bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-04. CORRELATIVE PERFORMANCE OF CEREBROSPINAL FLUID (CSF) CIRCULATING TUMOR CELLS (CTC) AND CELL-FREE TUMOR-DERIVED DNA (CTDNA) IN LEPTOMENINGEAL METASTASES (LM) AND PARENCHYMAL BRAIN METASTASES (BM)
Authors: Diaz Maria , Reiner Anne , Huereca Claudia , Young Robert , Arcila Maria , Rosenblum Marc , Ramanathan Lakshmi , Bale Tejus , Pentsova Elena 
Published: November 2022

Abstract

BACKGROUND
CSF-CTC analysis through the CellSearch® platform has been studied as a diagnostic and prognostic tool for LM from solid tumors. CSF-ctDNA can be detected in LM and/or BM, with unclear significance. We aimed to evaluate CSF-CTCs and CSF-ctDNA as predictors of LM diagnosis and survival in LM and BM.

METHODS
We retrospectively reviewed charts of patients with solid tumors who underwent CSF-CTC and ctDNA evaluation from the same lumbar puncture between 2016-2021 at Memorial Sloan Kettering Cancer Center. LM was diagnosed by MRI and/or CSF cytology; CSF-ctDNA was considered “positive” if next-generation sequencing (NGS) detected ≥ 1 mutations using clinically validated thresholds. Associations with newly diagnosed LM were performed using logistic regression, and with development of LM using cause-specific competing risks models. Survival analyses were performed using Cox proportional hazards modeling from date of first CSF collection, and adjusted by LM as a time-dependent variable.

RESULTS
Out of 151 total patients, 99 had LM at the time of CSF analysis (58/99 with newly diagnosed LM, within 30 days of first CSF collection), and 52 had BM only, of which 8/52 (15%) developed LM later (median time from CSF to LM=235 days, range 57-364). CSF-CTCs and CSF-ctDNA were predictive of newly diagnosed LM (OR=1.006, 95% CI:1.002-1.01, p=0.002 for continuous CSF-CTCs; OR=3.60, 95% CI:1.65-7.87, p=0.001 for positive CSF-ctDNA). In a small cohort of patients without LM, CSF-ctDNA was almost statistically significant in predicting later development of LM (HR=4.14, 95% CI: 0.98-17.57, p=0.054) while continuous CSF-CTCs were not (HR=1.02, 95% CI: 0.99-1.04, p=0.21). In all patients, both CSF-CTCs (OR=1.004, 95% CI: 1.001-1.006, p=0.002) and CSF-ctDNA (OR=2.49, 95% CI: 1.51-4.15, p=0.0004) predicted survival.

CONCLUSION
CSF-ctDNA could predict development of LM in patients with BM. Presence of CTCs and ctDNA in CSF were associated with poor survival in patients with central nervous system metastases.
BIOM-10. CIRCULATING EXTRACELLULAR VESICLES AS A TOOL FOR DIAGNOSIS, PROGNOSIS AND MONITORING IN GLIOMA
Authors: Ricklefs Franz , Wollmann Kathrin , Maire Cecile , Drexler Richard , Westphal Manfred , Lamszus Katrin , Dührsen Lasse 
Published: November 2022

Abstract

OBJECTIVE
Extracellular vesicles (EVs) represent a population of lipid bilayer nanoparticles released by all cell types, including tumor cells that can serve as a noninvasive source for liquid biopsy. To date, MRI images have been the established method for monitoring treatment efficacy in brain tumor patients. We investigated the potential of pure EV count for diagnosis, prognosis, and treatment monitoring in gliomas.

METHODS
Plasma samples, differential blood counts, at multiple timepoints before and after surgery of glioblastoma patients (n=101) were collected. Follow-up samples were obtained every 3 months. Healthy donors served as controls (n=29). Plasma EVs concentration was measured by Nanoparticle Tracking Analysis (NTA). EVs were characterized by electron microscopy and imaging flow cytometry. Tumor burden was measured by MRI images. Clinical characteristics were prospectively recorderd. In addition plasma EVs from Mut3 tumor bearing mice were analysed at d3, d5, d7, d10, d12 after tumor injection (n=20). MRI images and differential blood counts were analyzed.

RESULTS
Glioblatoma patients have a 5-fold increase of plasma EVs compared to HD; p &lt; 0.0001). Circulating EVs counts correlated only with FLAIR hyperintensity and with no other MRI or blood-based parameter. Similar results were obtained from Mut3 tumor mice. Dichotomisation of GBM patients in EVhigh and low revealed a significant overall survival and progression free survival benefit for EVlow patients (p=0.004). After surgery, EVs decreased significantly (5-fold, p&lt; 0.0001). A massive drop in EVs was associated with gross-total resection (p &lt; 0.05). At the time of tumor recurrence, the number of circulating EVs increased in all patients during a follow-up (9 months).

