bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-08. IL13RA2 AS A LIQUID BIOPSY BIOMARKER FOR NERVOUS SYSTEM TUMORS
Authors: Khristov Vladimir , Nesterova Darya , Patel Neel , Smith Nataliya , Shenoy Ganesh , Zacharia Brad , Harbaugh Kimberly , Rizk Elias , Connor James 
Published: November 2022

Abstract
While tumors of the nervous system (NS) are rare, they contribute to significant morbidity and mortality. Despite advances in imaging technology, initial diagnosis and characterization of treatment response remains problematic for devastating tumors such as glioblastoma (GBM). A liquid biopsy can provide a minimally-invasive and serial source of biomarkers to supplement current diagnostic methods. Here, we utilize a unique characteristic of NS tumors including GBM and schwannoma/neurofibroma – the overexpression of the a2 variant of the IL-13 receptor which is not detectable in normal tissue. Previously, we have shown that IL13Ra2 is elevated in the plasma of some GBM patients above baseline levels. We hypothesize that the presence of circulating IL13Ra2 not only predicts the level of this receptor in the tumor tissue, but also has clinical prognostic value. Here, we used ELISA to measure the plasma levels of IL13Ra2 in the GBM (n=77) and schwannoma/neurofibroma (n=15) patients and correlated these levels to tumor levels, diagnosis, and clinical characteristics. We have demonstrated that elevated levels of plasma IL13Ra2 correlated with tumor presence compared to non-tumor controls for both GBM and schwannoma/neurofibroma patients, indicating this biomarker’s diagnostic utility. Further, for both GBM and schwannoma/neurofibroma patients the plasma concentration of IL13Ra2 is correlated to its tumor concentration, indicating that sampling patient plasma could provide insight into the tumor’s composition. Finally, elevated levels of IL13Ra2 protein in the tumor and plasma of GBM patients predicted longer patient survival. These exciting findings lay the groundwork for a plasma-based NS tumor liquid biopsy.
BIOM-09. GUIDING PRECISION THERAPEUTICS THROUGH INTERROGATING ONCOGENIC PATHWAY ACTIVATION
Authors: Nobre Liana , Levine Adrian , Milos Scott , Johnson Monique , Laxer Ben , Ryall Scott , Bennett Julie , Ku Michelle , Siddaway Robert , Tabori Uri , Hawkins Cynthia 
Published: November 2022

Abstract
The deregulation of canonical oncogenic pathways are largely responsible for driving pediatric cancers and can be targeted for therapeutics. Currently, we interrogate these pathways clinically by looking for gene mutations, but these are not found in all cases, and in others multiple genes are. We hypothesized that assessing transcriptomic and proteomic-based pathway activation will allow a better understanding of the most active oncogenic pathways and help guide therapy. To do this, we developed and validated a nanostring based assay that interrogates 4 key actionable pathways (MAPK, PI3K-AKT-mTOR, JAK-STAT, and NFkB) including RNA, protein and phosphoprotein expression. The assay was clinically validated using isogenic cell lines and a cohort of 40 gliomas with previous RNAseq. We then interrogated over 400 tumor samples, including 15 ependymomas, 11 medulloblastomas, 250 low grade gliomas (LGG), 145 high grade gliomas and 10 control normal brain specimens. Interestingly, although pediatric LGG exhibited higher MAPK activation than control tissue and other tumor types, a subset of these tumors have increased activity in PI3K , JAK and NFKB pathways. Furthermore, high PI3K activation score was correlated with worse PFS in a subset of pediatric LGGs that required adjuvant chemotherapy (p=0.018). To further explore the therapeutic implication of the assay, we analyzed a cohort of patients treated with MEK inhibitors (n=20). Strikingly, on top of universal RAS/MAPK activation, crosstalk between additional activated pathways such as PI3K and JAK-STAT may contribute to lack of response. In particular, pre-treatment and post-progression PLGG who failed therapy, revealed mild reduction in MAPK signature accompanied by increased PI3K phospho-proteins (p-S6/p-4EBP1,p-AKT)(p&lt; 0.01). We conclude that assessing oncogenic pathway activation can add to DNA sequencing to predict different outcome and response to targeted therapies in childhood brain tumors. This can inform future therapeutic strategies including the identification of potential responders and combination strategies for non-responders.
BIOM-19. NEXT-GENERATION SEQUENCING (NGS) FOR IDENTIFYING ACTIONABLE MOLECULAR ALTERATIONS IN NEWLY DIAGNOSED AND RECURRENT IDHWT-GLIOBLASTOMA (GBM) PATIENTS: A LARGE MONO INSTITUTIONAL EXPERIENCE
Authors: Padovan Marta , Maccari Marta , Bosio Alberto , Vizzaccaro Salvatore , Cestonaro Ilaria , Corrà Martina , Caccese Mario , Cerretti Giulia , Fassan Matteo , Zagonel Vittorina , Lombardi Giuseppe 
Published: November 2022

Abstract

BACKGROUNDNGS
panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment.

