tbuckley/cabot-search huggingface dataset:
KS01.4.A CHARACTERIZATION AND THERAPEUTIC TARGETING OF ASTROCYTE REACTIVITY STATES DURING PROGRESSION FROM PRIMARY TO POST-RADIOTHERAPY RECURRENT GLIOBLASTOMA
Authors: P Jeannot, R Rosberg, D Lindgren, K I Smolag, D Manou, T J Berg, J Dawson, R Elliott, C Ceberg, N Carragher, A Pietras
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite early response to radiotherapy, glioblastomas invariably recur, frequently within the field receiving high-dose irradiation. Stromal radiation responses remain poorly characterized, but recent evidence suggest that cells of the tumor microenvironment generate tumor-supportive conditions in the post-radiotherapy brain. Here, we explored the character of astrocyte reactivity states induced during tumor progression and treatment, identified compounds to target such states, and evaluated their suitability as therapeutic targets for glioblastoma. MATERIAL AND METHODS Murine glioblastomas were generated using the RCAS/tv-a system and treated (or not) with 10 Gy radiation upon symptoms. Healthy brain and tumor tissues were subjected to single cell RNA sequencing and spatial transcriptomics, and further analyzed using highly multiplexed immunohistochemistry. An image-based approach was developed and validated to quantify astrocyte reactivity, and this approach was utilized in high-throughput screens to identify compounds able to block astrocyte reactivity. RESULTS Single cell RNA sequencing revealed distinct astrocyte states in healthy brains and tumor tissues, and relative changes in state abundance as tumors progressed from primary to recurrent glioblastomas. Astrocyte states were spatially separated, with some enriched in peri-tumoral regions and others within the tumor core. Using an image-based method to quantify astrocyte reactivity in vitro, we screened 1600 compounds and identified 31 drugs able to inhibit astrocyte reactivity induced by radiotherapy. Among them, Flunarizine, a calcium-entry blocker approved to treat migraine, was confirmed to inhibit radiation-induced astrocyte reactivity and reactive astrocytes’ effect on glioblastoma cells in vitro. In a mouse model of glioblastoma, Flunarizine significantly extended the survival of mice in combination with radiotherapy while not affecting the outcome for non-irradiated mice, suggesting that Flunarizine targets a radiation-induced phenotype. Flunarizine treatment had no effect on primary glioblastoma cells, supporting the idea of microenvironmental targeting. CONCLUSION Astrocytes react to the tumor microenvironment by adopting cell states distinct from those present in healthy brain, and further adapt their phenotypes as tumors undergo radiotherapy. Screening for compounds able to inhibit astrocyte reactivity revealed Flunarizine as a promising candidate for glioblastoma treatment.
P19.17.B THE PREOPERATIVE LEVELS OF CIRCULATING ERYTHROCYTIC HEMOGLOBIN ARE INDEPENDENT PREDICTORS FOR WHO GRADE 2-3 HISTOLOGY IN FALCINE AND PARASAGITTAL MENINGIOMAS
Authors: F Gagliardi, P De Domenico, M Braga, L R Barzaghi, G Nocera, P L Poliani, P Mortini, F Roncelli, S Silvia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Falcine and parasagittal lesions stand out among other intracranial meningiomas for their extreme histological heterogeneity, accounting for the highest rate of high-grade lesions. The ability to preoperatively estimate the lesion’s grade and its clinical outcome would be of great value in orienting and customizing the treatment approach in these patients. To date, no validated clinical or radiological predictive factors for tumoral grade and prognosis are available. MATERIAL AND METHODS This is a single-center, retrospective, clinical study designed to assess the diagnostic and prognostic role of pre-operative peripheral blood markers in patients harboring falcine (FM) and parasagittal (PM) high-grade meningiomas. A total of 121 patients undergoing surgical resection for a single FM/PM lesion at San Raffaele Hospital between November 2007 and April 2021 were included. A propensity score-matched analysis has been performed to account for gender imbalances in the low-grade (LG) vs high-grade (HG) cohorts. RESULTS A total of 75 tumors FM (62%), and 46 PM (38%) meningiomas were included. The median tumoral volume was 31.1 cm3 (IQR 17.1-65.4). Low-grade lesions comprised n=77 WHO grade 1 tumors, whereas the high-grade group (HG) included n=35 grade 2 (28.9%), and n=9 grade 3 lesions (7.4%). Patients harboring HG lesions showed significantly higher baseline Hb levels significantly compared to LG (mean 14.4 ± 1.59 vs 13.7 ± 1.25 g/dl, p=0.04). Preoperative Hb demonstrated a predictive value of lesional grade (OR 1.35, 95% CI: 1.01-1.85, p=0.04). Accordingly, patients showing increased Hb levels &amp;gt;15.4 g/dl achieved shorter OS (60.4 months, 95% CI: 14.7-106.1 vs 137.4 months, 95% CI: 111.2-163.6), p=0.0011 compared to patients with lower preoperative Hb values. CONCLUSION Increased levels of circulating erythrocytic hemoglobin might be independent predictors for high-grade histology, and correlate with shorter overall survival in falcine and parasagittal meningiomas.
