bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-38. CRISPR BASED GENOME EDITING OF HUMAN T CELLS TO TARGET H3.3K27M MUTATION IN GLIOMAS
Authors: Hegde Bindu , Roth Theodore , Nguyen David , Chheda Zinal , Apathy Ryan , Marson Alex , Okada Hideho 
Published: November 2019

Abstract
We recently identified an HLA-A*02:01-restricted CD8 T cell epitope encompassing the H3.3K27M mutation, which is common in diffuse midline glioma, and a corresponding high-affinity T cell receptor (TCR) that recognizes the epitope. While recombinant viral vectors have been widely used for genetic reprogramming of T cells, viral vectors are far from ideal as they typically integrate randomly into the genome and are not governed by the molecular regulatory mechanisms of the cell. We used a non-viral, CRISPR-Cas9-based approach to replace the endogenous TCR with H3.3K27M TCR at the TCR a constant region (TRAC) in human T cells. Co-electroporation of healthy donor-derived T cells with homology-directed repair (HDR) templates encoding the full-length sequence of H3.3K27M TCR along with CRISPR-Cas9 ribonucleoprotein (RNP) resulted in the integration of the new TCR into the TRAC locus by HDR. Antibody staining of TCR α/β and H3.3K27M dextramer showed replacement of endogenous TCR with H.3.3K27M TCR in ~5–10% of TCR+ CD8 T cells. Modifying the HDR template to include a binding site for Cas9, which contains the nuclear localization signal that acts as a “shuttle”, further enhanced the integration efficiency (~15% of TCR+ CD8 T cells). Furthermore, HLA-A2+ H3.3K27M TCR-engineered T cells selectively killed U87 glioma cells expressing the H3.3K27M epitope. In addition, the engineered T cells exhibited a stem memory-like phenotype when expanded in the presence of a cocktail of IL-2, IL-7 and IL-15. Taken together, these data provide evidence for non-viral genome editing as a strategy to engineer T cells with specific TCR for cancer immunotherapy.
IMMU-48. RATIONAL DEVELOPMENT AND CHARACTERIZATION OF MULTIVALENT TARGETING TANDEM AND PARALLEL CAR T CELLS FOR GLIOMA
Authors: Yin Yibo , Thokala Radhika , Zhang Logan , Kainth Devneet , Haddad Leila , Binder Zev , Lin Zhiguo , O’Rourke Donald 
Published: November 2019

Abstract
High grade glioma is the most common malignant primary brain tumor. Despite the best available therapy, the median survival is limited. Chimeric antigen receptor (CAR)-T cells effectively attack target positive tumor cells, demonstrating a promising possible treatment. Based on our previous clinical and pre-clinical studies, we utilized epidermal growth factor receptor variant III (EGFRvIII) and interleukin 13 receptor subunit alpha 2 (IL13Rα2) targeting single-chain variable fragments (scFvs) to generate bi-specific tandem CAR T cells and bi-specific parallel CAR T cells to decrease the potential of antigen escape and tumor recurrence. 5, 10, 15 or 20 flexible amino acids were utilized to link scFvs in tandem CARs. Ribosomal “skipping” 2A peptides were utilized to generate parallel CAR T cells. Flow-based IL13Rα2 staining on glioma stem cells (GSCs) showed 7 out 11 cases positive (64%) heterogeneous intratumoral expression. Tandem CAR T cells and parallel CAR T cells upregulated CD69 expression (P< 0.0001), generated IFNγ, interleukin 2 and TNFα (P< 0.0001), as well as exhibiting cytotoxic activity (P< 0.0001) when compared against un-transduced T cells, in co-culture with either single- or double-target positive GSCs. There was no significant difference between different lengths of linker in tandem CAR T cells. Parallel CAR T cells generated a larger cytokine response (P< 0.0001) and more effectively killed target positive cells (P< 0.05) than tandem CAR T cells. In summary, glioma associated target expression is heterogeneous in GSCs. Multivalent tandem CAR T cells and parallel CAR T cells effectively respond to target expressing tumor cells. The function of tandem CAR T cells is not relative with the length of linker. Parallel CAR T cells are a more promising strategy in generating gene modified multivalent targeting T cells.
INNV-23. GLIOBLASTOMA AND FACEBOOK: AN ANALYSIS OF PERCEIVED ETIOLOGIES AND TREATMENTS.
Authors: Kumar Reddy Naveen , Blondin Nicholas 
Published: November 2019

