bluuebunny/crossref_metadata_2025_split huggingface dataset:
CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA
Authors: Sponagel Jasmin , Zhang Shanshan , Chinnaiyan Prakash , Rubin Joshua , Ippolito Joseph 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.
CSIG-21. DE-ORPHANIZING GPR133 - AN ADHESION GPCR REQUIRED FOR GLIOBLASTOMA PROGRESSION
Authors: Frenster Joshua , Erdjument-Bromage Hediye , Stephan Gabriele , Chidambaram Shravanthi , Alghamdi Abdulhakeem , Bready Devin , Straeter Norbert , Liebscher Ines , Schoeneberg Torsten , Neubert Thomas , Placantonakis Dimitris 
Published: November 2019

Abstract
We previously found GPR133 (ADGRD1), an orphan adhesion GPCR, is de novo expressed in glioblastoma (GBM) and enriched in patient-derived glioblastoma stem cells (GSCs). Knockdown of GPR133 reduces GBM cell proliferation and tumorsphere formation, and abolishes orthotopic tumor initiation in vivo in mice. Analysis of TCGA data indicates that increased GPR133 transcription inversely correlates with patient survival in GBM. While these findings underscore the importance of GPR133 in GBM and suggest an essential role in tumor growth, its ligand and mechanism of activation remain unknown. Toward identifying GPR133 ligands, we used GPR133’s N-terminal ectodomain as bait and performed affinity co-immunoprecipitation (CoIP) followed by mass spectrometry as an unbiased screening approach. We identified 490 extracellular proteins with enriched binding to GPR133 compared to control. Reverse CoIP using the 15 most abundant candidate ligands as bait to purify the receptor confirmed this interaction reproducibly in 4 candidates. Despite this binding, overexpression of these candidate ligands, or addition of purified recombinant protein, is not sufficient to increase receptor signaling as assessed by cAMP levels in HEK293 cells. This suggests that ligand binding to the GPR133 ectodomain may not be sufficient by itself to induce receptor activation. We hypothesize receptor activation requires mechanical forces in addition to ligand binding. Consistent with this hypothesis, the GPR133 binding proteins we have identified may be anchored to the extracellular matrix, mediating such mechanical force. To test whether mechanical shearing of the extracellular domain is sufficient for receptor activation, we used Dynabeads coupled to antibody against GPR133’s N-terminal ectodomain, and indeed observed receptor activation leading to elevated cAMP levels. No activation was observed when Dynabeads devoid of antibody were used. This mode of GPR133 activation might indicate a role in sensing mechanical/viscoelastic properties of GBM extracellular matrix, which may be relevant to tumor cell migration and invasion.
CSIG-22. REGULATION OF GLIOMA STEM CELL SELF-RENEWAL AND TUMORIGENESIS BY CARBOHYDRATE BINDING PROTEINS
Authors: Sharanek Ahmad , Fatakdawala Idris , Jahani-Asl Arezu 
Published: November 2019

Abstract
Glioma Stem Cells (GSC) are a population of malignant self-renewing stem cells in glioblastoma (GBM) tumors, the most common and aggressive primary brain tumor in the adult brain. GSC promote tumor growth and recurrence and acquire resistance to therapy. Strategies to target GSC in the tumor bulk are urgently needed in order to develop more effective therapeutic strategies for GBM. EGFRvIII/STAT3 signaling is a major oncogenic pathway in GBM. Here, we report our discovery that Galectin1, a family member of carbohydrate-binding proteins with affinity for b-galactosides, promotes GSC self-renewal and tumor growth in EGFRvIII-expressing subset of tumors. Analysis of RNA-Seq data shows that LGALS1, the gene encoding Galectin1, is highly expressed in human EGFRvIII-expressing GSC and its expression correlates with the expression of transcription factor STAT3. Importantly, STAT3 directly binds the promoter of LGALS1 to upregulate its expression and knockdown of STAT3 significantly attenuates LGALS1 mRNA levels. Genetic knockdown of LGALS1 impairs the ability of GSC to form spheres, as assayed in limiting dilution assay, suggesting that LGALS1-STAT3 signaling regulates glioma stem cell fate in EGFRvIII tumor subset. Strikingly, we employed genetic and pharmacological approaches in patient derived xenografts and found that LGALS1/Galectin1 impairs gliomas stem cell growth and tumorigenesis. Subcutaneous and stereotactic intracranial implantation of CRISPR knockout LGALS1 EGFRvIII-expressing GSC into SCID mice showed significantly reduced in vivo tumor xenografts growth and increased survival rate compared with controls. Treatment of GSC with OTX008, a specific inhibitor of galectin-1, significantly attenuates the self-renewal ability of these cells and impairs tumorigenesis. Together, our findings suggest that targeting LGALS1/Galectin1 in combination with current standards of care may provide an effective strategy for the future treatment of these deadly brain tumors.
CSIG-31. ALTERNATIVE RECEPTOR TYROSINE KINASE SIGNALING AS A RESISTANCE MECHANISM TO ERK INHIBITION IN HIGH-GRADE GLIOMAS
Authors: Stanton Ann-Catherine , Koncar Robert , Golbourn Brian , Wassell Michelle , Agrawal Nishant , Dey Brittany , Myers Max , Mack Stephen , Pollack Ian , Agnihotri Sameer 
Published: November 2019

