tbuckley/cabot-search huggingface dataset:
OS03.6.A MITOCHONDRIA TRANSFER IN GBM IS MEDIATED BY TGF-Β AND PROMOTES INCREASED INVASIVENESS
Authors: S S Moreino, S Storevik, F Pinaz, M C Lourido, J Han, M T Augustsson, K Sarnow, J V Joseph, L A R Ystaas, L Neises, J Meiser, R Bjerkvig, T Daubon, J A Hossain, H Miletic
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Acquisition of intact mitochondria from the tumor microenvironment (TME) is a ubiquitious phenomenon in tumors of glioblastoma multiforme (GBM),promoting mitochondrial respiration and metabolic pathways tied to proliferation and tumorigenicity 1. The Transforming growth factor β (TGFβ) pathway is a major molecular pathway upregulated in GBM compared to low grade gliomas 2 and recent studies have shown its involvement in invasion associated microtube (MT) formation 3. We hypothesized that TGFβ affects the mitochondria transfer process between GBM and members in the TME, namely astrocytes. We speculated that mitochondria transfer would lead to increased invasiveness as oxidative metabolism has been previously linked to invasion 1. Furthermore, we postulated that inducing metabolic stress conditions via mitochondria depletion would have an impact on the GBM-TME mitochondria transfer process. METHODOLOGY We utilised specifically transduced cell lines, immunofluorescence, confocal imaging and flow cytometry to measure mitochondria transfer under TGFβ treatment, MT formation and downstream SMAD signaling. Invasion data was elucidated via collagen invasion assays. Mitochondria depletion experiments in vitro were conducted using electron transport chain inhibitor treatment and flow cytometry. Orthotopic xenograft models were utilised to study this mitochondria depletion in vivo, and immunohistochemical analyses were performed to quantify mitotransfer. RESULTS Our in vitro results show that treatment of GBM - astrocyte cocultures with TGFβ directly impacted mitotransfer rates, MT formation and downstream SMAD signaling. Results obtained from collagen assays show promoted invasion in GBM with acquired mitochondria from the TME. Our mitochondria depletion model experiments show an amplified transfer of mitochondria from the TME by mitochondria deficient GBM cells - further characterizing the reliance of GBM on this process to promote its aggressive tumorigenic phenotype. CONCLUSION We identified a new mediating role of TGFβ in GBM interactions with the TME and canonical SMAD as a specific downstream signaling pathway involved. Our collagen invasion and mitochondria depletion studies also demonstrated the importance of mitochondria transfer from TME astrocytes to GBM in cellular functions related to proliferation, invasion and cell rescue. REFLECTION The findings of our study provide new insights into GBM disease progression and therapy resistance, indicating new opportunities for treatment development.
P17.19.A RESECTION OF BRAIN METASTASES WITH FLUORESCENCE GUIDANCE - COMPARISON BETWEEN SODIUM-FLUORESCEIN AND 5-ALA
Authors: A Neumeister, T Meier, A C Lawson McLean, N Andreas, C Senft
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Complete neurosurgical resection is an integral part of treatment in cancer patients with metastatic brain disease. The distinction between metastatic and healthy brain tissue is of critical importance in this context. Whereas the use of 5-ALA fluorescence has been established for gliomas, reportedly not all metastases enhance with 5-ALA. Therefore, resection using sodium-fluorescein (Na-Fl) may be more helpful to delineate tumors and their margins. MATERIAL AND METHODS We performed a retrospective analysis of resected brain metastases (BM) and use of intraoperative fluorescent agents from 2021 to date. The surgical reports were analyzed whether 5-ALA or Na-Fl was used and if fluorescence was visible using the specific microscope filter. The histopathological findings were then documented. Finally, a chi-square independence test was performed. RESULTS Of 56 patients with BM, Na-Fl was applied in 30 cases, whereas 26 BMs were resected with use of 5-ALA. Following Na-Fl-administration, in 2 of 30 cases, there was no visible fluorescence in the Yellow 560 nm filter (6.7 %), but fluorescence was positive in the remaining 28 metastases (93.3 %). In contrast, 5-ALA induced fluorescence in the Blue 400 nm filter was negative in 11 (42.3 %), positive in 10 (38.5 %). In 5 cases, the fluorescence pattern was not documented (19.2 %). The difference in positive fluorescence between Na-Fl and 5-ALA was statistically significant (p=0.0007). CONCLUSION In intracranial metastases, Na-Fl-induced fluorescence was more frequently observed in contrast to 5-ALA. Na-Fl can therefore be useful in the identification of brain metastases as well as the rapid and cost-effective differentiation of metastatic from healthy brain tissue. Further studies should be carried out to investigate whether use of Na-Fl influences the extent of resection.