Abstract

Facebook has become one of the most widely used platforms by patients and caregivers for information on GBM. As such, physicians treating GBM are challenged with reconciling their medical advice with online media sources. In many cases, the information from these online sources can run counter to the advice given by physicians.

OBJECTIVE
This study sought to understand the type of information being shared on a popular GBM Facebook community titled, “GLIOBLASTOMA SURVIVORS TO THRIVERS!” with regards to 1. The perceived causes of GBM and 2. The therapies that led to GBM remission.

METHODS
All the posts in a 30-day period (5/01/2019-6/01/2019) were screened for information on GBM etiologies and GBM therapies. Within each group, posts were sorted into distinct sub-categories with posts of similar content. The sub-categories were ranked to determine which etiologies and therapies were most commonly seen by group members.

RESULTS
A total of 83 posts were on the topic of “GBM Etiologies” and 80 on the topic of “GBM Therapies.” Within the “GBM Etiologies”, the reasons for developing GBM were due to 1. Unknown (31.3%) 2. Previous Radiation Exposure (24.1%) 3. Chemical Exposure (17%) 4. Genetic (12%) 5. Infectious Disease (6%) 6. Losartan/Valsartan (4.8 %). and 7. Head Trauma (2.4%) and Emotional Trauma (2.4%). Within the GBM Therapy category, the therapies that led to remission were 1. Standard of Care (36.3%) 2. CBD/THC (16.3%) 3. Ketogenic Diet (12.5%) 4. Avastin (7.5%) and Optune (7.5%) 5. IV Vitamin C (6.25%) and COC Protocol (6.25%) 6. Meditation/Yoga/Acupuncture (5.0%) and 7. Faith Healing (2.5%).

CONCLUSION
In the Facebook group titled, ““GLIOBLASTOMA SURVIVORS TO THRIVERS!,” the top three most commonly posted reasons for developing GBM were “Unknown” “Previous Radiation Exposure” and “Chemical Exposure.” The top three therapies that led to remission were “Standard of Care” “CBD/THC” and “Ketogenic Diet.”
INNV-27. THE IMPACT OF A DEDICATED MULTIDISCIPLINARY TUMOR BOARD ON CARE FOR PATIENTS WITH BRAIN METASTASES
Authors: Wang Nancy , Cohen Justine , Goss Nathaniel , Bertalan Mia , Keeley Maura , Parsons Michael , Nahed Brian , Cahill Daniel , Oh Kevin , Brastianos Priscilla 
Published: November 2019

Abstract

Brain metastases (BM) are the most common tumors to affect the central nervous system (CNS). Treatment options have recently evolved with the use of new targeted therapies, immune checkpoint inhibitors, and increased access to clinical trials. We describe our institutional experience with a weekly tumor board dedicated to BM.

METHODS
We conducted a single-institution cohort study at an academic hospital. Attendance at tumor board included representatives from neuro-oncology, medical oncology, radiation oncology, neurosurgery, neuropsychology, and neuroradiology. We prospectively gathered data on patient demographics, clinical history, and tumor board recommendations. Patients were followed to assess treatment course and survival. The Kaplan Meier method was used to calculate time to progression.

