bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-43. SURGICAL TREATMENT FOR SPINAL CORD HEMANGIOBLASTOMA - DIFFERENCE IN SURGICAL INDICATION FROM CEREBRAL HEMANGIOBLASTOMA
Authors: Takayanagi Shunsaku , Takami Hirokazu , Tanaka Shota , Saito Nobuhito 
Published: November 2023

Abstract

Objective
Spinal cord hemangioblastoma (HB) is a tumor with abundant blood flow with feeders and drainers, and is often accompanied by large cysts and syringomyelia. About 25% of HB cases are said to be von Hippel-Lindau (VHL) disease cases, which is a hereditary tumor disease. In VHL disease, multiple surgeries are often performed because HB occurs frequently. To consider whether spinal cord HB requires a different surgical indication from brain HB cases, this report analyzed the treatment results of HB cases at our hospital.

Methods
From 1988 to 2021, 85 patients with HB underwent surgery at our hospital investigated.

Results
There were16 cases of spinal cord, 58 of cerebellum, and 10 of brainstem. Of these, 46 cases (13 families, 21 patients) had VHL disease. There were 13 cases (81%) with syringomyelia and 8 cases (50%) with cysts in spinal cord HB. The mean tumor volume at spinal cord, cerebellum and brainstem were 3.2, 15.9 and 5.8 cm3, respectively. Changes in mRS before and after surgery were as follows; spinal cord HB: improvement 10 (63%)/deterioration 3 (19%), cerebellar HB: improvement 35 (60%)/deterioration 7 (12%), brainstem HB: improvement 7. (70%)/0 deterioration. In spinal cord HB, total resection was achieved in all cases, and no significant complication was observed. Conversely, 12 patients (17%) underwent shunting for postoperative hydrocephalus in cerebellum/brain stem HB. In spinal cord HB, no local recurrence was observed during the follow-up period of median 54 months (4-188 months).

Conclusion
Spinal cord HB was operated when the tumor volume was smaller than that of brain HB, but there was no significant difference in the symptom improvement rate. However, there were a certain number of patients who deteriorated after surgery, and it was thought that further analysis would be necessary in the future regarding appropriate surgical indications for spinal cord HB.
SURG-44. VENTRICULAR CEREBROSPINAL FLUID SAMPLING IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PATIENTS: INSTITUTIONAL EXPERIENCE AND REVIEW OF THE LITERATURE
Authors: Li Daphne , Stellpflug Wendy , Romanski Kathleen , Speck Stacy , Saratsis Amanda 
Published: November 2023

Abstract

BACKGROUND
Increasing evidence suggests that circulating biomarkers may serve diagnostic and longitudinal monitoring purposes in pediatric neuro-oncology. Mutant tumor DNA is detectable in the cerebrospinal fluid (CSF) of pediatric diffuse midline glioma (DMG) patients and quantity can reflect disease burden. CSF sampling (“liquid biopsy”) via a CSF access device could therefore play a role in DMG management. Therefore, we set to evaluate the incidence of hydrocephalus (HCP) in DMG patients, and to characterize ventricular reservoir placement and access practices.

METHODS
A single institution retrospective review of DMG patients &lt;21-years-old was performed (1984-2019). MEDLINE searches for reports of ventricular reservoir or shunt placement in DMG, and reservoir access for intraventricular chemotherapy (IVC) were performed.

RESULTS
At our institution, 62.6% of DMG patients (67/108) required intervention for HCP: 19.4% provided transient CSF access (ETV alone n = 3, EVD n = 8, unspecified n = 2), and 80.6% permanent CSF access (ETV + reservoir n = 13, shunt n = 41). Further, 22/34 patients with initially transient CSF devices required conversion to a permanent device. Five devices were revised for malfunction, one for infection. Seventeen articles cited HCP in 22% to 100% of DMG patients. IVC administration was described in 632 patients (seven articles), with 42 infectious and 63 non-infectious complications.

