tbuckley/cabot-search huggingface dataset:
P09.06.A ELEVATED TRANSLOCATOR PROTEIN 18KDA BINDING IN LOW MEAN DIFFUSIVITY CLUSTERS OF THE TRANSFORMING GLIOMA MICROENVIRONMENT
Authors: J Breese, E Agushi, D Lewis, R Hinz, B Alfaifi, A Jackson, D Coope
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Approximately 95% of low-grade gliomas (LGGs) undergo anaplastic de-differentiation into high-grade gliomas, a process only partially understood from the current suite of in vivo clinical imaging methods. MATERIAL AND METHODS 11 patients with suspected transforming gliomas undertook a comprehensive magnetic resonance imaging (MRI)/positron emission tomography (PET) imaging protocol, incorporating post-contrast T1W/FLAIR acquisition for tumour delineation, and diffusion tensor imaging. PET imaging with the radiotracer [11C]-(R)-PK11195 assessed the distribution of translocator protein 18kDa (TSPO), whose upregulation is associated with inflammation and glioma progression. [11C]-(R)-PK11195 binding potential (BPND) maps were generated, utilising the simplified reference tissue model, with the grey-matter cerebellar time activity curve serving as the tissue input function. KMeans clustering of MD intensity values within the tumour FLAIR (minus contrast enhancement) region marked spatially distinct “habitats” of high/low MD voxel clusters. BPND values within the high and low MD clustering habitats were collected and subsequently compared between tumour grades. RESULTS Within the FLAIR (minus contrast enhancement) tumour region of grade 2 and 3 gliomas (n = 6), mean BPND values in low MD habitats (0.042 ± 0.125) were significantly higher than habitats of high MD (-0.066 ± 0.130) (p = 0.000007). In grade 4 tumours (n = 5), no significant difference was observed in the mean TSPO BPND values between habitats of low MD (0.498 ± 0.297) and high MD (0.509 ± 0.167) clusters (p = 0.892). CONCLUSION Our findings demonstrate a unique aspect of spatial heterogeneity in grade 2 and 3 tumours, absent from grade 4 gliomas, indicating differences in the underlying inflammatory processes. Regions of restricted diffusion with high TSPO signal in grade 2 and 3 tumours may signify heterogenous distributions of active immune cells and/or neoplastic cell populations in the microenvironment. Conversely, grade 4 tumours may exhibit uniform patterns of immune cell activation/neoplastic cell infiltration throughout their surrounding microenvironment.
P20.13.B LHERMITTE-DUCLOS DISEASE - AN ILLUSTRATED SURGICAL CASE REPORT
Authors: C D Casimiro, M Carneiro, J Monteiro, F Dias
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Dysplastic gangliocytoma of the cerebellum/Lhermitte-Duclos disease is a rare pathologic condition of uncertain etiology, characterized by the presence of a slow growing cerebellar tumor with very typical appearance on MRI and benign histopathological features. In adults it is part of the Cowden syndrome, an autosomally dominant genetic disorder characterized by the development of multiple body hamartomas and also an increased likelihood of malignant neoplasms. METHODS Report of a surgical case. RESULTS We report the rare case of a 31 years old female that presented with a history of headache, episodes of vomiting and progressive visual impairment since the previous year. The patient had several malformative features such as macrocephaly, retrognathism and short hands. The neurological examination was positive for mild appendicular dysmetria and bilateral papilledema. A CT scan showed an enlargement of the supratentorial ventricular system and a hypodense left cerebellar hemispheric lesion with moderate mass effect. A subsequent MRI showed an intrinsic expansive hemispheric lesion, with striated folial pattern (“tigroid” appearance), hyperintense on T2 and with no contrast enhancement; there was moderate cerebellar amygdala ectopy, a constitutive reduced amplitude of the posterior fossa and an extensive cervico-dorsal syrinx, features compatible with a Chiari type 1 malformation. The patient underwent surgery for lesion removal via a sub-occipital craniotomy and EVD placement, later removed without need for shunting. Post operative MRI was negative for complications but raised the question about a small antero-lateral residue. Pathology showed a dysplastic gangliocytoma (WHO grade 1) compatible with Lhermitte Duclos (which in adults is pathognomonic of Cowden Syndrome). During follow up the patient developed neck stiffness due to cervical muscle contracture which progressively improved. Headache and visual impairment also progressively improved. Given this diagnostic the patient is now under extensive clinical and serial imaging follow up. MRI at 3 months after surgery showed mass effect resolution on the posterior fossa, with improvement of the cerebellar tonsils ectopy and a smaller residual syrinx. CONCLUSION We report a rare case of Lhermitte Duclos disease that was diagnosed and treated successfully with surgery. The subsequent improvement of ventriculomegaly, the Chiari-like findings, and syrinx was remarkable, without the need for additional posterior fossa decompression surgery. A close and long follow up is needed in order to anticipate and diagnose the possible manifestations of this rare syndrome.
