tbuckley/cabot-search huggingface dataset:
P09.16.B THE ROLE OF PERFUSION-MRI IN THE DETECTION OF PROGRESSIVE DISEASE OR THERAPY RELATED CHANGE AFTER PROTON-BOOST IRRADIATED IN PRIMARY GLIOBLASTOMA
Authors: H Goett, L Singer, T Struffert, E Uhl, M Stein
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Therapy related change (TRC) in glioma patients after radiotherapy are common. In daily practice TRC is difficult to differentiate from true progressive disease (PD). Perfusion-MRI could be a helpful tool to differ between PD and TRC after radiotherapy. However, data for the evaluation of perfusion-MRI after proton therapy in glioblastoma is still missing Our study aims to evaluate perfusion MRI for the differentiation between PD and TRC in primary glioblastoma patients after proton-boost radiotherapy. METHODS We evaluate MRI scans from 37 patients with newly diagnosed glioblastoma, who received either photon irradiation (60Gy) or photon irradiation with proton boost (50 + 10Gy). A retrospective analysis regarding T1 contrast enhancement, FLAIR hyperintensity and correlating leakage-corrected relative DSC-CBVmax (relCBVmax) values of the contrast enhancing or FLAIR hyperintense areas in a ratio to a corresponding ROI in the contralateral white matter were performed. Whether scans showed PD or TRC was defined afterwards depending on histology or proceeding growth in the follow up scans. Groups were compared via Mann-Whithney U-Test. For the CBVmax values AUC analysis was performed. RESULTS MRI scans in patients after proton therapy showed more often increase of contrast enhancement (59.34%) compared to patients after photon therapy (46.15%). However, the difference was not statistically significant (p=0.1001). RelCBVmax of the FLAIR hyperintense area was not significantly correlated with PD after photon therapy. To predict PD after proton-boost irradiation the cut-off value for the relCBVmax of the FLAIR hyperintense area was &amp;gt;86.3% (sens.: 81.82%/spec.: 58.7%;p=0.0009). For prediction of PD the relCBVmax of contrast enhancing areas the cut-off value after photon irradiation was &amp;gt;145.8% (sens.: 66.67%/spec.:84.21%; p=0.0037). PD after proton-boost therapy could be predicted with a cutoff value of the relCBVmax of 180.7% (sens.:60.61%/spec.:86.21%; p=0.0003). CONCLUSION The observed sensitivity was low. However, hyperperfusion in relCBVmax can help for the differentiation between PD and TRC. Perfusion-MRI is a very cost-effective technique and could be a useful tool to determine which patients should receive PET-scans for further diagnostics.
P04.03.A TARGETING SCD TRIGGERS LIPOTOXICITY OF CANCER CELLS AND ENHANCES ANTI-TUMOR IMMUNITY IN BREAST CANCER BRAIN METASTASIS MOUSE MODELS
Authors: A Sammarco, G Guerra, K M Eyme, K Kennewick, Y Qiao, J El Hokayem, K J Williams, B Su, V Zappulli, S J Bensinger, C E Badr
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Breast cancer brain metastases (BCBM) are a significant cause of mortality and are incurable. Thus, identifying BCBM targets that reduce morbidity and mortality is critical. BCBM upregulate Stearoyl-CoA Desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids. This finding highlights a potential metabolic vulnerability of BCBM, but the lack of brain-penetrant inhibitors of SCD has precluded their pre-clinical effectiveness. Additionally, increasing evidence suggests that fatty acid homeostasis in immune cells represents a key regulatory node to control inflammation, and manipulation of fatty acid metabolism has significant effects on immune cell functions. In this study, we tested the effect of a brain-penetrant clinical-stage inhibitor of SCD (SCDi), on breast cancer cells and mouse models of BCBM. MATERIAL AND METHODS Lipidomic analyses, qPCR, and western blot were used to study the in vitro effect of SCDi on breast cancer cells. Single-cell RNA sequencing (scRNAseq) was used to explore the effects of SCDi on cancer and immune cells in the tumor microenvironment (TME) in a BCBM mouse model. RESULTS Pharmacological inhibition of SCD markedly reshaped the lipidome of breast cancer cells and resulted in endoplasmic reticulum stress, DNA damage, loss of DNA damage repair, and cytotoxicity. Importantly, SCDi alone or combined with a PARP inhibitor prolonged the survival of BCBM-bearing mice. When tested in a syngeneic mouse model of BCBM, scRNAseq revealed that pharmacological inhibition of SCD enhanced antigen presentation by dendritic cells, was associated with a higher interferon signaling, increased the infiltration of cytotoxic T cells, and decreased the proportion of exhausted T cells and regulatory T cells in the TME. Additionally, interaction analysis between immune cells in the TME revealed that pharmacological inhibition of SCD decreased engagement of immunosuppressive pathways, including the PD-1:PD-L1/PD-L2 and PVR/TIGIT axes. CONCLUSION These findings suggest that SCD inhibition could be an effective strategy to intrinsically reduce tumor growth and reprogram anti-tumor immunity in the brain microenvironment to treat BCBM.