Abstract
Pediatric High-Grade Gliomas (PHGG), which include Diffuse Midline Gliomas (DMG), are a leading cause of brain tumor death in children. Our recent work has identified extracellular signal-regulated kinase 5 (ERK5) as a critical mediator of cell survival in PHGG. Suppression of ERK5 genetically or pharmacologically leads to decreased cell proliferation and increased apoptosis both in vitro and in vivo in multiple PHGG and H3K27M mutant DMG cell lines. Mechanistically, we show that ERK5 directly stabilizes the proto-oncogene MYC at the protein level, providing rationale to clinically target ERK5. ERK5 contains both a kinase domain (KD) and a transactivation domain (TAD), unlike all other ERKs. Unexpectedly, we found that our ERK5 depleted cells could be partially rescued by an ERK5 kinase domain dead (ERK5-KDD) but TAD intact construct. Additionally, persistent ERK5 depletion does not result in complete growth inhibition and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. To address this, we performed RNA sequencing of DMG cells, comparing control cells to ERK5 knockdown cells, and performed gene-ontology (GO) pathway analysis to identify transcriptional changes that occur in response to ERK5 depletion. We identified 105 differentially expressed genes, and GO analysis identified alternative receptor tyrosine kinase (RTK) gene-expression as one of the top biological processes upregulated in response to ERK5 loss. We validated our top targets at the RNA and the protein level. Our top targets were Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) and Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), both clinically actionable targets. Our future work will focus on functional validation of these RTKs as potential resistance mechanisms to ERK5 loss. Identification of resistance mechanisms to ERK5 loss will have both biological and translational relevance and may lead to effective therapeutic combinations.
CMET-04. RADIOMICS FEATURES CAN DIFFERENTIATE THE EGFR MUTATION STATUS OF BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Won Park Yae , Soo Ahn Sung , Choi Dongmin , Kim Hwiyoung 
Published: November 2019

Abstract

BACKGROUND AND PURPOSE
To assess whether radiomics features on DTI and conventional postcontrast T1-weighted (T1C) images can differentiate the epidermal growth factor receptor (EGFR) molecular status in brain metastases from non-small cell lung cancer (NSCLC).

MATERIALS AND METHODS
Radiomics features (n = 5046) were extracted from preoperative MRI including T1C and DTI from pathologically confirmed brain metastases of 59 patients with underlying NSCLC and known EGFR mutation status (31 EGFR wild type, 28 EGFR mutant). A subset of 4317 features (85.6%) with high stability (intraclass correlation coefficient > 0.9) were selected for further analysis. After feature selection by the least absolute shrinkage and selection operator, the radiomics classifiers were constructed by various machine learning algorithms. The prediction performance of the classifier was validated by using leave-one-out cross-validation. Diagnostic performance was compared between multiparametric MRI radiomics models and single imaging radiomics models using the area under the curve (AUC) from ROC analysis.