P18.40.B SET UP AND RECRUITMENT TO A RANDOMISED CONTROLLED TRIAL OF MEDICINAL CANNABINOIDS IN RECURRENT GLIOBLASTOMA - THE ARISTOCRAT TRIAL
Authors: J Savage, R Mant, A Kirkham, P Buckle, E Banks, S Meade, F Boele, M Williams, F Collinson, C Billingham, S C Short
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ARISTOCRAT is a unique, randomised, double-blind, placebo-controlled phase II trial of cannabinoids (nabixomols) alongside temozolomide in patients with MGMT-methylated recurrent GBM. MATERIAL AND METHODS This UK based trial was funded through a crowdfunding campaign run by The Brain Tumour Charity in 2020 and a multi-disciplinary team of co-applicants including PPI representatives designed the protocol, which randomises patients with first recurrence of IDH wild-type GBM patients in a 2:1 ratio between nabiximols or matched placebo with standard dose temozolomide. Unique aspects include self-titration of nabiximols based on individual tolerance, and fully blinded randomisation with matched placebo. The primary outcome measure is overall survival time with key secondary outcomes including survival at 6, 12 and 24 months, progression-free survival time, health-related QoL and adverse events. The trial initially aimed to recruit a total of 234 patients over 18 months. Intermediate assessment of feasibility to confirm safety, compliance and achievability of recruitment was planned after 40 patients are randomised. RESULTS The trial opened in February 2023 and has promoted a high level of patient and public interest, including national press coverage. Despite this, recruitment has been slower than anticipated due to factors including slow site activation complicated by the blinding of a controlled drug, and low numbers of patients screened. We have not identified specific issues in our screening data but did, on request of local PIs broaden inclusion criteria to include patients who received short course (40Gy in 15 fractions) radiotherapy first line. To further address this we have highlighted the use of genomics data from Tessa Jowell BRAIN MATRIX, to identify eligible patients at first diagnosis who can then be flagged for study consideration at relapse. We have also initiated a unique collaboration to use real-world data [the GlioCova data set] to re-test our estimates for potential patient recruitment in the UK, which may suggest specific remedies to ensure the study can deliver definitive data in a realistic time frame. CONCLUSION ARISTOCRAT will provide unique, robust clinical data on the role of nabiximols (combined with temozolomide) in improving overall survival and the impact on QoL for patients with recurrent GBM and is the first of its kind in cancer patients. Challenges to set up and recruitment are being addressed using national support through the BRAIN MATRIX genomics platform and real-world modelling approaches.
