bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-05. CASE SERIES OF MULTI-INSTITUTIONAL UTILITY OF CNSide TO MANAGE LEPTOMENINGEAL DISEASE IN PATIENTS WITH METASTATIC BREAST CANCER
Authors: Kumthekar Priya , Blouw Barbara , Mayer Julie , Fisher Deanna , Dugan Michael , Azadi Amir , Blondin Nicholas 
Published: November 2021

Abstract

INTRODUCTION
Leptomeningeal Disease (LMD) occurs in 5% of breast cancer patients. Diagnosing LMD remains challenging. Current standard of care has limited sensitivity and is inadequate for monitoring treatment response. Biocept’s CNSide™ is a proprietary assay utilizing a 10-antibody capture cocktail with microfluidic chamber that quantitatively detects tumor cells in the cerebrospinal fluid (CSF). We present a case series using CNSide to manage LMD of 4 unique breast cancer patients treated at three different institutions and demonstrate its impact on clinical management.

METHODS
Patients were treated at Smilow Cancer Hospital at Yale-New Haven (1 patient), Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute (1 patient) and Barrow Neurological Institute (2 patients). All patients received intrathecal treatment (IT) via an Ommaya Reservoir. CSF tumor cells were detected via cytology and CNSide at diagnosis (3 patients) and throughout treatment (4 patients).

RESULTS
At diagnosis, CNSide detected tumor cells in 3/3 patients, vs 2/3 patients for cytology. The fourth patient was diagnosed with LMD before CNSide was available. CNSide detected CSF tumor cells in 9/9 (100%) of measurements, vs 4/9 (44%) for cytology for samples analyzed in parallel. Throughout treatment, CNSide was able to track the quantitative LMD response and showed a decrease in CSF tumor cells in all four patients, ranging from 99.7% (from 773 to 2 cells, 1 patient) to 100% (from 4447 to 0 cells; and from 33 to 0 cells, 2 patients).

CONCLUSION
Intrathecal treatment of LMD via Ommaya reservoir is not widely adopted across the US. Our experience suggests that using CNSide for quantitative CSF tumor cell detection may aid in diagnosing LMD, as well as in quantifying response to treatment particularly in the setting of intrathecal therapy. However, larger prospective clinical trials are needed to establish the role of CNSide in the diagnosis and management of LMD.
BIOM-06. MOLECULAR SIGNATURES UNDERLIE THE DISTINCT FAILURE PATTERNS OF MALIGNANT GLIOMAS
Authors: Choi Seung Won 
Published: November 2021

Abstract

BACKGROUND
Malignant gliomas exhibit varied failure patterns upon recurrence; however, genomic backgrounds of these distinct phenotypes have not been evaluated. We aimed to explore the genomic traits associated with distinct failure patterns in malignant glioma patients.

METHODS
This study involved 272 malignant glioma patients. Failure pattern was defined for the spatial relationship between recurrent tumor and the original tumor as follows: local recurrence (LR), remote recurrence, leptomeningeal seeding (LMC), and combined failure pattern. Molecular characteristics underlying different failure patterns were investigated for the mutation profile, copy number variation (CNV), and transcriptomic signatures.

RESULTS
Local recurrence was the most prominent failure pattern (62.9%), followed by combined recurrence (22.8%). Multivariate Cox regression analysis confirmed failure pattern as one of the independent prognostic factors. Patients with combined failure patterns exhibited the worst prognoses, whereas patients with remote recurrence exhibited the most favorable outcomes (median overall survival = 11.4 and 25.2 months, respectively). In IDH1-wild type glioblastoma (GBM) patients, TERT and PIK3CA mutation were significantly associated with the development of combined failure pattern and leptomeningeal seeding, respectively (p-value=0.015 & p-value=0.004, respectively). Transcriptomic analysis exhibited that inter-neuronal synaptic transmission was enriched in GBMs with combined failure pattern and this finding was further validated in proteomic analysis; neuronal myelination and synaptic transmission-related pathways were upregulated in GBMs which exhibited combined failure pattern.

