tawbi, E P Sulman, C M Sullaway, A L Thomas, K R Noll, C Tang, R Ferrarotto, J Welsh, N Guha-Thakurta, I C Glitza, A Diab, S P Patel, M K Wong, M A Davies, E Burton, C Chung, J Li
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Digital approaches to measuring and monitoring cognitive function (CF) are of interest as screening measures to enhance clinical care and clinical research. Validity related evidence for such measures is required prior to adopting these in practice and trials. Four investigator-initiated clinical trials evaluated CF in patients with brain metastases (BM) with both clinically validated CF tests and experimental computerized CogState (CS) tasks. Construct validity of the CS tasks was evaluated. MATERIAL AND METHODS 140 pts with BM who completed both CF testing and computerized CS tasks prior to treatment were included. Within sample mean/SD were used to convert raw to standardized test scores. The following domains and tests were evaluated: Processing Speed (CS Detection, TMTA, TMTB, Coding), Attention (CS Identification, Digit Span, Coding, TMTA, TMTB), Working Memory (CS One Back, Digit Span), and Learning and Memory (CS One Card Learning and International Shopping List, HVLT-R). Spearman correlations were computed between CF tests and CS tasks, with significance set at the 0.01 level. Impairment was classified as a z-score ≤-1.5 and concordance rates were examined between HVLT-R and ISL. RESULTS On average, pts were 58.3 years old(SD 12.9), completed 14.7 years of education(SD 3.0), 48% female, and 84% right-handed. Spearman correlation coefficients between CS tasks and related CF tests were weak to moderate for processing speed (rs=0.39-0.55) and attention (rs=0.34-0.56), weak for working memory (rs=0.28), and weak to strong for learning and memory (rs=0.36-0.69). Spearman correlations were stronger, while intraclass correlation coefficients were moderate, between the ISLT and HVLT-R TR (rs=0.69 and ICC=0.58) and ISLR and HVLT-R DR (rs=0.69 and ICC=0.58). Concordance rates of impairment for the most highly correlated and parallel measures of learning and memory were poor with no to minimal correspondence based on Cohen kappa coefficients (ISLT and HVLT-R TR k=0.11; ISLR and HVLT-R DR k=0.29). CONCLUSION Spearman correlations between CS tasks and clinically validated CF tests in similar domains were weak with the exception of highly parallel measures of verbal learning and memory. ICC were less robust and Cohen kappa coefficients was negligible for these measures of verbal learning and memory. The substantial lack of agreement in identifying abnormal episodic memory performance is concerning in terms of utilizing the CS ISL task as a surrogate for the HVLT-R. Further associations between clinical variables and these measures of CF will help to determine ability to assess clinically relevant differences due to disease burden. Longitudinal evaluations will further shed light on sensitivity to treatment and disease effects.
P12.04.A CAR-ENGINEERED PRIMARY NK CELLS SHOW PROMISING EFFECTS AS TARGETED THERAPY AGAINST EGFR-POSITIVE GLIOBLASTOMA
Authors: B Roller, L Reindl, F Strassheimer, L Ziegener, P Elleringmann, A Kiefer, J Röder, J Steinbach, W Wels, E Ullrich, M Burger
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GB) is the most frequent primary brain tumor with a dismal prognosis despite multimodal treatment regimens. Effector cells such as T cells or natural killer cells (NK) carrying tumor-specific chimeric antigen receptors (CAR) hold promise for the development of more effective treatment strategies. CAR-engineered derivatives of the human NK cell line NK-92 targeting EGFR or EGFRvIII showed potent antitumor activity against glioblastoma cell lines in vitro and in vivo. Nevertheless, NK-92 does have limitations when compared to primary NK cells, such as the required irradiation prior to application in humans. MATERIAL AND METHODS To overcome this restriction, we evaluated the suitability of peripheral blood derived human primary NK cells (pNK) as carriers for a CAR targeting the common GB antigen epidermal growth factor receptor (EGFR) and the tumor-specific EGFR variant EGFRvIII. pNK cells from healthy donors were transduced with a lentiviral vector encoding the cetuximab-derived 225.28.z CAR (CAR-pNK), which recognizes an epitope common to both receptors. Specific