P13.16.B TARGETING RBM19 TO ENHANCE RADIOTHERAPY IN GLIOBLASTOMA
Authors: Z Gong, D Li, K Cao, T Liu, Z Wan, H Wang, F Gao, T Xu, Y Yang, Y Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) treatment faces challenges due to radioresistance. This study focuses on RNA binding motif protein 19 (RBM19), a protein implicated in crucial cellular functions yet underexplored in enhancing radiosensitivity. Our research aims to elucidate the potential of RBM19 in improving radiotherapy outcomes for glioblastoma patients. MATERIAL AND METHODS RBM19 expression in GBM patients and normal brain tissue was analyzed using GEO datasets. The expression of RBM19 and its correlation with patient survival were assessed using clinical and follow-up data from TCGA. In vitro, we manipulated RBM19 expression in U87 and U251 glioblastoma cell lines. The radiosensitivity of cancer cells was determined through colony formation assay, apoptosis, and CCK-8 assay. The comet assay and γH2AX assay were used at different time points to detect the kinetics of DNA damage and repair. Western blot assay was applied to explore the functions of RBM19 on DNA damage response after ionizing radiation, further highlighting its role in DNA damage repair pathway. Co-immunoprecipitation was conducted to study the interaction between RBM19 and CHK1 protein. Xenografts were performed to investigate the in vivo effects of RBM19 on tumor growth. RESULTS Differential gene analysis identified RBM19 as consistently upregulated in GBM across multiple GEO datasets. TCGA data analysis revealed a negative correlation between RBM19 expression and overall and disease-free survival in post-radiotherapy GBM patients. In vitro, alterations in RBM19 expression influenced glioblastoma cell viability post-irradiation, knockdown reduced viability and enhanced radiosensitivity, while overexpression had the opposite effect. Comet assays demonstrated that RBM19 modification affects the extent of DNA damage post-irradiation, with knockdown exacerbating DNA damage. Immunofluorescence for γ-H2AX foci confirmed increased DNA damage in RBM19-knockdown cells. Furthermore, RBM19 knockdown significantly increased apoptosis post-irradiation. Western blot analysis showed that RBM19 influences key proteins in the DNA damage repair pathway, potentially affecting therapeutic resistance in glioblastoma cells. Co-immunoprecipitation found interactions between RBM19 and Checkpoint kinase 1 (CHK1) and ataxia telangiectasia and Rad3-related (ATR), again shedding light on its role in DNA damage repair pathways. In vivo experiments demonstrated that RBM19 knockdown extended survival and reduced tumor volume in irradiated glioblastoma-bearing mice. More DNA damage was observed in RBM19 knockdown xenografts. CONCLUSION RBM19 may serve as a new molecular target for radiosensitization in glioblastoma. This study provides a new direction for research and a potential therapeutic approach for the radiosensitization of clinical glioblastoma treatments.
