bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-14. INCREASED RATIO OF GLUTAMATE TO TOTAL CREATINE IN GLIOBLASTOMA PATIENTS WITH THE POST-OPERATIVE EPILEPSY
Authors: Tanaka Kazuhiro , Hashiguchi Mitsuru , Yamanishi Shunsuke , Nagashima Hiroaki , Sasayama Takashi 
Published: November 2023

Abstract
Epilepsy in glioblastoma patients significantly reduces their quality of life; however, little is known about the association between predicting epilepsy and metabolites in tumors. In this study, we used 3.0-T magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) to quantify metabolite concentrations in patients with varying epilepsy histories. MRS data were quantified with linear combination model (LC-Model) software. From January 2013 to April 2020, fifty-one patients with primary glioblastoma underwent pretreatment 3.0-T MRI/1H-MRS scanning. Twenty-one patients (41%) suffered from epilepsy during the postoperative course, although forty-seven patients (97%) took anti-epileptic drug after surgery. MRS data were compared between groups with and without the post-operative epilepsy. The higher ratios of glutamate (Glu) and glutamate + glutamine (Glx) to total creatine (tCr) in the tumor were significantly associated with epilepsy history (Glu/tCr P &lt; 0.001, Glx/tCr P = 0.004, respectively). The receiver operating characteristic curve analysis showed that a Glu/tCr value of 1.81 was 70% sensitive and 90% specific for the prediction of epilepsy during the postoperative course (area under curve: 0.82). These results suggest that the Glu/tCr ratio in tumors can be a predictive maker for early detection of epileptic seizures after surgery in glioblastoma patients.
BIOM-22. CLINICAL ASSESSMENT OF SIGNALING PATHWAY ACTIVITY IN GLIOMA
Authors: Beccari Sol , Voong Viva , Hervey-Jumper Shawn , Berger Mitchel , Phillips Joanna 
Published: November 2023

Abstract
Despite advances in our understanding of tumor biology, many targeted therapies for diffuse glioma have failed without an understanding of why. Improved patient stratification and assessment of biologic activity in window of opportunity clinical trials will address this failure. The clinically validated, robust biomarkers available, however, are limited. Moreover, evidence-based criteria for biospecimen acquisition are lacking. To address this need we investigated the preanalytic variables that impact the assessment of PI3K/AKT/mTOR and MAPK signaling activity at single cell resolution. To replicate the conditions in window of opportunity clinical trials, tumor tissue from a murine model for glioblastoma (GBM) was utilized and the impact of cold ischemia time (CIT), slide storage duration and temperature on detection of key phospho-proteins was determined. We then validated our findings using human glioma samples acquired in the operating room. To assess the PI3K/AKT/mTOR signaling, phosphorylation of proteins at three nodes of the pathway were investigated. Phosphorylated-PRAS40 (p-PRAS40) is upstream of mTOR and phosphorylated-RPS6 (p-RPS6) and phosphorylated-4EBP1 (p-4EBP1) are downstream of mTOR. Detection of cells expressing p-RPS6 was the most robust with no significant alterations up to 6hrs cold ischemia time (CIT). p-4EBP1 signal was unaltered up to 20min CIT, however, decreased at 2h and 6h (p&lt; 0.001). The detection of p-PRAS40 was variable at 20min and showed a decreased tendency at 2h and 6h. For p-RPS6, p-4EBP1, and p-PRAS40 the assessment of protein intensity per cell was highly variable at all time points analyzed (p&lt; 0.05 at 20min, 2h, and 6h). Thus, for assessment of the PI3K/AKT/mTOR pathway in diffuse glioma using clinical samples, the detection of p-RPS6 is the most stable when time elapsed between sample acquisition and downstream processing (CIT) is long, while p-4EBP1 requires short (≤20 min) delays and p-PRAS40 is more variable.
BIOM-24. PREDICTION OF DISTANT RECURRENCE IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD THERAPY
Authors: Chiranth Shivani , Trip Anouk , Christensen Ib , Grunnet Kirsten , Møller Søren , Hasselbalch Benedikte , Muhic Aida , Lassen Ulrik , Poulsen Hans , Urup Thomas 
Published: November 2023

Abstract

BACKGROUND
Infiltrative growth is a hallmark of glioblastoma (GBM) and is a major factor in therapeutic failure. We aimed to identify clinical and molecular factors associated with distance recurrence in glioblastoma patients treated with standard therapy (radiotherapy with concomitant and adjuvant temozolomide).