P24.02.A INSIGHTS FROM A CASE OF TRANSTENTORIAL HERNIATION IN A LEFT ANTERIOR-THIRD PARASAGITTAL MENINGIOMA PRIOR TO SURGERY: A SYSTEMATIC REVIEW AND ILLUSTRATIVE CASE
Authors: J R Torio, V Buenviaje, E Meceda
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas account for one-third of all CNS tumors and categorized into three grades by the WHO. While tumor size has been identified as an independent risk factor, surgery has been established as primary treatment. Prior studies have identified links between prognosis and factors like tumor characteristics and patient demographics, yet studies regarding outcomes of patients with pre-operative herniation complicated by socio-economic delays in treatment remains unexplored, prompting our study to investigate this specific population’s outcomes. MATERIAL AND METHODS We report a case of a 55-year-old female managed as a case of left anterior third parasagittal meningioma who underwent Bifrontal craniotomy excision of tumor (Simpson I) with resection of anterior third superior sagittal sinus and did a systematic search using MeSH keywords “Meningioma”, “Herniation”, and “Outcomes”. Six studies were included in the final qualitative analysis. RESULTS A review of six studies included 75 patients with meningiomas revealed a female predominance (66.7%) and an average age of 52.3 years, with tumors primarily located at the falx (90.67%). Surgical interventions predominantly involved gross total tumor resection (79.45%), yielding favorable outcomes in 83.09% of cases with low morbidity (13.33%) and mortality rates (1.41%), although pre-operative complications such as intratumoral hemorrhage and herniations were noted, and the recurrence rate varied across studies with a median follow-up ranging from 1 to 36 months. CONCLUSION Meningiomas manifest symptoms gradually depending on tumor location, with peritumoral brain edema contributing significantly to morbidity. While delays in surgery often influenced by socioeconomic factors are associated with unfavorable outcomes, underscoring the importance of timely intervention to prevent disease progression and enhance patient quality of life.
PL01.5.A ASSOCIATION BETWEEN RESTING-STATE-NETWORK FUNCTIONAL CONNECTIVITY AND SURVIVAL IN RECURRENT GLIOMAS DIAGNOSED USING FET PET
Authors: M Friedrich, J M Werner, J P Steinbach, M Sabel, U Herrlinger, M Piroth, G Stoffels, C P Filss, P Lohmann, N J Shah, M I Ruge, F M Mottaghy, R Goldbrunner, K J Langen, G R Fink, M Kocher, N Galldiks
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Functional connectivity between glioma-infiltrated brain tissue and remote cortical regions has been linked to overall survival (OS) in patients with newly diagnosed glioblastoma. Here, we studied the association of functional connectivity between tumor and resting-state networks and OS in patients with recurrent gliomas. PATIENTS AND METHODS The study included 82 patients (age range, 26-81 years; median ECOG performance score, 0) with recurrent gliomas (CNS WHO grade 4 glioblastoma, n=57; CNS WHO grade 3 and 4 astrocytoma, n=12; CNS WHO grade 2 and 3 oligodendroglioma, n=13) who had undergone first-line therapy by current guidelines. In addition to the RANO criteria for anatomical MRI, diagnosis of glioma recurrence was confirmed by amino acid PET using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). FET PET and resting-state functional MRI were simultaneously acquired on a 3T hybrid PET/MR scanner. A seed-based dual regression analysis was performed to determine the functional connectivity between metabolically active recurrent tumors and a set of seven canonical resting state networks. RESULTS Average functional connectivity was significantly higher (p=0.028) in oligodendrogliomas (z-score, 6.9±1.9) and astrocytomas (z-score, 5.5±1.3) than in glioblastomas (z-score, 4.9±2.6) and was inversely related to the tumor grade (p=0.031). Univariate Cox regression analysis revealed a significant positive association between OS and tumor connectivity with the visual, somatomotor, and dorsal attention network (all p&amp;lt;0.05). Subsequent stepwise multivariate Cox regression analysis refined this association to the dorsal attention network alone (HR, 0.88; 95% CI, 0.80-0.97; p=0.007). Patients with the highest functional connectivity (z-score &amp;gt;8.3, n=21) had a median OS of 31.4 months, while those with the lowest functional connectivity (z-score &amp;lt;4.3, n=21) had a median OS of 10.6 months. Functional connectivity between tumors and the dorsal attention network showed an independent association with OS (p=0.002) in a multivariate model, including the metabolic tumor volume (p=0.003). CONCLUSION Recurrent gliomas exhibit significant functional connectivity to most of the major known resting-state networks, which was generally higher in astrocytomas and oligodendrogliomas. The data suggest that high functional connectivity between the tumor and the dorsal attention network is an independent prognostic factor for improved OS.