METHODS
From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOne®CDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase.

RESULTS
We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of newly diagnosed and recurrent GBM samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing.

CONCLUSIONNGS
is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples.
BIOM-20. IDENTIFICATION OF BLOOD BIOMARKERS FOR DIFFERENTIATING PSEUDOPROGRESSION FROM RECURRENCE IN GLIOBLASTOMA
Authors: Nakada Mitsutoshi , Ohtsuki Sumio , Uchida Yasuo , Nakajima Riho , Sabit Hemragul , Tamai Sho , Ichinose Toshiya , Kinoshita Masashi ,   team BIRD-DOG
Published: November 2022

Abstract
After the initial treatment of glioblastoma, we occasionally encounter difficulty in distinguishing between pseudoprogression and recurrence. Observation without obtaining a pathological diagnosis is a common strategy in clinical practice. If the differentiation can be achieved easily, and reliably, early treatment can be introduced appropriately, leading to the benefits of early glioblastoma treatment. In this study, we attempted to identify blood biomarkers that help distinguish between recurrence and pseudoprogression. Blood samples were collected in 25 cases of primary glioblastoma, IDH wild type, at three time points: before treatment, after standard treatment: operation and temozolomide chemotherapy with concomitant radiation therapy, and when an enhancing lesion was recognized (21 cases of recurrence, 4 cases of pseudoprogression). Gelsolin (GSN), Apolipoprotein A-IV, Osteopontin, SERPINA3, ITIH2/4 Ceruloplasmin, LRG1, Collagen-1A2, which we previously extracted as diagnostic markers, using the comprehensive proteomics SWATH method, in blood samples of healthy volunteers and patients with glioblastoma (PLoS One. 2018, J Proteome Res. 2020), were analyzed. Absolute quantitative values of candidate molecules in the blood were obtained using a commercially available enzyme-linked immunoassay. Among the candidate molecules, GSN was significantly lower in pseudoprogression than in recurrence (p = 0.0032), and ROC analysis showed sensitivity of 95%, specificity of 100%, and an AUC = 0.98, which makes GSN a useful molecule to consider as a differential marker. We previously reported that GSN, actin binding protein, and inflammation markers are downregulated in glioblastoma (Cancer Sci. 2020). In summary, GSN was extracted as a candidate blood biomarker for the diagnosis of pseudoprogression. We are planning to validate the research with nationwide multi-institutional studies.
BIOM-28. AN EXOSOME BASED LIQUID BIOPSY DIAGNOSTIC FOR GLIOMA
Authors: Ray Amit , Lath Rahul , Reddy Madhan , Ippili Kaushal , Ratnam Boola , Vohra Tarang , Reddy Arjun , Prasad Brahma , Ranjan Alok , Reddy Rajesh , Panigrahi Manas , Rao Venkateshwara , Balasubramanium Anandh , Kaur Inderjeet 
Published: November 2022

Abstract

BACKGROUND
Liquid biopsy has gained popularity of late in the diagnosis and management of several cancers. This study aims to diagnose suspected lesions suspected of being gliomas on neuro-imaging by obtaining a peripheral venous blood sample- with a specificity and sensitivity that approaches a tissue biopsy. MATERIALS AND

METHODS
After clearance from Ethics Committees, specimens of the tumour tissue along with blood from a peripheral or vein was collected from all 80 adult patients with a suspected diagnosis of glioma. Clinical details along with the neurological status, the functional score, the extent of resection, pathological diagnosis and survival data were also collected. The tumour tissue transported in RNA-later and stored at -80C. Following exosome isolation, RNA-seq was performed on the exosomal sample obtained from the serum and the tumour sample. Exome analysis was performed on the tumour tissue (somatic mutations) and the WBC (for germline mutations) to a depth of 100.