RESULTS
A total of 49 patients were presented over 2 months. The median age at presentation was 63 yrs with a median ECOG of 1. The primary malignancy was 35% melanoma, 29% lung, 23% breast, the remainder other. Most patients had advanced, heavily pretreated disease: 69% had Stage IV disease with a median of 2 prior lines of systemic therapy, 73% had multiple BM, 39% had prior surgical resection of BM, and 57% had prior CNS radiation. Change in management was recommended in 26/53 case presentations, with active BM-directed therapy (surgery, radiation, systemic therapy) recommended in 25/26 patients. The median time to start active therapy was 7 days. Only 3 patients have died at a median follow-up of 62 days. 9 patients have progressed, with a median time to progression of 57 days.

CONCLUSIONS
Multidisciplinary BM tumor board provides unique opportunities in the management of complex BM patients in an era of rapidly evolving therapeutic options. Additional follow-up is needed to assess long-term outcomes.
INNV-35. INTRODUCING THE EDUCATIONAL NEURO-ONCOLOGY APP
Authors: Alnahhas Iyad 
Published: November 2019

Abstract

BACKGROUND
The purpose of the Neuro-Oncology Trials App is to promote evidence-based practice in neuro-oncology and educate learners about the clinical trials that have been completed in the field. Evidence-based practice means consulting the literature when treating patients and applying the results of well-designed clinical trials to questions that we encounter in clinical practice. Being well versed in the literature is essential for high-quality patient care.

METHODS
We have developed a reference tool in the form of a smartphone app to provide easily-searched, easy-to-read detailed summaries of the methodology and results of selected pivotal clinical trials in the field of neuro-oncology.

RESULTS
The Neuro-Oncology Trials App includes summaries of select published clinical trials in the field of neuro-oncology. The topics include newly diagnosed glioblastoma, recurrent glioblastoma, low-grade gliomas, primary central nervous system lymphoma and management of gliomas in the elderly. The app includes an intuitive search function that facilitates looking up trials by: tumor histology, names of authors, names of journals, names of chemotherapy medications and acronyms of names of trials. Finally, it is continually updated and made available free of charge to users.

CONCLUSIONS
The Neuro-Oncology Trials App is ideal for practitioners at all levels and learners (medical students, residents and fellows) to look up information and quick summaries of trials in neuro-oncology when seeing patients in clinics or during rounds. The Neuro-Oncology App is soon to be available on the Apple and Android stores.
MNGI-03. ESTROGEN HORMONE REPLACEMENT THERAPY IN INCIDENTAL MENINGIOMA - A GROWTH RATE ANALYSIS
Authors: Kamson David , Yuen Carlen , Castillo Saavedra Laura , Jenkins Vogel Tilley , Merrell Ryan , Walker Matthew 
Published: November 2019

Abstract

BACKGROUND
Meningiomas are common intracranial neoplasms with female predominance and sharply rising incidence in the perimenopausal years. As they often express estrogen receptors, hormone replacement therapy (HRT) poses a theoretical risk inducing accelerated growth. Although HRT has been linked to slightly increased incidence, its actual effect on meningioma growth-rate had not been studied in a clinical population. AIM: We aimed to retrospectively compare tumor characteristics and grow-rates of incidental meningiomas of those with a ≥6-month history of estrogen-based HRT (e-HRT) before or during surveillance compared to those without (no-HRT).

METHODS
Forty females with e-HRT and 80 age-matched HRT-naïve females were identified from the NorthShore Incidental Meningioma Database. Tumor characteristics and diameters were analyzed on initial and all follow-up MRIs. Progression-free survival (PFS) was assessed.

RESULTS
Twenty-one patients completed e-HRT before, 10 started before and continued during, and 9 started e-HRT during surveillance. Patient and radiographic characteristics were similar between the groups (mean age 62y in both, parity; tumor calcification, T2W-intensity), whereas those with e-HRT had significantly lower body weight (68±16kg vs. 77±21kg; p=0.01) and tended to have longer follow-up (6.7±3.9yrs vs. 5.3±3.9yrs; p=0.07). Those with e-HRT had significantly smaller meningiomas (13±6mm vs. 16±9mm at diagnosis and 15±7mm vs. 19±11mm at end of follow-up; p=0.03 for both), and slower absolute grow-rates (0.5±0.8 vs 1.0±2.1mm/year; p=0.05) than those of no-HRT. Proportional growth-rate differences were not significant (3.3%/year vs. 5.4%/year p >0.05). Subgroup analyses showed no difference between vaginal vs. oral/subcutaneous/transdermal route e-HRT vs. no-HRT. PFS defined by RECIST1.1, RANO and clinical (new symptoms or treatment) criteria were 11.1, 6.6 and 14.7years in e-HRT versus 10.5, 5.4 and 11.4years in no-HRT. None of the differences were significant (log-rank p >0.1).

