bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-36. CLINICO-RADIOLOGICAL PARAMETERS, MOLECULAR AND CHROMOSOMAL ALTERATIONS AFFECTING SURGICAL OUTCOME OF PETROCLIVAL MENINGIOMAS
Authors: Suri Ashish , Suri Vaishali 
Published: November 2023

Abstract
Petroclival meningiomas were reviewed for correlation of extent of resection with clinico-radiological parameters and molecular/chromosomal alterations. 53 surgical procedures in 50 patients of petroclival meningioma were performed. Cavernous sinus and sellar extension were present in 37(69.8%) and 5(9.4%) respectively; contralateral extension in 10(20%). Modified anterior transpetrous rhomboid-MATRA (44=83.0%) was the most commonly used approach, followed by retrosigmoid (2=3.8%), and combined (7=13.2%) approaches. Hypointense tumors on T2-weighted MRI (OR:5.85;95%CI:1.70-20.41) and presence of brainstem edema (OR:4.53;95%CI:1.36-15.12) were found to be significant factors increasing the likelihood of subtotal resection-STR (p = 0.004 & p = 0.011 respectively). In the presence of both tumor T2-hypointensity and brainstem edema, there was significant increase in the likelihood of STR (p = 0.001;OR:25;95%CI:3.52-177.48). The most common cranial nerve to suffer new-onset deficit postoperatively was found to be VI nerve(19=35.8%) followed by V(9=16.9%) and VII(8=15.8%) nerves. On long-term follow-up, 38 patients had good outcome. Out of the 16 cases for which molecular analysis was performed, no specimen was found to have pTERT-C228T,C250T, AKT-1, E17K and SMO-L412F,W535L mutations. Eight (50.0%) cases showed H3K27me3 loss while 5 (31.25%) had hemizygous CDKN2A deletion. All(100%) patients harboring H3K27me3 loss and/or hemizygous CDKN2A deletion had cavernous sinus extension compared to 62.5% patients without H3K27me3 loss and 72.7% with hemizygous CDKN2A retention. Similarly, hemizygous CDKN2A deletion and H3K27me3 loss are associated with increase in the rate of brainstem edema from 27.3% to 60% and 25% to 50% respectively. Cases (n = 4) with both these alterations have 100% cavernous sinus extension and 75% chances of brainstem edema and lack of arachnoid plane. The MATRA is a versatile approach for petroclival meningiomas with good surgical outcome and acceptable complication rates. T2 hypointense tumor and brainstem edema on pre-operative imaging are significant predictors of STR. H3K27me3 loss and hemizygous CDKN2A deletion may be associated with cavernous sinus extension suggesting their role in tumor spread.
SURG-42. FACTORS INFLUENCING TUMOR RECURRENCE AFTER RESECTION OF SKULL-BASE MENINGIOMAS
Authors: Begley Sabrina , McBriar Josh , Park Jung , Dehdashti Amir 
Published: November 2023

Abstract

BACKGROUND
Resection of skull-base meningiomas is challenging, given the proximity of and adherence to neurovascular structures. We characterize the benefits of neurosurgical resection of meningiomas, comparing clinical and surgical outcomes based upon tumor location within and outside the skull base.

METHODS
Data were retrospectively collected from 85 patients who underwent surgical resection of meningioma between 2008 – 2018, for whom long-term follow-up was available. Outcomes were compared between locations: non-skull base, anterior fossa, middle fossa, and posterior fossa. Logistic regression analysis was used to analyze pre-operative and pathologic factors influencing recurrence.

RESULTS
Forty-five (54.1%) tumors were located on the skull base: 29 anterior fossa, 22 middle, and 6 posterior. Simpson grade 1 or 2 resection was achieved in 63 patients. Mean Ki-67 showed a statically significant difference between all tumor locations: non-skull base (7.1), anterior fossa (4.0), middle fossa (10.8), posterior fossa (2.8) (p = 0.009). Simpson grade differed significantly by tumor location with percentage of Simpson grade 1 resections as follows: non-skull base supratentorial (45.7%), non-skull base infratentorial (0.0%), anterior (71.5%), middle (30.0%), posterior (16.7%) (p = 0.022). Tumors recurred in 11 patients with recurrence differing significantly between locations: non-skull base (18.2%), anterior (3.8%), middle (36.4%), posterior (0.0%) (p = 0.046). Median progression-free survival was 115.5 months and did not significantly differ by location. Larger tumor volumes (p = 0.018), Simpson grade 3 resection (p = 0.016), and increased Ki67 (p = 0.046) were associated with higher recurrence risk. No variables predicted post-operative neurological deficits.