METHODS
Two prospective cohorts of consecutive, non-selected GBM patients administered standard therapy as primary treatment between year 2005-2016 (Cohort 1) and 2016-2021 (Cohort 2) at Rigshospitalet, Copenhagen were included. Distant recurrence was defined as a new contrast-enhancing tumor &gt; 2 cm from the gross tumor volume. Clinical and molecular factors were screened for association with time to distant recurrence using univariate Cox regression analysis. The final model was generated employing multivariate analysis.

RESULTS
Cohort 1 and 2 included 628 and 395 patients, respectively. Out of the recurrence pattern evaluable patients, distant recurrence was observed in 117 patients (23%) in Cohort 1 and 73 patients (22%) in Cohort 2. PRELIMINARY

RESULTS
In Cohort 1, multivariate analysis showed that corticosteroid use, age, multifocal disease, ECOG performance status, and degree of tumor resection were not associated (p &gt; 0.10) with distant recurrence. Two factors were independently associated with a higher likelihood of distant recurrence, namely non-methylated promoter of the MGMT gene (HR = 1.93; 95% CI:1.27-2.95; p = 0.002) and positive expression of Epidermal Growth Factor Receptor (EGFR) (HR = 3.70; 95% CI: 1.61-8.33; p = 0.002). In Cohort 2, the EGFR status was not available but the association of non-methylated MGMT with distant recurrence was validated (HR = 2.67; 95% CI: 1.62-4.42; p = 0.0001).

CONCLUSION
Non-methylated MGMT and positive EGFR expression were independent predictors of distant recurrence. Non-methylated MGMT was validated in Cohort 2 and can be used for risk stratification and to enrich clinical trials aiming at improved local or distant tumor control.
BIOM-57. UNRAVELING THE DYSREGULATION OF MIR-17/92 CLUSTER IN AGGRESSIVE PEDIATRIC BRAIN TUMORS: IMPLICATIONS FOR NOVEL THERAPEUTIC STRATEGIES
Authors: Arif Shehbeel , Rathi Komal , Naqvi Ammar , Coyle Anne , Hollawell Madison , Storm Phillip , Resnick Adam , Madsen Peter , Koptyra Mateusz 
Published: November 2023

Abstract
The miR-17/92 cluster, commonly referred to as “OncoMir-1,” is extensively studied in cancer due to its oncogenic role, but it has yet to be fully characterized in pediatric brain tumors. In this study, we conduct a comprehensive investigation involving miRNA profiling of 262 pediatric brain tumors, along with sample-matched data from the Pediatric Brain Tumor Atlas, including WGS, RNA-sequencing, proteomics, and phospho-proteomics data. Through miRNA-based unsupervised clustering, we identified four distinct miRNA signatures that transcend histological boundaries. An aggressive cluster (consisting of Medulloblastoma, ATRT, High-Grade Astrocytic Tumors, and some Ependymomas) exhibited the shortest survival and displayed an enriched network of co-expressed miR-17/92 cluster family members and paralogues, specifically miR-106b/25 and miR-106a/363 (p&lt; 0.001). These tumors exhibited significant upregulation of the MIR17HG gene, which encodes the miR-17/92 cluster of miRNAs (p&lt; 0.001). Further exploration of the upstream regulatory mechanisms of MIR17HG identified n-MYC and E2F1/2/3 significantly upregulated (p&lt; 0.01). Additionally, utilizing sample-matched phospho-proteomics data, we found hyperphosphorylation of RB1, the upstream regulator of E2F, at three sites, providing additional evidence of RB1-E2F regulation upstream of MIR17HG. RB1 hyperphosphorylation and subsequent complete inactivation are mediated by the CDK2/Cyclin E complex, which is inhibited by the tumor suppressor p21. Interestingly, p21 (CDKN1A) gene expression was entirely depleted in the aggressive brain tumors group. In summary, our findings reveal the aberrant upregulation of the oncogenic miR-17/92 cluster in a group of aggressive brain tumors, potentially resulting from inactivating hyperphosphorylation of RB1 caused by p21 loss. This event frees E2F transcription factors and enables transcription of MIR17HG. Additionally, our study highlights E2F1/2/3 and CDK2 as potential therapeutic targets not only for aggressive brain tumors but also for other cancers overexpressing the miR-17/92 cluster. Future research will focus on molecular validation and targeting of the miR-17/92 regulatory pathway using available brain tumor cell line models.
CNSC-24. NEURONAL ACTIVITY PROMOTES GLIOMA PROGRESSION THROUGH INDUCING RNA M6A DEMETHYLATION AND PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOMA STEM CELLS
Authors: Guo Xiaofan , Wei Qiu , Li Gang 
Published: November 2023