OS10.5.A MINIMALLY INVASIVE BRAIN METASTASES ARE CHARACTERIZED BY AN ACTIVE, ANTI-CANCER IMMUNE INFILTRATE
Authors: S M Maritan, E Karimi, M Dankner, A Hernandez-Corchado, M W Yu, M Rezanejad, B Liu, B Fiset, Y Wei, A Nehme, M Park, Y Riazalhosseini, H Najafabadi, K Petrecca, M C Guiot, D F Quail, L A Walsh, P M Siegel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cancer metastasis to the brain is a common complication of advanced disease with limited therapeutic options. Although immune checkpoint inhibition has shown some efficacy in treating brain metastases (BrM), patient response is variable, in part due to the unique composition of the brain tumor immune microenvironment (TIME). Our group has shown that BrM can grow in two distinct patterns, either as minimally invasive (MI) masses with well-defined borders, or as tumors with highly invasive (HI) growth into surrounding brain tissue. Here, we investigate how the TIME differs between MI and HI BrM. MATERIAL AND METHODS We use Nanostring Digital Spatial Profiling coupled with the Cancer Transcriptome Atlas panel on BrM from 20 patients to quantify 1,825 cancer-specific RNA targets in cancer cells at the tumor-brain interface. Additionally, we perform imaging mass cytometry (IMC) on 119 BrM from 46 patients, encompassing over 350,000 cells. Samples represent BrM from various primary sites (lung, breast, melanoma, other), and include patient-matched samples from the brain-tumor interface and the centre of the metastatic lesion. Additional multiplexed immunohistofluorescence staining was performed on a subset of 18 patients with lung cancer BrM. RESULTS Gene set enrichment analyses revealed elevated interferon gamma signalling in MI versus HI BrM, which was confirmed by immunohistochemical staining for pSTAT1, consistent with an “immune hot” TIME in MI BrM. IMC revealed that MI BrM had significantly higher frequencies of lymphocytes, including B cells, CD4+, CD8+, CD4- CD8-, and regulatory T cells compared to HI BrM. Pairwise cellular association analyses revealed increased interactions between lymphoid cell populations in MI versus HI BrM, suggestive of specific regions enriched in B and T cells in MI BrM, rather than a generally diffuse infiltrate. Indeed, cellular neighbourhood analyses revealed a lymphoid-rich cellular neighbourhood that was more abundant in MI versus HI BrM and localized to the tumor-brain interface. Multiplexed immunohistofluorescence staining revealed that T cells were more likely to be cytotoxically active and exhausted in MI versus HI BrM. CONCLUSION These data suggest that HI BrM invade into an immunosuppressed microenvironment while MI BrM are characterized by an active anti-tumor immune infiltrate, predominantly localized to the tumor-brain interface. Together, this work suggests potential immune regulation of BrM invasion. Work is ongoing to identify factors present in the HI BrM environment that enforce an immunosuppressive environment. This research has been supported by grants from the Terry Fox Foundation and the Quebec Breast Cancer Foundation (Grant #: 251427-251690) and the Canadian Institutes of Health Research (CIHR PJT-175066) to P.M.S.
P02.02.A AN MRI-LSM PLATFORM TO ASSESS BLOOD-BRAIN BARRIER DISRUPTION AND BIODISTRIBUTION OF IMMUNOTHERAPIES IN EXPERIMENTAL GLIOMA
Authors: J G Scheck, B Boztepe, L Heinz, V Sturm, C Pan, M Fischer, S Heiland, F Winkler, W Wick, K Schregel, A Abdollahi, M Platten, M Bendszus, I Weidenfeld, M O Breckwoldt
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The inherent resistance of glioma including the recent failure of immune checkpoint blockade to prolong survival in glioma has partly been attributed to tumor heterogeneity leading to insufficient drug availability. Magnetic resonance imaging (MRI) is the main clinical modality to monitor tumor growth and treatment response but cannot assess drug availability within the tumor microenvironment (TME). To this end, we developed a platform to assess blood-brain barrier disruption utilizing high field multiparametric MRI and correlative light sheet microscopy (LSM) to investigate the underlying mechanisms of response and resistance towards immunotherapy in brain tumor models. MATERIAL AND METHODS Orthotopic gliomas were grown in the syngeneic GL261 or SB28 mouse glioma models. Longitudinal contrast enhanced multiparametric MRI was performed weekly after baseline. To correlate drug distribution with BBB-D and the microvasculature, mice either received a single dose of fluorescently labelled anti-PD1 or TLR7 agonist encapsulated nanoparticle CDNP-R848 at different tumor stages. After 24 hours circulation time, vasculature was labelled through lectin-FITC perfusion. Brains were cleared with fDisco and LSM was performed. Images were segmented with Ilastik and further analysis was carried out in Imaris, Fiji and VesselVio. RESULTS In Gl261 gliomas we achieved a response rate of 87.5% to CDNP-R848, as previously established by our group, whereas SB28 tumors were fully resistant to CDNP-R848 validating the strong immunotherapeutic resistance of SB28. In both glioma models, immunotherapies were CNS-penetrant and reached the TME without off targeting, while showing cellular specificity for myeloid cells or T cells, respectively. Gadofluorine M and Gd-DOTA allowed the assessment of different spatio-temporal patterns of BBB-D. Microbleedings as assessed by T2* imaging and BBB-D as assessed by perfusion imaging were more prominent in SB28, indicating pronounced heterogeneity in the SB28 model, likely contributing to its resistance. GfM and perfusion MRI were strongly correlated with drug distribution, indicating that these MR parameters can predict drug distribution in the TME. CONCLUSION Our correlated MR-LSM approach therefore allows the assessment of the 3-dimensional biodistribution of checkpoint inhibitors and immunotherapeutic NP in the TME in relation to BBB-D. By validating MR-based imaging biomarkers, we aim to non-invasively predict drug availability in the complex TME of glioma.