CONCLUSIONS
Collectively, we demonstrated that the inherent molecular characteristics of the tumors might contribute to the eventual relapse patterns; tracking their evolutionary pathways may unravel novel therapeutic vulnerabilities of these tumors.
BIOM-08. DNA METHYLATION-BASED SUBGROUPING PREDICTS SURVIVAL BENEFIT FROM LOMUSTINE/TEMOZOLOMID COMBINATION THERAPY IN MGMT PROMOTOR-METHYLATED GLIOBLASTOMA
Authors: Weller Johannes , Waha Andreas , Schneider Matthias , Seidel Clemens , Steinbach Joachim , Hau Peter , Schlegel Uwe , Tonn Jörg-Christian , Grauer Oliver , Sabel Michael , Krex Dietmar , Schnell Oliver , Ringel Florian , Tabatabai Ghazaleh , Goldbrunner Roland , Radbruch Alexander , Schuss Patrick , Güresir Erdem , Vatter Hartmut , Glas Martin , Schmid Matthias , Schäfer Niklas , Tzaridis Theophilos , Giordano Frank , Zeyen Thomas , Schaub Christina , Németh Robert , Pietsch Torsten , Herrlinger Ulrich 
Published: November 2021

Abstract

BACKGROUND
The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy.

METHODS
All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis of their tumor and methylation subgroup annotation (Heidelberg brain tumor methylation classifier v11b4; calibrated score &gt; 0.5 required). Overall survival (OS) was compared between a pooled cohort of tumors of the RTK I/MES subgroups and RTK II tumors.

RESULTS
In the CCNU/TMZ arm of CeTeG/NOA-09, OS was prolonged in RTK I/MES (n = 16; median not reached, 4-year OS 69%) as compared to RTK II patients (n = 14; median 20.6 months, 4-year OS 23%; p = 0.004 logrank test). In the standard temozolomide arm of CeTeG/NOA-09, OS tended to be shorter in RTK I/MES (n = 7; median 23.7 months, 4-year OS 17%) as compared to RTK II patients (n = 17; median 35.2 months; 4-year OS 38%, p = 0.15).

CONCLUSION
The CCNU/TMZ-dependent survival prolongation in patients with RTK I/MES tumors as opposed to RTK II seen in CeTeG/NOA-09 suggests that methylation-based subgrouping could be predictive for CCNU/TMZ efficacy in newly diagnosed MGMT-methylated glioblastoma.
BIOM-19. DECIPHERING THE METHYLATION SIGNATURE OF CIRCULATING EXTRACELLULAR VESICLE DNA FOR CNS TUMOR CLASSIFICATION
Authors: Ricklefs Franz , Ricklefs Tammo , Maire Cecile , Salviano da Silva Amanda , Wollman Kathrin , Sauvigny Thomas , Dührsen Lasse , Schüller Ulrich , Westphal Manfred , Lamszus Katrin 
Published: November 2021

Abstract
Genome-wide methylation profiling has recently been developed into a tool that allows subtype tumor classification in central nervous system (CNS) tumors. We previously showed that extracellular vesicle (EV) DNA faithfully reflects the tumor methylation class, including information on the IDH mutation and MGMT promoter methylation status. Furthermore we showed that circulating plasma EVs are elevated in CNS tumor patients in comparison to non-tumor donors (HD) controls with tumor related protein profiles. We now investigated, whether the methylation signatures of circulating DNA (both EV and cfNDA) can be used in liquid biopsy approaches for CNS tumor detection and classification. We isolated DNA from circulating EVs (n=27), cfDNA (n=27) and tumor tissue DNA (n=90) of patients with glioblastoma (GBM), meningioma (MGN) and cerebral metastases (CM). Patients undergoing epilepsy surgery as well as aneurysm clipping were used as non-tumor controls (HD, n= 7). EVs were classified by nanoparticle analysis, immunoblotting, imaging flow cytometry and electron microscopy. Isolated EV-DNA comprised many sorts of molecular weight (up tp &gt;10Kb) in comparison to cfDNA (130-140bp). Healthy donors and tumor patients showed not differences in their DNA size profiles. We performed genome-wide methylation profiling by 850k Illumina EPIC arrays for all DNA analytes and tumor entities. Linear models and empirical Bayes methods identified significant differentially methylated CpGs (GBM vs. HD, MGN, vs HD, CM vs. HD), that revealed tumor specific signatures to detect and discriminate different CNS tumor entities. Visualization of differentially methylated CPGs by dimension reduction (PCA, t-SNE, Umap) verified tumor specific clusters. cfDNA and EV-DNA exhibited distinctive individual CpG profiles. Our study shows that the methylation signature of circulating EV DNA and cfDNA can be used to separate healthy individuals from tumor patients and could potentially complement standard-of-care imaging to improve tumor detection, classification and surveillance.
BIOM-24. PROTEIN SURFACE SIGNATURE ON SERUM EXTRACELLULAR VESICLES FOR NON-INVASIVE DETECTION OF TUMOR PROGRESSION IN GLIOBLASTOMA PATIENTS
Authors: Tzaridis Theophilos , Weller Johannes , Bachurski Daniel , Shakheri Farhad , Schaub Christina , Hau Peter , Buness Andreas , Schlegel Uwe , Steinbach Joachim , Seidel Clemens , Goldbrunner Roland , Schäfer Niklas , Wechsler-Reya Robert , Scheffler Björn , Glas Martin , Haeberle Lothar , Herrlinger Ulrich , Coch Christoph , Reiners Katrin , Hartmann Gunther 
Published: November 2021

