bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-22. EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AS A MOLECULAR DETERMINANT OF GLIOBLASTOMA RESPONSE TO DOPAMINE RECEPTOR 2 (DRD2) INHIBITORS
Authors: He Yuyu , Li Jie , Koga Tomoyuki , Ma Jun , Dhawan Sanjay , Suzuki Yuta , Furnari Frank , Prabhu Varun , Allen Joshua , Chen Clark 
Published: December 2020

Abstract

BACKGROUND
There are ongoing clinical trials exploring the efficacy of dopamine receptor 2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy.

METHODS
The Cancer Genome Atlas (TCGA) glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and EGFR expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201, a DRD2 inhibitor.

RESULTS
Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, EGFRvIII, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (p = 0.037).

CONCLUSIONS
High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.
BIOM-23. MOLECULAR PROFILING IDENTIFIES NOVEL BIOMARKERS IN A RURAL COHORT OF PATIENTS WITH GLIOBLASTOMA
Authors: Bystrom Rebecca , Craig Wendy , Rueter Jens , Lu-Emerson Christine 
Published: December 2020

Abstract

BACKGROUND
The rural state of Maine has one of the highest incidences of primary malignant brain cancer in the United States. We sought to investigate the genomic landscape of glioblastoma (GBM) in Maine.

METHODS
Targeted next generation sequencing of 209 cancer related genes was performed on tumor samples from 60 patients diagnosed with GBM at our institution between 2014 and 2019. We compared mutation frequencies between patients grouped according to the published median overall survival for GBM: &lt; 14 months (n = 14) and ≥ 14 months (n = 43, including 23 patients still alive). We excluded patients who were alive but diagnosed less than 14 months prior to analysis (n = 3).

RESULTS
Across all groups frequent molecular markers included EGFR (49%), TP53 (38%), CDKN2A (17.5%), PIK3R1 (15.8%), PDGFRA (12.2%), PIK3CA (10.5%), PTEN (19%), NF1 (10.5%) and IDH1/2 (10%); frequencies did not differ significantly between groups. MGMT methylation was similar between groups (6/14 (42.9%) in shorter survivors and 18/41 (43.9%) in longer survivors). FANC group mutations were more frequent in longer survivors (13/43 [30%] versus 0/14 [0%], p = 0.025). Among shorter survivors CDKN2A deletions were slightly more frequent (5/14 (45%) versus 5/43 (11%), p = 0.099). FES, KIAA1524, FLT (all 5/43,11.6%) and EPH (6/43, 14.0%) were only observed in longer survivors. These mutations co-occurred with 4/5 CDKN2A deletions in longer survivors. After excluding those 4 cases, CDKN2A deletions were significantly associated with shorter survival (5/14 [35.7%] versus 1/39 [2.6%]), p=0.004.

CONCLUSION
FANC group mutations may be a novel prognostic biomarker for longer survival in a rural cohort with GBM. CDKN2A deletions may be associated with shorter survival, but this may be ameliorated by co-occurring FES, KIAA1524, FLT, and EPH mutations.
BIOM-33. LOW EXPRESSION OF DYNLT3 PREDICTS BETTER PROGNOSIS FOR FEMALE GLIOBLASTOMA PATIENTS
Authors: Hu Yuanjun , Wang Jing , Chen Zhong-ping 
Published: December 2020

Abstract

BACKGROUND
Glioblastoma (GBM) is the most malignant tumor in the central nervous system. It has been confirmed that the prognosis of GBM has obvious gender predilection. As female patients have an advantage than males, it is increasingly accepted to take gender into account while treating GBM. Therefore, it is important to figure out molecular mechanisms related to gender predilection.

METHODS
We first analyzed the protein expression of GBM (Male=24, Female=16) based on the dataset from Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute’s（NCI）and mainly focused on those differential expression proteins between males and females on X chromosome. Then the differentially expressed genes from CPTAC was further confirmed in TCGA data and their role in the overall survival of GBM patients were analyzed.