RESULTS
Thirty-seven significant radiomics features (6 from ADC, 6 from fractional anisotropy [FA], 25 from T1C) were selected. The best performing multiparametric radiomics model (AUC 0.97, 95% CI 0.94–1) showed better performance than any single radiomics model using ADC (AUC 0.79, p = 0.007), FA (AUC 0.75, p = 0.001), or T1C (AUC 0.96, p = 0.678); the accuracy, sensitivity, and specificity of this model were 94.4%, 96.6%, and 92.0%, respectively.

CONCLUSION
Radiomics classifiers integrating multiparametric MRI parameters may be useful to differentiate the EGFR mutation status in brain metastases from lung cancer.
CMET-11. RESPONSE TO STEREOTACTIC RADIOSURGERY FOR MULTIPLE BRAIN METASTASES BASED ON HISTOLOGY-SPECIFIC SUBTYPE STATUS
Authors: Rooney Michael K , Chandler James , Kalapurakal John , Stupp Roger , Lesniak Maciej S , Sonabend Adam , Kumthekar Priya , Tate Matthew , Kruser Timothy , Lukas Rimas , Dixit Karan , Sachdev Sean 
Published: November 2019

Abstract

BACKGROUND
This retrospective study evaluated the relationship between histologic subtype and treatment outcomes following SRS for the treatment of multiple brain metastases (MBM).

METHODS
We analyzed patients with MBM, defined here as >= 3 lesions, treated with SRS at our institution. Primary histologies examined were NSCLC, breast, and melanoma. Patients were categorized according to histology-specific subtypes (NSCLC-EGFR, ALK, KRAS, PD-L1%; breast-HER2, ER, PR; melanoma-BRAF). The primary outcome was local control (defined by RANO-BM) and secondary outcomes included intracranial progression-free survival (iPFS) and overall survival (OS).

RESULTS
141 patients met inclusion criteria (66 NSCLC, 61 breast, and 14 melanoma). HER2+ and BRAF V600E+ lesions had increased rates of local control following SRS (P=0.0048 and P=0.0256, respectively) compared to other breast/melanoma subtypes. EGFR mutation was not associated with increased local control with SRS (71 vs 74%), but increased iPFS (P=0.0031). On multivariable analysis, EGFR+ was independently associated with a decreased time-dependent risk of death (P=0.011). The use of progressively newer generations of EGFR-directed therapies was associated with stepwise decreasing risk of intracranial progression and death. HER2+ disease had improved iPFS and OS (P=0.0058 and P< 0.0001, respectively; it was not an independent risk factor for progression or death; however, the use of HER2-directed antibodies was associated with decreased risk of death (p=0.036). The use of tyrosine kinase inhibitors (i.e. lapatanib) was not associated with improvements, although this was a small subset.

CONCLUSIONS
Some histologic subtypes appear to have better control with SRS, with HER2+ breast cancer and BRAF V600E+ melanoma associated with improved outcomes – this requires further validation; a volumetric analysis is pending. This the protective effect of EGFR mutation appears to be partly related to use of EGFR inhibitors, with the use of newer-generation therapies leading to improved outcomes; although local control with SRS remains excellent regardless of the mutation.
CMET-17. RENAL CELL CARCINOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIATION THERAPY AND NIVOLUMAB DOES NOT ALTER LESIONAL OR CLINICAL OUTCOMES
Authors: Mohammadi Homan , Tolpin Aaron , Figura Nicholas , Peacock Jeffrey , Oliver Daniel , Sim Austin , Palm Russel , Ahmed Kamran , Liu James , Tran Nam , Etame Arnold , Vogelbaum Michael , Robinson Timothy , Yu Michael 
Published: November 2019