Abstract

INTRODUCTION
Detection of tumor progression in glioblastoma patients remains a major challenge for clinicians due to equivocal MRI results. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of tumor patients. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as a marker for tumor progression in adjunction with MRI assessment.

METHODS
Glioblastoma patients from two independent cohorts, one from the multicenter Phase III CeTeG/NOA-09 trial (n=36) and the other from patients treated at the University of Bonn (n=31), were included in this study. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria.

RESULTS
EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29 (p=0.08), CD44 (p&lt; 0.0001), CD81 (p&lt; 0.0001), CD146 (p&lt; 0.0001), C1QA (p=0.003), and histone H3 (p&lt; 0.0001) as compared to serum EVs from healthy volunteers. For both independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. Notably, six patients with worse survival compared to the median survival of the cohort did not fulfill RANO criteria at the time of suspected progression, yet showed an elevation of at least one out of these three markers. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76.

CONCLUSION
Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, could improve detection of true tumor progression and thus be a useful tool for clinical decision making.
BIOM-33. EV-ASSOCIATED IL13Ra2 AS A LIQUID BIOPSY BIOMARKER FOR GBM
Authors: Khristov Vladimir , Nesterova Darya , Zacharia Brad , Connor James , Madhankumar Achuthamangalam 
Published: November 2021

Abstract
Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1%. Despite advances in imaging technology, distinguishing between pseudoprogression and pseudoresponse remains problematic and there is a dire need for additional diagnostic methods. Tumor-derived extracellular vesicles are found in a variety of biofluids and are good candidates for a liquid biopsy. A unique characteristic of GBM is the overexpression of the α2 variant of IL-13 receptor (IL13Rα2) in 78-96% of patients while virtually undetectable in normal brain tissue. We hypothesize that biofluids of patients with GBM contains sufficient IL13Rα2-positive extracellular vesicles (EV) to inform the clinical picture regarding disease status such as tumor recurrence and response to therapy. We have measured the levels of IL13Rα2 in the EV fraction of plasma from GBM patients and correlated these levels to patient survival, and patient clinical characteristics (n=35). We have demonstrated that the EV fraction of some patients with GBM is enriched for the IL13Rα2 receptor. The plasma level of IL13Rα2 could also predict the level of IL13Rα2 in the GBM tumor (n=9). Further, IL13Rα2 positive EVs from patient-derived GBM cell lines could be immunoprecipitated for further interrogation of genomic and proteomic molecular markers. These exciting findings lay the groundwork for a GBM liquid biopsy based on tumor-specific EVs in patient biofluids.
BIOM-34. GENOMIC PROFILING IDENTIFIED COPY NUMBER VARIATIONS OF CDK4/6 AS A NOVEL PROGNOSTIC BIOMARKER FOR THALAMIC GLIOMA
Authors: Lai Mingyao , Zhou zhaoming , Li Hainan , Zhou Jiangfen , Li Juan , Zhen junjie , Zhou Cheng , Cai Linbo 
Published: November 2021

Abstract

BACKGROUND
Thalamic glioma is a rare tumor, which is poorly understood in adults. The genetic variation of this tumor is still unknown. In this study, we investigated the mutation landscape of thalamic glioma and compared the clinical outcomes between different mutation situations in thalamic glioma.