RESULTS
18 proteins, differentially expressed between male and female were selected. 12 out of them expressed higher in female while the other 6 were higher in male (P&lt; 0.05). We found one protein, DYNLT3 might be a predictor for GBM patients’ survival through analyzing the transcriptome profiling database of TCGA. The low expression of DYNLT3 was related to a longer survival of female group. The median survival was 556 days (95% CI, 446 to 665) with lower expression level of DYNLT3, compared with 375 days (95% CI, 291 to 459) in higher expression group (P=0.011 by log-rank test) in all cases including both male and female. For female group, the median survival was 653 days (95% CI, 464 to 842) with lower expression of DYNLT3, which was much better than 305 days (95% CI, 379 to 642) (P=0.008) with higher expression of DYNLT3. No significant predicting value of DYNLT3 expression was found in male group.

CONCLUSIONS
The expression of DYNLT3 might be a positive predictor for survival of GBM patients, especially for female cases.
BIOM-38. PI3K/AKT/mTOR SIGNALING PATHWAY ACTIVITY IN IDH-MUTANT DIFFUSE GLIOMA
Authors: Mohamed Esraa , Kumar Anupam , Hilz Stephanie , Wang Albert , Shai Anny , Taylor Jennie , Clarke Jennifer , Molinaro Annette , Lee Julieann , Costello Joseph , Solomon David , Phillips Joanna 
Published: December 2020

Abstract
PI3K/AKT/mTOR signaling pathway activation is a common mechanism of tumor progression in diffuse lower grade glioma. Robust and accurate biomarkers are needed to stratify patients for therapies targeting this pathway. To investigate the potential of phosphoprotein quantification to provide a direct and functional pathway readout, we analyzed 90 tumors from 83 patients with IDH-mutant diffuse glioma. The cohort comprised 50 IDH-mutant astrocytomas, 40 IDH-mutant and 1p/19q-codeleted oligodendrogliomas, 7 of whom had paired samples from initial diagnosis and recurrence. We developed and validated a pipeline using multiplex immunofluorescence to quantify tumor cell-specific phospho-protein expression of 3 pathway nodes, ribosomal protein S6 (RPS6), PRAS40, and 4E-BP1. In oligodendroglioma the fraction of tumor cells expressing each of the three phosphorylated proteins increased with tumor grade (p&lt; 0.05). Comparing tumors at initial diagnosis (n=48) and at recurrence (n=42), p-RPS6 and p-PRAS40 increased in tumor cells (p&lt; 0.05) and there was an overall increase in intertumoral heterogeneity of signaling activity at recurrence (p&lt; 0.04). Analysis of paired samples demonstrated increased signaling pathway activity in a subset at recurrence. Robust signaling activity, defined as a phospho-positive tumor cell fraction ≥ median for all three phosphoproteins, was identified in 71.4% of grade 3 IDH-mutant astrocytoma(5/7) and 45.4% of grade 3 IDH-mutant, 1p/19q-codeleted oligodendroglioma(5/11). In a subset of cases analyzed by targeted NGS, robust signaling pathway activity was identified in 38%(11/29) at the protein level while genetic alterations predicted to activate the pathway were present in only 17.2% (5/29). Our results demonstrate robust PI3K/AKT/mTOR signaling activity in a significant fraction of IDH-mutant diffuse glioma, an association with increasing tumor grade in oligodendroglioma, and an increase at recurrence in both oligodendroglioma and astrocytoma. Overall, our data suggest that quantitative evaluation of phosphoproteins may be a sensitive method to detect PI3K/AKT/mTOR pathway activity and may be useful for patient stratification.
BIOM-47. LONGITUDINAL MONITORING OF PLASMA H3K27M IN DIFFUSE MIDLINE GLIOMA PATIENTS TREATED WITH ONC201
Authors: Tarapore Rohinton S , Field Amanda , Hill D Ashley , Allen Joshua 
Published: December 2020