CONCLUSION
Our findings highlight the potential of circulating EVs as a biomarker tool for diagnosis, prognosis and treatment monitoring in GBM patietns, as they seem to reflect the presence of a tumor mass and thus may assist in clinical decision making.
BIOM-12. PROLONGED RESPONSE TO THIRD-LINE TREATMENT WITH COMBINATION CCNU/TMZ IN AN MGMT METHYLATED IDH-WILDTYPE GLIOBLASTOMA
Authors: Pan Peter , Haggiagi Aya , Iwamoto Fabio 
Published: November 2022

Abstract

INTRODUCTION
Multiply recurrent glioblastoma suffers from poor response rates to treatment, and limited durability. We describe a case of an impressive response to third-line CCNU/TMZ.

BACKGROUND
Headaches brought a 76-year-old man to medical attention. MRI identified an enhancing right temporal mass -- path following resection demonstrated glioblastoma (IDH-wildtype, MGMT-methylated, TERT mutant; PTEN Y68H, CDKN2A/B loss, CCND3 amplification; VUS in POLE, ATM, GRIN2A, and ROS1). He received hypofractionated RT 40.05Gy/15-fractions plus 21-days concurrent TMZ 75 mg/m2, then 5-day-on / 23-day-off TMZ (150 mg/m2 cycles #1-3; 200 mg/m2 subsequent). MRI pre-cycle #6, nearly 6 months post-RT, showed increased enhancement/FLAIR consistent with local progression (POD).Second-Line: After screen-fail for clinical trial, initiated off-label regorafenib 160 mg/d, 21-days-on/7-days-off -- with partial response in enhancement at 3 weeks. With dose-reduction to 120 mg/d cycles #2-3 (for mounting fatigue), enhancement progressively worsened. Despite resuming higher 160 mg/d for cycle #4, enhancement progressed, consistent with POD.Third-Line: Given presence of MGMT promoter methylation (and extrapolating from CeTeG/NOA-09), combination CCNU 100 mg/m2 (day 1) and TMZ 100 mg/m2 (days 2-6; 8-week cycle) was started. There was improvement in enhancement/FLAIR, which continued to improve gradually through 6 cycles of CCNU/TMZ. Durability of response was surprising -- MRIs stable/improved at 15 months since starting CCNU/TMZ.

DISCUSSION
This case illustrates impressive response to CCNU/TMZ in the third-line. Delayed RT treatment effect is less likely given time elapsed from RT at initial progression (after 5 cycles of adjuvant TMZ), convincing but short-lived improvement to regorafenib (that progressively worsened through 3 more regorafenib cycles), and robust response only with CCNU/TMZ. He was also never on steroids (except post-operatively) nor bevacizumab. This suggests that improvement was mediated by antitumor effect against progressing tumor, rather than delayed RT treatment effect. MGMT methylation may have played a role in this patient's response to dual alkylator therapy.
BIOM-22. BMX EXPRESSION LEVEL IN GLIOBLASTOMA PREDICTS HYPERSENSITIVITY TO IBRUTINIB TREATMENT
Authors: Shakya Sajina , Sundar Swetha , Recinos Violette , Hubert Christopher 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most prevalent and aggressive form of primary brain cancer and is notoriously drug and radiation resistant. The tumor recurrence and therapeutic resistance typically seen in GBM are largely driven by a small population of self-renewing, highly tumorigenic cells termed cancer stem cells (CSCs). The stem-cell-like properties of GBM CSCs are promoted, at least in part, by abnormal activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. This activation can occur through aberrant expression of bone marrow and X-linked (BMX) protein, a non-receptor tyrosine kinase that is upregulated in glioma stem cells and may be targeted by the drug ibrutinib, currently undergoing clinical trials in GBM. In contrast, BMX is not expressed in normal non-cancerous stem cells of the brain. We discovered a striking dissimilarity where a subset of our patient-derived GBM specimens are up to 100-fold more sensitive to ibrutinib than others. We investigated the mechanisms behind this hypersensitivity by analyzing the expression levels of JAK/STAT3 signaling proteins. Here we discovered that the baseline expression value of BMX prior to treatment has a strikingly high predictive value for later later response to ibrutinib, primarily explaining the variation in a specimen’s ibrutinib sensitivity. Furthermore, we found that pediatric GBM tumor models are typically BMX-low and most likely to be hypersensitive to ibrutinib compared to their adult counterparts. Ibrutinib further suppresses GBM and DIPG proliferation in CSC-rich proliferative regions of organoid models. Our data suggest the potential use of BMX as a predictive biomarker of ibrutinib sensitivity, and provide an impetus for mechanistic and preclinical investigation of ibrutinib sensitivity, particularly in pediatric disease.
BIOM-26. GENOME-WIDE SOMATIC COPY NUMBER ALTERATION SIGNATURES HAVE PROGNOSTIC IMPLICATIONS FOR ADULT ASTROCYTIC GLIOMA
Authors: Nuechterlein Nicholas , Li Beibin , Shapiro Linda , Cimino Patrick , Holland Eric 
Published: November 2022

Abstract

BACKGROUND
The molecular landscape of adult diffuse glioma has been extensively characterized by gene expression and DNA methylation profiling, but less attention has been paid to somatic copy number alteration (SCNA) data. This study aimed to give a rigorous, survival-focused analysis of glioma genome-wide SCNA data that builds on our previous work.