P03.02.B DECIPHERING THE IDENTITY AND CHARACTERISTICS OF LONG-TERM LABEL RETAINING GLIOBLASTOMA CELLS AND THEIR ROLE IN TUMOUR RELAPSE
Authors: H Chow, A Kourtesakis, L Hai, S Schaffranek, S Pusch, D Hoffmann, D Reibold, W Wick, R Wagener
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GB) stem cells (GSCs) are described to recapitulate the expression signatures of stem and progenitor cell classes in the neurodevelopmental hierarchy and are implicated in driving therapeutic resistance. However, the heterogeneity of both the GSC subclasses and their expression of stemness markers hinders comprehensive labelling of these cells. Cellular dormancy is a key feature of GSCs that can be captured by label retention method to track slowly dividing cells. We used CellTrace (CT) dye to identify long term label retaining GB cells (LRGC) in orthotopic xenograft model. We analysed the distribution of LRGC versus the tumour bulk in histology. Additionally, we analysed the transcriptional signature by FAC-sorting LGRC for single cell RNA sequencing. Further, we demonstrated that LRCs survived through temozolomide (TMZ) treatment in vivo and re-initiated tumour proliferation in a faster pace than other surviving glioma cells, signifying its role in therapeutic relapse. MATERIAL AND METHODS To label LRGC, patient derived GB cell lines were stained with CT dye before transplantation into the striatum of immunodeficient mice. After 6 weeks of growth the brains were cryosectioned, histologically stained and imaged via confocal microscopy, followed by histologic AI assisted analysis with the AIVIA software. LRGC and non-label retaining tumor cells were FAC-sorted for single-cell RNA sequencing (SMART seq2). To explore the role of LGRC in therapeutic resistance, tumors were treated with TMZ. Re-initiation of tumor growth was tracked by subcutaneous surgical implantation of BrdU pumps at different timepoints after therapy. The proliferation patterns of LRGC versus other surviving tumor cells were analysed in histology again using an AI assisted software. RESULTS LRGC could be identified in histology 6 weeks after tumor growth. LRGC were found near the centre of tumor but rarely at the invasion front. Single cell RNA-seq of LRGC showed differentially expressed pathways related to lipid metabolism and neurodevelopment. Re-initiation of tumor growth started 12-14 days after therapy. LRGC showed a more intense proliferation compared to other surviving tumor cells, indicating the ability of LRGC to not only survive TMZ treatment, but also drive GB relapse. CONCLUSION LRGC could be visualized 6-8 weeks after tumor growth in an orthotopic xenograft model. On a transcriptional level these cells share similarities with stem cells in normal brain development but also show distinct features. An important role of LRGC in re-initiation of tumor growth after therapy could be confirmed.
P23.05.B LOCKED-IN SYNDROME: A CHALLENGING COMPLICATION FOR SURGERY OF FORAMEN MAGNUM MENINGIOMAS: A SYSTEMATIC REVIEW AND ILLUSTRATIVE CASE
Authors: J R Torio, E Meceda, C Concepcion, J Sylva
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Locked-in syndrome (LiS) as a complication from foramen magnum meningiomas (FMM) surgery is rare but impactful. Its exact occurrence rate isn’t well-documented due to its scarcity, often emerging from surgical maneuvers near the brainstem. MATERIAL AND METHODS We present a case of a 63-year-old female who was admitted for 5-month history of progressive bilateral lower extremity weakness who underwent a left suboccipital craniectomy, C1 laminectomy under neuronavigation and intra-operative neuromonitoring for MEP and SEP. We did a systematic search using MeSH keywords “Foramen Magnum Meningioma”, “Surgical Outcomes”, “Surgical Complications” and “Locked-In Syndrome” on November 26 2023, across multiple databases: PubMed, Google Scholar and Cochrane Library, wherein nine studies were included in the final qualitative analysis. RESULTS Majority of the surgically managed cases had FMM located anterolaterally with a median size of 2.06 -6.7cm. 32 cases had tumors encasing the vertebral artery. Morbidity rate was 38.6%, with most of the complications involved neurologic deficits secondary to the proximity of lesions to the brainstem and lower cranial nerves and hydrocephalus. No literature was able to report incidence of locked-in syndrome. CONCLUSION Incidence of LiS as a complication of FMM surgery is low but can have significant implications. Although vascular related etiology portends higher mortality as compared to non-vascular causes, role of prompt stroke treatments such as EVT can increase chance of better recovery. Outcomes tend to be challenging with limited prospects for complete recovery.
