tbuckley/cabot-search huggingface dataset:
P01.07.A HOW IS A RECURRENT GLIOBLASTOMA SELECTED?
Authors: K Göhring, A Kässer, S Konig, H Strobel, G Karpel-Massler, M A Mulaw, K M Debatin, M A Westhoff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is the most common primary brain tumour in adults and one of the most lethal cancers per se. Despite aggressive therapeutic approaches, patient survival remains dismal, typically not exceeding 15 months. Standard treatment involves maximal safe resection followed by irradiation of the surgical cavity and chemotherapy with Temozolomide. However, recurrence is inevitable, and additional interventions provide only limited survival benefits. MATERIAL AND METHODS We conducted a study using two pairs of stem cell-like cell populations and their differentiated progeny obtained from the same patient, either before standard therapy or upon recurrence. Our objective was to investigate the selective forces driving the recurrent phenotype and identify potential therapeutic targets. RESULTS Our findings revealed an increased resistance to apoptosis in cells harvested after recurrence, albeit less pronounced than anticipated. The population doubling time was also reduced in post-recurrence cell populations, suggesting that they proliferate faster. However, the most striking changes we observed was a phenotypic shift towards a more mesenchymal phenotype. This was corroborated by increased expression of epithelial-mesenchymal transition (EMT) markers, the presence of oncostreams in differentiated progeny, and enhanced migratory velocity, suggesting heightened invasiveness post-standard intervention. Interestingly, detailed expression pattern analysis suggested that the recurrent phenotype might be expressed by cells more closely related to the cells of origin than those found in the primary tumour, implying recurrence may occur due to therapeutic clearance of the ecological niche. CONCLUSION Analysis of signalling networks identified potential druggable targets upregulated in cells from recurrent tumours, including phosphorylated STAT1 and various extracellular matrix components. Pharmacological inhibition of these targets exhibited a greater effect on recurrent tumour cells, indicating promise for inclusion in complex combination therapies. Our findings underscore the need to consider recurrent glioblastoma as an independent entity from the primary tumour and suggest further analysis may unveil additional therapeutic targets for novel combination therapies.
Probability of lymph node metastases in patients undergoing adequate lymphadenectomy during surgery for intrahepatic cholangiocarcinoma: a retrospective multicenter study
Authors: Carlo Sposito, Alessandro Cucchetti, Francesca Ratti, Laura Alaimo, Francesco Ardito, Stefano Di Sandro, Matteo Serenari, Giammauro Berardi, Marianna Maspero, Giuseppe Maria Ettorre, Matteo Cescon, Fabrizio Di Benedetto, Felice Giuliante, Andrea Ruzzenente, Giorgio Ercolani, Luca Aldrighetti, Vincenzo Mazzaferro
Journal: Liver Cancer (2024)

Introduction: Nodal metastases (lymph node metastasis [LNM]) are one of the major determinants of prognosis following surgery for intrahepatic cholangiocarcinoma (ICC). Previous studies investigating the correlation between clinical-radiological features and the probability of LNM include patients undergoing inadequate nodal sampling. Aim of this study was to develop a model to predict the risk of LNM in patients undergoing adequate lymphadenectomy using preoperative clinical and radiological features. Methods: Patients undergoing radical surgery for ICC with adequate lymphadenectomy at seven Italian Centers between 2000 and 2023 were collected and divided into a derivation and a validation cohort. Logistic regression and dominance analysis were applied in the derivation cohort to identify variables associated with LNM at pathology. The final coefficients were derived from the model having the highest c-statistic in the derivation cohort with the lowest number of variables included (parsimony). The model was then tested in the external validation cohort, and the linear predictor was divided into quartiles to generate four risk categories. Results: A total of 693 patients were identified. Preoperative CA 19-9, clinically suspicious lymph nodes at radiology, patients’ age, and tumor burden score were significantly associated with LNM. These factors were included in a model (&lt;ext-link ext-link-type="uri" xlink:href="https://aicep.website/calculators/" xmlns:xlink="http://www.w3.org/1999/xlink"&gt;https://aicep.website/calculators/&lt;/ext-link&gt;) showing a c-statistic of 0.723 (95% CI: 0.680, 0.766) and 0.771 (95% CI: 0.699, 0.842) in the derivation and validation cohort, respectively. A progressive increase of pathological lymph node positivity across risk groups was observed (29.9% in low-risk, 45.1% in intermediate-low risk, 51.5% in intermediate-high risk, and 87.3% in high-risk patients; p = 0.001). Conclusions: A novel model that combines preoperative CA 19-9, clinically suspicious lymph nodes at radiology, patients’ age, and tumor burden score was developed to predict the risk of LNM before surgery. The model exhibited high accuracy and has the potential to assist clinicians in the management of patients who are candidate to surgery.
