bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANGI-09. BEVACIZUMAB IN ATYPICAL AND ANAPLASTIC MENINGIOMAS: THE BEMEN STUDY
Authors: Cerretti Giulia , Bosio Alberto , Maccari Marta , Padovan Marta , Caccese Mario , Zagonel Vittorina , Lombardi Giuseppe 
Published: November 2022

Abstract

BACKGROUND
the current standard to treat meningiomas can include surgical resection and radiotherapy. Despite the high rate of relapse no systemic treatment is indicated. Few data are available regarding the effectiveness of bevacizumab (BEV) in this setting. We performed a retrospective analysis investigating the efficacy and safety of BEV in meningioma patients relapsed after receiving surgery and radiotherapy. Gene mutations were also collected. Material and

METHODS
we analyzed pts treated with off-label BEV from Jul 2019 to Feb 2022. Inclusion criteria were diagnosis of grade 2-3 meningioma, previous treatment with surgery and radiotherapy, no indication to further surgery or reirradiation, absence of contraindications to the use of BEV. Data were estrapolated from clinical records.

RESULTS
Median follow up was 13 months (3-30 range). 26 pts were enrolled. Median age was 68 ys (29-84); male pts were 16 (61%);61% (16 pts) with atypical meningioma, 38.5% (10 pts) with anaplastic meningioma; 27% (7 pts) underwent 2 or more surgeries; 58% had 2 or more RT treatments; 96.1% (25 pts) received &lt; 2 previous lines of systemic treatment. 61% of patients (16 pts) had NGS analyses available; 62% (10 pts) had NF2 mutations (1 pt had a confirmed diagnosis of neurofibromatosis type 2), 23% (6 pts) CDKN2A/2B deletion, 11% (3 pts) PTEN mutation. OS rate was 82% and 62% at 6 and 12 months respectively; 6 months PFS rate was 83%. The DCR was 71% and the ORR was 19%. Median PFS and OS weren't reached. 19% (5 pts) experienced CTCAE grade 1 or 2 toxicity, mainly hypertension.

CONCLUSION
BEV showed very promising activity in recurrent grade 2-3 meningioma. The treatment was well tolerated. BEV should be considered an optimal therapeutic option in this setting of meningioma patients. The NGS results might be useful in identifying targetable mutations in case of further recurrence.
ANGI-10. IMPLICATIONS OF EPITHELIAL MEMBRANE PROTEIN-2 (EMP2) IN THE PATHOGENESIS OF MENINGIOMAS
Authors: Mozaffari Khashayar , Aguirre Brian , Chandla Anubhav , Wadehra Madhuri , Yang Isaac 
Published: November 2022

Abstract

INTRODUCTION
VEGF-A is an important mediator of angiogenesis in meningiomas. However, targeting this protein with bevacizumab has offered only a modest improvement in survival, suggesting that there are other compensatory mechanisms involved, enabling vascularization despite ongoing treatment. Epithelial membrane protein 2 (EMP2), a cell surface protein, promotes angiogenic processes in gynecological cancers and brain tumors including gliomas and glioblastoma. However, little is known about its etiology and mechanism of action within meningiomas.

OBJECTIVE
We aimed to evaluate EMP2 expression in non-pathologic brain tissue, tumor specimens, and in meningioma cell lines. We also aimed to understand its mechanism within cells with regard to proliferation and invasion.

METHODS
Non-pathologic brain tissues from routine autopsies and tumor specimens from surgical resection were analyzed. Additionally, four meningioma cell lines were obtained (CH157, BEN-MEN1, SF1335 and IOMM-LEE) and changes in cellular proliferation and invasion were measured. Furthermore, EMP2 expression was modulated using lentiviral infection. A p-value &lt; 0.05 was considered statistically significant.

RESULTS
EMP2 mRNA and protein expression were significantly higher in the meningioma specimens compared to non-pathologic meninges. Its expression also positively correlated with an angiomatous pattern and VEGF-A mRNA expression. In vitro, high EMP2 protein expression was noted in all cell lines, and quantification demonstrated highest expression in the malignant cell line, the IOMM-LEE. Viral vectors were subsequently utilized to create EMP2 overexpressing and knockdown IOMM-LEE models. Western analysis demonstrated a correlation between EMP2 overexpression and HIF1α, a key mediator of tumor growth and angiogenesis.