METHODS
Next-generation sequencing targeting 425 cancer-relevant genes was performed with 34 thalamic glioma tissue samples. Gene mutations and copy number variations were investigated for prognostic effect with overall survival data.

RESULTS
Several diagnostic and prognostic biomarkers appeared in our thalamic glioma cohort, including TP53 (56%), EGFR (41%), TERT (35%), M CL1 (26%), PDGFRA (26%), PTEN (26%), CDK4/6 (24%), POLE (24%), PIK3CA (24%), NF1 (21%), ATR (21%), ATRX (18%), BRAF (15%), and ROS1 (12%). Among all genetic aberrations with a more than 10% occurrence rate, two mutations (TERT and PTEN) were associated with poor overall survival and one copy number variation (CDK4/6) was associated with favorable overall survival (univariate P &lt; 0.1). Among these genes, CDK4/6 copy number variations (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.035–0.704; P = 0.016) remained significant survival associated in multivariate analyses. Copy number variations of CDK4/6 was seldom reported as a prognostic biomarker for glioma, especially for thalamic glioma in public databases. Besides, several gene mutations (BRIP1, MRE11A, MAP2K1, ROS1, MUTYH, JARID2, CTCF, and EGFR) were found positively associated with CDK4/6 copy number variations. Gene enrichment analysis demonstrated that those genes were related to astrocyte differentiation.

CONCLUSIONS
In our study, CDK4/6 copy number variation was determined as a favorable overall survival biomarker for thalamic glioma, and CDK4/6 copy number variation associated mutant genes were related to astrocyte differentiation, which could be the potential therapeutic targets for thalamic glioma.
BIOM-44. PRE-SURGICAL ADVANCED MRI IS USEFUL FOR FORECASTING DRUG DISTRIBUTION IN BRAIN TUMORS
Authors: Jackson Pamela , Kim Minjee , Hawkins-Daarud Andrea , Singleton Kyle , Mohammad Afroz , Burns Terence , Parney Ian , Hu Leland , Kaufmann Timothy , Elmquist William , Sarkaria Jann , Swanson Kristin 
Published: November 2021

Abstract
Choosing effective chemotherapies for intravenous delivery to brain tumors is challenging, especially given the protective nature of the blood brain barrier (BBB). Connecting drug distribution to non-invasive, pre-surgical magnetic resonance imaging (MRI) could allow for predictive insight into drug distribution. In a previous study, we found that T2Gd images were predictive of a low BBB penetrant drug (Cefazolin), and FLAIR images were predictive of a high BBB penetrant drug (Levetiracetam). While these results are promising, we further seek to explore how advanced MRI sequences might inform image-based models of drug distribution. Prior to surgery, we acquired advanced dynamic contrast enhanced (DCE) and diffusion weighted imaging (DWI) MRI sequences for eight brain tumor patients (7 gliomas and 1 metastatic adenocarcinoma) in addition to the anatomic MRIs. All resulting quantitative maps and acquired images were co-registered. Prior to incision, patients received injections of cefazolin and levetiracetam. Next, multiple blood samples and biopsies were collected during surgery. Biopsies and plasma samples were analyzed for drug concentration using liquid chromatography mass spectrometry (LCMS), and biopsy drug levels were reported as Brain-Plasma Ratio (BPR). Mean image intensity was extracted from a 15x15 voxel window surrounding the biopsy location. We performed linear regression analyses to determine which combination of images were predictive of BPR. We found that considering quantitative imaging improved our initial ability to predict BPR for both drugs. For cefazolin, the third diffusion tensor eigenvalue (L3) map was significantly correlated with BPR (p&lt; 0.001, R2= 0.36). For levetiracetam, the best model consisted of a combination of images and maps with the L3 map and the isotropic diffusion map (P) being the most influential (p= 0.001, R2= 0.63). Advanced MRI-based modeling is a promising tool for forecasting drug distribution in brain tumors and could be of great importance for understanding efficacy and selecting therapeutic strategies.
STEM-01. PHAGE DISPLAY BIOPANNING IDENTIFIES AMOT REGULATING CELL MOTILITY OF BRAIN METASTATIC STEM-LIKE CELLS
Authors: She Chunhua , Kim JongMyung , Potez Marine , Liu James 
Published: November 2021