P16.01.B DOXORUBICIN GLYCOSYLATION AS A NOVEL APPROACH TO SPECIFICALLY TARGET GLIOBLASTOMA
Authors: A Iorio, C Marzano, B Tirinnanzi, E Lenci, E Bucaletti, B Castelli, C Fonte, M Tellini, M Guidi, M Di Nicola, L Giunti, C La Torre, A Trabocchi, I Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite recent advances in the treatment of cancer, malignant brain tumors such as Glioblastoma (GBM) are still a major challenge in oncology with a poor prognosis. This evidence can be partly explained by the inability of most drugs, such as Doxorubicin (DOX), to be delivered within the brain due to the presence of drug resistance mechanisms including the active efflux mediated by ATP-binding cassette transporters, which are overexpressed on the blood brain barrier (BBB).Malignant tumors like GBM also show a significant glycolytic rate and a high glucose request through glucose transporters (Warburg Effect). In this context, GLUT1 is reported to be implicated in glucose uptake through the BBB.In our study we have developed an innovative approach able to increase drug efficiency and selectivity, by conjugating the anticancer agent DOX to glucose. MATERIAL AND METHODS DOX glycoconjugates were obtained using oxime-based linkers with hydroxylamine-containing spacers between position number 6 of glucose and carbonyl group of DOX. Two different glycoconjugates (EB73 and EB74) were synthesized and characterized for their absorbance, fluorescence and binding affinity to ctDNA. MTT assay was performed to evaluate the cytotoxic effect of EB73 and EB74, compared to DOX, in two GBM cell lines (A172 and DOX resistant T98G). These cells were also used to evaluate the effect of glucose deprivation on the expression levels of GLUT1 and breast cancer resistance protein (BCRP) by Western Blot. Molecules uptake by cells was evaluated using an in vitro BBB model and immunofluorescence (IF) in glioblastoma and neuroglia cell lines. RESULTS Our results showed that EB73 and EB74 have kept Ka binding constants comparable to DOX itself, confirming that functionalization with glucose did not alter DOX intercalation capability and fluorescence.The in vitro cytotoxicity results demonstrated that EB74 has the major effect in A172 compared to DOX and revealed a high efficacy in T98G DOX-resistant cells starting from 24 hours of treatment. Moreover, glucose deprivation showed a GLUT1 overexpression and BCRP downregulation in both cell lines improving EB74 efficacy. According to MTT results, BBB in vitro model and IF experiments revealed that only EB74 was able to accumulate in cells nuclei as conventional DOX. CONCLUSION In conclusion, these results indicated that glycoconjugation of DOX and glucose deprivation may be helpful instruments to increase drugs uptake and effectiveness in aggressive and chemoresistant tumor cells.