CONCLUSION
Our data from primary tumor samples and in vitro models implicate EMP2 in meningioma pathogenesis. This warrants further investigation by evaluating the effects of anti-EMP2 therapy on tumor growth and invasiveness in both in vitro andin vivo models.
ANGI-11. RAB27 IS REQUIRED FOR REGULATING INTACT VASCULATURE IN GLIOBLASTOMA
Authors: Adnani Lata , Meehan Brian , Rak Janusz 
Published: November 2022

Abstract
Rab27 is a GTPase involved in the biogenesis of extracellular vesicles (EVs) and cellular secretion pathway. Among two Rab27 isoforms (a and b) Rab27a has been identified in regulating angiogenesis during development and wound healing via VEGFR1. Here, we show that Rab27 plays a role in the development and stability of the brain vasculature including pathological angiogenesis in glioblastoma.. Thus, relative to wild-type C57bl/6 (WT) and double heterozygous Rab27a+/-;Rab27b+/- (dHET) mice, animals with Rab27a/b double knock-out (Rab27a/b-dKO) exhibit reduced microvascular density in brain cortices. Additionally, we also observed a reduction in permeability of Evans Blue in the Rab27 dKO cortices relative to controls. When neoangiogensis was induced following orthotopic inoculation of mouse glioma cells (GL261), a similar reduction and morphological anomalies were observed in the tumour vasculature relative to tumours established in control mice. Moreover, vascular permeability of tumours in Rab27a/b-dKO mice markedly exceeded that of similar tumours in wild type or heterozygous controls. Our results suggest Rab27a and Rab27b may play a critical role in ensuring stability of the vasculature under physiological conditions and in glioma.
BIOM-01. GENOMIC ALTERATIONS IN ALK FUSION-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS WITH BRAIN METASTASES
Authors: Eichholz Jordan , Miao Emily , Lebow Emily , Walch Henry , Flynn Jessica , Zhang Zhigang , Hubbeling Harper , Beal Kathryn , Moss Nelson , Yu Kenny , Yang Jonathan , Meng Alicia , Kelly Daniel , Boerner Thomas , Gomez Daniel , Rimner Andreas , Schultz Nikolaus , Drilon Alexander , Imber Brandon , Pike Luke 
Published: November 2022

Abstract

PURPOSE
Brain metastases (BM) are common in patients with anaplastic lymphoma kinase fusion-positive NSCLC (ALK+ NSCLC). We characterized the genomics of patients with ALK+ NSCLC BM treated with alectinib with or without local therapy to identify correlations of co-mutations with CNS-specific outcomes.

METHODS
We retrospectively reviewed ALK+ NSCLC patients with BMs who received alectinib for the definitive treatment of BM from 1/2012 and 5/2021. Genomic characteristics of 27 specimens from 27 patients were assessed with MSK-IMPACT, a 505-gene next-generation sequencing (NGS)-based tumor sequencing assay with &gt;700x coverage. Intracranial progression-free survival (iPFS) and overall survival (OS) from BM diagnosis were analyzed using standard statistical methods.

RESULTS
The median age at BM diagnosis was 57 years (range 25-83). Median iPFS was 1.94 years (95%CI: 1.58- not reached) and median OS was 6.08 years (95%CI: 1.7– not reached). All patients received alectinib for the treatment of brain metastases (78% as 1st-line TKI) and 22% received local therapy. The most frequently altered co- alterations were CDKN2A (48%), TP53 (22%), MAP2K4 (15%), SMARCA4 (11%), CREBBP (11%), and ATM (7%). CDKN2A alterations were more common in patients with intracranial progression (64% vs 31%). MAP2K4 alterations were enriched in metastatic samples (p = 0.028, q = 0.113). SMARCA4 co- alterations were associated with inferior OS (HR: 8.76, 95%CI = 1.74-44.2, p= 0.009) and trended toward association with iPFS but was insignificant (HR: 3.25, 95%CI = 0.83-12.4, p=0.089). We identified missense ALK alterations in CSF from a patient who acquired resistance to alectinib and had leptomeningeal progression (G1269A, I1171T, L1108P).