CONCLUSIONS
High variability exists within skull-base meningiomas, depending on the cranial fossa of origin. Location may impact the molecular make-up, extent of resection, and patient outcomes. Due to the high-risk anatomy of the skull base, confirming these predictors of recurrence is vital to optimize initial treatment and decrease the risk associated with salvage treatment.
SURG-45. THE EFFECT OF STAPEDECTOMY IN POSTOPERATIVE OUTCOME OF SUPERIOR SEMICIRCULAR CANAL DEHISCENCE: A CASE SERIES OF 349 REPAIRS
Authors: Torres Lisette , Vohra Sanah , Mekonnen Mahlet , Pandey Aryan , Chow Ariana , Gopen Quinton , Yang Isaac 
Published: November 2023

Abstract

INTRODUCTION
Superior Semicircular Canal Dehiscence (SSCD) is a pathology of the otic capsule, in which, a “third mobile window” is formed on the osseous labyrinth surrounding the superior semicircular canal. Otosclerosis, another otic capsule pathology, can occur concurrently, therefore obscuring the symptoms seen in patients with SSCD. It is currently unknown whether the surgical procedures to treat otosclerosis such as stapedectomy can affect symptom resolution in patients following SSCD repair. Objective: To examine the association between post-SSCD repair symptom resolution and history of stapedectomy.

METHODS
A single institution retrospective review was conducted to evaluate post-operative symptom resolution in patients undergoing SSCD repair from 2011-2021. 349 SSCD repairs performed in a cohort of 279 patients were included, and among those were 10 patients with a history of stapedectomy. A p-value &lt; 0.05 was considered statistically significant.

RESULTS
A total of 349 surgical repairs were analyzed. The patient population was composed of 63% female and 37% male with patient ages’ ranging from 13-84 years. Patients were divided into two different cohorts based on their history of stapedectomy. We compared these cohorts looking at their post-SSCD repair symptom changes and found no statistically significant differences between patients with and without history of stapedectomy. We also compared pre- and post-operative symptoms amongst the 10 patients with a history of stapedectomy and found no statistically significant differences in symptom resolution post-SSCD repair. Post-operative symptoms analyzed included amplification (p = 0.2), aural fullness (p = 0.2), autophony (p = 0.8), disequilibrium/imbalance (p = 0.8), dizziness (p = 0.3), headache (p = 0.7), hearing loss (p = 1), hyperacusis (p = 1), tinnitus (p = 0.4), and vertigo (p = 0.3).

CONCLUSIONS
With respect to symptom resolution post-SSCD repair, there were no significant differences between patients with and without a history of stapedectomy. Hence, previous stapedectomy surgery should not be considered an adverse condition to SSCD repair, with similar rates of improvement after SSCD surgery.
TMET-04. SENSITIZING DIPGS TO ANTIFOLATES: A PRECLINICAL STUDY ON PURINE BIOSYNTHESIS TARGETS
Authors: Mersich Ian , Congrove Sunny , Dasgupta Biplab 
Published: November 2023

Abstract
Diffuse Intrinsic Pontine Gliomas (DIPGs), among the most devastating pediatric brain tumors, present a desperate need for innovative treatment strategies, given the lack of effective therapies. Our study unveils a significant metabolic vulnerability in DIPGs, rooted in purine biosynthesis, a key facilitator of tumor progression. Contrary to prior reports, we demonstrate DIPG cell lines' sensitivity to methotrexate, an antifolate that targets purine metabolism, underscoring a potential reappraisal of its therapeutic role. Further, our research reveals a promising therapeutic synergy between antifolates, namely methotrexate and LSN-3213128, and SHMT inhibition, offering a potential novel treatment combination. This synergy, demonstrated in a proof-of-concept study, curtailed tumor progression in our DIPG mouse model, underscoring a promising new treatment strategy. Importantly, we identify a paradoxical antifolate resistance mechanism: while typical resistance is linked to dysfunctional folate transport, our findings intriguingly show an upregulation of folate transporters and intracellular folate in DIPGs. This paradox suggests that elevated intracellular folate levels may be effectively outcompeting antifolate metabolites for their targets. Significantly, the failure of physiological concentrations of purines in the cerebrospinal fluid (CSF) to restore DIPG cell viability under antifolate treatment further reinforces our rationale for targeting purine metabolism. The resistance mechanism is further validated by the observed synergy with SHMT inhibition, which disrupts the folate cycle allowing for the antifolates to out-compete the intracellular folates for their intended target. Our findings challenge conventional wisdom, open new avenues in DIPG therapeutic strategy, and highlight a paradoxical antifolate resistance mechanism that necessitates further exploration in the field.
TMET-10. INVESTIGATING HOW GLIOBLASTOMA TUMOUR CELLS EXPLOIT THEIR METABOLIC MICROENVIRONMENT
Authors: Shard Chloe , Ormsby Rebecca , Poonnoose Santosh , Toubia John , Trim Paul , Ebert Lisa , Patil Ashwini , Gomez Guillermo 
Published: November 2023