RESULTS
The analysed data was quality checked for all glioma associated genes including but not limited to ATRX, H3F3A, IDH1, MGTM and TERT driver genes related to DNA repair, cytoskeleton and cellular proliferation-related genes EGFR, FLT1/(VEGFR), BRAF, GFAP, MKi67, NES, OLIG2, PIK3CA, SMAD3, S1001A and VIM and tumour suppressor genes SMARCB1/INI1 and TP53. Open-source cloud based genomic analysis platforms were used for analysis. Machine learning clustering algorithms identified serum exosome based clusters that corresponded to already identified glioma tissue based genomic subgroups, with specificity and sensitivity approaching 95%.

CONCLUSION
Liquid biopsies provide a reliable and effective way of diagnosing gliomas in patients who present with an intracranial lesion on radiology.
BIOM-33. TEMPORAL HETEROGENEITY OF DNA METHYLATION SUBCLASSES BETWEEN MATCHED NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA
Authors: Drexler Richard , Schüller Ulrich , Eckhardt Alicia , Sauvigny Thomas , Ricklefs Tammo , Bode Helena , Khatri Robin , Hausmann Fabian , Hänzelmann Sonja , Huber Tobias , Bonn Stefan , Lamszus Katrin , Westphal Manfred , Dührsen Lasse , Ricklefs Franz 
Published: November 2022

Abstract
Spatiotemporal heterogeneity is a major factor contributing to the devastating prognosis of isocitrate-dehydrogenase (IDH)-wildtype glioblastoma. Genome-wide DNA methylation profiling allows the stratification into several DNA methylation subgroups of IDH-wildtype glioblastoma, which were shown to have a spatial heterogeneity in newly diagnosed tumors. However, the temporal heterogeneity and its clinical relevance of DNA methylation subgroups remains inconclusive. Tumor tissue obtained from first and recurrence surgery of 31 patients diagnosed with IDH-wildtype glioblastoma was subjected to DNA methylation profiling. DNA methylation profiles were analyzed for temporal heterogeneity and correlated with clinical data, survival outcome and copy number variations. In addition, deconvolution of immune cells and unsupervised hierarchical clustering using pairwise Pearson correlation coefficients of the 10.000 most variable CpG features was performed. Of all patients with matched tumor tissue, 4 (12.9%) patients had a non-matching brain tumor classifier output at recurrence. Within the remaining 27 patients, a transition of the dominant DNA methylation subclass was observed in 8 (29.6%) glioblastomas with a most frequent transition to the mesenchymal subclass (62.5%). A subclass transition was more likely after incomplete removal of contrast-enhanced tumor parts at first surgery (p = 0.04). Tumor location, adjuvant treatment, and time between primary and recurrence surgery did not influence the transition. Immune cell proportions from deconvolution data, tumor purity or specific CpG sites were not correlated with a subclass transition. Survival analyses revealed a comparable outcome for patients with or without subclass transition. Our findings demonstrate the temporal heterogeneity of DNA methylation subclasses in 29.6% of IDH-wildtype glioblastoma. We identified clinical factors and showed that a subclass transition did not impact the survival outcome. However, a possible DNA methylation subclass transition must be taken into consideration for future targeted therapies at recurrence.
BIOM-40. COMPARATIVE STUDY OF INFLAMMATORY MARKERS IN THE CEREBROSPINAL FLUID OF PATIENTS WITH GLIOMA AND CENTRAL NERVOUS SYSTEM MALIGNANT LYMPHOMA
Authors: Sasayama Takashi , Tanaka Kazuhiro , Nagashima Hiroaki , Fujita Yuichi , Iwahashi Hirofumi , Kodama Yoshinori , Nishihara Masamitsu 
Published: November 2022

Abstract

INTRODUCTION
Cytokines in the cerebrospinal fluid (CSF) are useful as markers for primary central nervous system malignant lymphoma (PCBSL). However, there are few reports of CSF markers in glioma. We analyzed and examined glioma and PCNSL CSF inflammation-related mediators.

MATERIALS AND METHODS
The patients with glioma and PCNSL who were operated on at Kobe University between 2006 and 2017 and whose histology was diagnosed, and whose CSF was stored at -80 °C before treatment. Using Bio-Plex Pro Human Inflammation Assays (Bio-Rad Laboratories, Inc.), 37 types of inflammation-related molecules such as TNF superfamilies, interferonss, and Interleukines were measured and compared with glioma and PCNSL.