Abstract
High-grade gliomas are lethal brain cancers whose progression is highly driven by neuronal activity. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and plays a significant role in the resistance of glioma to conventional therapies as well as cancer recurrence. Activity-regulated release of growth factors and electrical synaptic integration promotes glioma growth; however, it is unclear whether neuronal activity plays a role in the mRNA N6-methyladenosine (m6A) level changes in patient glioma tissue. By using chemogenetics techniques, we enhanced and inhibited neuronal activity in vitro and in vivo, and studied how neuronal activity regulates GSC behaviors. Here, we identified that neuronal activity promotes glioma progression and radioresistance through neuronal exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. We revealed that neuronal activity upregulates critical microRNA expression in NDEs (neuro-derived exosomes) and subsequently induces PMT by activating the STAT3 pathway. Chemogenetically activating cortical neurons increases the growth of GSC xenografts in situ. Conversely, reducing neuronal activity inhibited the GSC xenograft growth. Anti-seizure medication treatment suppresses GSC PMT and sensitizes GSCs to radiotherapy in vitro and in vivo. Together, these findings indicate that exosomes of active neurons can promote glioma progression and radioresistance by inducing GSC PMT via neuro-derived extracellular vesicles
CTIM-12. IMMUNOGENICITY OF AN ADDITIONAL DOSE OF COVID-19 VACCINE IN FULLY VACCINATED PATIENTS WITH GLIOMA TO EVALUATE NEW NATIONAL VACCINATION GUIDELINES - A PROSPECTIVE COHORT STUDY
Authors: Schmidt Teresa , Rohn Hana , Trilling Mirko , Agkatsev Sarina , Oster Christoph , Kleinschnitz Christoph , Sure Ulrich , Stuschke Martin , Scheffler Björn , Kebir Sied , Glas Martin 
Published: November 2023

Abstract
Patients diagnosed with glioma belong to a high-risk group during the COVID-19 pandemic. These patients have a compromised immune function due to the malignancy itself, specific anticancer therapies such as temozolomide and symptom-alleviating corticosteroid treatments. While earlier studies have reported successful seroconversion after SARS-CoV-2 immunization in oncological patients, inclusive of those with glioma, the resulting antibody titers remain markedly inferior compared to the healthy population. The recent modification of COVID-19 vaccine guidelines in Germany advocates an additional annual vaccination for glioma patients. Our prospective cohort study endeavors to delineate the immunogenicity in fully immunized glioma patients through assessment of humoral and adaptive immune response post-administration of the supplementary vaccine dose. In this single-center study, glioma patients undergoing tumor-specific therapy will receive an adjunctive dose of the COVID-19 vaccine in conjunction with the seasonal influenza vaccine. A cohort of 70 glioma patients is planned for inclusion, and a comparative analysis will be conducted against a control group consisting of healthy relatives and healthcare professionals. Blood samples will be procured at two distinct intervals: T1, preceding the extra vaccine administration, and T2, 28 days following vaccination. Immunogenicity will be assessed by quantifying anti-SARS-CoV-2 spike (S) protein and nucleocapsid protein (N) concentrations and T-cell responses ascertained using the ELISPOT assay and flow cytometry. In parallel, a comprehensive evaluation of clinical data relevant to therapeutic interventions and corticosteroid usage will be undertaken. At the time of abstract submission, patient recruitment is in progress. Preliminary immunological and clinical data from this investigation, which seek to appraise immune competence and ascertain the clinical implications of the revised COVID-19 vaccination guidelines in glioma patients, will be presented.
CTNI-67. FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS
Authors: Arakawa Yoshiki , Goldlust Samuel , Colman Howard , Reardon David , Welch Mary , Yamaguchi Shigeru , Butowski Nicholas , Li Jian , Iino Shuichi , Song Gregory , Jackman Aimee , Xie Yuran , Wagle Marie-Claire , Lebedinsky Claudia , Narita Yoshitaka 
Published: November 2023