METHODS
Detailed survival analyses were conducted on the substructure of UMAP projections of all TCGA glioma (Nf1092), exclusively astrocytic glioma (Nf914), and exclusively IDH-wildtype glioma (Nf528). Results were validated with data from the Glioma Longitudinal Analysis Consortium (GLASS) (Nf224). Clinical factors such as age and MGMT methylation were tested in multivariate survival analyses.

RESULTS
A UMAP projection of TCGA glioma SCNA data generated three distinct clusters composed of entirely oligodendroglioma, predominantly IDH-mutant astrocytoma (C-IDHmut-astro), and predominantly IDH-wildtype glioma (C-IDHwt), respectively. For astrocytic tumors, cluster assignment was independently prognostic of IDH status (p&lt; 0.001): TCGA IDH-mutant astrocytomas that clustered in C-IDHwt had poorer outcomes than their counterparts (p&lt; 0.04) and IDH-wildtype tumors that clustered in C-IDHmut-astro fared better than those that did not (p&lt; 0.01). The distribution of GLASS astrocytic tumors, which is skewed for better survival, supported our results in IDH-wildtype glioblastoma (p&lt; 0.001, Fisher’s). Among four distinct subclusters of TCGA IDH-wildtype glioblastomas, the largest was significantly or marginally significantly negatively prognostic compared to each other cluster (p=0.048, p=0.059, p=0.027) and their combination (p=0.002). In the GLASS dataset, inclusion in the largest subcluster was also prognostic (p=0.013) and similar trends were observed between individual clusters (p=0.21, p=0.036, p=0.083). Furthermore, membership to the largest cluster was independently prognostic of MGMT methylation status and several published IDH-wildtype glioblastoma subtypes in the TCGA.

CONCLUSIONS
Unsupervised learning of genome-wide SCNA has prognostic implications for astrocytic glioma. SCNA cluster membership is independently prognostic of MGMT methylation status.
BIOM-50. THE IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF CIRCULAR RNA CIRC_63706 IN SONIC HEDGEHOG MEDULLOBLASTOMAS
Authors: Pokhrel Rudramani , Katsushima Keisuke , Stapleton Stacie , Jallo George , Raabe Eric , Eberhart Charles , Perera Ranjan 
Published: November 2022

Abstract
Medulloblastoma is a central nervous system tumor that develops through various genetic, epigenetic, and non-coding (nc) RNA-related mechanisms, but the roles played by ncRNAs, particularly circular RNAs (circRNAs), remain poorly defined. CircRNAs are increasingly recognized as stable noncoding RNA therapeutic targets in many cancers, but little is known about their function, subtype specificity, and therapeutic potential in medulloblastomas. To determine medulloblastoma subgroup-specific circRNAs, we subjected RNA-seq data from 175 clinical medulloblastoma samples in four subgroups (SSH, WNT, G3, and G4) to a statistical and machine learning (random forest) pipeline and identified a group of medulloblastoma specific circular RNAs. CircRNA, circ_63706 was identified as sonic hedgehog (SHH) group specific and confirmed its expression by RNA-FISH analysis in clinical tissue samples (tissue microarrays). To identify the molecular function of circ_63706, we depleted circ_63706 in DAOY and ONS76 cells and subjected them to global RNA sequencing and lipid profiling. Circ_63706 resides in the coding gene Pericentrin (PCNT), which is known to be involved in congenital disorders. When Circ_63706 gets depleted by shRNA, it shows a significant decrease in cell proliferation and invasion in SSH cells, and mice implanted with circ_63706-deleted cells showed reduced tumor growth and extended survival compared to parental cells implant. At the molecular level, we identified circ_63706-deleted cells elevated total ceramide and oxidized lipids and reduced total triglyceride (TG). Our study implicates an identification of a novel oncogenic circular RNA in the medulloblastoma subgroup SSH and establishes its potential as a future therapeutic target.
BIOM-56. MIR-497 AND 219 IN BLOOD AID MENINGIOMA CLASSIFICATIONMIR-497 AND 219 IN BLOOD AID MENINGIOMA CLASSIFICATION
Authors: Hanemann Clemens Oliver , Abdelrahman Ahmed , Adams Claire , Sahm Felix , Urbanic-Purkart Tadeja , Khalil Michael , Vergura Raffaella , Morelli Cristina 
Published: November 2022