RESULTS
The subjects were 53 glioma patients and 24 PCNSL patients. There were 22 types of significant differences between glioma and PCNSL, 18 with high PCNSL and 4 with high glioma. In addition to IL-10, which has been reported so far, the significant higher concentrations in PCNSL was found in Osteopontin, TNFSF8, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, sTNF-R1, sTNF-R2, IL-6Ra, IL-8, IL-12(p40), IL-20, IL-27, sCD163, MMP2, MMP3, CHI3L1. On the other hand, IL-2, Il-12(p70), IL-22, and MMP-1 levels were significant higher in CSF in glioma. Although CD163 is an important molecule as a marker for M2 macrophages, immunostaining of tissues showed no significant difference in infiltration between Glioblastoma and PCNSL. This suggests that M2 macrophages infiltrating PCNSL and Glioblastoma have different activation states.

CONCLUSION
PCNSL had higher levels of inflammatory mediators such as TNF-related molecules. PCNSL was significantly higher in sCD163 than in glioblastoma, suggesting different activation of intratumoral M2 macrophages.
BIOM-41. IDENTIFICATION OF GLIOMA CELLS BY PROFILING SINGLE-CELL BIOPHYSICAL PROPERTIES THROUGH MULTICONSTRICTION MICROFLUIDIC CHANNELS
Authors: Ren Xiang , Ji Hongming , Geng Xin 
Published: November 2022

Abstract
This study introduces a multicontraction microfluidic channel that can differentiate glioma cells from normal glio cells. As cells pass through successive constriction channels, the incremental velocity and varying size profiles of the cells will be collected, reflecting their biophysical properties. The data of high-dimensional variables were analyzed , including the cell sizes, velocities, and velocity increments. The prediction value is used to represent the difference between two groups using the established classification model from high-dimensional variables. At the same time, we prepared three groups of primary tumor cells from patients with different grades of glioma to verify the efficacy of this classification method. The results show that in this microfluidic channel, the diagnostic model made of cell biophysical properties can well identify glioma cells, which gives a novel method for efficient identification of circulating tumor cells and rapid pathological diagnosis.
BIOM-49. A PILOT STUDY OF CEREBROSPINAL FLUID EXOSOMAL SMALL RNA-SEQUENCING IN PEDIATRIC MEDULLOBLASTOMA PATIENTS ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL
Authors: Bell Erica , Webb Amy , Stanek Joseph , Blue Megan , Patel Parth , Thomas Diana , Pierson Christopher , Mladkova Nikol , Fleming Jessica , Miller Katherine , Grischow Olivia , Liszkay Thomas , Olshefski Randall , Chi Susan , Comito Melanie , Friedman Gregory , Bendel Anne , Coven Scott , Hastings Caroline , Sayour Elias , Garvin James , Davidson Tom , Cornelius Albert , Moertel Christopher , Mazewski Claire , Walter Andrew , Greiner Robert , Puccetti Diane , Gorsi Hamza , Dorris Kathleen , Khatib Ziad , Chakravarti Arnab , Cottrell Catherine , Asgharzadeh Shahab , Huang Annie , Rassekh Rod , Limbrick David , Boue Daniel , Biegel Jaclyn , Mardis Elaine , Dhall Girish , Finlay Jonathan , Leonard Jeffrey 
Published: November 2022

Abstract

BACKGROUND
Head Start 4 is a randomized clinical trial to determine whether dose-intensive tandem consolidation, compared with a single cycle, with autologous hematopoietic progenitor cell rescue provides a survival benefit in pediatric patients with medulloblastoma or other embryonal tumors. The trial incorporates upfront molecular subgrouping and non-mandatory, prospective blood and cerebrospinal fluid (CSF) collection. This pilot study aimed to identify exosomal non-coding RNAs (exo-ncRNAs) that might serve as novel diagnostic and/or treatment response biomarkers.

METHODS
CSF(1-2mLs) from 11 controls (non-tumor) and 27 medulloblastoma participants including 23 obtained at baseline, 22 at the end of induction, 3 post-consolidation, and 4 relapse time points, were profiled. Exosome isolation and small RNA-sequencing were performed by System Biosciences. Differential gene expression (DGE) was performed in R (DESeq2). Variations in gene expression profiles between samples were visualized using principal component analysis.

RESULTS
After limiting to ncRNAs with expression of 2 counts per million in 50% or more of the samples in each comparison, ~9,500 ncRNAs were detected. DGE analyses revealed 118 ncRNAs with log2 fold change(FC) &gt;2 and 1 ncRNA with log2FC&lt; -2 in baseline CSF samples compared to controls. In contrast, 11 ncRNAs(log2FC &gt;2) and 1 ncRNA(log2FC&lt; -2) were detected in end of induction CSF samples compared to controls. Comparing end of induction to baseline CSF samples accounting for paired samples, 0 ncRNAs(log2FC &gt;2) and 52 ncRNAs(log2FC&lt; -2) were detected.