P17.21.B SEIZURE OUTCOMES IN PATIENTS WITH BRAIN METASTASES: A SYSTEMATIC REVIEW ON THE EFFICACY OF ANTITUMOR TREATMENT AND ANTISEIZURE MEDICATION
Authors: J C C Scheepens, P B van der Meer, L Dirven, M J Vos, M J B Taphoorn, J A F Koekkoek
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) are the most common type of malignant brain tumor and their incidence is rising. As many patients with BMs develop epileptic seizures, adequate seizure management is warranted. However, most research has focused on patients with primary malignant brain tumors instead of BMs. We conducted a systematic review on seizure outcomes after antitumor treatment and antiseizure medication (ASM) in patients with BMs from solid tumors. MATERIAL AND METHODS We performed a systematic literature search in six databases up to February 2024. The endpoints of interest were efficacy (i.e., the ability to achieve seizure freedom) and tolerability (for ASM only) (i.e., the incidence, severity, and impact of ASM-related adverse events). Extracted outcomes included rates for: (1) seizure freedom; (2) ≥50% seizure reduction; and (3) ASM treatment failure. If possible, we calculated a weighted average (WA) of each seizure outcome. The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used to systematically judge the overall risk of bias of each study as low, moderate, serious, or critical based on seven bias domains. The ROBINS-I tool recommends to exclude studies at critical risk of bias. RESULTS Our search yielded 2244 references, of which 16 studies were included. Eight studies were at critical, and 8 at serious risk of bias. The WAs of seizure freedom at 3 and 6 months after surgical resection were 84% and 67% (n=145 and n=164 patients), respectively. When excluding studies at critical risk of bias, seizure freedom at 3 months was 88% and at 6 months 64% (n=59 and n=151 patients). For other treatments and outcomes, no WAs could be calculated because of a limited number of studies with varying follow-up times. Based on 3 studies (n=85 patients total), seizure freedom with ASM ranged from 77% to 57%, and treatment failure from 0% to 50% after 1 month to a median of 11 months of follow-up. However, these results on the efficacy and tolerability of ASM were unreliable, as all 3 studies were at critical risk of bias. CONCLUSION Limited available evidence demonstrated that in most patients with epilepsy due to BMs seizure freedom is achieved within 6 months after surgical resection. Due to the high risk of bias of available studies, the efficacy and tolerability of ASM in patients with epilepsy due to BMs remains to be elucidated.
OS03.5.A A PHASE I CLINICAL TRIAL ON THE INTRACRANIAL ADMINISTRATION OF AUTOLOGOUS CD1C(BDCA-1)+ /CD141(BDCA-3)+ MYELOID DENDRITIC CELLS IN COMBINATION WITH IPILIMUMAB AND NIVOLUMAB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA
Authors: J Duerinck, L Lescrauwaet, I Dirven, J Del’haye, M Cammaert, W Geens, X Geeraerts, L Stevens, S Brock, M Kockx, H Everaert, a Vanbinst, S Tuyaerts, B Neyns
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intracranial (iCran) administration of the PD-1 and CTLA-4 blocking monoclonal antibodies nivolumab (NIVO) and ipilimumab (IPI) at the time of resection of recurrent high-grade glioma (rHGG) is safe and resulted in encouraging survival (NCT03233152). CD1c(BDCA-1)+ /CD141(BDCA-3)+ myeloid dendritic cells (myDC) play a pivotal role in initiating an adaptive anti-tumor immune response and licensing immune anti-tumor effector cells within the tumor microenvironment. iCran injection of autologous myDC in pts with rHGG was found to be safe but the potential added benefit for survival has not been established. MATERIAL AND METHODS rHGG pts (after prior RT and TMZ, not in need of supraphysiological doses of corticotherapy), underwent leukapheresis followed by isolation/cryopreservation of myDC. NIVO (10 mg IV) was administered preoperatively. Autologous myDC (5-, 10-, or 20.106 cells) were injected into the brain tissue lining the resection cavity (iCer) following a maximal safe resection (MSR) or intratumorally (iTum) following a stereotactic core needle biopsy (SCNB). IPI (5 mg) plus NIVO (10 mg) were co-injected iCer or iTum with the myDC. Postoperative NIVO was administrated intracavitary via an Ommaya reservoir (iCav, 10 mg) and intravenously (IV, 10 mg) Q2w (max 11x). RESULTS 21 pts (13 M; med 49 y [range 20 -78]; IDHwt 17 pts, ECOG PS 0 or 1: 18-, 3 pts) underwent procurement of myDC; intraoperative administration of myDC was preceded by MSR in 19 pts, and SCNB in 2 pts. Respectively 6-, 3-, and 12 pts were treated at the 3 myDC dose levels. All pts received the peri-op iTum/iCer/IV-administration of IPI and NIVO as planned. The median postoperative iCav and IV NIVO-administration was 7 (range 0-11) and 8 (0-11). Study treatment was discontinued early at first progression in 9- and AE in 3 pts. Most important TRAEs: bacterial colonization of the Ommaya reservoir (n=4), craniotomy wound dehiscence (n=2), and bacterial meningitis (n=1). At DBL (01MAY2024), 6 pts (29%) remain progression-free (incl. 3 pts with &amp;gt;2y PFS). PFS (med. 24w [95% CI 8- 39]) is superior when compared to the pts (n=70) with resectable rHGG treated in 4 other cohorts of the GlITIpNi trial (p=.003). When including a durable benefit from bevacizumab at first PD in 3 pts (out of 10 pts who were treated with a low-dose bevacizumab regimen at first progression), PFS compared favorably to a historical pooled cohort (n: 469) of rHGG treated with VEGF(R)-inhibitors (p=.007). The 1-year OS-rate was 50% [95% CI 24-76]. CONCLUSION Intracranial administration of autologous myDC combined with IPI/NIVO is feasible, safe and associated with encouraging survival, deserving further investigation.
P12.03.B CAN COGNITIVE PERFORMANCE PREDICT NEUROTOXICITY INCIDENCE FOLLOWING CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR LYMPHOMA?
Authors: R Ursu, C Barsan, C Belin, S Cuzzubbo, C Carreau, M El Soudany, R Sivapragassame, C Cristinelli, R Di Blasi, A Ouedrani, S Caillat-Zucman, C Thieblemont, A Carpentier
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the landscape of cancer treatment, particularly in haematological malignancies, and while these therapies have demonstrated significant efficacy against malignancies, they are associated with a spectrum of side effects. Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are unique to CAR-T cell therapy and distinguish it from other forms of autoimmune toxicity. Predicting which patients will develop neurotoxicity remains a challenge. The pattern of ICANS is cognitive dysfunction, suggesting a plausible relationship between cognitive status and neurotoxicity. Understanding the interplay between cognitive function and neurotoxicity may provide valuable insights for early detection. The primary endpoint of this study was to investigate whether the cognitive performance of patients at the time of leukapheresis is associated with the subsequent development of ICANS. MATERIAL AND METHODS We report here on a prospective study of an adult patient population with aggressive B-cell lymphoma treated with CAR-T cell therapy at our centre between May 2020 and November 2023. All patients underwent neurological examination, cerebral MRI and global cognitive assessment using the Montreal Cognitive Assessment (MoCA) test with a cut-off of less than 26 points. We retrospectively recorded total metabolic tumour volume (TMTV) and International Prognostic Index (IPI) at lymphodepletion. Biological data including lactate dehydrogenase (LDH), albumin, ferritin and C-reactive protein (CRP) were also collected at the time of treatment. A retrospective analysis of pre-infusion serum neurofilament light chain (NfL) levels at the time of the decision to proceed with CAR-T cell therapy and at the time of treatment was performed. RESULTS 156 patients, median age 64 years (range 21 to 79 years), 55 females / 101 males, all treated for lymphoma, were included in this study. The mean MoCA score was 26 (range 12 to 30 points), 63 patients (40%) had a MoCA test below the cut-off at baseline. Following infusion of CAR T cells, 32% of patients developed ICANS within 6 days (grade 1-2: 72%; grade 3-4: 30%). The most common sign of neurotoxicity was cognitive impairment. In univariate analyses, the occurrence of ICANS was not significantly associated with baseline cognitive performance (p 0.58). As the study is ongoing, an update on the results will be available at the EANO meeting. CONCLUSION Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This study does not suggest an association between the occurrence of ICANS and baseline cognitive performance. Despite progress in understanding the mechanisms underlying neurotoxicity, predicting its occurrence remains a challenge.