CONCLUSION
This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.
BIOM-15. GLIOBLASTOMA CELLS SHOW ELEVATED CHITINASE 3-LIKE PROTEIN 1 GENE EXPRESSION IN RESPONSE TO HUMAN CEREBROSPINAL FLUID WITH INCREASED MIGRATION AND EPITHELIAL-MESENCHYMAL TRANSITION RELATED ACTIVITY
Authors: Whaley Lauren , Norton Emily , Corcino Victoria , Jones Vanessa , Chaichana Kaisorn , Quiñones-Hinojosa Alfredo , Guerrero-Cazares Hugo 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. GBM tumors proximal to the lateral ventricles have a worse prognosis with multifocality, recurrence, and lower overall survival. Studies suggest this increased aggressiveness is attributed to cerebrospinal fluid (CSF), as we have previously observed transcriptomic changes in GBM cells upon CSF exposure. GlioVis database reveals chitinase 3-like protein 1 (CHI3L1), a glycoprotein secreted by immune and cancer cells, is associated with poor prognosis and co-expressed with pro-inflammatory and tissue remodeling genes. We suggest exposure to CSF elevates CHI3L1 expression, consequently impacting malignancy-associated gene expression in patient-derived GBM lines. We first evaluated if patient CSF influences the expression of CHI3L1. GBM cells were treated with artificial CSF, non-cancer CSF, or cancer CSF for 72 hours. qPCR revealed significant increases in CHI3L1 (p&lt; 0.0001), SPP1, and CD44 expression in cancer CSF groups compared to artificial CSF. CHI3L1 expression at the protein level is also increased by cancer CSF when profiled using Western Blot. Additionally, ELISA results indicated significantly higher levels of CHI3L1 in CSF samples obtained from patients with high-grade tumors compared to non-cancer samples. Next, we assessed if exogenous CHI3L1 stimulates GBM malignancy at the cellular level. An effective concentration of recombinant human CHI3L1 was determined through Alamar Blue assay, showing 500 ng/ml CHI3L1 increases viability in primary patient cell lines compared to non-treated media. Recombinant CHI3L1 also increases cell migration in Transwell assay. qPCR revealed Vimentin (p&lt; 0.001) and Twist (p&lt; 0.0001) expression significantly increases while E-cadherin (p&lt; 0.001) significantly decreases in CHI3L1-treated groups, consistent with EMT and migratory activity. Ultimately, this study shows CHI3L1 is a CSF-induced factor in GBM and could be a therapeutic target as it enhances tumor malignancy by increasing proliferation, migration, and malignancy-promoting gene expression.
BIOM-24. TARGETED NEXT-GENERATION SEQUENCING (NGS) OF TEMPORALLY MATCHED CEREBROSPINAL FLUID (CSF) AND TUMOR TISSUE IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)
Authors: Abdalla Aseel , Till Jacob , Yee Stephanie , O'Rourke Donald , Brem Steven , Amankulor Nduka , Chen Isaac , Binder Zev A , Desai Arati , Phillips Richard , Hussain Jasmin , Kry Yolanda , Caldwell Michael , Beaubier Nike , Bagley Stephen , Carpenter Erica L 
Published: November 2022

Abstract

BACKGROUND
GBM genomic profiling relies on sequencing a limited tumor tissue sample, which is invasive and may underrepresent molecular heterogeneity. CSF, which can be obtained less invasively, is in intimate contact with tumor lesions and may better capture the full genomic profile of the tumor. However, datasets with contemporaneously collected CSF and tissue to support this claim have been lacking. To evaluate the performance of CSF NGS, we conducted a pilot study in patients with GBM undergoing a resection for suspected recurrence following first-line chemoradiotherapy.

METHODS
Paired CSF and tissue samples were sequenced using a hybrid capture-based NGS assay. Clinically meaningful variants were defined as those that are potentially targetable using off-label or clinical trial options, exhibit prognostic value, or may predict response or resistance to specific treatments.

RESULTS
Eighteen patients were enrolled, and 13 of 18 CSF samples (72.2%) were sequenced successfully. At least one variant was detected in all CSF samples analyzed. A median of 7 variants (range 1—67) was detected per sample across 54 genes. The median variant allele fraction was 0.6% (range 0.2—72.4%). Among 38 clinically meaningful genes, 102 variants were detected; 25 (24.5%) were detected in both tissue and CSF, while 60 (58.8%) were detectable solely in CSF. Hypermutation was detected by CSF in one patient. Of the 82 variants detected in this patient’s tumor, 15 (18.3%) were identified in both tissue and CSF, 15 (18.3%) were identified only in the tissue, and 52 (63.2%) were identified only in the CSF.