Abstract
Metastases (BM) carries the risk of hemorrhaging lesions and can be effectively treated using stereotactic radiotherapy (SRT). Nivolumab is a recently approved immunotherapy for stage IV RCC. We evaluate whether patients with RCC BM treated with SRT overlapping with nivolumab have altered clinical and BM outcomes. METHODS: 38 consecutive patients were identified in our retrospective database from 1/2011 to 6/2018. Analyses were performed on a per-lesional basis (n=170), per-treatment session basis (n=79), and per-patient basis (n=38). Patients who received nivolumab within 6 months of SRT were considered to have overlapping treatments. ROC curve, chi-squared, Kaplan-Meier, log-rank, and Cox regression model were employed for statistical analyses. RESULTS: A total of 7 (18.4%) patients received overlapping treatments for 64 (37.6%) eligible lesions. Median follow-up was 15.4 months and median overall survival from first BM treatment was 14.8 months (0.5 – 98.4). Median time to subsequent distant brain and non-brain failures were 3.4 and 2.2 months, respectively. Median time to local failure was 20.2 months (two lesions). There were 11 hemorrhagic toxicities (7 in the nivolumab group) and 17 radionecrosis toxicities (4 in the nivolumab group) with no significant difference amongst the groups. Lesions receiving nivolumab within 6 months of SRT did not exhibit a higher rate of toxicity (p=0.521) but had a shortened time to hemorrhage (p< 0.001). Patients who received SRT > 1 month after nivolumab had a prolonged time to subsequent distant brain failure (median 11.1 months) than patients who received SRT > 1 month before (median 3.1 months) or within 1 month (median 1.6 months) of nivolumab, p=0.014. CONCLUSIONS: Overlapping nivolumab with SRT is safe with no increased risk of hemorrhagic lesions. An optimal treatment sequence of nivolumab administration followed by SRT prolongs the time to subsequent BM and warrants further investigation.
CMET-20. ANALYSIS OF NANO-SIZED PARTICLE IN HUMAN CEREBROSPINAL FLUID: A MEASUREMENT OF EXTRACELLULAR VESICLE CONCENTRATION CHANGE WITH MIR-21 EXPRESSION AFTER CHEMOTHERAPY FOR LEPTOMENINGEAL CARCINOMATOSIS
Authors: Lee Kyue-Yim , Lin Wei-wei , Gwak Ho-Shin , Heon Kim Jong , Chul Yoo Byong , Kim Tae-Hoon , Bae Park Jong , Jin Park Hyeon , Kim Ho-Jin , Woong Kwon Ji , Hoon Shin Sang , Yoo Heon 
Published: November 2019

Abstract

PURPOSE
For comparing the distribution and concentrations of nano-sized micro-molecules in cerebrospinal fluid (CSF) according to different central nervous system (CNS) disease

METHODS
We have collected CSF of 447 patients from 6 different groups (systemic cancer, healthy control, leptomeningeal carcinomatosis (LMC), brain metastasis, other brain tumor, and other CNS disease). After cell down by centrifugation, proportion of nano-sized particle is measured by Nano-sizer and absolute number of extracellular vesicle (EV, 100–1,000 nm) is counted by Nano-sight. We verified exosomes in our CSF samples by exosome purification and Western blot.

RESULTS
In Nano-sizer, two peaks appeared at mean 10.5 nm and 174 nm. The small peak is presumed to be nucleic acid and protein as we could decrease or eliminate the peak by nucleic acid elimination kit or proteinase. The proportion of large peak, presumed to represent EVs, is significantly higher in LMC group than all other groups (mean 64% vs. 44%, p < 0.001). And also, the count of EV is significantly higher in patients with LMC (7.15 x 108 vs. 3.46 x 108, p < 0.001). Furthermore, we evaluated paired EV concentration of pre- and post-treatment of intra-CSF chemotherapy in non-small lung cancer patients with LMC (n=33). Overall survival of patients was significantly prolonged in patients with increased EV count compared to those of decreased or ‘no-change’ (< 20%) (442 vs. 165 days, p < 0.001). The expression level of onco-microRNA (miR-21) is decreased significantly after the treatment in this favorable prognostic group (p < 0.01).

CONCLUSION
We expect to obtain appropriate variables representing cancer cell activity in the CSF samples by observing this nano-sized molecule proportion and EV concentration with onco-miR expression. KEY WORDS: cerebrospinal fluid, exosome, extracellular vesicle, microRNA, leptomeningeal carcinomatosis
CMET-24. PLATEAU WAVE EVENTS: A COMMON, CURABLE, AND ROUTINELY MISDIAGNOSED SYNDROME IN PATIENTS WITH NEOPLASTIC MENINGITIS (NM)
Authors: Padmanaban Varun , Zammar Samer , Zacharia Brad , Rizk Elias , Ryan Sandra , Glantz Michael 
Published: November 2019

Abstract

INTRODUCTION
NM is defined clinically by multilevel neurologic dysfunction. Seizures occur in less than 15% of patients. We describe a curable phenomenon (“plateau wave events”) that mimics and may be more common than seizures, but is not responsive to anticonvulsant medication.