Abstract
A significant challenge in neuro-oncology is identifying the metabolic fuel sources that underpin glioblastoma malignancy. Metabolic reprogramming is a hallmark of tumorigenesis, providing malignant cells with an adaptation advantage to survive and grow under environmental stresses, including anti-cancer therapies. Incorporating single-cell RNA sequencing data from 56 glioblastoma patient biopsies, we have identified distinct subpopulations of malignant cells which diverge in their metabolic activities. These metabolic subpopulations are conserved across patient datasets but vary in abundance from patient to patient, contributing to glioblastoma heterogeneity. We are also employing spatial transcriptomics to build a map of the metabolic tumour landscape. This analysis showed that these malignant sub-populations occupy distinct spatial regions in the tumour landscape. Environmental influences like distance to blood vessels, which impact oxygen and nutrient supply, can vary significantly between regions. This suggests that as malignant cells colonise different regions of the tumour, they modify their metabolism as an adaption response. Importantly these niches vary in their compositions of native brain and immune cells, contributing to the diverse ecosystems inhabited by these malignant subpopulations. The next steps are to explore the specific metabolite dependencies of these tumour cells by mass spectrometry imaging and identify metabolite fluxes within the microenvironment that we can target therapeutically.
TMET-13. DNA DAMAGE SIGNALING ACTIVATES GTP SYNTHESIS TO PROMOTE GLIOBLASTOMA TREATMENT RESISTANCE
Authors: Scott Andrew J , O'Brien Alexandra , Zhou Weihua , Xu Jie , Palavalasa Sravya , Kothari Ayesha , Wilder-Romans Kari , Lin Angelica , Zhao Zitong , Yang Annabel , Korimerla Navyateja , Peterson Erik , Yang John , Zhang Li , Andren Anthony , Chandrasekaran Sriram , Venneti Sriram , Heth Jason , Umemura Yoshie , Qi Nathan , Woulfe John , Morgan Meredith , Lawrence Theodore , Al-Holou Wajd , Lyssiotis Costas , Wahl Daniel 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most common type of invasive brain tumor in adults and is uniformly fatal due to inherent resistance to radiation therapy (RT) and chemotherapy. Our group and others have found that metabolites can regulate DNA repair and therapy resistance in brain tumors, but little is known about how DNA damage regulates metabolic pathway activity in cancer. Here we show that following treatment with RT, GBMs increase rates of de novo guanylate synthesis in vitro and in orthotopic patient-derived xenograft models via signaling through the DNA repair protein DNA-PK. To determine if disrupting this regulation can augment GBM treatment efficacy, we combined an FDA-approved inhibitor of purine synthesis (mycophenolate mofetil, MMF) with chemoradiation in a variety of mouse models of GBM. Critically, targeting GTP synthesis improved the efficacy of both RT alone and chemoradiation in multiple patient-derived and syngeneic intracranial models. Our translational studies have shown that mycophenolic acid, the active metabolite of MMF, penetrates the blood-brain barrier at concentrations sufficient to inhibit GTP synthesis in GBMs of human patients. The phase 1 arms of our study, which are ongoing, are testing the safety and efficacy of combining MMF with standard of care chemoradiation for patients with primary and recurrent GBM.
TMET-18. METABOLOMIC APPROACH TO IDENTIFICATION OF PROGNOSTIC BIOMARKERS OF GLIOBLASTOMA
Authors: Aboubechara John Paul , Liu Yin Allison , Fiehn Oliver , Fragoso Ruben , Lee Han , Riess Jonathan , Hodeify Rawad , Bloch Orin , Aboud Orwa 
Published: November 2023