P14.06.B ADVANCES IN INTRAOPERATIVE MAPPING AND VISUALIZATION TECHNIQUES FOR HIGH-GRADE GLIOMA RESECTION: AN UPDATE ON CONTRAST AGENTS AND EMERGING STRATEGIES
Authors: C Dib, J Zaatar, O El Ghawi, J Khalil, K Saroufine, L Elias, M Alagha, M Sayegh, J El Khoury, I Moubayed, M Tout
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumor mapping is crucial for achieving optimal resection, particularly for deep-seated tumors near eloquent areas. Although preoperative contrast-enhanced imaging guides neurosurgeons, its reliability diminishes intraoperatively, necessitating real-time methods for delineating tumor margins. Numerous novel contrast agents and imaging modalities are being investigated for intraoperative visualization of high-grade gliomas (HGG). MATERIAL AND METHODS A narrative review was conducted using the PubMed database to gather review articles and clinical trials published within the past 10 years that focus on the intraoperative use of diverse contrast agents and imaging techniques that guide HGG resection. Search terms included “high-grade glioma”, “contrast agents”, “intraoperative mapping”, and “image-guided tumor resection”. RESULTS Fluorescein sodium (FNa), an affordable and safe fluorescent agent, can be intravenously administered during incision. When combined with preoperative imaging, it achieved an 81% gross total resection rate in HGG patients, surpassing the 74% rate associated with the more costly and specific oral fluorescent agent, 5-aminolevulinic acid (5-ALA). Indocyanine green (ICG), a near-infrared (NIR) fluorescent agent, accumulates in highly vascular tumors. Recent studies suggest its efficiency matches that of fluorescein and 5-ALA in tumor localization. However, ICG, particularly in the second near-infrared window (NIR-II), is better suited for identifying necrotic areas and residual tumor cells, especially in deep tumors. Furthermore, the application of methylene blue staining on resected gliomas has yielded promising outcomes, suggesting its potential utility in intraoperative tumor detection. Additionally, contrast-enhanced ultrasonography is a novel and highly specific approach that combines ultrasound with unique intravascular contrast agents to pinpoint tumor localization and vascularity. CONCLUSION Current evidence supports the intraoperative utilization of various contrast agents like FNa, 5-ALA, and ICG during resection of HGG, particularly when integrated with other pre and intraoperative imaging techniques. Nevertheless, their efficacy may be limited by factors such as potential adverse effects, variability in tissue uptake, and the need for specialized equipment and skills to ensure their optimal use. Also, novel approaches such as contrast-enhanced ultrasonography offered promising early results, but further research is needed to study its impact on surgical outcomes.
OS06.7.A PLATFORM-AGNOSTIC METHYLATION CLASSIFICATION OF 184 CLASSES OF CNS TUMOURS
Authors: A Patel, D Schrimpf, N Jäger, M Loose, W Wick, S Krieg, M Schlesner, S M Pfister, A von Deimling, D T W Jones, M Sill, F Sahm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The 2021 WHO classification underscores the importance of methylation-based Central Nervous System (CNS) tumour diagnostics. The Heidelberg MNP classifier has been widely used for methylation classification. However, current approaches for methylation classification warrant the use of methylation arrays which suffer from technical complexity, considerable equipment and reagent cost, as well as lengthy turnaround times. Recent advances in nanopore sequencing have demonstrated the feasibility of methylation classification of broad classes of CNS tumours. Here we introduce and validate MNP-Flex- a platform agnostic methylation classifier that classifies 184 classes of CNS tumours and is compatible with the version v12.8 of the Heidelberg MNP classifier. MNP-Flex is made available as a web-based service. MATERIAL AND METHODS We trained a gradient boosted model on a training set comprising 7,495 methylome profiles spanning 184 classes and covering multiple sparsity levels. We validated the model on a comprehensive multi-centric dataset comprising over 79,000 samples processed using diverse approaches like- methylation arrays, nanopore shallow and deep whole genome sequencing using cryopreserved or FFPE tissue, intraoperative and post-hoc nanopore adaptive sampling (Rapid-CNS2) data, whole genome bisulphite sequencing using tissue and liquid biopsy samples, as well as methylation panels. RESULTS We achieved an overall accuracy of 94% across a diverse, cross-platform, global cohort of 79,000 samples spanning 9 different sequencing conditions. MNP-Flex could also successfully classify 85% of samples with sparse profiles including those obtained using nanopore sequencing in an intraoperative setting and from liquid biopsies. CONCLUSION MNP-Flex addresses the crucial need for accessibility of methylation-based CNS tumour diagnostics. It offers a single platform-agnostic methylation classifier applicable across diverse sample types and sequencing conditions which is provided as a web-service. The ability to effectively classify samples with sparse profiles extends its clinical utility to low throughput conditions. MNP-Flex aims to streamline methylation-based classification, ultimately improving access to molecularly-informed patient care in neuro-oncology.