CONCLUSIONS
In this preliminary analysis, those with e-HRT had smaller tumors that grew slower, suggesting that e-HRT may be safe in incidental meningioma.
MNGI-07. TRIMETHYLATED H3K27 AND EZH2 EXPRESSION IN MENINGIOMA: CORRELATION WITH TENDENCY TO RECUR
Authors: Calatozzolo Chiara , Patanè Monica , Farinotti Mariangela , DiMeco Francesco , Finocchiaro Gaetano , Pollo Bianca 
Published: November 2019

Abstract
Meningiomas are the most frequent primary CNS tumors, usually benign (WHO grade I), but in the 25–30% more aggressive tumors (grade II-III). Histopathological criteria (WHO 2016) are unsatisfactory to recognize meningiomas with tendency to recur. Recent studies have identified some mutations associated with histological features and location (i.e. BAP1 mutation in rhabdoid subtype), while risk stratification schemes based on DNA methylation subgroups have been proposed. Epigenetic modifications of histones play a pivotal role in tumorigenesis, the methylation of lysine 27 (K27) of histone H3 controlled by EZH2 subunit of PRC2 complex. BAP1 could be also involved in epigenetic regulation of PRC2 complex. The deregulation of H3K27 methylation has been found associated with recurrence risk in grade II meningiomas. Aim of the present study was to evaluate histone H3 methylation profile in a group of meningiomas of different grade with follow-up longer than 10 years, comparing non-recurrent to recurrent ones. We performed an immunohistochemical study on 145 meningiomas (50 grade I, 80 grade II and 15 grade III), investigating the expression of trimethylated H3K27 (H3K27me3), EZH2 and BAP1. The results were related to clinical data obtained from our Institutional Tumor Registry and evaluation of clinical reports. We observed a loss of H3K27me3 expression only in grade II and III meningiomas in 18% of cases, without correlation with tendency to recur. EZH2 showed increased percentage of positive nuclei related to the grade. In the group of grade I meningioma EZH2 expression was associated to recurrences. We didn’t observe loss of BAP1 expression. In conclusion, our data suggest that immunohistochemical evaluation of H3K27me3 and EZH2 could be a useful tool to better stratify meningioma with high risk of recurrence. Moreover, EZH2 could be of interest as therapeutic target. Molecular investigations in a larger cohort are needed to confirm these results.
PATH-03. DIFFERENCES IN CLINICAL COURSE OF GROUP-A AND GROUP-B POSTERIOR FOSSA EPENDYMOMA (PFA, PFB) AS DEFINED BY H3K27ME3 IMMUNOHISTOCHEMICAL ANALYSIS
Authors: Yonezawa Ushio , Yamasaki Fumiyuki , takano Motoki , Taniguchi Hiroki , Sugiyama Kazuhiko , Kurisu Kaoru 
Published: November 2019

Abstract

PURPOSE
Posterior fossa ependymoma is classified as PFA and PFB based on underlying genetic/mutational characteristics, and PFA is reported to have poor prognosis compared to PFB. Recently, immunohistochemical findings of negative H3K27me3 have been reported to suggest PFA and attracted the attention as a surrogate marker. We classified our cases into PFA and PFB guided by immunohistochemical staining results of H3K27me3 and examined their clinical course.