Abstract

BACKGROUND
Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models.

METHODS
This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥ 1 prior therapy; no treatment options beyond standard of care; KPS ≥ 70.

RESULTS
As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥ 9 months. Dose dependent changes in PK and PD were observed.

CONCLUSIONS
DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.
PATH-53. ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA WITH BEND5-NTRK2 FUSION IN A YOUNG ADULT WITH A HISTORY OF CRANIAL RADIATION FOR CHILDHOOD RHABDOMYOSARCOMA
Authors: Fischer Julie , Gilbert Andrea , Shah Shafqat 
Published: November 2023

Abstract
INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of circumscribed astrocytic glioma. While PXA typically has a favorable prognosis, anaplastic (WHO Grade III) PXA (aPXA) has a poorer prognosis. Molecular analysis of PXA often reveals BRAF mutations or CDKN2A/B homozygous deletions. NTRK fusions have been identified in a few cases of pediatric gliomas including PXA. BEND-5 gene alterations have been rarely reported in CNS tumors such as glioblastoma but have not been previously reported in PXA. Case Presentation The patient is a 24-year-old female with history of nasopharyngeal embryonal rhabdomyosarcoma treated with chemotherapy and radiation at age 3. She was tested for Li-Fraumeni Syndrome and was reportedly negative. One year ago, she presented with visual changes and was found to have an occipital aPXA. She underwent a gross total resection but declined further treatment with radiation. Next-generation sequencing (NGS) identified a BEND5-NTRK2 fusion, and she began treatment with Larotrectinib. Serial MRI scans have shown no evidence of disease recurrence. Discussion Pediatric patients are at increased risk for glioma after radiation which is age- and dose/volume-dependent. Radiation-induced gliomas are typically higher grade, present in atypical sites, and have a poor prognosis. Development of PXA following radiation is rare but has been reported. Our patient was diagnosed with aPXA almost 20 years after initial treatment for rhabdomyosarcoma. Her aPXA exhibited a BEND5-NTRK2 fusion and lacked classical BRAF alterations and CDKN2A/B deletions that are present in de novo cases. A Neuro-Onc Panel did not identify her fusion or include testing for BEND5 alterations. However, an expanded RNA Exome Fusion Panel NGS identified a unique fusion, which opened her up to targeted treatment with an NTRK inhibitor. Our patient is now 1 year from resection without disease progression on larotrectinib. This case highlights the importance of expanded NGS testing, particularly in rare tumors.
NIMG-16. THE PROGNOSTIC VALUE AND BIOLOGICAL SIGNIFICANCE OF MRI CE-T1-BASED RADIOMICS MODELS IN CNS5-IDENTIFIED GBM
Authors: Zhang Mingwei , Wang Xuezhen , Li Xiaoxia , Li Shan , Yue Qiuyuan , Hong Jinsheng 
Published: November 2023

Abstract

BACKGROUND
Following the publication of the 2021 WHO Classification of CNS Tumors (Fifth Edition) (CNS5), prognostic markers to guide the individualized treatment of patients with glioblastoma (GBM) (CNS5) need to be explored. Radiomics is a non-invasive, reproducible, and cost-effective method that has been used in the prognostic assessment of multiple solid tumors. The prognostic value and biological significance of MRI T1 - weighted enhancement (CE-T1) - based radiomics models in GBM (CNS5) has not been reported.