Abstract
There is a need for blood biomarkers for meningioma. The role of circulating micro RNA in cancer diagnosis has been the objective of several studies. One of the extensively studied miRNA in different types of cancer is the microRNA-497 (miR-497). This study systematically evaluated miR-497 as a meningioma biomarker for disease diagnosis and classification. We studied exosomal and serum miR-497 in 74 meningioma samples (WHO grade I=25, WHO grade II=25, and WHO grade III=24), and 53 healthy controls. We also tested two different normalisers, endogenous and external, and evaluated their impact on the diagnostic value of miR-497. Another microRNA studied in meningioma is miR-219, which increased with increasing tumour grade. We combined miR-497 and miR-219 and estimated the sensitivity and specificity of the joint biomarkers to indicate meningioma grade and the relationship between miR-497 and miR-219 expression level and methylation class of meningioma. The serum and exosomal level of miR-497 distinguished meningioma from the control samples. Moreover, miR-497 was a suitable identifier for meningioma grade. When we combined miR-497 and miR-219, the efficacy of the combined biomarker was higher than miR-497 or miR-219 when used individually in meningioma classification. Both miR-497 and miR-219 showed a noticeable change with the methylation class of meningioma.
BIOS-02. CLINICAL OUTCOMES OF OVER 600 PATIENTS WITH GLIOBLASTOMA TREATED AT A CANADIAN TERTIARY CENTER IN THE PAST 15 YEARS: A COMPARATIVE ANALYSIS WITH THE PIVOTAL STUPP TRIAL
Authors: Rousseau Julien , Desforges Sara-Maude , Jabbour Gilbert , Lemieux Bernard , Lapointe Sarah , Bélanger Karl , Moumdjian Robert , Cayrol Romain , Florescu Marie , Masucci Giuseppina Laura , Berthelet France , Lemieux-Blanchard Émilie , Bahary Jean-Paul 
Published: November 2022

Abstract
Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.
CNSC-01. THE GENE LANDSCAPE OF LUNG ADENOCARCINOMA PATIENTS WITH PROGRESSIVE DISEASE OF LEPTOMENINGE
Authors: Yang Hainan , Wen Lei , Zhou Caicun 
Published: November 2022

Abstract

BACKGROUND
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear.

METHODS
Forty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients had matched plasma (PLA).

RESULTS
The common gene alterations discovered in the CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p=0.2). Cohort 1 had more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.
CNSC-09. THE NEUROENDOCRINE FACTOR VGF IS NECESSARY FOR THE MAINTENANCE OF THE TUMOR STEM CELL POPULATION IN GLIOBLASTOMA
Authors: Kundu Somanath , Venskus Abigail , Quiruz Lee , Longo John , Longo Sharon , Walker Jamie , Richardson Timothy , Viapiano Mariano 
Published: November 2022

Abstract
A major factor that contributes to the unchecked growth and recurrence of glioblastoma (GBM) tumors is the presence of a heterogeneous population of GBM stem-like cells (GSCs) that continuously replenish the tumor mass. Targeting strategies against this key cell population have rarely considered the trophic signals from peritumoral neural cells, which can protect the tumor cells during therapy and therefore promote recurrence. Here, we have focused on the little-known secreted factor VGF and its derived neuropeptides, which are largely restricted to the CNS and mediate paracrine communication between neural cells. We analyzed over 200 tissue specimens and cultured GBM cells, demonstrating that VGF is upregulated in malignant gliomas and expressed in GSCs of different subtypes, although it is markedly reduced in differentiated GBM cells. More importantly, we detected VGF expression in peritumoral astrocytes, even though this neuroendocrine factor has never been described in glial cells in normal brain. Co-culture experiments and scRNAseq data from clinical tumors confirmed that VGF is expressed in tumor-associated astrocytes, suggesting that these cells are a paracrine source of VGF in GBM. Accordingly, purified exogenous VGF increased the proliferation of GSCs and rescued GSC viability when the tumor cells were treated with the chemotherapeutic temozolomide. Moreover, purified VGF decreased the expression of inflammatory cytokines in activated macrophages, suggesting that this factor may also contribute to local immunosuppression in gliomas. Conversely, knockdown of VGF in GSCs was sufficient to decrease their viability, self-renewal, and expression of stemness-related genes. At the molecular level, VGF increased intracellular calcium and Akt/mTOR signaling in GSCs, suggesting a possible G protein coupled receptor-mediated mechanism of action. Taken together, our results explore for the first time the role of brain-derived VGF in GBM progression, highlighting the importance of disrupting the communication between the tumor and its microenvironment to achieve long-term anti-tumor efficacy.