P22.10.B LOW-GRADE GLIOMA PATIENTS WITHOUT PROBLEMS IN DAILY FUNCTIONING: A SILENT MINORITY
Authors: F F Siebenga, H L van der Weide, F Gelmers, S E Rakers, M C A Kramer, A van der Hoorn, R E Enting, I Bosma, R J Groen, H Jeltema, M Wagemakers, J M Spikman, A M Buunk
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors. Although all patients with LGG face similar challenges in coping with an incurable disease, interestingly, a subset of patients reports no (significant) problems in daily functioning and appear to resume their activities without changes. It is crucial to identify the group of patients that seem to cope so well, in order to find possible indications to help patients who do experience problems in daily functioning. Therefore, the present study aims to characterize the LGG patient group without problems in daily functioning. MATERIAL AND METHODS 144 patients with LGG were included post-surgery and before adjuvant therapy. Patients were divided into two groups: patients with and without problems in daily functioning, based on the Patient Competency Rating Scale (PCRS). Demographic variables, disease characteristics (tumor location, tumor volume), anxiety, depression (HADS), coping (UCL) and general cognition (neuropsychological tests) were analysed to identify characteristics specific to the patient group without problems in daily functioning. RESULTS Of the entire LGG cohort (mean age= 43 ± 12), 26.4% of the patients no (significant) problems in daily functioning. No significant differences were found for demographics (gender, age and educational level), disease characteristics and general cognition between patients with and without problems in daily functioning (p&amp;gt;0.05). However, patients without problems had significantly lower scores for anxiety (p&amp;lt;.01), depression (p&amp;lt;.01), avoidant (p=&amp;lt;.01) and passive coping (p&amp;lt;.001), compared to patients with problems in daily functioning. CONCLUSION More than a quarter of the patients with LGG experience no (significant) problems in daily functioning, after surgery and before adjuvant therapy. Notably, this subset of patients did not differ from patients with problems in daily functioning considering demographics, disease characteristics and cognitive functioning. However, the cohort of patients with no problems in daily functioning report lower levels of anxiety and depression, and use a more effective coping style, compared to patients who do experience problems in daily functioning. Therefore, it seems to be crucial addressing coping strategies, serving as a potential to help patients who do experience problems in daily functioning. Future research should focus on whether the patient group without problems in daily functioning continues to report zero complaints after adjuvant therapy, i.e. examining if an initial problem-free status serves as a protective factor during and after treatment.
P12.13.B LOCOREGIONAL BI-SPECIFIC CAR-T CELLS TARGETING CD44 AND CD133 IN RECURRENT GLIOBLASTOMA: THE FIRST IN-HUMAN CLINICAL TRIAL RESULTS
Authors: Y Zhai, G Li, T Jiang, W Zhang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recurrent glioblastoma (rGBM) remains no standard of care exists, with a median overall survival of less than 1 year. Here, we report the pre-clinical data and the first four patients with rGBM in a phase I study of locoregionally administration of newly developed tandem CAR-T cell, targeting CD44 and CD133, armored with a modified IL7Ra intracellular domain (Tris-CAR-T). MATERIAL AND METHODS Target screening and verification were based on primary glioma stem cells, GBM patient samples, and corresponding sequencing datasets. The antitumor activity of Tris-CAR-T cells was verified in patient-derived tumor stem cells, intracranial xenograft models, GBM patient-derived xenograft models and glioblastoma organoids. Single-cell RNA sequencing and mass spectrometry were used to assess the immune phenotype of Tris-CAR-T cells. The study’s primary outcomes were safety and any adverse events associated with Tris-CAR-T administration. Secondary outcomes include the distribution and persistence of Tris-CAR-T cells, cytokine concentration, and the therapeutic effect according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. RESULTS CD44 and CD133 are two inverse-correlated targets. Locoregionally administered Tris-CAR-T cells in vivo induced long-term tumor control with preferable safety. Patient-derived autogenous CAR-T showed robust antitumor capacity in the matched glioblastoma organoid model. All four patients had progressive disease at the time of treatment. At present, the first patient had 1 dose of 107 Tris-CAR-T cells administration, the second patient had multiple doses of 107 Tris-CAR-T cells administration, and the third and fourth patient had multiple doses of 108 Tris-CAR-T cells administration. No neurotoxicity or adverse event greater than grade 2 was observed until now. Radiographic tumor regression or suppression was observed within days after the first dose infusion. The improvement of signs and symptoms were also recorded. CONCLUSION The newly constructed Tris-CAR-T cells are capable of GBM suppression with limited side effects. The inspiring early-stage efficacy requires confirmation with subsequent doses of administration, additional patients, biospecimen investigation, and follow-up. The therapeutic response may mainly correlated with tumor burden, product quality, and dose level. ClinicalTrials.gov identifier: NCT05577091.