P04.04.B THE FUNCTIONS AND MECHANISMS OF OSGIN1 INVOLVED IN FERROPTOSIS RESISTANCE OF GLIOBLASTOMA
Authors: L Huo, Z Luo, X Liang, X Du
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, with an average survival time of less than 15 months despite treatment. Recurrence and chemotherapy resistance are major challenges, with ferroptosis emerging as a potential mechanism contributing to chemotherapy resistance. The role of oxidative stress-induced growth inhibitor 1 (OSGIN1) in GBM, particularly its localization and function, remains poorly understood, though it is associated with poor prognosis. MATERIAL AND METHODS We utilized bioinformatics to analyze OSGIN1 expression and GBM patient prognosis from the Cancer Genome Atlas (TCGA). Experimental approaches included C-terminal EGFP tagging of OSGIN1, overexpression, and knockdown experiments in GBM cells. We assessed the effects on cell proliferation, apoptosis, and ferroptosis sensitivity using CCK8 assays, flow cytometry, and lipid peroxidation sensors. The relationship between OSGIN1 and drug sensitivity was explored using data from the Cancer Therapeutics Response Portal (CTRP). Regulatory interactions between OSGIN1 and the cystine transporter SLC7A11 were investigated through polymerase chain reaction, Western blotting, dual luciferase assays, and chromatin immunoprecipitation. RESULTS High OSGIN1 expression correlates with poor prognosis in GBM. OSGIN1 does not localize with mitochondria in GBM cells nor induce apoptosis. Instead, OSGIN1-modulated cells exhibited altered ferroptosis sensitivity. Knockdown of OSGIN1 increased ferroptosis sensitivity, an effect reversible in OSGIN1-rescued cells. Moreover, OSGIN1 positively regulates SLC7A11 expression, impacting cystine uptake and ferroptosis resistance. Animal models confirmed that GBM cells overexpressing OSGIN1 are more resistant to ferroptosis. CONCLUSION OSGIN1 is a prognostic marker and potential therapeutic target in GBM. It regulates SLC7A11 expression and contributes to ferroptosis resistance, highlighting its role in the chemotherapeutic response. Targeting OSGIN1 could enhance GBM treatment efficacy by modulating ferroptosis sensitivity.
P17.20.A REVERSAL OF EPIGENETIC DYSREGULATION IN BREAST CANCER BRAIN METASTASIS VIA HDAC1/2 INHIBITION
Authors: L Luzietti, G Gomez, W Zwart, S Prekovic, L Young, D Damir Vareslija
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Breast cancer metastasising to the brain poses significant clinical challenges due to its severe prognosis and limited treatment options. Investigating the molecular mechanisms behind breast cancer brain metastasis (BCBM) is crucial for the development of targeted therapies. The adaptability of cancer cells in the brain, likely driven by epigenetic modifications, highlights the potential for targeted epigenetic interventions. MATERIAL AND METHODS We analysed a clinically characterised cohort of primary breast tumours and brain metastases using RNA sequencing for pathway enrichment. This was complemented by integrating Chromatin-Immunoprecipitation (ChIP)-seq data with brain metastasis transcriptomes and conducting pharmacological screening across various cell line models to pinpoint vulnerabilities. RESULTS Our research identified a pivotal role for the co-REST transcriptional network and its associated histone deacetylases (HDACs) in managing brain metastasis. Elevated REST levels were linked to poorer outcomes in brain metastasis cases. Pharmacological assessments pointed to the HDAC pathway as a viable therapeutic target, corroborated by in vitro and ex vivo validations using patient-derived organoids. Crucially, targeting HDAC1/2 with quisinostat effectively hindered metastatic progression—a notable improvement over outcomes from singular HDAC targeting, as seen in glioblastoma studies. Further mechanistic investigations highlighted the involvement of the HER/AKT/mTOR and TGF-β pathways in BCBM. CONCLUSION Our findings establish the REST/HDAC axis as a key promoter of BCBM. Quisinostat, by specifically inhibiting HDAC1/HDAC2, demonstrated significant effectiveness, indicating its potential as a management strategy for brain metastases. This approach underscores the promise of HDAC inhibitors with enhanced selectivity and brain penetration as emerging tools in neuro-oncology.