Abstract
Diffuse midline glioma, H3 K27M-mutant (DMG) is a 2016 WHO Grade IV glioma that has no established treatment beyond first-line radiation. ONC201 is an investigational small molecule that has been shown to be clinically active in recurrent DMG clinical trials. While biopsies of DMG are sometimes feasible, many patients defer secondary to complication risk. MR scans have many limitations in monitoring DMG progression, including distinguishing pseudoprogression and pseudoresponse and measuring diffuse lesions that often do not contrast enhance. Digital droplet PCR (ddPCR) is capable of sensitively detecting and quantifying the allelic frequency of circulating-tumor DNA (ctDNA) fragments against a backdrop of non-tumor DNA. Using sequence-specific probes for H3F3A (H3.3 K27M) and HIST1H3B (H3.1 K27M) ddPCR detects very low frequency variants and provides an assessment of mutational burden. A pilot cohort of 5 patients treated with ONC201 who had a range of outcomes were assessed with serial ctDNA analyses. Two patients with immediately progressive disease had a concordant H3 K27M ctDNA increase that precedes radiographic detection by 4 weeks. Two patients with &gt;50% tumor regressions while on ONC201 had concordant H3 K27M ctDNA burden at the onset of response and subsequent radiographic progression was preceded by increases in ctDNA 8–16 weeks prior. One patient who had prolonged stable disease had decreased H3 K27M ctDNA burden over time. Upon radiographic progression, the addition of bevacizumab with ONC201 caused a radiographic pseudoresponse, however H3 K27M ctDNA remained stable. These pilot results suggest H3 K27M ctDNA may be a sensitive and accurate biomarker of disease burden. Longitudinal evaluation of H3 K27M ctDNA in a cohort of 34 recurrent contrast-enhancing H3 K27M-mutant glioma patients while on ONC201 will be reported. Primary tumor locations range across the thalamus, cerebellum, basal ganglia, temporal lobe, and midbrain; median age is 31 years old (range 20–70).
BIOM-49. SERUM microRNA IS A PROGNOSTIC AND POST-OPERATIVE MONITORING BIOMARKER IN GLIOMA
Authors: Jones Jordan , Morokoff Andrew , Drummond Kate 
Published: December 2020

Abstract
Although magnetic resonance imaging (MRI) provides accurate anatomical and spatial details regarding gliomas, it is not reliable at predicting biological behaviour and is confounded by problems such as pseudo-progression. A circulating biomarker has potential to improve predictions of glioma outcomes and identify tumor progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA (miRNA) serum biomarker for longitudinal monitoring of glioma patients as well as identify miRNAs that are predictive of survival outcomes. To investigate this a prospectively collected cohort of 91 gliomas and 17 healthy controls underwent pre- and post-operative serum miRNA profiling using the next-generation sequencing platform Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow-up samples and compared to tumor volume based on MRI. A lasso-regression model was used to identify candidate miRNAs from pre-operative serum that were associated with both progression-free and overall survival. We identified a 9-gene miRNA signature that could distinguish between glioma and healthy controls with 99.8% accuracy. From this signature, we identified two miRNAs that demonstrated dynamic changes which correlated closely with tumor volume in both LGG and GBM. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. Additionally, altered expressions of 6 miRNAs were found to be associated with overall and progression-free survival and were incorporated in a predictive model with already known survival factors. In conclusion, we have identified a highly accurate 9-miRNA signature associated with glioma serum and observed specific miRNAs that both correlated with tumor volume over long-term follow up and were predictive of survival. These results support a large prospective validation study of serum miRNA biomarkers in glioma.
BIOM-50. GENETIC PREDISPOSITION TO LONGER TELOMERE LENGTH AND RISK OF CHILDHOOD, ADOLESCENT AND ADULT-ONSET EPENDYMOMA
Authors: Zhang Chenan , Ostrom Quinn , Semmes Eleanor , Ramaswamy Vijay , Hansen Helen , Morimoto Libby , de Smith Adam , Pekmezci Melike , Vaksman Zalman , Hakonarson Hakon , Diskin Sharon , Metayer Catherine ,   The Glioma International Case Control Consortium, Taylor Michael , Wiemels Joe , Bondy Melissa , Walsh Kyle 
Published: December 2020

Abstract

INTRODUCTION
Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. Telomerase reactivation in somatic cells has been linked to ependymoma progression, recurrence, and survival, and has been implicated as an important prognostic marker and potential therapeutic target.

METHODS
To investigate whether inherited predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: 1) a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), 2) a hospital-based pediatric posterior fossa type A ependymoma (EPN-PF-A) case-control study from Toronto’s Hospital for Sick Children and the Children’s Hospital of Philadelphia (83 cases, 332 controls), and 3) a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). We investigated the individual effect of telomere-length associated SNPs on ependymoma risk, as well as the combined effect of these SNPs through polygenic score and Mendelian randomization analyses.