METHODS
We queried a multinational NM registry to identify patients with episodic neurologic dysfunction suspected of having seizures. Detailed demographic, disease, treatment, and outcome data were collected.

RESULTS
Forty-three patients (21.2% of 203) were identified. Twenty patients (46.5% of 43) demonstrated a stereotyped constellation of symptoms including episodic severe headache and loss (19 patients) or impaired level (1 patient) of consciousness, nausea, vomiting, and gait instability lasting 30–180 seconds, with abrupt resolution and without post-ictal symptoms. Events developed a median of 74 (0–350) days following NM diagnosis. Fourteen patients (74%) were female. Median age was 54.8 [IQR 46.8, 61.6] years. Fourteen patients had solid tumors (11 breast), 5 had hematologic malignancies, and 1 had a primary brain tumor. Thirteen (68%) had ventriculomegaly. All patients demonstrated increased ICP [median 30.0 cm H2O, IQR 22.5, 30.0]. CSF cytology was positive and CSF protein was increased in 100% of patients, but no demographic, laboratory, or disease characteristic was associated with plateau wave events on multivariate analysis. Inter-ictal EEG in 8 patients showed no epileptiform activity. One intra-ictal EEG showed marked brainwave slowing and bradycardia during the clinical event. One intra-ictal ICP tracing showed an abrupt and dramatic increase in intracranial pressure during the event. Nineteen patients underwent ventriculoperitoneal shunting and experienced immediate symptom resolution. Anticonvulsant medication, initiated in 11 of these patients prior to shunting, provided no benefit.

CONCLUSIONS
Plateau wave events are common in patients with NM. They are frequently mistaken for seizures but are easily recognized by a constellation of defining signs and symptoms. Ventriculoperitoneal shunting is curative.
CMET-32. DNA METHYLATION ALTERATIONS IN LUNG ADENOCARCINOMAS THAT DEVELOP BRAIN METASTASES
Authors: Zuccato Jeffrey , Mamatjan Yasin , Aldape Kenneth , Zadeh Gelareh 
Published: November 2019

Abstract

INTRODUCTION
The development of brain metastases from primary cancer profoundly impacts patient prognosis. Metastases are the most common adult brain tumor with up to one quarter of lung cancers developing metastases and median overall survival after metastasis being one year. Clinical factors do not reliably predict brain metastasis development and over 90% are identified after symptoms develop. DNA methylation signatures predict outcomes in other cancers and so identifying signatures that predict metastasis development may allow for treatment strategies that prevent development in high risk patients.

METHODS
Whole genome DNA-methylation profiling was undertaken on N=124 lung adenocarcinoma patients after bisulfite conversion of DNA from formalin-fixed paraffin-embedded tissue. In a randomly selected 70% training cohort, the most differentially methylated CpG sites between patients developing and not developing brain metastases were identified with p< 0.05. A generalized boosted regression model built on these selected features output brain metastasis risk scores for patients in the independent 30% testing cohort.

RESULTS
Brain metastases developed in 49/124 (39.5%) of patients and 2.3K CpG sites were significantly differentially methylated between patients developing and not developing metastases. Methylation-based brain metastasis risk scores predicted time to brain metastasis in a univariate cox regression model (HR=3.2, 95% CI 1.1–9.4, p=0.03). A corresponding area under the receiver operating characteristic curve at 52 months was 0.64. A multivariate cox analysis including tumor size and nodal status, representing the non-metastatic components of cancer stage, identified methylation score as the only independent predictor of brain metastasis (HR=4.3, 95%CI 1.1–17, p=0.038).

CONCLUSIONS
DNA methylation signatures in lung adenocarcinoma predict brain metastasis development independent of stage components, which classically predict patient outcome in cancer. Future work developing a comprehensive nomogram utilizing methylation scores together with other clinical factors to determine patient specific risk values may aid in treatment decisions and patient prognosis counselling.