P22.11.A POOR SELF-REPORTED PHYSICAL FUNCTIONING IN GLIOMA PATIENTS ACROSS THE DISEASE TRAJECTORY
Authors: M E C Blom, M Gorter, V Belgers, J G Röttgering, P C de Witt Hamer, M R van Lingen, H Knoop, M Klein, L Douw
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Few studies have investigated physical functioning at multiple moments in the disease trajectory of glioma patients, nor have the correlates of physical functioning been determined. We therefore analyzed physical functioning in a large sample of glioma patients both at time of diagnosis and after primary treatment. MATERIAL AND METHODS In this retrospective study (patients were diagnosed between 2007-2023), the self-reported physical functioning subscale of the 36-Item Short Form Health Survey (SF-36) was used. Each patient was matched with two general population controls based on age, sex, and educational level. First, we compared physical functioning at time of diagnosis and after treatment with matched controls. Next, we determined correlates of patients’ physical functioning at both time points, namely age, sex, educational level, tumor histology, location, lateralization and grade, type of treatment, presence of epilepsy, usage of dexamethasone, Karnofsky Performance Status (KPS) and the National Institutes of Health Stroke Scale (NIHSS). Finally, in patients with assessments both at diagnosis and after treatment, we determined change in physical functioning over time. RESULTS We included 260 glioma patients at time of diagnosis and 109 glioma patients after treatment. Compared to controls, physical functioning of patients was significantly lower at the time of diagnosis (p = 0.022) and after treatment (p = 0.002). At both time points, poorer physical functioning was associated with having a tumor grade III, and KPS lower than 80. Moreover, at diagnosis only, poorer physical functioning correlated with lower educational level and right-sided tumor lateralization. Within the 77 glioma patients with data available at both time points, there was a large individual variability in change over time (28% increased; 40% decreased), but there was no significant change at the group level (p = 0.300). CONCLUSION Physical functioning is poor in glioma patients, regardless of phase of the disease. The main correlates of poor physical functioning are tumor and patient characteristics, such as KPS, tumor grade, educational level, tumor lateralization. Interestingly, neurological deficits were not related to physical functioning. Interventions aimed at improving physical functioning in glioma patients should be explored.
JS04.6.A EVOLUTION OF GLIOBLASTOMA THERAPY IN TWO DECADES: COMPARISON OF TWO PROSPECTIVE, CONTROLLED TRIALS ON THE RESECTION OF GLIOBLASTOMA: THE 5-ALA AND IMRI VS. 5-ALA-TRIALS
Authors: C Roder, i Study group, A Study group, P Haas, M Tatagiba, W Stummer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Two prospective, controlled multicenter trials on the resection of glioblastomas are published to date spanning almost 2 decades of medical evolution. The 5-ALA (ALA) trial, published 2006, comparing the extent of resection (EOR) and overall survival (OS) of patients after 5-ALA fluorescence-guided and white-light surgery, and the iMRI vs. 5-ALA (iMRI/ALA) published 2023, comparing 5-ALA fluorescence-guided and iMRI-guided surgery. Both studies had comparable inclusion criteria, therefore this analysis aims to compare surgical and survival results of both studies. MATERIAL AND METHODS We analyzed the data of both trials in terms of baseline, peri- and postoperative clinical data, as well as EOR and OS. RESULTS Data of 243 patients of the ALA and 277 patients of the iMRI/ALA trial were analyzed. Median age and preoperative NIHSS were comparable between cohorts. Tumors were rated “eloquent” in 56% in the ALA and 51% in the iMRI/ALA trial. Total resection of contrast enhancement was achieved in 36.1% (white-light), 64.5% (ALA in ALA trial), 78% (ALA in iMRI/ALA trial) and 81% (iMRI). 19.5% (ALA trial) compared to 8% (iMRI/ALA trial) of patients deteriorated neurologically postoperatively. OS differed significantly between both studies, especially depending on the EOR: Patients with incomplete resections had a median OS of 11.8 (ALA-trial) and 19.4 (iMRI/ALA trial), in contrast to 16.9 and 25.4 months for completely resected tumors, respectively. Incomplete resections led to worse OS in both studies, regardless of residual tumor size. Patients with the prognostically “worst” tumors (MGMT non-methylated, subtotal resection) in the iMRI/ALA trial had a comparable median OS (16.1 months) to patients with the prognostically “best” tumors (total resection) have from the ALA-trial (16.9 months). First-line adjuvant treatment was radiotherapy in 92.6% of patients in the ALA trial and a combined radiochemotherapy with temozolomide in 84% of patients in the iMRI/ALA trial. CONCLUSION Most likely due to increasing experience with5-ALA fluorescence guidance, the numbers of complete resections using this technology increased from 64.5 to 78% within the last two decades. Further, the role of complete resections without any residual contrast enhancing tumor remains a highly significant prognostic factor. OS has significantly improved throughout the last years, most likely caused by the routine use of combined radiochemotherapy in combination with better surgical results.