tumor cell lysis by the CAR-pNK cells was then investigated in FACS-based cytotoxicity assays with GB cells expressing EGFR, EGFRvIII, or both target antigens. In addition, we tested in vivo CAR-pNK cell therapy in the subcutanous and intracranial LNT-229/EGFRvIII glioblastoma xenograft models. RESULTS When compared to non-transduced pNK cells, CAR-pNK cells achieved enhanced lysis of LNT-229 GB cells expressing EGFR and EGFRvIII. Likewise, markedly increased cytotoxicity of CAR-pNK was observed against the murine EGFR transduced GB cell line GL261 and the human cell lines SKMG-3 and BS153 with intrinsic EGFR gene amplification or expression of EGFRvIII, respectively. Furthermore, we observed delayed tumor growth following a single intravenous injection of CAR-pNK cells in the subcutaneous LNT-229/EGFRvIII glioblastoma xenograft model. CONCLUSION In summary, these results demonstrate promising efficacy of primary CAR-NK cells targeting EGFR and EGFRvIII both in vitro and in vivo. Ongoing work is currently evaluating CAR-pNK cell therapy in the orthotopic LNT-229 glioblastoma xenograft mouse model and an in vitro organoid model, which may provide the rationale for early clinical testing.
P12.01.B ANTI-VEGF TREATMENT EFFECT AGAINST GLIOMA IS IMMUNE DEPENDENT AND MEDIATED BY ENHANCED T CELL ACTIVITY
Authors: C Maire, M Mohme, K Fita, M Reetz, S Heinemann, E Tolosa, M Alawi, C Casar, M Spohn, J Gempt, M Westphal, K Lamszus
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The majority of glioblastoma patients receive corticosteroids at some point during the course of disease to treat brain edema. Since steroids are immunosuppressive, immunotherapy trials increasingly avoid the use of steroids and consider bevacizumab as alternative. Targeting VEGF in the context of immunotherapy may additionally have immune stimulatory effects, as VEGF is a potent immunosuppressive factor. We explored whether anti-VEGF treatment has immune-mediated components and which mechanisms are involved. MATERIALS AND METHODS Murine glioma cells were injected intracerebrally into C57BL/6 wild-type mice or immunodeficient Pfp/Rag2 knockout (KO) mice. Animals were treated with B20 (anti-murine VEGF) or dexamethasone. Tumor-infiltrating and peripheral immune cells were profiled by flow cytometry, and RNAseq analyses were performed on sorted tumor and immune cells at different timepoints. T cells and NK cells were depleted using specific antibodies. RESULTS B20 prolonged the survival of immunocompetent mice (p &amp;lt; 0.0001) but not of Pfp/Rag2 KO mice, indicating that the immune system is important for the effect of anti-VEGF treatment. At an early timepoint when controls became symptomatic, B20 “early” tumors (B20-ea) showed increased infiltration with T cells and myeloid cells, and decreased vessel density, while B20 tumors at the survival endpoint resembled IgG-controls. Gene expression in B20-ea tumor cells was dominated by hypoxia, neural development, invasion, TGF-β, Notch and Wnt signatures as well as concerted upregulation of Kmt2 H3K4 methyltransferases. In CD11b+ myeloid cells from B20-ea tumors, M1 hallmark genes and T cell activation genes were upregulated, while M2 genes were downregulated. Bioinformatic deconvolution revealed a transient shift towards pro-immune microglia/macrophages as well as increased NK cells and DCs. In CD8+ and CD4+ T cells, B20 increased the expression of S1pr1 and of α/β TCR genes, indicating oligoclonal expansion. Further, the proportion of progenitor-like exhausted CD8+ cells, which can be reinvigorated by PD-1 blockade, was increased in B20-ea. Among CD4+ T cells, B20 caused skewing towards the CD4+ TFH cell lineage, while dexamethasone increased expression of TH2 cytokines. Immune cell depletion in B20-treated animals demonstrated that CD8+ and CD4+ T cells but not NK cells were necessary for the survival-prolonging effect of anti-VEGF treatment. CONCLUSION Anti-VEGF therapy has significant immunostimulatory effects, mediated by CD8+ and CD4+ T cells as well as pro-immune modulation of the myeloid compartment. However, pro-immune effects are largely transient, so that an early treatment window of opportunity may exist during which anti-VEGF treatment in combination with an effective immunotherapy could have a substantial supportive effect, extending beyond its anti-edema activity.