CONCLUSIONS
Management of HCP is often necessary in children with DMG. Given the low rate of clinical risk associated with VAD placement and access, and the potential utility of longitudinal disease monitoring via CSF analysis, VAD placement could be considered in future clinical trials to guide DMG treatment.
TMET-01. THERAPEUTIC TARGETING OF CROSSTALK BETWEEN MITOCHONDRIAL FITNESS AND CELL ADHESION/MIGRATION IN DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Cartaxo Rodrigo , Ji Sunjong , Schwark Kallen , Koschmann Carl 
Published: November 2023

Abstract
Diffuse midline gliomas (DMGs) are aggressive tumors characterized by infiltration into normal midline brain tissue, hindering surgical resection and contributing to overall morbidity and mortality. To study which genes are driving this invasive phenotype, we established a novel two-step pooled whole genome CRISPR-Migration screen for DMG primary cell cultures (n = 3) derived from patients. After selecting for genes critical for cell survival, each cell line was seeded in the upper chamber of a transwell assay optimized for DMG cells to promote complete serum-free cell attachment and migration through laminin, one of the major components of the blood vessels basement membrane. Following sgRNA library sequencing of low and high-migratory populations, we found a strong positive correlation with genes directly involved in the focal adhesion machinery (ITGB1, CRKL, RAPGEF1, PARVA, PTK2, FERMT2). Stable CRISPR knockout of these genes validated significant reduction in adhesion/migration, without affecting proliferation. Interestingly, we also identified in the screen genes controlling different aspects of mitochondrial function (NDUFAF6, PITRM1, MINOS1, MICU3, LIPT1, MRPL38), especially affecting outer-inner mitochondrial membrane integrity. This finding is in line with the higher sensitivity of multiple DMG cell cultures to Bcl-2 family inhibitors, readily prompting apoptosis in combination with sub-lethal doses of various drugs. Agents that specifically modulate mitochondrial oxidative phosphorylation (OXPHOS) (Rotenone, Oligomycin A, Antimycin A) reduced DMG cell migration without affecting proliferation. Surprisingly, silencing of ITGB1 and CRKL led to a marked decrease in glycolysis and OXPHOS levels, again without any changes in proliferation. Additionally, silencing of ITGB1 (primarily responsible for cell adhesion to laminin) led to the decreased expression (RNA) of multiple mitochondrial NADH dehydrogenases, pointing to an intricate bi-directional mechanism connecting mitochondrial fitness to DMG cell migration. Studies are underway to validate these findings in vivo and to determine an optimal therapeutic disruption of this critical DMG malignant phenotype.
TMET-03. REPROGRAMMING OF GLIOBLASTOMA GLUCOSE METABOLISM FUELS TUMOR GROWTH
Authors: Scott Andrew J , Mittal Anjali , Al-Holou Wajd , Palavalasa Sravya , Meghdadi Baharan , O'Brien Alexandra , Zhou Weihua , Yang Annabel , Zhao Zitong , Lin Angelica , Tarnal Vijay , Lyssiotis Costas , Nagrath Deepak , Wahl Daniel R 
Published: November 2023

Abstract
Metabolic adaptation can promote oncogenic phenotypes in glioblastoma (GBM), but the metabolic pathways utilized by GBM and how they differ from the pathways utilized in normal cortex are poorly understood. Here, we utilize in vivo stable isotope tracing in mice and patients with GBM to define carbon fate and metabolic rewiring in cancer. We infused uniformly-labeled 13C glucose into mice bearing orthotopic GBM patient-derived xenografts or into patients undergoing surgical resection for likely GBM. Tumor and cortex were physically separated in mice by fluorescence-guided microdissection. In humans, samples of enhancing tumor, non-enhancing tumor and normal cortex were separated intraoperatively using MRI guidance. Samples were subsequently analyzed by liquid chromatography mass spectrometry to determine the downstream metabolic fates of infused 13C glucose. Of eight patients infused with 13C6-glucose, six were confirmed to have GBM while the others had non-GBM high grade gliomas. In mice and in patients, glucose-derived carbon effectively entered glycolysis and labeled glycolytic intermediates equivalently in tumor and cortex. Compared to GBM tissue, cortical tissue preferentially oxidized glucose-derived carbon in the TCA cycle and used glucose-derived carbon to synthesize neurotransmitters. Cortical tissue utilized glucose-derived carbon to synthesize the amino acid and neurotransmitter precursor serine, while GBM tissue derived serine from extracellular sources. By contrast, GBM tissue preferentially utilized glucose-derived carbon for the synthesis of purines, pyrimidines and NAD+/NADH. Using time-course isotope tracing studies in mice with GBM and a novel metabolic flux analysis framework, we quantified absolute metabolic fluxes in vivo and confirmed elevated nucleotide synthesis and serine salvage in GBM. Consistent with these results, eliminating dietary serine in mice slowed GBM PDX growth. These studies are the first measurements of numerous metabolic pathways in humans and indicate that GBMs suppress the physiologic utilization of glucose carbons to fuel biosynthesis, which represents a targetable metabolic liability.
TMET-06. METABOLOGENOMIC CHARACTERIZATION UNCOVERS HETEROGENEITY AMONGST IDH MUTANT
Authors: Ajisebutu Andrew , Nassiri Farshad , Mamatjan Yasin , Patil Vikas , Wang Justin , Voisin Mathew , Mansouri Sheila , Zadeh Gelareh 
Published: November 2023