KS05.7.A INTRATHECAL DELIVERY OF PEPTIDE-PULSED TYPE 1 CONVENTIONAL DENDRITIC CELL VACCINE IS HIGHLY EFFICACIOUS FOR THE TREATMENT OF BREAST CANCER-ASSOCIATED LEPTOMENINGEAL DISEASE
Authors: V Law, C Snyder, Z Chen, P Kolinski, B J Czerniecki, P A Forsyth
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease, a rare form of metastasis in the meninges, a membrane surrounding the brain and spinal cord. The prognosis for BC-LMD is dismal where current treatments are ineffective. For examples, intrathecal (IT) therapy such as trastuzumab, and proton cranial spinal radiotherapy have only showed modest success. Dendritic cells are a master regulator of the immune system and play a critical role in bridging the innate and adaptive immune response. Here, we used a novel preclinical model to administer MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) intrathecally in mice harbouring either HER2+ or triple negative breast cancer (TBNC) LMD. The data from our preclinical studies led to an FDA-approved Phase 1 clinical trial of cDC1s in HER2+ and TNBC-LMD (NCT05809752; in progress). MATERIAL AND METHODS Our lab developed a “murine Ommaya” which mimics the clinically used Ommaya reservoir and allows for repeated intrathecal (IT) injections of novel drugs at 3 - 7μl volume directly into the CSF. A pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers was developed and using these targets we generated tumor-targeting cDC1 vaccines. The efficacy of this therapy was examined in murine BC-LMD models. RESULTS We found cDC1 vaccine was highly effective against HER2+ LMD and TNBC-LMD; LMD mice that received IT cDC1s had reduced tumour burden and prolonged survival. Complete responses to treatment ranged between 30 - 70% in HER2+ LMD and TNBC-LMD and were CD4+ T cell and B cell dependent. Notably, some cured mice were protected against LMD reinoculation. Subsequent single cell RNA-sequencing (scRNA-seq) analyses of pre- and post-treatment CSF revealed an adaptive change in the immune cellular landscape. We noted an elevation of Th1 cytokines such as IFN-γ in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going Phase 1 trial, where early data showed IT cDC1 vaccine triggered a dramatic increase in the concentration of several Th1 proinflammatory cytokines. CONCLUSION Our preclinical data suggest IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. We are currently investigating the mechanism(s) by which IT cDC1-initiates the CD4 Th1 adaptive immune response against LMD. By employing an scRNA-seq approach, we hope to further determine the roles of different immune cells and their subtypes in the CSF to IT cDC1s in mice and in patients. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).
KS02.6.A SINGLE-CELL MULTIMODAL ANALYSIS OF IDH-MUTANT GLIOMAS UNCOVERS SHIFT FROM EPIGENETIC TO GENETIC DRIVERS WITH TUMOR PROGRESSION
Authors: L Gonzalez Castro, J Wu, S Battaglia, C El Farran, J D’Antonio, T Miller, M Suva, B Bernstein
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) mutant gliomas are progressive, invariably fatal brain tumors affecting young and middle-age adult patients. Previous single-cell transcriptomic characterization of IDH-mutant gliomas has uncovered a heterogeneity of cell states, with a developmental hierarchy that starts with neural progenitor-like stem cells that transition to more differentiated malignant cell states. Despite this understanding, the dynamics of these cell state transitions as tumors undergo grade progression, and the factors that facilitate or restrict cell state transitions remain poorly understood. MATERIAL AND METHODS Here, we characterize the cell states of IDH-mutant gliomas via single-cell gene expression (scRNA-seq) and single-cell analyses of accessible chromatin (scATAC-seq) in tumors spanning all grades using fresh patient samples and compare them with transcriptional programs and chromatin accessibility profiles of normal brain cells. We perform mechanism validation experiments using IDH-mutant glioma organoids. RESULTS We find that tumor transcriptional cell states experience a marked shift as tumors undergo progression. In low-grade tumors, predominant cell states mimic slow-cycling oligodendrocyte progenitor-like cells (OPCs). With grade progression, predominant cell states transition to resemble highly proliferative neural progenitor-like cells (NPCs). Additionally, scATAC-seq analyses revealed novel permissive chromatin states, which could facilitate this transition. Genetic analyses identified several molecular alterations in high-grade tumors, including loss of DNA methylation, oncogene amplification, and the deletion of genes associated with the interferon (IFN) response. Those IFN genes, as well as tumor suppressors, are initially repressed by DNA hypermethylation in low-grade tumors. Lastly, we validate the role of DNA hypomethylation in favoring immune evasion with grade progression using an IDH-mutant glioma organoid model. CONCLUSION Overall, our findings provide evidence that tumor progression in IDH-mutant gliomas is driven by an interplay of epigenetic and genetic mechanisms, with the former being determinant in low-grade tumors and the latter in high-grade tumors. The emergence of genetically-driven mechanisms promotes more mitotically active cell states as well as decreased anti-tumoral immune activation.