MATERIALS AND METHODS
Between 1999 and 2018, 17 cases of posterior fossa ependymoma were treated at our institute. Negative immunostaining for H3K27me3 was classified as PFA, and positive as PFB. We evaluated age, gender, pathological diagnosis, progression free survival (PFS) and overall survival (OS) in both groups.

RESULTS
Nine cases were classified as PFA and eight as PFB. The median age of the PFA group was 4 years-old, 4 males, 5 females, pathological diagnosis was ependymoma in 5, and anaplastic ependymoma in 4 cases. The median follow-up period was 50 months, recurrence was confirmed in 5 cases (56%), PFS was 27.6 months. Three of the 5 patients who relapsed died (33%), and the OS was 50 months. The median age of the PFB group was 50 years, 4 males and 4 females, the pathological diagnosis was ependymoma in 6, and the anaplastic ependymoma in 2 cases. The median follow-up period was 111 months, recurrence was observed in 2 cases (25%), PFS was 98 months and all patients were alive during the period of this research.

CONCLUSION
Immunohistochemical results of H3K27me3 correlated with prognosis, implying the possibility of it being a surrogate marker of posterior fossa ependymoma.
PATH-06. A TARGETED NGS-BASED OVERALL SOLUTION TO SUPPORT DIAGNOSTICS AND THERAPY PREDICTION IN NEUROONCOLOGY: CONSIDERATIONS FOR A FLEXIBLE AND COST-EFFICIENT PLATFORM CHOICE AND PANEL DESIGN
Authors: Riemenschneider Markus , Rudolf Andras , Hau Peter , Pukrop Tobias , Kölbl Oliver , Corbacioglu Selim , Brawanski Alexander , Proescholdt Martin , Lorenz Julia 
Published: November 2019

Abstract
Continuous updates add novel molecular markers to the WHO classification of CNS tumors. Additionally, molecularly informed trials may provide the basis for the introduction of additional predictive biomarkers. All these developments will prospectively require molecular testing to a yet unknown extent and still pose challenges to many neuropathology labs. Some of the relevant alterations (e.g. C11orf95-RELA) are hard to assess or complex subclassifications (e.g. for medulloblastomas) are required. Some labs rely on a two-tiered approach: i) methylation arrays for tumor classification and ii) targeted NGS panel sequencing for identifying actionable mutations. However, high initial investment and annual costs for running two platforms in parallel hinder a fast expansion of the new techniques in the breadth of neuropathology. We decided to focus on the sole use of the relatively cost-efficient Mini-Seq NGS platform (Illumina). First, we designed a DNA panel (FFPE, HaloPlex, Agilent; no Covaris required) that is suited for detection of DNA mutations, copy number alterations and chromosomal alterations (459 kbp, 58 genes, 4082 SNPs, 98.83% coverage). We successfully used this platform to support tumor classification in astrocytomas, oligodendrogliomas, meningiomas and medulloblastomas and identified actionable targets of clinical use. We then designed a RNA panel (FFPE, Sure Select, Agilent) that detects gene fusions and covers a broad range of alterations particularly relevant to pediatric tumors (e.g. pediatric glioblastomas, ependymomas, CNS PNETs) (148 kbp, coding sequence of 31 genes, 99.88% coverage). With these two panels we cover the most relevant molecular alterations in the field of neurooncology. The cost-efficient and flexible single platform approach enables state-of-the-art molecular diagnostics in virtually every neuropathology lab in a quality-controlled manner. Functionality is guaranteed for future revisions of the WHO classification as novel biomarkers can be easily included in an adapted panel design.
PATH-19. TUMOR HETEROGENEITY IN GLIOMAS: A PILOT STUDY OF HISTOPATHOLOGY-ASSOCIATED PROTEOME PROFILES ASSESSED BY LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY OF FFPE SAMPLES
Authors: Paixao Becker Aline , Hlavin Bell Erica , Jaharul Haque S , McElroy Joseph , Fleming Jessica , Han Chunhua , Popp Illinca , Prinz Marco , Staszewski Ori , Grosu Anca , Chakravarti Arnab 
Published: November 2019