CONCLUSIONS
CSF NGS detects clinically meaningful variants at a substantial rate and frequently identifies mutations not detected by matched tissue NGS. These results suggest that CSF may be a suitable source material for tumor profiling, overcoming the limitations of tissue, and may also provide a more comprehensive tumor profile.
BIOM-31. TEMPOROSPATIAL PROTEIN PROFILING OF HUMAN GLIOBLASTOMAS REVEALS MOLECULAR MECHANISMS AND BIOMARKERS UNDERLYING RESPONSES TO IMMUNE CHECKPOINT INHIBITION
Authors: Young Jacob S , Lucas Calixto-Hope , Seo Kyounghee , Nguyen Minh , Chen William , Solomon David A , Berger Mitchel S , Phillips Joanna J , Aghi Manish , Raleigh David 
Published: November 2022

Abstract
Glioblastoma responses to immune checkpoint inhibition (ICI) are rare, and the molecular mechanisms underlying ICI responses are incompletely understood. Thus, serial glioblastoma samples are valuable resources for identifying biomarkers or therapeutic targets to increase the efficacy of ICI in patients with glioblastoma. We obtained paired glioblastoma samples from 7 patients who underwent sequential surgery, ICI, and eventual salvage surgery for recurrence. Patients were distinguished as ICI responders (n=3) or non-responders (n=4) based on (1) MRI evidence of tumor stability/reduction over 6+ months after ICI, or (2) pathologic evidence of predominant treatment effect at the time of salvage surgery after ICI. FFPE sections from each tumor (n=14) were stained using H&E or IHC/IF for macrophages/microglia (CD68) or T cells (CD3) and analyzed using light or fluorescence microscopy. Six regions-of-interest (ROIs) comprising viable tumor were selected neuropathologist from each sample (n=84 ROIs). ROIs were analyzed using quantitative spatial profiling of 72 proteins on the Nanostring Digital Profiler platform. Glioblastomas responding to ICI were enriched in T-cell proteins (CD3, CD4, CD8) and T-cell activation markers (CD25) at the time of salvage compared to initial surgery. Markers of MAPK signaling were suppressed in pre-ICI samples compared to post-ICI samples in responders. p-ERK was suppressed in post-ICI samples compared to pre-ICI samples in non-responders. Myeloid proteins (CD68, CD163, CD11c) were enriched in post-ICI samples compared to pre-ICI samples in non-responders. Principle components analysis revealed p-ERK and immune proteins (CD3, CD4, CD8, CD20, CD11c, CTLA4, CD68, CD45, CD56, and CD127) accounted for 62% of the variance among pre-ICI and post-ICI samples in responders. In conclusion, temporospatial protein profiling of human glioblastomas reveals molecular mechanisms and biomarkers underlying responses to immune checkpoint inhibition. These data establish a foundation for functional studies to reprogram the immunosuppressive glioblastoma microenvironment and sensitize tumors to immune checkpoint inhibition.
BIOM-32. DNA METHYLATION SUBCLASSES PREDICT THE BENEFIT FROM GROSS TOTAL TUMOR RESECTION IN IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Drexler Richard , Schüller Ulrich , Eckhardt Alicia , Filipski Katharina , Hartung Tabea , Harter Patrick , Divé Iris , Forster Marie-therese , Czabanka Marcus , Jelgersma Claudius , Onken Julia , Vajkoczy Peter , Capper David , Siewert Christin , Sauvigny Thomas , Lamszus Katrin , Westphal Manfred , Dührsen Lasse , Ricklefs Franz 
Published: November 2022