Abstract
Glioblastoma, the most common malignant primary brain tumor, is associated with poor prognosis despite aggressive treatment. Alterations in cellular metabolism driven by acquired mutations contribute to tumor progression and recurrence. Metabolic changes in plasma can serve as potential biomarkers, offering insights into treatment response and prognostic value. In this prospective study, we enrolled 36 patients with isocitrate dehydrogenase (IDH) wild type glioblastoma (18 MGMT methylated, 16 MGMT unmethylated, 2 MGMT unknown) and performed untargeted metabolomics on patient plasma before and after surgery, as well as before and after concurrent chemoradiation. Our analysis focused on examining changes in 157 metabolites throughout each stage of treatment. We conducted correlations between metabolite levels and treatment stages, as well as associations between metabolite levels and disease progression or overall survival to identify clinically relevant biomarkers. Preliminary results demonstrate positive correlation between specific metabolite levels at the time of diagnosis and eventual overall survival. Notably, metabolites such as trans-4-hydroxyproline, ribose, pipecolinic acid, phenol, kynurenine, inositol-4-monophosphate, indole-3-propionic acid, glucose, arachidonic acid, 5-methoxytryptamine, and 3-aminopiperidine-2,6-dione show significant positive correlations (p&lt; 0.05) with overall survival. However, no metabolites exhibited negative associations with overall survival. Ongoing analysis will further explore the relationship between metabolite levels at different treatment stages and survival outcomes. By future planned machine learning techniques integration to our study, we aim to enhance our understanding of the metabolomic changes associated with treatment response and prognosis. This study represents a step toward unraveling the metabolomic alterations in glioblastoma patients throughout treatment. Although the underlying metabolic pathways and potential shared mechanisms are not yet fully understood, the identified metabolites associated with overall survival hold promise as potential biomarkers for prognosis. Furthermore, the integration of machine learning techniques will provide a more comprehensive understanding of the complex metabolic changes in glioblastoma.
TMIC-04. IMMUNE PROFILING OF PEDIATRIC ONCOHISTONE GLIOMAS REVEALS DIVERSE MYELOID POPULATIONS AND TUMOR-PROMOTING BEHAVIORS
Authors: Andrade Augusto Faria , Topouza Danai , McNicholas Michael , Gonzalez Santiago Eduardo G , De Cola Antonella , Gehlhaar Arne , Jessa Selin , Chandarana Bhavyaa , Russo Caterina , Faury Damien , Danieau Geoffroy , Zeinieh Michele , Krug Brian , Wei Yuhong , Wu Qing , Nakada Emily M , Juretic Nikoleta , Larouche Valerie , Weil Alexander G , Dudley Roy , Karamchandani Jason , Agnihotri Sameer , Ellezam Benjamin , Quail Daniela , Konnikova Yelizaveta , Kleinman Claudia , Walsh Logan , Pathania Manav , Jabado Nada 
Published: November 2023