RESULTS
We observed an association between genetic predisposition to longer LTL and increased risk of adolescent-onset (P= 3.97x10-3) and adult-onset (P =0.042) ependymoma, but not ependymoma diagnosed in children &lt; 12 years old (P=0.21), or among the pediatric EPN-PF-A sample (P=0.59). Comparing ependymoma patients ages 12–19 to those under 12 years of age demonstrated that age significantly modified the association between longer telomere length and ependymoma risk (P=0.021).

CONCLUSIONS
These findings complement emerging literature suggesting that dysregulated telomere maintenance is important for ependymoma pathogenesis and that longer telomere length is a risk factor for various neoplasms of the peripheral and central nervous system.
BIOM-51. FACTORS ASSOCIATED WITH DECLINING SEX DISCREPANCY IN MENINGIOMA WITH INCREASING TUMOR AGGRESSIVENESS: RETROSPECTIVE REVIEW OF A RURAL PENNSYLVANIA COHORT
Authors: Sofoluke Richard , Chu Sally , Bross Shane , Gatson Na Tosha 
Published: December 2020

Abstract

INTRODUCTION
Meningioma is the most common benign primary brain tumor in adults comprising 37% of all primary CNS tumors. Approximately 81.1% of meningiomas are grade I, 16.9% - grade II, and 1.7% - grade III. While females are 2.5 times more likely to have meningiomas, males more commonly have aggressive grades. Loss of progesterone receptor (PR) and presence of androgen receptor (AR) are associated with tumor aggressiveness. We observed a declining sex-discrepancy with increasing tumor grade. We present an ongoing assessment of a rural population to define potential factors contributing to this observation.

METHODS
We completed a single institutional retrospective review of 406 pathology confirmed meningiomas in rural Northeast Pennsylvania. We compared WHO grade, hormone receptors, and proliferative indices between males and females. We further evaluated tumor location and comorbid endocrine disease for possible association.

RESULTS
Our patient cohort had a high frequency of aggressive tumors 73.5% (n= 297) grade I, 24% (n= 99) grade II, and 2.5% (n= 10) grade III. The ratio of females versus males was 3.1:1, 1.3:1, and 1:1 in grades I, II, and III respectively. Factors contributing to closing the sex-gap were: (1) grade II: males expressed less PR than females (76% vs 94%); (2) grade III: females expressed less AR than males (0% vs 100%), while PR expression remained equivalent; and (3) males had higher tumor proliferative indices compared to females (7% and 22% vs 2% and 14%), grades I and II respectively. There was no relationship determined for tumor location or comorbid endocrine disease between the sexes.

CONCLUSION
The association between declining sex discrepancy in meningioma with increasing tumor aggressiveness is potentially related to the expression PR, AR, and increased tumor proliferation indices with increasing meningioma grade.
BIOM-53. DIFFUSION MR IMAGING DERIVED APPARENT DIFFUSION COEFFICIENT AS A POTENTIAL BIOMARKER OF CLINICAL OUTCOME IN RECURRENT CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Ho Ka-wai , Nosov Anton , Young Robert , Grommes Christian 
Published: December 2020

Abstract

BACKGROUND
Studies have shown that diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) measurements inversely correlate with tumor cell density and may have prognostic value in newly-diagnosed CNS lymphoma patients. This study characterizes ADC measurements in a relapsed/refractory CNS lymphoma population and describes the potential prognostic value of ADC measurements in these patients.

METHODS
ADC measurements were assessed in immunocompetent patients enrolled on a prospective clinical trial studying ibrutinib-based treatment in recurrent/refractory CNS lymphoma (NCT02315326; 42 treated with single agent ibrutinib and 15 with an ibrutinib containing combination). Measurements were normalized to values contralateral to the lesion to generate an ADC measurement ratio. Imaging and clinical variables were correlated with treatment response. High-quality lesions were defined as areas with clear delineation from preserved brain parenchyma ≥ 10mm in maximal transverse dimension. Cerebral spinal fluid (CSF) was collected at time of MR imaging in all patients.