Abstract

OBJECTIVE
Metastatic brain tumors (MBTs) are the most common type of malignant brain tumors. Due to the deviation of MBTs from the parental tumors, the effective therapies for primary tumors often are not useful in brain metastases. Even more new intracranial lesions were developed though the primary lesion was under control. The model of brain metastatic stem-like cells (BMSCs) could partially explain the progression of intracranial lesions. Here we aimed to explore the biological behavior in cell motility of BMSCs and understand the potential mechanisms.

METHODS
In vitro and in vivo phage display biopanning strategies were used to isolate dodecapeptides that specifically target BMICs by selecting against primary lung cancer cells and normal brain cells. In silico analysis was used to derive specific protein targets in BMICs. Potential targets were narrowed down through analysis in patient databases and verified for their presence in BMIC through RT-PCR. Cell migration and adhesion in BMICs were analyzed using Transwell, scratch, and adhesion assays. Protein expression and cell morphology were detected by immunofluorescence. Immune blot was performed to detect the epithelial-mesenchymal related molecules and explore protein-protein interactions.

RESULTS
In silico analysis of BMSCs specific peptides revealed Angiomotin (Amot) as a potential target in BMSCs. Amot was found to be overexpressed in BMSCs compared to primary lung cancer cells. Kaplan-Meier analysis demonstrated Amot was negatively correlated with overall survival among lung adenocarcinoma patients. Functionally, knockdown of AMOT in BMSCs decreased the capability of cell migration and adhesion by reduced active Cdc42/Rac1 signals caused by downregulation of E-Cadherin. Amot was found to maintain the E-Cadherin in BMSCs through reducing ubiquitination of E-Cadherin.

CONCLUSIONS
Amot plays a role in promoting migration and adhesion in BMSCs through preservation of E-cadherin.
STEM-07. PRC2 MAINTAINS A CANCER STEM CELL PHENOTYPE IN GLIOBLASTOMA MULTIFORME VIA CHROMATIN MODIFICATION OF H3K27me3
Authors: Korleski Jack , Shudir Sweta , Caputo Christopher , Lal Bachchu , Rui Yuan , Green Jordan , Lopez-Bertoni Hernando , Laterra John 
Published: November 2021

Abstract
Multi-potent stem-like cells (i.e. cancer stem cells, CSCs) are critical determinants of tumor propagation, therapeutic resistance, and recurrence in glioblastoma (GBM). Modifications in chromatin architecture play a fundamental role in the tumor cell phenotype of GBM. The polycomb repressor complex 2 (PRC2) is a key histone modifier that supports multi-potency and oncogenesis via H3K27 trimethylation (H3K27me3). Understanding how these epigenetic modifications cooperatively drive cancer cell stemness should unveil new targets for therapeutic development in GBM. Using a combination of next-generation sequencing, bioinformatics, and molecular approaches we identified EZH2, the catalytic domain of the PRC2 complex, as a critical mediator of reprograming events in GBM cells. We found that EZH2 is highly induced in response to transgenic Oct4/Sox2 with global increases in H3K27me3. Pharmacological inhibition of EZH2 diminishes self-renewal capacity of GBM neurospheres concurrent with a reduction in gene expression levels of markers and drivers of stemness. Furthermore, we identified and validated a set of 6 putative tumor suppressor genes repressed by Oct4 and Sox2 in a PRC2-dependent manner. We identified miR-217 as an EZH2 regulator in GBM cells and miR-217 reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed tumor suppressors, inhibited tumor growth and enhanced the effects of ionizing radiation in an orthotopic model of GBM. Taken together, these data show that PRC2-mediated chromatin changes in H3K27me3 help regulate the stem-cell phenotype induced by Oct4 and Sox2 in GBM cells and predict that targeting EZH2 could have therapeutic benefit in GBM.