METHODS
The tumor region of MRI CE-T1 phase was segmented, and radiomics features were extracted. The consistency analysis, univariate Cox regression and two machine learning algorithms were used for feature reduction. Then, the radiomics prognostic model was established to calculated the radiomics score (RS). The independent external validation was independently verified using the bicenter radiotherapy cohorts. The enrichment analyses of the differential genes between RS-high and -low groups were implemented to explore the biological significance.

RESULTS
A prognostic model composed of six radiomics features were built. A high RS (HR=3.718, 95%CI: 2.222−6.220, P&lt; 0.001) was an independent risk factor for overall survival (OS). The result was externally validated by two cohorts. Through biological significance exploration, RS was found to be significantly correlated with DNA repair (P=0.009) and glycolysis (P=0.001) pathway enrichment scores. RS was associated with γδT cell infiltration and the expression of LAG3.

CONCLUSION
The MRI CE-T1 based radiomics prognostic models constructed can predict GBM (CNS5) prognosis noninvasively and effectively, which is relevant to DNA repair, and may guide the screening of radiosensitive populations.
NCOG-26. CORE OUTCOME SETS FOR USE IN FUTURE MENINGIOMA CLINICAL STUDIES: RESULTS OF THE COSMIC PROJECT
Authors: Millward Christopher , Islim Abdurrahman , Keshwara Sumirat , Srikandarajah Nisaharan , Brodbelt Andrew , Marson Anthony , Williamson Paula , Jenkinson Michael 
Published: November 2023

Abstract

OBJECTIVE
Core Outcome Sets (COS) define the minimum outcomes that should be measured and reported in all clinical trials for a specific health condition or health area. The aim was to develop two COS for intracranial meningioma; one for clinical trials (COSMIC: Intervention) and one for observational studies (COSMIC: Observation).

METHODS
A study advisory group was formed with representation from international stakeholders of charities (IBTA, TBTC, brainstust), neurosurgery societies (SBNS, BIMS) and neuro-oncology societies (BNOS, EANO, EORTC, ICOM, RANO-PRO, SNO). Two systematic literature reviews and trial registry searches were performed to identify outcomes reported in published and ongoing 1) meningioma clinical trials, and 2) studies of incidental/untreated meningioma. Outcomes were deduplicated and categorised. Individuals were recruited from stakeholder groups (including meningioma patients and carers, healthcare professionals, researchers) to participate in 2-round, international, modified eDelphi surveys. The final core outcome sets were ratified through online consensus meetings.

RESULTS
The COSMIC: Intervention systematic review identified 660 verbatim outcomes, rationalized into 24 Delphi survey items. Following the consensus meeting, 15 outcomes were included in the final set. For COSMIC: Observation, 267 verbatim outcomes were identified and rationalized into 17 Delphi survey items. 16 outcomes were included in the final set. There were eight core outcomes common to both COSMIC: Intervention and COSMIC: Observation COS, namely tumour growth, physical, emotional, and neurocognitive functioning, overall quality of life, progression-free survival, meningioma specific mortality and overall survival. Role and social functioning were core outcomes in COSMIC Observation but not COSMIC intervention.

CONCLUSIONS
The COSMIC study has defined the core outcome sets for use in future meningioma clinical trials and studies. Role and social functioning were important to incidental meningioma patients and likely reflects the anxiety and uncertainty around clinical treatment. International stakeholder agreement should ensure widespread use and adoption.
NCOG-37. BELZUTIFAN IN ADULTS WITH VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA: A SINGLE-CENTER EXPERIENCE
Authors: Neth Bryan , Webb Mason , White Jessica , Uhm Joon , Pichurin Pavel , Sener Ugur 
Published: November 2023

Abstract

INTRODUCTION
Belzutifan is a selective inhibitor of hypoxia-inducible factor 2-alpha that has been FDA approved for Von Hippel–Lindau (VHL) syndrome-associated tumors. There is limited real-world evidence in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan.

METHODS
We retrospectively 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 2023.

RESULTS
4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated. The most common adverse effect was anemia. No patients had treatment pauses or dose adjustments due to toxicity. No patients experienced hypoxia.

DISCUSSION
We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.