RESULTS
Thirty-nine out of 57 patients had lesions with measurable ADC of which 17 (44%) were high-quality ADC lesions. The median ADCmean ratio was 0.909 (range 0.497–1.444). There was no association between ADC ratios and tumor volume, CSF cell count, or CSF protein. The high-quality lesions had a median ADCmean ratio of 0.774 (range 0.497–1.051). These patients with a high ADCmean ratio (≥ 0.774) had increased rates of partial and complete responses (p=0.057) as well as a longer progression free survival (PFS; median not reached) compared to those with low ADCmean ratios (&lt; 0.774; median PFS=1.5 months, p=0.016).

CONCLUSION
ADC ratios in the recurrent CNS population do not correlate with tumor size, cell count, or protein in the CSF. In high-quality DWI measurements, ADC might be a prognostic marker in relapsed/refractory CNS lymphoma patients treated with ibrutinib.
CBIO-07. CELL DEATH INDUCED BY AN OSCILLATING MAGNETIC FIELD IN PATIENT DERIVED GLIOBLASTOMA CELLS IS MEDIATED BY REACTIVE OXYGEN SPECIES
Authors: Hambarde Shashank , Sharpe Martyn , Baskin David , Helekar Santosh 
Published: December 2020

Abstract
Noninvasive cancer therapy with minimal side effects would be ideal for improving patient outcome in the clinic. We have developed a novel therapy using strong rotating magnets mounted on a helmet. They generate oscillating magnetic fields (OMF) that penetrate through the skull and cover the entire brain. We have demonstrated that OMF can effectively kill patient derived glioblastoma (GBM) cells in cell culture without having cytotoxic effects on cortical neurons and normal human astrocytes (NHA). Exposure of GBM cells to OMF reduced the cell viability by 33% in comparison to sham-treated cells (p&lt; 0.001), while not affecting NHA cell viability. Time lapse video-microscopy for 16 h after OMF exposure showed a marked elevation of mitochondrial reactive oxygen species (ROS), and rapid apoptosis of GBM cells due to activation of caspase 3. Addition of a potent antioxidant vitamin E analog Trolox effectively blocked OMF-induced GBM cell death. Furthermore, OMF significantly potentiated the cytotoxic effect of the pro-oxidant Benzylamine. The results of our studies demonstrate that OMF-induced cell death is mediated by ROS generation. These results demonstrate a potent oncolytic effect on GBM cells that is novel and unrelated to any previously described therapy, including a very different mechanism of action and different technology compared to Optune therapy. The effect is very powerful, and unlike Optune, can be seen within hours after initiation of treatment. We believe that this technology holds great promise for new, effective and nontoxic treatment of glioblastoma.
CBIO-09. INTRATUMORAL HETEROGENEITY OF DIELECTRIC PROPERTIES IN GLIOBLASTOMA
Authors: Proescholdt Martin , Haj Amer , Doenitz Christian , Schmidt Nils Ole , Bomzon Zeev 
Published: December 2020

Abstract

INTRODUCTION
Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dielectric properties of GBM by analyzing resected tissue following a fast acquisition protocol. To account for the intratumoral heterogeneity, different regions of the tumor were analyzed separately.

METHODS
A cohort of 38 patients with newly diagnosed GBM were analyzed. Tissue probes were acquired from the vital tumor area and perinecrotic compartment. The tissue was measured immediately to avoid artifacts. A fragment was dissected from each tissue sample and was placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz using a software specifically developed for this study, which controls the LCR meter. The measured impedance was translated into dielectric properties of the sample (conductivity and relative permittivity) based on the parallel plate model, the recorded complex impedance and the geometry of the samples. Each tissue probe was fixed, and stained with H&E to visualize cellularity, luxol fast blue to analyze the myelinated fiber content and against factor VIII related antigen to assess tumor vascularity.

RESULTS
We found significant differences between the conductivity and permittivity of tissue samples from each individual tumor (mean conductivity [S/m]: 0.302; range: 0.607 – 0.100; mean permittivity [Farad/m]: 3519.8; range: 11182.5 – 135.7). Consistently, the perinecrotic areas displayed lower conductivity values compared to the solid tumor compartments. Histological analysis revealed significantly higher cellularity and lower myelinated fiber content in tissue samples with high conductivity and permittivity.

CONCLUSION
The dielectric properties of GBM show a high intratumoral heterogeneity which correlate to the extent of cellularity and myelin fiber content within the tissue.