P10.04.A A STRATEGY FOR MULTIMODAL INTEGRATION OF TRANSCRIPTOMICS, PROTEOMICS, AND RADIOMICS DATA FOR THE PREDICTION OF RECURRENCE IN PATIENTS WITH IDH-MUTANT GLIOMAS
Authors: T Chouleur, C Etchegaray, L Villain, O Saut, A Bikfalvi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Isocitrate dehydrogenase-mutant gliomas are lethal brain cancers that impair quality of life in young adults. Although less aggressive than glioblastomas, IDH-mutant gliomas invariably progress to incurable disease with unpredictable recurrence. A better classification of patient risk of recurrence is needed. MATERIAL AND METHODS We describe a multimodal analytical pipeline integrating imaging, transcriptomic, and proteomic profiles using machine learning. RESULTS 1) description of the biological characteristics of IDH-mutant glioma subtypes categorized by positron emission tomography (PET) and histology, 2) integration of positron emission tomography (PET) metrics in the classification of IDH-mutant gliomas, and 3) improvement of patient stratification with novel signatures of patient risk of recurrence based on gene expression, protein level, and imaging. CONCLUSION We provide herein a useful road-map for the stratification of IDH-mutant glioma patients and their risk of recurrence, which will lead to better monitoring of the clinical evolution of the disease.
P10.05.B ADVANCED MACHINE LEARNING TO DETECT HETEROGENEITY OF CELL CYCLE ALTERATIONS DURING TMZ CHEMOTHERAPY AT SINGLE CELL LEVEL
Authors: G Villa, J Kückelhaus, Y Yabo, O Schnell, D Delev, J K Benotmane, H D Heiland
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) stands as the most aggressive tumor of the CNS. Current treatment typically involves surgical intervention followed by cycles of Temozolomide (TMZ) chemotherapy in combination with radiotherapy. However, the efficacy of these treatments remains limited due to GBM’s ability to adapt and resist therapy. TMZ treatment leads to significant alterations in the cell cycle of GBM cells, with a decrease in cells in the G0-G1 phase and an increase in cells in the S or G2 phases. This shift in cell cycle distribution suggests a dual response: re-entry of tumor cells into the cell cycle and concurrent arrest induced by TMZ, potentially contributing to tumor resistance and disease progression. Here, we leverage the variable patterns of Ki-67, a marker of cellular proliferation, which expression fluctuates throughout the cell cycle, peaking during S, G2, and M phases to evaluate cellular response to TMZ treatment across various primary cell lines and tissue samples. MATERIAL AND METHODS We developed an image-based approach to investigate and reconstruct the cell cycle using advanced machine learning for pattern recognition to identify the detailed cell cycle status on single cell level. To characterized primary cell lines (n=6), we performed whole-genome DNA sequencing, whole-genome methylation sequencing and RNA-sequencing. For functional read-outs, we performed large-scale TMZ treatment in a time- and concentration dependent manner in cell culture and GBM-tissue slice models. RESULTS Our machine learning model of cell cycle reconstructions demonstrated a robust reconstruction of detailed cell cycles stages across all cell lines with the majority of cells assigned to G0-G1 stated without treatment. TMZ treatment resulted in a significant shift towards enhanced S/G2 phase (p &amp;lt; 0.02) in 3 of 6 tested cell lines. Pseudo-time reconstruction revealed a dose-dependent alteration of the cell cycle showing significant changes with TMZ-doses below 50µmol. Cell lines which enhanced stem-like phenotypes based on epigenetically and transcriptionally characterisation demonstrated no cell cycle alterations even in high-dose treatment conditions (&amp;gt;150µmol) regardless their MGMT promotor methylation status. This heterogeneity underscores the complexity of GBM and highlights the importance of personalized treatment strategies. CONCLUSION Our findings provide valuable insights into GBM’s cell cycle alterations and adaptive mechanisms of resistance independent of the MGMT methylation status as a known biomarker for TMZ response. TMZ-induced cell cycle alterations can provide a novel biomarker to detect treatment response and offer a foundation for developing personalized therapeutic approaches.