Abstract

INTRODUCTION
Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas through the accumulation of oncometabolite R-2-hydroxyglutarate which drives the widespread restructuring of the DNA methylome; however, beyond R-2-hydroxyglutarate , a comprehensive metabologenomic characterization of IDH-mutant gliomas has yet to be performed. We aimed to characterize the global metabolic profile of IDH-mut and IDH-wt gliomas, identify clinically relevant subgroups based on distinct metabolic differences, and utilize matched epigenetic and transcriptional data to characterize these distinct groups. Method: Glioma samples from a cohort of 154 patients underwent multiplatform molecular analysis, including metabolomic studies, genome-wide DNA methylation profiling and bulk RNA sequencing. A integrative analysis was performed, including hierarchical clustering and principal component analysis of identified metabolites, differentially methylated probes, copy number alteration and bulk mRNA data. Survival analysis as well as multivariable hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models.

RESULTS
We discovered a group of IDH-mutant gliomas whose metabolic profile highly resembled IDH wildtype tumors. Notably, these IDH-mutant gliomas with dysregulated metabolism were distinguished from their IDH-mutant counterparts by significantly shorter overall survival (median OS 118.9 months vs 173.6 months, p=0.048). The IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles. The prognostic relevance of dysregulated metabolism complements, but was not wholly explained by canonically recognized prognostic classifications in IDH-mutant gliomas including 1p/19q codeletion, glioma CpG Island Hypermethylator (GCIMP) status and CDKN2A homozygous deletion.

CONCLUSION
Utilizing a cross-platform analysis we have uncovered a novel subtyping of IDH-mutant gliomas with dysregulated cellular metabolism with similar survival to IDH-wildtype tumors. The metabolic profile provides unique information on glioma phenotypes, which may facilitate a more comprehensive understanding of glioma biology, and provide a window to target novel dependencies.
TMET-11. BERBERINE AS A POTENTIAL ENHANCER FOR 5-ALA-MEDIATED FLUORESCENCE IN GLIOBLASTOMA: INCREASING DETECTABILITY OF INFILTRATING GLIOMA STEM CELLS TO OPTIMIZE 5-ALA-GUIDED SURGERY
Authors: Suehiro Satoshi , Ohtsuka Yoshihiro , Inoue Akihiro , Ohnishi Takanori , Yamashita Daisuke , Nishikawa Masahiro , Watanabe Hideaki , Kunieda Takeharu 
Published: November 2023

Abstract

OBJECTIVE
The prognosis of glioblastoma multiforme correlates with residual tumor volume. In fluorescence-guided surgery, 5-aminolevulinic acid (5-ALA) has been used to maximize safe resection. We searched for repositioning drugs that affect mitochondrial functions and energy metabolism, identifying berberine (BBR) as a potential enhancer of 5-ALA-mediated protoporphyrin IX (PpIX) fluorescence (5-ALA-fluorescence). Here, we investigated whether BBR can be applied to clinical practice as a 5-ALA-fluorescence enhancer.

METHODS
Effects of BBR on 5-ALA-fluorescence in glioma cells and GSCs were evaluated by flow cytometry (fluorescence-activated cell sorting; FACS) analysis. As 5-ALA is metabolized for heme synthesis, effects of BBR on mRNA expressions of seven enzymes in the heme-synthesis pathway were analyzed. Enzymes showing significantly higher expression than control in all cells were identified and protein analysis was performed. To examine clinical availability, the detectability and cytotoxicity of BBR in tumor-transplanted mice were analyzed.