CD36 cell surface expression as a surrogate marker to identify ABL/JAK-class kinase fusions in pediatric BCP-ALL
Authors: Marion Strullu, Aurélie Caye-Eude, Elie Robert, Jean-Marie Renard, Amandine Chaye, Julie Galimand, Odile Fenneteau, Chloé Arfeuille, Wendy Cuccuini, Alexandre Theron, Sandrine Thouvenin, Catherine Paillard, Arnaud Petit, Pierre-Simon Rohrlich, Hélène Cavé, André Baruchel, Elodie Lainey
Journal: Leukemia (2024)
P27.03.B BIOPSY VERSUS RESECTION IN GLIOBLASTOMA TREATMENT: A PROPENSITY SCORE-MATCHED ANALYSIS OF A RETROSPECTIVE COHORT
Authors: Y de Haan, A Moussa, J K W Gerritsen, S J P Schnitzler, C M F Dirven, A J P E Vincent
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Overall survival (OS) of glioblastoma patients remains poor, even with surgical treatment and adjuvant therapy. Gross-total resection is preferred whenever possible; when this cannot be achieved due to e.g. age or critical tumour localization, biopsy is often performed. To date, no objective guidelines are available to determine what type of surgery is most appropriate for glioblastoma patients. The choice between resection or biopsy remains a comparative assessment between maximizing survival and preventing postoperative neurological deficits. We aimed to identify which treatment strategy benefits specific subgroups of glioblastoma patients with regards to OS and maintaining neurological function. MATERIAL AND METHODS This retrospective cohort consists of patients recruited in a tertiary hospital in The Netherlands. Eligible patients were 18 years or older and had undergone either biopsy or resection. Secondary glioblastomas or patients with a Karnofsky Performance Status (KPS) of 50 or lower were excluded. Nearest-neighbor propensity score matching was utilized to create comparable biopsy versus resection cohorts based on sex, age, hemisphere, location, ASA score, year of presentation, pre-operative NIHSS, pre-operative KPS, tumour volume, tumour crossing of the midline and undergoing of adjuvant treatment. Survival outcomes were analyzed using the log-rank test, while NIHSS deterioration (increase of at least 1 point) was assessed using a Chi-squared test. RESULTS Between January 1st 2018 and December 31st 2022, 317 patients were recruited, with 98 undergoing biopsy and 219 undergoing resection. Matching resulted in equal cohorts of 86 patients each. The median OS of the unmatched cohort was 9.4 months. However, in the matched cohort, median OS significantly favored resection over biopsy, with 8.8 months versus 3.2 months respectively (p=.004). Regarding NIHSS deterioration at 6 weeks postoperative, we found a possible favoring of resection with 38.5% deterioration in the biopsy group (n=20 of 52 who had follow-up data) and 25.9% in the resection group (n=21 of 81 who had follow-up data). Non-significance of this finding (p=.182) might possibly be due to unequal missingness in follow-up data. We are currently expanding our recruitment to include patients from 2010 onwards to allow for predictive regression analysis and subgroup analysis with regards to age, pre-operative NIHSS score, pre-operative KPS score, midline location and multifocality. CONCLUSION Analysis of this matched cohort of glioblastoma patients undergoing biopsy and resection, favors resection with regards to both OS and preserving neurological functioning. Subgroup analysis will follow to better inform physicians and patients in their clinical decision-making.