P14.03.B A PROSPECTIVE MULTI-CENTERED, ASSESSOR BLINDED INTERIM STUDY FOR BRAIN TUMOR DIAGNOSIS BY USING CONFOCAL FLUORESCENCE ENDOMICROSCOPY (CCELL - EX VIVO)
Authors: S Kang, Y Byun, D Hong, J Won, H Kang, J Kim, S Lee, M Kim, Y Kim, K Park, D Kong, C Park
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To address an intraoperative brain tumor diagnosis by frozen section(FS) which is time-consuming and traumatic, confocal laser endomicroscopy (CLE) has actively been explored as a promising alternative tool. In this study, we aimed to demonstrate that novel CLE image evaluation by a neuropathologist is as effective as frozen section diagnosis for histopathological assessment during brain tumor surgery. MATERIAL AND METHODS Utilizing a novel confocal endomicroscopy (cCeLL) wherein tissues were pretreated with indocyanine green, a prospective multicenter, assessor-blinded interim analysis was conducted at three tertiary medical institutions in the Republic of Korea. Patients newly diagnosed with brain tumors between May 2023 and April 2024 were included. Each tissue sample was divided into three smaller pieces for permanent section analysis, frozen section analysis and cCeLL-Ex vivo imaging. A designated neuropathologist interpreted all cCeLL-Ex vivo images. Statistic evaluation was performed by comparing both frozen section analysis and cCeLL-Ex vivo with permanent H&amp;E diagnosis. The total time from sample preparation to diagnosis was also calculated. RESULTS A total of 274 samples were acquired from 242 patients. The predominant tumor types were meningioma (32.1%), glioma (24.8%) and pituitary adenoma (9.49%). The majority of tissue samples (86.9%) were obtained from the tumor core. Non-diagnostic tissues constituted 4.38% in frozen section and 6.57% in cCeLL-Ex vivo imaging. The diagnostic accuracy of cCeLL-Ex vivo was on par with frozen section analysis, with 96.1% and 96.9%, respectively. Both methods demonstrated comparable diagnostic sensitivity (FS vs cCeLL-Ex vivo: 99.2% vs 98.3%) and specificity(FS vs cCeLL-Ex vivo: 76.0% vs 77.8%). There were no statistically significant differences in diagnostic accuracy between frozen section (FS) and cCeLL imaging for each tumor type. The average number of cCeLL images required for neuropathologic assessment was 15.84, varing based on the tumor type, with a range of 5.05 to 27.8. The mean duration from sample preparation to diagnosis was 8 minutes and 40 seconds in cCeLL-Ex vivo and 24 minutes and 35 seconds in frozen section (p-value &amp;lt; 0.001). CONCLUSION cCeLL-Ex vivo has shown promising tool as an alternative intraoperative brain tumor diagnosis compared to frozen section analysis. Future studies are anticipated to further validate its clinical utility and provide additional evidence supporting the potential of cCeLL imaging in clinical practice.
Ancient secretory pathways contributed to the evolutionary origin of an ecologically impactful bioluminescence system
Authors: Lisa Y Mesrop, Geetanjali Minsky, Michael S Drummond, Jessica A Goodheart, Stephen R Proulx, Todd H Oakley
Journal: Molecular Biology and Evolution (2024)

Abstract Evolutionary innovations in chemical secretion—such as the production of secondary metabolites, pheromones, and toxins—profoundly impact ecological interactions across a broad diversity of life. These secretory innovations may involve a “legacy-plus-innovation” mode of evolution, whereby new biochemical pathways are integrated with conserved secretory processes to create novel products. Among secretory innovations, bioluminescence is important because it evolved convergently many times to influence predator–prey interactions, while often producing courtship signals linked to increased rates of speciation. However, whether or not deeply conserved secretory genes are used in secretory bioluminescence remains unexplored. Here, we show that in the ostracod Vargula tsujii, the evolutionary novel c-luciferase gene is co-expressed with many conserved genes, including those related to toxin production and high-output protein secretion. Our results demonstrate that the legacy-plus-innovation mode of secretory evolution, previously applied to sensory modalities of olfaction, gustation, and nociception, also encompasses light-producing signals generated by bioluminescent secretions. This extension broadens the paradigm of secretory diversification to include not only chemical signals but also bioluminescent light as an important medium of ecological interaction and evolutionary innovation.