Abstract
DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. We performed a multicentric cohort study including 430 patients with newly diagnosed glioblastoma whose tumors were subjected to DNA methylation profiling. The primary outcome was overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the prognostic relevance of EOR and MGMTpromoter methylation status as well as surgical benefit for recurrent glioblastoma. After stratifying patients in accordance with their DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES), outcome analyses revealed no significant differences between these three methylation subclasses (p = 0.06). RTK I or RTK II tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients (p &lt; 0.01). In the MES subclass, no survival benefit for a maximized EOR was found (p = 0.33). In multivariate analysis, the therapy response-predictive value of MGMT promoter methylation was evident for RTK I (p &lt; 0.01) and RTK II (p = 0.02) but failed to be an independent factor in the MES subclass (p= 0.06). For local recurrence, re-resection conveyed a progression-to-overall survival (POS) benefit (p &lt; 0.01), which was evident in the RTK I (p = 0.03) and RTK II (p &lt; 0.01) subclasses, but not in the MES subclass (p = 0.33).This study demonstrates a survival benefit from maximized EOR at surgery for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II subclass but not the MES subclass. Hence, it needs to be carefully considered whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.
BIOM-36. A STUDY OF CLINICAL AND MOLECULAR PROGNOSTIC FACTORS FOR RESPONSE TO REGORAFENIB IN RECURRENT GLIOBLASTOMA
Authors: Chiesa Silvia , Mangraviti Antonella , Martini Maurizio , Cenci Tonia , Mazzarella Ciro , Gaudino Simona , Bracci Serena , Martino Antonella , Della Pepa Giuseppe M , Offi Martina , Gessi Marco , Russo Rosellina , Martucci Matia , Bartoli Francesco Beghella , Bonaventura Rina Di , Larocca Luigi M , Lauretti Liverana , Olivi Alessandro , Pallini Roberto , Balducci Mario , D'Alessandris Quintino Giorgio 
Published: November 2022

Abstract

Introduction
Following the results from the REGOMA study, regorafenib has become the first chemotherapeutic option for recurrent glioblastoma, IDH-wildtype, in many countries. However, predictive factors for response to regorafenib are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform.

METHODS
We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a rapid, cheap, and clinically validated platform. MGMT methylation was assessed using methylation-specific PCR, and EGFRvIII expression was assessed using RT-PCR.

RESULTS
In our series, six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months: these data are consistent with current literature. Among clinical variables, gross-total resection was endowed with a positive prognostic value for PFS (p=0.0296, log-rank test). NGS analysis revealed a mutation in the EGFR pathway (EGFR and/or PIK3CA) in 18% of cases; a mutation in the mitogen-activated protein-kinase (MAPK) pathway (RAS and/or RET) in 18% of cases; no mutations in the remaining cases. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p=0.0061; for OS, 7 vs 9 months, p=0.1076). By combining NGS analysis with RT-PCR for EGFRvIII, we identified 14 patients with EGFR pathway activation, who had a significantly longer PFS and OS after regorafenib treatment. Multivariate analysis confirmed that MAPK pathway mutations predicted a scarce response to regorafenib treatment.

Conclusions
Through an easy-to-use and cheap platform, we identified a mesenchymal, MAPK-altered signature in IDH-wildtype glioblastoma, predictive of scarce response to regorafenib at recurrence. We thus provide a molecular selection criterion to implement in the clinical practice.
BIOM-38. TETRASPANIN 12 AS A TUMOR SUPPRESSOR AND BIOMARKER PREDICTING GOOD PROGNOSIS OF MALIGNANT GLIOMA
Authors: Lee Yeo Song , Kim Chungyeul , Choi Hye Won , Lee Jungsul , Jung Hyena , Suh Sangil , Kim Hyungsin , Kang Shin-Hyuk , Kwon Taek-Hyun , Chong Kyuha 
Published: November 2022

Abstract
Tetraspanin 12 (TSPAN12), a member of the tetraspanin family that are increasingly known to be involved in various mechanisms of tumor progression, mediates various cellular signaling processes in cancer cells. With respect to the brain, previous studies have shown that TSPAN12 is related with the maturation of a membrane-associated metalloproteinase 10 and the production of amyloid β plaque, but there are no studies related to brain tumors to date. Therefore, we designed this study to investigate the role of TSPAN 12 on malignant glioma (MG) cells and patients. TSPAN12 silencing in MG cells significantly progressed cell proliferation, migration and invasion capacities, and extracellular matrix adhesion ability as well as stem cell properties, in vitro. Mechanistically, we identified that FAK and ERK signaling were involved in MG cells with TSPAN12 expression. Moreover, clinical analysis of MG patient tissues microarray showed that the expression level of TSPAN12 was negatively correlated with the prognosis in MG patients. Collectively, more studies are needed, but we suggest that TSPAN12 can be used as an alternative biomarker to predict the prognosis of MG patient and help develop MG treatment strategies.