P06.04.A FIRST IN HUMAN - TARGETING ANDROGEN RECEPTOR FOR GLIOBLASTOMA THERAPY
Authors: I Lavon, A Mordechai, A Lossos
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma represents a significant therapeutic challenge due to its aggressive nature, necessitating the development of effective targeted therapies. In a pivotal study, the amplification of the androgen receptor in 56% of glioblastomas was observed, shedding light on its therapeutic potential. Through extensive research, our team demonstrated the efficacy of the androgen receptor antagonist, enzalutamide (Xtandi), in prolonging lifespan in a mouse model of human glioblastoma. Collaborating with the Cyclotron and PET/CT teams, we established [18F]-FDHT PET/CT imaging, facilitating real-time detection of androgen receptor expression within brain tumors and enabling precise patient selection for targeted therapy. METHODS To proceed with a clinical trial, we conducted several steps. Initially, we examined the pharmacokinetics of enzalutamide and temozolomide, both as monotherapy and in combination, over multiple time points up to 96 hours, analyzing plasma and brain samples by LC-MS/MS. Additionally, we assessed the efficacy of PET/CT imaging for therapy response monitoring. After confirming androgen receptor expression via PET scan, patients underwent a 10-day regimen of escalating doses of the androgen antagonist Xtandi, administered daily, followed by a second PET scan. RESULTS In the pharmacokinetic analysis, we found that the half-life (t1/2) of enzalutamide remained consistent in both plasma and brain tissue when combined with temozolomide, compared to monotherapy. Notably, the t1/2 of temozolomide increased significantly when administered concurrently, rising from 1.8 to 4.45 in plasma and from 0.88 to 7.25 in brain tissue, respectively. These results informed the clinical trial protocol design. Regarding the PET/CT study, the outcomes were promising: two potential responders identified through imaging received either 40 or 80 mg of Xtandi. The patient who received 80 mg exhibited a significant reduction in tracer uptake after ten days of treatment, accompanied by tumor shrinkage and tangible improvements in mobility and quality of life, highlighting the transformative potential of our approach. PLANS AND DISCUSSION Encouraged by these results, we initiated a clinical trial to determine the safety and tolerability of Enzalutamide in conjunction with radiotherapy (RT) and temozolomide (TMZ), to assess clinical response using Response Assessment in Neuro-Oncology (RANO) criteria and to characterize the pharmacokinetics of Enzalutamide combined with TMZ. We have recently enrolled two patients for this study, and eagerly anticipate presenting the results of these participants, along with potentially others, during the forthcoming meeting. With the potential to rapidly translate these findings into clinical practice, our fast-track trial represents a beacon of hope for Glioblastoma patients worldwide.