P16.02.A FRENCH NATIONAL STUDY ON THE EPIDEMIOLOGY OF CHILDHOOD BRAIN TUMORS
Authors: M Khettab, E Chirpaz, S Zouaoui, F Ah-pine, V Rigau, A Rolland, A Darlix, S Ng, T Roujeau, L Bauchet
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary central nervous system tumors (PCNST) in children aged 0 to 19 years are a heterogeneous group of pathological entities that continue to present significant challenges. This abstract provides exhaustive data on histologically confirmed pediatric PCNST cases in France. MATERIAL AND METHODS Patients were identified from the French Brain Tumor Database, a comprehensive national database. The study included children (0 to 19 years) who were diagnosed with histologically confirmed PCNST between 2006 and 2015. For each histological subtype, including rare variants, data such as the number of cases, incidence rates, gender distribution, and surgical approach (resection or biopsy). RESULTS Between 2006 and 2015, a total of 6,691 cases of newly diagnosed and histologically confirmed primary central nervous system tumors (PCNST) were recorded in France, with a gender distribution of 3,692 males and 2,999 females. The principal histological categories included 4,863 neuroepithelial tumors (72.68%) including 2,829 gliomas (42.29%), 819 neuronal and mixed neuronal-glial tumors (12.24%), and 1,005 embryonal tumors (15.02%). Additionally, there were 746 tumors of the meninges (11.15%), which included 140 meningiomas (2.09%), 551 mesenchymal tumors (8.23%), and 55 other types (0.82%). Other categories reported were 251 tumors of cranial and paraspinal nerves (3.75%), 223 germ cell tumors (3.33%), 284 craniopharyngiomas (4.24%), and 324 other types (4.84%).The overall crude incidence rate (CR) was 4.334 per 100,000 person-years, with age-specific rates of 4.418 per 100,000 for ages 0-4 years, 4.184 per 100,000 for ages 0-14 years, and 4.789 per 100,000 for ages 15-19 years. Age-standardized incidence rates (adjusted to European, US, and world standard populations), demographic characteristics, along with other relevant data, will be further elaborated in the presentation. In addition, specific attributes for the age groups of 0-4 and 15-19 years, relating to histological subtypes and sex predominance, will be provided in detail. For example, anaplastic ependymomas constituted 101 out of 171 cases (59.06%) in the 0-4 years age group, compared to 16 out of 99 cases (16.16%) in the 15-19 years age group. Embryonal tumors represented 422 out of 1,715 cases (24.61%) in the 0-4 years age group, and 100 out of 1,835 cases (5.45%) in the 15-19 years age group. Among mesenchymal tumors, lipomas accounted for 98 cases in the 0-4 years age group and 10 cases in the 15-19 years age group. CONCLUSION To our knowledge, this constitutes the most extensive report of histologically confirmed PCNST cases diagnosed in children and adolescents within the French population. The report meticulously details all histological subtypes along with their respective frequencies and distributions. The findings hold significant implications for epidemiology, clinical practice, and future research.