Abstract
Herein, we aimed to scrutinize tumor heterogeneity of infiltrative gliomas based on histopathological phenotypes, through proteomic profiling of formalin-fixed, paraffin embedded (FFPE) tissue. FFPE tissues are promising samples for proteomic studies, which can support the elucidation of glioma evolution and identify therapeutically vulnerable proteins and signaling pathways that drive recurrence and resistance mechanisms. We represented 2–3 adjacent, phenotypically distinct areas from 12 grade II-IV gliomas diagnosed according to the 2016 WHO classification, in a total of 35 samples (1.0mm cores), that were analyzed employing liquid chromatography tandem mass spectrometry (LC-MS/MS) for label-free expression proteomics. The statistical analysis was performed using R and Qlucore™ omics explorer software. Overall, 9222 peptides were mapped to 1758 non-redundant proteins, 320 of which had a significant (p< 0.05) differential expression in glioblastomas versus lower grade gliomas (Wilcoxon test comparing average expression). Principal component analysis (PCA) of the whole set of proteins showed clustering of the samples by tumor grade and IDH status. Unsupervised hierarchical analysis of the most significantly expressed proteins (p= 0.01, FDR= 0.05) showed that IDHwt gliomas had high expression of proteins related to cell movement, DNA structure, and fatty acid metabolism throughout the samples. IDHmut gliomas largely displayed high expression of mitochondrial enzymes related to energy production and neurotransmitter metabolism, with subsets closely related to 1p19q status and histological grade. Importantly, we demonstrated that LC-MS/MS analysis of FFPE core samples is feasible and enables recognition of different proteome signatures across histopathological phenotypes within a single tumor. This is the first study, to our knowledge, exploring proteome profiles addressing histopathological heterogeneity in gliomas by LC-MS/MS analysis of FFPE samples, which warrants further validation in independent datasets including ones that utilize frozen specimens. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to AC).
PATH-24. CXCR4 IS A POTENTIAL THERAPEUTIC TARGET FOR GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Zorofchian Soheil , Zhu Ping , Takayasu Takeshi , Rios Adan , Quezado Martha , Esquenazi Yoshua , Ballester Leomar Y 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common adult malignant brain tumor with poor prognosis and Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric type of glioblastoma for which there is no effective therapy. CXCR4, a G-protein coupled receptor, has been shown to play a role in GBM invasion, cell survival, proliferation and angiogenesis. A CXCR4 inhibitor (AMD3100/Plerixafor) has been suggested as a potential therapeutic strategy for GBM with an isolated case report of a long-term survivor and an ongoing clinical trial evaluating its effects in GBM patients. However, there is a poor understanding of the expression of CXCR4 in GBM and DIPGs. In this study, we evaluated the expression of CXCR4 in 21-DIPG and 36-GBM cases. In GBMs, CXCR4 was expressed in 5.6% of cases in tumor cells and in 19.4% of cases in endothelial cells in blood vessels. In DIPGs, we observed expression of CXCR4 in 28.6% of cases in tumor cells and in 14.3% of cases in endothelial cells. We observed absence of CXCR4 expression in all IDH-mutant GBMs. There was no correlation between CXCR4 or EGFR expression, p53-mutations or H3F3A p.K27M mutations in DIPGs. There was a trend of poorer prognosis in CXCR4 positive DIPGs but the difference did not reach statistical significance. Furthermore, we evaluated the effects of Plerixafor in the survival of DIPG and U87-GBM cell lines and observed a dose-dependent reduction in cell viability. RT-PCR and immunohistochemistry of DIPG cells showed variable CXCR4 expression in the cell lines that did not correlate with sensitivity to Plerixafor. In conclusion, in vitro experiments show that the CXCR4 inhibitor Plerixafor is a potential therapeutic strategy for GBM and DIPGs. However, CXCR4 is not universally expressed in glioblastomas and its expression should be considered in clinical trials that evaluate the efficacy of CXCR4 inhibitors in GBM and DIPGs.