RESULTS
Fluorescence microscopy revealed much more intense 5-ALA-fluorescence in both GSCs and non-stem cells with 5-ALA and BBR than with 5-ALA alone. FACS disclosed that BBR greatly enhanced 5-ALA-fluorescence compared to 5-ALA alone and enhancement was much higher for GSCs than for glioma cells. Among the seven enzymes examined, BBR upregulated mRNA expressions of ALA synthetase 1 (ALAS1) more highly in all cells, and activated ALAS1 through deregulating ALAS1 activity inhibited by the negative feedback of heme. In vivo study showed that 5-ALA-fluorescence with 5-ALA and BBR was significantly stronger than with 5-ALA alone, and the sensitivity and specificity of BBR-enhanced fluorescence were both 100%. In addition, BBR did not show any cytotoxicity for normal brain tissue.

CONCLUSIONS
BBR enhanced 5-ALA-mediated PpIX fluorescence by upregulating and activating ALAS1 through deregulation of negative feedback inhibition by heme. BBR is a clinically used drug with no side effects. BBR is expected to augment fluorescence-guided surgery and photodynamic therapy.
TMET-12. CDKN2A DELETION REMODELS LIPID METABOLISM TO PRIME GLIOBLASTOMA FOR FERROPTOSIS
Authors: Minami Jenna , Morrow Danielle , Bayley Nicholas , Fernandez Elizabeth , Salinas Jennifer , Tse Christopher , Zhu Henan , Su Baolong , Sammarco Alessandro , Liau Linda , Graeber Thomas , Williams Kevin , Cloughesy Timothy , Dixon Scott , Bensinger Steven , Nathanson David 
Published: November 2023

Abstract
Glioblastomas (GBM) are universally lethal brain tumors that exhibit extensive genetic and transcriptional heterogeneity. GBMs acquire metabolic adaptations in response to a multitude of intrinsic (oncogenotype) and extrinsic (tumor microenvironment) factors to fuel neoplastic progression. Large-scale multi-omic studies in cancer cell lines have further advanced our understanding of the intersection between molecular diversity and metabolic heterogeneity, indicating distinct metabolic vulnerabilities may exist within defined molecular subsets of cancer. However, the translatability of these observations into effective cancer therapies remains limited due to gaps in our understanding of the physiologic fidelity of metabolic studies conducted only in vitro. Thus, accounting for both the molecular diversity and environment of human tumors is crucial to identify translatable metabolic targets.
TMET-15. THE COMBINATIONAL EFFECT OF INHIBITOR FOR A FATTY ACID DESATURASE AND A FATTY ACID TRANSPORTER ON GLIOMA GROWTH
Authors: Yamasaki Tomohiro , Zhang Lumin , Dowdy Tyrone , Lita Adrian , Kurozumi Kazuhiko , Larion Mioara 
Published: November 2023

Abstract

BACKGROUND
It is not well understood how much exogenous fatty acids uptake and de novo fatty acid synthesis affect the cell proliferation in glioma. In this study, we examined the combinational effect of inhibitor for a fatty acid desaturase (SCD) and a fatty acid transporter (CD36) on glioma growth.

METHODS
Normal human astrocytes (NHA) were used as glial cells, and U251 transfected with IDH wild-type or IDH mutant gene and patient-derived glioma cells (BT142, TS603, GSC923S) were used as glioma cells. The function of SCD was suppressed by SCD inhibitor and SCD siRNA, and Sulfo-N-succinimidyl oleate (SSO) was used to inhibit the CD36 function.

RESULTS
We treated U251 cells with palmitic acid (C16:0), stearic acid (C18:0), palmitoleic acid (C16:1) or oleic acid (C18:1) after SCD inhibitors treatment or SCD knockdown, and cell proliferation was rescued only after the treatment with C16:1 and C18:1. NHA was not affected by SCD inhibitor, although CD36 inhibitor suppressed cell proliferation of both U251 and NHA. The combination of SCD inhibitor and CD36 inhibitor under the addition of exogenous fatty acid, oleic acid, suppressed the proliferation of U251 cells more effectively than SCD inhibitor or CD36 inhibitor alone. Discussion: The SCD inhibitory effect on gliomas was attenuated by the presence of exogenous monounsaturated fatty acids, whereas the CD36 inhibitor enhanced the cell-killing effect. On the other hand, it should be noted that CD36 inhibitors affect the proliferation of glial cells.
TMET-21. PROTON MAGNETIC RESONANCE SPECTROSCOPY (1H MRS) FOR THE DIAGNOSIS OF AGGRESSIVE MENINGIOMAS WITH RECURRENCE POTENTIAL
Authors: Ijare Omkar , Baskin David S , Powell Suzanne , Pichumani Kumar 
Published: November 2023