P26.09.A METFORMIN REPURPOSING FOR GLIOBLASTOMA TREATMENT
Authors: A Barciszewska, A Belter, J F Barciszewski, I Gawrońska, M Giel-Pietraszuk, M Z Naskręt-Barciszewska
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Being the most common and aggressive malignant primary brain tumor in adults, glioblastoma (GBM) is, simultaneously, the best-studied central nervous system neoplasm with the continuous development of new treatments, including targeted therapies and immunotherapy, to improve outcomes for GBM patients. However, even with such a big effort, GBMs are still challenging to manage, with poor prognosis. Recurrence is certain, and the average survival time is relatively short. In the search for effective therapies, the focus switches now to existing drugs with the aim of repurposing. One of the possible candidates is the first-line drug for type 2 diabetes - metformin (MTF). It acts mainly through decreasing liver glucose production and improving insulin sensitivity. However, the exact mechanism of MTF’s action is not fully understood. Its positive influence is observed in many aspects of cardiovascular disease, gut microbiota modulation, hormonal balance, cancer prevention and treatment, as well as longevity and aging. These multiple effects highlight the potential of MTF as a versatile medication beyond its traditional use in diabetes. They also drive attention to possible underlying molecular processes responsible for such a broad action. The only phenomenon that can explain such a complex influence on diverse biological processes is epigenetics. One of the main epigenetic processes is DNA methylation, which directly influences gene expression. 5-methylcytosine (m5C) in DNA is the best-characterized epigenetic mark. Our project aimed to evaluate the total DNA methylation level after MTF administration on the GBM cell lines. MATERIAL AND METHODS Using the nucleotide post-labeling method, we analyzed the total amount of m5C in DNA of GBM (T98G, U138), and normal (HaCaT) cell lines treated with MTF. RESULTS No significant changes in total DNA methylation were observed in non-cancer cell lines (HaCaT) treated with MTF, due to small toxicity confirmed also with global DNA guanosine oxidation (8-oxo-dG). On the opposite, DNA hypomethylation was observed for GBM cell lines (T98G and U138) with increasing MTF concentration and incubation time. We also analyzed the combined effects of MTF with temozolomide (TMZ), the first-line chemotherapeutic for GBM. MTF potentiated the demethylating effect of TMZ. The concomitant application of both drugs induced DNA oxidation. CONCLUSION Total DNA methylation changes in GBM cell lines under MTF treatment suggest the new mechanism of that drug action and promote clinical implications for adjusting MTF and TMZ therapy in GBM patients. Our results show the potential and possible obstacles of the combined therapy of TMZ with MTF. Combined therapy with both drugs leads to total DNA hypomethylation. Therefore it is necessary to adjust MTF administration during TMZ therapy. FUNDING M.Z.N.-B. is supported by the OPUS 19 (2020/37/B/NZ5/03249)
P14.17.B MINI-CRANIOTOMY FOR RESECTION OF INTRA-AXIAL TUMOURS: EVALUATION OF TECHNIQUE USING PROPENSITY-SCORE MATCHING
Authors: M Waqar, A Dainton, A Abdelaal, R Nambiar, H Maye, K Karabatsou, P D'Urso
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Minimally-invasive neurosurgical techniques are increasingly utilised in neurosurgery and there is growing evidence to support their use in intra-axial tumour resection. In this case control study, we compare outcomes between patients undergoing mini-craniotomy and larger sized craniotomies for intra-axial tumours using propensity-score matching. MATERIAL AND METHODS Review of prospective institutional database (N = 465) of adult patients undergoing intra-axial tumour resection from 2014-2021. Propensity-score matching was used to create matched groups of patients who had a mini- (≤3 cm), intermediate-sized (3-5cm) and standard (&amp;gt;5cm) craniotomies. Outcomes included extend of resection, length of postoperative stay and 6-month complications. RESULTS 138 patients were included distributed equally between mini- (46), intermediate-sized (46) and standard (46) craniotomy groups. The primary comparison was between the mini- and standard craniotomy groups. There was no significant difference in baseline characteristics between these groups except craniotomy size (2.8 cm vs. 6.1 cm, p&amp;lt;0.001). Importantly, the maximum tumour diameter was similar between the groups (p=0.116). A significantly greater proportion of patients in the mini-craniotomy group had a gross-total or near total resection (80% v 52%; p=0.014). Patients in the mini-craniotomy group had a shorter mean length of post-operative hospital stay at 5 days compared to 7 days (p=0.001). There was no statistical difference in the rate of 6-month complications between the two groups (p = 0.197). A secondary analysis compared the mini- and intermediate-sized craniotomy groups. The mini-craniotomy group had a shorter mean length of postoperative stay (p=0.002) and greater proportion of gross-total/near total resections (p=0.008). CONCLUSION Mini-craniotomy was associated with superior extent of resection and a lower length of postoperative stay. It demonstrated non-inferiority for post-operative complications. This report adds to the growing literature demonstrating the safety, feasibility and efficacy of mini-craniotomy in neuro-oncological surgery.