KS02.5.A THE ONCOMETABOLITE D-2-HYDROXYGLUTARATE PROMOTES DNA HYPERMETHYLATION AT LINEAGE-SPECIFIC ENHANCERS CONTROLLING MICROGLIAL ACTIVATION IN IDH-MUTATED GLIOMAS
Authors: A Laurenge, P Pugliese, B Mathon, Q Richard, S Jouannet, Y Hayat, S Scuderi, P Marijon, K Labreche, A Alentorn, M Verreault, A Idbaih, C Birzu, E Huillard, N Pottier, A Desmons, I Fayache, G A Kaas, P J Kingsley, L J Marnett, E Duplus, E El-Habr, L A Salas, K Mokhtari, S Tran, M L Suvà, A Iavarone, M Ceccarelli, M Touat, F Bielle, M Mallat, M Sanson, L Castro-Vega
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Resident microglia are highly plastic myeloid cells. Their phenotype and immune response are determined by the microenvironment composition. Although microglial cells are highly abundant in IDH-mutated (IDHm) gliomas, how this particular environment modulates the transcriptional programs and cell states of these cells remain largely uncharacterized. Herein we investigated whether and how D-2HG, the oncometabolite produced by the IDH mutation and released into the tumor microenvironment, impinges upon the phenotypic and functional properties of resident microglia. MATERIAL AND METHODS We analyzed bulk DNA methylome (Methylation EPIC array) and transcriptome of CD11b+magnetic-purified fractions from IDHm (n= 25) and IDH-wildtype (n=11) gliomas, as well from normal brain tissues (n=6). To determine direct effects of D-2-hydroxyglutarate (D-2HG), the oncometabolite produced by IDHm glioma cells, we optimized human primary microglial cultures obtained from glioma or drug-resistant epilepsy surgery. Microglia exposed to 5mM D-2HG or vehicle for 14 days were analyzed with DNA methylome (LC-MS/MS, EPIC arrays and single-base resolution approaches) and transcriptome (RNA-seq). Using snRNA-seq, we analyzed microglial transcriptome from a paired sample of one IDHm glioma patient before and after treatment with the IDH-inhibitor vorasidenib, which is known to deplete tumor D-2HG levels. RESULTS We uncovered that CD11b+ myeloid cells in human IDHm gliomas exhibit DNA hypermethylation predominantly at enhancer elements. Hypermethylation was linked to decreased expression of genes involved in inflammatory responses and glycolytic metabolism, as well as inactivation of transcription factors that regulate microglial responses to environmental stimuli. Prolonged exposure of human primary microglia to D-2HG inhibited TET-mediated 5mC oxidation, resulting in a reduced accumulation of global 5hmC levels. We observed high 5mC/5hmC ratios particularly at lineage-specific enhancers. Consistent with the remodeled enhancer landscape, D-2HG-treated microglia showed reduced proinflammatory capacity and enhanced oxidative phosphorylation. Conversely, depletion of D-2HG levels following vorasidenib treatment in an IDHm glioma patient was associated with overexpression of genes related to microglial activation. CONCLUSION Our findings provide a mechanistic rationale for the hyporesponsive state of microglia in IDHm gliomas and support the hypothesis that oncometabolites such as D-2HG may disrupt the function of immune cells residing in the tumor microenvironment.
P20.05.B BELZUTIFAN TREATMENT OF VON HIPPEL-LINDAU-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: A Thomsen, A Valerius, J H Uhm, M Ruff, D Baykal, S Caron, J D White, B J Neth, M J Webb, P N Pichurin, U Sener
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease associated with tumors in multiple organs. VHL is characterized by mutation of the VHL gene which leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. Conventional management of VHL-associated tumors involves surgical resection and radiation therapy. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). Belzutifan was approved by the United States Food and Drug Administration (FDA) in August 2021 as a targeted therapy option for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Our objective here is to report on our clinical experience with use of belzutifan for VHL-associated CNS hemangioblastomas. MATERIAL AND METHODS We retrospectively chart reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2024. RESULTS Nine adults (5 female, 4 male) were included in the study. Of those able to continue the therapy without interruption (6 patients), the median duration of therapy at last follow-up was 11.5 months (range 3-22 months). Seven had radiographic response to therapy after a median of 3 months (1-5 months), with a maximal response to therapy after a median of 13 months (3-29 months). One patient had a mixed radiographic response, and 1 patient had tumor progression while on belzutifan noted at 5 months. The most common adverse effect was fatigue. Seven patients reported fatigue, 4 patients experienced anemia, and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects, specifically fatigue and hypoxia. One patient had to take multiple medication pauses, once due to seizure and once due to kidney injury, but resumed treatment with dose reduction. CONCLUSION Among patients with VHL-associated CNS hemangioblastomas, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to FDA approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, duration of treatment, and effects of cessation after long-term use.