Abstract
In our previous study, we have observed elevated steady state levels of both alanine and glutamine in surgically resected tissue specimens from atypical meningioma (grade-II) patients compared to the benign (grade-I) meningioma patients. We have shown that meningioma cells utilize glutamine for the biosynthesis of alanine and other amino acids which may help in the cellular proliferation. While the role of elevated alanine in meningiomas is not well understood, this metabolite may serve as a metabolic marker for the diagnosis of aggressive meningiomas which may recur in the future. Here, we present a case of a large meningioma (7 cm x 4 cm x 8 cm) in a male patient (age: 68 years) who was diagnosed with an anterior cranial fossa, dural based extra-axial enhancing mass with the sinonasal extension compatible with a meningioma. The patient underwent multiple surgeries for the resection of the original tumor mass. Tumor tissue was collected from 2 regions: Nasal cavity and deeper tumor. Surgical pathology classified the tumor as a grade-I meningioma with MIB-1 index of ~10%. However, 1H MRS analysis of the tumor specimen showed elevated levels of alanine (Nasal cavity = 9.57 mM/g, tissue; Deep tumor = 5.50 mM/g, tissue), which are greater than the alanine levels reported for grade-II meningiomas (4.23 ± 1.92 mM). The elevated levels of alanine detected by 1H MRS suggested aggressive behavior of the tumor. After about 11 months, the repeat MRI examination showed tumor recurrence, and the patient underwent surgery again for the resection of the recurrent tumor. Surgical pathology of the recurrent tumor classified the tumor as a grade-I meningioma with increased proliferation rate (MIB-1 index of 10-12%). In conclusion, 1H MRS has potential to predict aggressive behavior of meningiomas and alanine can be used as a molecular marker for the differential diagnosis of meningiomas.
TMET-22. MULTI-OMIC SCREENING OF INVASIVE GBM CELLS IN ENGINEERED BIOMATERIALS AND PATIENT BIOPSIES REVEALS TARGETABLE TRANSSULFURATION PATHWAY ALTERATIONS
Authors: Choudhary Nikita , Garcia Joseph , Akins Erin , Jain Saket , Wolf Kayla , Zhang Jason , Lad Meeki , Shukla Poojan , Gill Sabraj , Carson Will , Carrete Luis , Zheng Allison , Kumar Sanjay , Aghi Manish 
Published: November 2023

Abstract
While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, hydrogen peroxide specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.
TMIC-02. SEX DIFFERENCES IN IMMUNE RESPONSE IN A MURINE GLIOBLASTOMA RESECTION MODEL CONFER A FEMALE SURVIVAL ADVANTAGE
Authors: Volovetz Josephine , Lee Juyeun , Lathia Justin 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of 15-20 months, despite standard of care treatment, which includes surgical resection, radiation, and chemotherapy. GBM is 1.6 times more common in males and overall survival can be up to 10 months shorter in males. Females are more responsive to standard of care therapy, but the mechanism behind these differences is not clear. The immune system is known to be suppressed in GBM patients, and recent studies have found sex differences in immune response. While pre-clinical GBM models are used to interrogate pathophysiology and response to therapeutic interventions, few of these models include surgical resection, despite its role in the standard of care for patients and as a defining therapy in prolonging survival. We developed a pre-clinical GBM resection model to evaluate whether there is a sex bias in survival and to interrogate sex-specific immune changes after surgery. We found that C57BL/6 mice implanted with syngeneic GBM cells demonstrate a sex bias after surgical resection, with males surviving for a median of 24 days compared to 33 days for females. To understand how the immune response is affected by surgical resection in males and females with GBM, we performed flow cytometry to characterize the immune phenotype and found that female mice who underwent resection of their tumors had significantly higher levels of CD4+ T cells in their resection cavity than male mice who underwent resection. The immune phenotype will be further characterized over time to evaluate how it evolves in each sex. These data support prior observations that the mechanisms of immunosuppression are different in males and females. They further underscore the complexity of sex bias in GBM and the need to account for surgical resection and sex in pre-clinical models to investigate next-generation therapeutic strategies.