Abstract
Pediatric high-grade gliomas pHGG are lethal and frequently bear missense mutations in histone H3, which drive tumorigenesis by altering the epigenome and cell fate/differentiation. While previous studies showed intrinsic contingencies associated with tumor development, limited information exists on the tumor microenvironment (TME) and immune cells for these tumors. To define the immune landscape of pediatric tumors at single-cell resolution, we profiled and compared 69 pediatric gliomas samples using the Chromium 10X technologies, H3.3 K27M (N=19) and G34R (N=16) mutant tumors, low-grade gliomas (N=11) and ependymomas (N=23). Additionally, to enable the spatial resolution of immune lineages, we performed Imaging Mass Cytometry (IMC) on H3-mutant samples (H3.3 K27M (N=7) and G34R (N=5)). We demonstrate that pediatric histone H3-mutant gliomas are highly infiltrated by myeloid cells, more specifically resident microglia, bone-marrow derived macrophages (BMDM) and monocytes, and are devoid of lymphoid infiltration. Different myeloid subsets were found to interact with H3-mutant cancer cells. Classical BMDM showed strong interactions with H3-mutant cancer cells while monocytes subsets showed tendency to interact only with G34R cells. We have generated a novel H3.3K27M glioma immunocompetent murine model, establishing a highly-penetrant and reliable tool. H3.3K27M murine tumors recapitulated the TME from human tumors, showing great myeloid infiltration. Using in vivo orthotopic serial engraftments, we observed that secondaries transplanted tumors had a significantly worse survival, possessing a less diverse immune infiltration compared to initial engraftments and a dominant presence of myeloid cells. Interestingly, in vivo myeloid depletion combined with PD-1 blockade extended overall mice survival. Our findings provide a valuable characterization of the biology of these tumors, reinforcing the several roles of myeloid cells in the context of pediatric brain tumours, providing a framework for understanding the H3.3K27M and G34R tumors, including other pediatric gliomas, and designing future immunotherapies.
TMIC-05. UNVEILING THE IMPACT OF PTN-PTPRZ1 SIGNALING ON GLIOBLASTOMA PROGRESSION THROUGH TUMOR MICROENVIRONMENT COMMUNICATION
Authors: Ge Weihong , Kan Ryan , Fazzari Elisa , Azizad Daria , Ito Joyce , Yilgor Can , Tse Christopher , Tum Andrew , Patel Kunal , Nathanson David , Bhaduri Aparna 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor with high rate of recurrence. GBM’s high inter- and intra-heterogeneity present a huge challenge to both disease modeling and treatment. Recent progress in the field has highlighted the role of signals associated with the microenvironment factor in driving tumor progression, suggesting that more detailed characterizations of the GBM microenvironment may provide novel therapeutic targets. In this study, we used a novel stem cell derived cortical organoid transplantation model, where we transplanted patient IDH wild type GBM cells onto organoids and provided multiple culture conditions to explore the impact of the environment on tumor cell identity. After several weeks of culture, single cell RNA-sequencing of tumor and non-neoplastic organoid cells was used to profile molecular features, demonstrating not only cellular composition of GBM and its surrounding normal brain cell, but also the bidirectional communication between the two. We observed functional heterogeneity where individual tumors responded differently to environmental perturbations. However, the most significant cell-cell interaction between tumors and the microenvironment was found to be PTN-PTPRZ1, which is well-maintained across all transplantation models we tested, as well as in re-analysis of published patient data that included tumor and normal cells. Encouraged by our previous works as well as others, which have revealed PTPRZ1 as an outer radial glia marker gene driving tumor invasion, we further verified PTN/PTPRZ1 expression not only in our organoid transplantation models but also on FFPE sections from GBM patients and mouse xenograft samples. These data suggest that this signaling axis promotes tumor progression through tumor – microenvironmental crosstalk, and using the organoid model we show a functional role for this communication. Together, this study presents a GBM organoid transplantation modeling system, which we leverage to detect a promising therapeutically target existing between GBM and its microenvironment.
TMIC-06. GLIOBLASTOMA PROGRESSION IS PROMOTED BY C5AR1 SIGNALING THROUGH EMT INDUCTION, AND ITS BLOCKADE BY W54011 ATTENUATES MALIGNANT PHENOTYPES
Authors: Yoo Jihwan , Oh Yoojung , Lee Dongkyu , Choi Seonah , Kim Eui-Hyun , Moon Ju Hyung , Chang Jong Hee , Kang Seok-Gu 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis. Tumor mesenchymal stem-like cells (tMSLCs) in GBM tissues secrete complement component 5a (C5a), which promotes tumor malignancy. This study aimed to investigate the impact of C5a on GBM tumorspheres (GBM-TS) and to evaluate the therapeutic potential of C5a inhibition using the C5a antagonist, W54011.

METHODS
RNA sequencing (RNAseq) was performed on tumor tissues to identify differentiaaly expressing genes (DEG) and perform gene set enrichment analysia (GSEA) to correlate with patient survival based on C5aR1 expression. GBM-TS and tMSLCs were cultured to create a conditioned medium (CM) containing C5a, which was used to stimulate GBM-TS. The effect of C5a on GBM-TS proliferation, invasion, and stemness was determined using WST/ATP assay, 3D invasion assay, and neurosphere formation assay. Western blot and RNAseq analysis were performed to validate the results. In vivo studies were conducted using orthotopic xenograft mouse models injected with GBM-TS alone or with CM and treated with W54011.

RESULTS
Patients with high C5aR1 expression had a poor prognosis. Treatment with CM increased proliferation, invasion, and stemness of GBM-TS, but W54011 reversed these effects. Treatment with CM induced epithelial-messenchymal transition (EMT) in GBM TSs, whereas W54011 restored the spherical morphology and induced apoptosis. Our results were supported by transcriptome analysis and marker expression in Western blots. In the orthotopic xenograft mouse model, co-injection of GBM-TS and CM resulted in larger tumors and poorer survival, while treatment with W54011 reduced tumor size.

CONCLUSIONS
C5a promotes the growth, invasion, and stemness of GBM-TS, and inhibition of C5a using W54011 may have therapeutic potential for patients with high C5a expression. These results provide insight into the underlying mechanisms of GBM progression and establish a knowledge base for the clinical efficacy of W54011 in GBM treatment.