CONCLUSIONS
Overall, our data indicate that exosomal small RNA-sequencing of limited CSF volumes is feasible. Differential expression and distinct clustering between tumor baseline samples compared to non-tumor controls was observed. CSF-derived exo-ncRNAs at end of induction also demonstrated “normalization” of ncRNA profiles, signifying CSF biomarkers may serve a role in diagnosis and molecular response assessment. A comprehensive analysis including multi-marker predictive model development and molecular subgrouping will be undertaken at completion of study enrollment.
BIOM-57. DISSECTING STEMNESS IN AGGRESSIVE MENINGIOMAS: PROGNOSTIC ROLE OF SOX2 EXPRESSION
Authors: Bonaventura Rina Di , Martini Maurizio , Cenci Tonia , Caccavella Valerio Maria , Barresi Valeria , Gessi Marco , Albanese Alessio , Lauretti Liverana , Pallini Roberto , D'Alessandris Quintino Giorgio , Olivi Alessandro 
Published: November 2022

Abstract
Aggressive meningiomas are prone to recur despite GTR and eventually progress: they represent a challenge and are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription regulator whose role is crucial for cell’s fate and maintenance of progenitor’s identity during embryogenesis, and homeostasis and regeneration in adult tissue through stem cell activity preservation. We reviewed meningioma cases surgically treated at Gemelli Hospital, Rome between 2014 and 2019. We included all patients with diagnosis of grade 3 meningiomas, both progressive and de novo, grade 2 with at least one surgical recurrence after GTR and benign grade 1 and grade 2 without recurrence at 10 and 5 years long follow-up respectively. SOX2 expression was evaluated through IHC and RT-PCR. Its role in predicting progression, recurrence, OS and PFS was investigated. 87 patients were included: 16 de novo grade 3 meningioma, 7 progressive grade 1, 13 progressive grade 2, 12 recurrent grade 2, 20 benign grade 1, 19 benign grade 2. The IHC method for SOX2 was validated by correlation between IHC score and mRNA levels (Spearman R=0.0398, p=0.001, AUC 0.87). Although SOX2 expression is related to WHO grade in the series, its status doesn’t change with progression. SOX2 expression at first surgery is related to risk of progression (p&lt; 0,0001) and represents a grade independent prognostic factor for PFS and OS (PFS 38,41 months in positive cases vs not reached in negative cases; p&lt; 0,0001; OS 173,9 months in positive cases vs not reached in negative cases; p=0,0001) and both in grade 1 and grade 2. Histomorphological criteria, cornerstone of the current WHO classification, are inadequate to predict aggressiveness. SOX2 expression since first diagnosis is able to point out meningiomas prone to recur and progress. SOX2 status could integrate current classification as molecular biomarker of stemness and aggressiveness.
BIOM-62. INTEGRATED GENOMIC PROﬁLING OF LONG-TERM GLIOBLASTOMA SURVIVORS
Authors: Xu PengFei , Chen ZhongPing 
Published: November 2022

Abstract
Glioblastoma (GBM) is a fatal brain tumor, and few patients survive beyond 5 years. Therefore, a study of genomic alterations in GBM long-term survivors is essential for insights into tumor biology and biomarker identiﬁcation. In our study, 13 GBM long-term survivors (overall survival &gt;60 months) and 19 short-term survivors (overall survival &lt; 24 months) were retrospectively collected, and surgically resected tumor tissues and normal blood controls were extracted and were performed whole exome sequencing and transcriptome sequencing. Our results revealed that although no significant differences were found in the composition of driver genes between the two groups, mutation signature analysis of two GBM groups revealed that the proportion of mutation signature 19 was higher in the longer survivors than in the shorter survivors (P=0.059). Analysis of copy number variants showed that the longer survivors group had higher copy number variants at the chromosomal level (P=0.049). At the chromosome Arm level, the proportion of 19p amplification and 19q amplification in the longer survivors group was significantly higher than in the short survival group (P=0.001/0.002). And in the TCGA GBM dataset, GBM patients with 19p amplification also had a better prognosis (log-rank P=0.04). In conclusion, the proportion of mutation signature 19 and amplification of 19p was potential prognostic molecular features for GBM.