P10.01.B A GRADIENT-BOOSTING MACHINE LEARNING MODEL PREDICTS PRIMARY TUMOR ORIGIN IN PATIENTS TREATED WITH GAMMA-KNIFE FOR BRAIN METASTASES
Authors: S Panchawagh, V Sanker, V Suresh, J Kirani Tan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastasis is a devastating consequence of cancer. It can present as focal neurologic deficits, following which a search for the primary tumor is mounted. Usually, after such an initial presentation, computed tomography or magnetic resonance imaging scans of the brain are performed to visualize the underlying pathology. Radiomics leverages quantitative texture analysis to understand unique image signatures that are otherwise incomprehensible to the naked eye. We propose a predictive machine learning model that can identify the locus of origin of brain metastasis using radiomic image analysis. MATERIAL AND METHODS We used magnetic imaging and segmentation data from 47 patients and 244 lesions from the open-source gamma-knife registry at the University of Mississippi Medical Center. After image pre-processing, 1688 radiomic features were extracted using different filters. Ensemble feature selection techniques were applied, and we retained 34 features deemed most important by the model. We fitted logistic regression, support vector kernel, random forest, and extreme gradient boosting models to the selected features to predict a multi-class outcome for tumor origin (lung, breast, kidney, melanoma, bladder, esophagus, ovary, or uterus). Local interpretable model-agnostic explanations were used to explain model predictions. RESULTS The cohort’s median age at diagnosis was 60, with 21 males (45%). For the multi-class prediction, the logistic regression (accuracy = 77.4%), support vector kernel (accuracy = 84.9%), and random forest (accuracy = 88.7%) models performed worse than the extreme gradient boosting (accuracy = 90.1%, precision = 89.9%, recall = 90.1%, and Dice score = 0.895) model. Gray-level co-occurrence matrix and gray-level dependence matrix features explained model predictions the best. CONCLUSION Our results suggest that quantitative radiomic analysis is useful in predicting tumor origin in brain metastasis. Specifically, features measuring texture, structure, and heterogeneity best explain model predictions. Refining the model further and using multicentric data can help create a robust, clinically useful software to aid physicians and radiologists in detecting tumor origin, improving patient care, and potentially reducing healthcare costs.
P11.08.A RESECTION OF GLIOMA FROM CLASSIC BROCA’S AREA IS FEASIBLE DUE TO PERITUMORAL AND DISTANT FUNCTIONAL LANGUAGE REORGANIZATION
Authors: G Rutten, J Verheul, B Brouwers, W De Baene
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Historically, Broca’s area has been assigned a critical role in motor language functions. Although there has never been consensus about its precise anatomical definition, most experts consider the left pars triangularis and pars opercularis as the core of classic Broca’s area. Electrocortical mapping and functional MRI (fMRI) routinely find naming and speech sites in this region. However, case reports and small series have indicated that gliomas can often be resected from Broca’s area without new or permanent language deficits, suggesting that in these patients there is functional reorganization due to tumor growth. To test this hypothesis, we compared the organization of the language system in patients with a glioma that encompassed classic Broca’s area (‘Broca group’) to patients with a glioma outside of Broca’s area (‘non-Broca group’). MATERIAL AND METHODS We retrospectively selected 13 patients from a prospective dataset of consecutive glioma patients (2010-2024) that had infiltration of left pars triangularis (n=13) and pars opercularis (n=8). There was additional infiltration of the middle frontal gyrus (n=4), insula (n=4), superior temporal gyrus (n=1) or ventral premotor cortex (n=1). All of these Broca group patients were operated under awake conditions with electrical stimulation mapping to delineate motor and language areas. Standardized preoperative MR imaging for all glioma patients included a language fMRI. RESULTS Broca group patients had either an oligodendroglioma (7 low grade, 1 high grade) or astrocytoma (3 low grade, 2 high grade). Clinical debut was a seizure (n=10), mild language (n=1) or cognitive (n=2) deficits. In 4 patients there were mild clinical language deficits prior to surgery. In 11 patients there were temporary language deficits after surgery (4 due to seizures) that resolved over time to initial clinical performance. All Broca group patients had a language dominant left hemisphere as deducted from clinical symptomatology and intraoperative mapping results. In none of these patients, electrocortical mapping found functional (language) sites over the tumor part in the pars triangularis and pars opercularis, and these areas were consequently resected. fMRI language maps of Broca versus non-Broca patients (n=276) showed lower activation in ipsilesional inferior frontal gyrus but higher activation in contralesional inferior frontal gyrus. CONCLUSION Language is represented differently in patients with a glioma in Broca’s area as compared to non-Broca glioma patients. Peritumoral and distant functional reorganization likely explains why gross total resection in classic Broca’s area is feasible and safe.