JS04.5.A THE ROLE OF SURGERY IN IDH WILDTYPE DIFFUSE ASTROCYTOMA
Authors: H Krenzlin, F Lange, A Dauth, D Kalasauskas, C Freyschlag, O Schnell, M Misch, C von der Brelie, A Wagner, A Krigers, V Rohde, B Meyer, P Vajkoczy, J Beck, C Thomé, F Ringel, N Keric
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Isocitrate dehydrogenase (IDH)1/2 wildtype astrocytomas, classified as CNS WHO grade 4 tumors in the latest WHO classification of 2021, have high recurrence rates. The role of surgery in these tumors remains uncertain.. In this study the impact of the extent of resection (EOR) on progression free (PFS) and overall survival (OS) in astrocytomas IDH1/2 wt (CNS WHO Grad 4) is compared to glioblastoma IDH1/2 wt (CNS WHO Grad 4). METHODS Data acquisition was conducted as a multi-center retrospective analysis at 6 University Hospitals (2016-2020). Patients with IDH 1/2 wildtype diffuse astrocytoma (CNS WHO grade 2-4) were included in our study. Patients presenting with IDH wildtype glioblastoma from one institution served as controls. Primary outcome parameters were EOR (GTR; &amp;lt;5% residual tumor (RT), subtotal resection (STR; 5-75% RT), and biopsy (&amp;gt; 75% RT) and OS. RESULTS 160 patients with IDH-wildtype glioblastoma (CNS WHO grade 4) (45.6 % females) and 138 patients with IDH-wildtype diffuse astrocytoma (CNS WHO grade 2-4), (37.7 % females) were enrolled. The median age was 68 years (37-86 years) in the classic glioblastoma cohort and 55 years (20-87 years) in those with astrocytomas. GTR was achieved more often in patients with classic glioblastoma: 58.8% compared to those with diffuse astrocytoma 39.1% (p = 0.0001); STR (32.6%, p = 0.0048) and biopsy (28.3%, p = 0.0032) were more often in astrocytomas. The overall survival was 12.7±10.4 months in classic glioblastoma compared to 27.3±2.9 months in astrocytoma. GTR significantly increased OS in both entities (glioblastoma: 15.3±10.4 months, 95% CI 13.13 - 17.40, p = &amp;lt;0.0001; diffuse astrocytoma: 26.7±17.9 months, 95% CI 20.13 - 33.25, p = &amp;lt;0.0001). Further, also STR significantly increased OS in glioblastoma (11.46±11.03 months, 95% CI 7.55 - 15.37, p = 0.0257) and astrocytoma (18.8±13.54 months, 95% CI 14.47- 23.13, p = 0.0035). ROC analysis identified a residual cut-off tumor volume of &amp;gt;20% in the glioblastoma cohort and &amp;gt;60% in the difuse astrocytoma cohort to be associated with impaired OS. Multivariate logistic regression analysis identified age and EOR, not radio-chemotherapy, as independent predictors of OS in diffuse astrocytoma. MGMT methylation had no impact on OS (p = 0.11). CONCLUSION The presented data suggests that resection prolongs OS in patients with IDH-wildtype astrocytomas and is of higher value than radio-chemotherapy. Of note, STR also positively influences OS in these patients. These results underline the importance of surgical resection even if GTR is not achievable and thus mark a potential paradigm shift in clinical decision making.