bluuebunny/crossref_metadata_2025_split huggingface dataset:
MNGI-14. PROGNOSTIC FEATURES OF MALIGNANT MENINGIOMA: EVALUATION OF AGGRESSIVE MENINGIOMAS WITHIN A LARGE RURAL HOSPITAL SYSTEM DATABASE AND FIRST REPORT OF A METASTATIC CHORDOID MENINGIOMA TO THE LUNG
Authors: Tosha Gatson Na , Manikowski Jesse , Bross Shane , Hinger Bradley , Mauer Tian , Garcia Tiffany , Lacroix Michel , Mahadevan Anand , Mongelluzzo Gino , Vadakara Joseph , Jaffar Kazmi Syed A 
Published: November 2019

Abstract
Meningiomas comprise 37% of primary brain tumors, arise extra-axially from the arachnoid cap cells, and are typically identified by classic imaging and histopathologic features. Blacks, females, and people age 65+ have higher incidence rate - partially correlated with hormonal states, high body mass index, and known genetic predispositions. Prognostication is otherwise based on histopathologic findings and 90% of meningiomas are classified as benign (WHO grade I). Despite use of these prognostic tools, clinicians often observe a more divergent post-operative clinical course. While several pre-clinical studies have identified putative oncogenic influencers, many have failed to show correlation in human trials. Here, we evaluate a single institutional meningioma database stratified by geodemographic and clinical data to identify novel integrated prognostic indicators for aggressive tumor natural history. Our database contains 3,528 image-confirmed meningiomas between 1992–2019. This report focused on 415 pathology-confirmed cases between 2006–2019: WHO grades I, II, III were 73% (n=303), 25% (n=103), and 2% (n=9) respectively, 71% female predominance (n=294), median age at diagnosis 57-years-old, and 97.5% were white race. Thus far, full exome sequencing has been completed on >50% of cases and >80% have available tumor tissue for future testing as part of this rural Pennsylvania database with high incident aggressive and/or multiply recurrent meningiomas. We selected four representative cases to compare post-operative prognostication to observed clinical outcomes and provide molecular/genetic, histopathologic, treatment modality, comorbid, and other clinical features associated with morbidity/mortality. Included in this patient review is the first reported case of a rare (< 1%) chordoid meningioma, multiply recurrent despite 8-years of aggressive treatment modalities, including surgery, radiation, chemotherapy and androgen-blockade, with eventual extracranial metastasis to the lung, a meningiocarcinoma, if you will. Thorough interrogation of the completed database could yield novel predictive indicators of clinically aggressive meningiomas and guide clinical decision-making for optimized surveillance in high-risk patients.
PATH-04. INFLUENCE OF INDIVIDUAL CpG METHYLATION STATUS OF THE MGMT PROMOTOR ON OUTCOME IN ADULT PATIENTS WITH GLIOBLASTOMA MULTIFORME RECEIVING ALKYLATING AGENT TREATMENT
Authors: Siller Sebastian , Lauseker Michael , Giese Armin , Tonn Joerg-Christian , Niyazi Karim-Maximilian , Thon Niklas , Suchorska Bogdana , Kreth Friedrich-Wilhelm 
Published: November 2019

Abstract

BACKGROUND
Methylation of O-6-methylguanine-DNA-methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG-site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG-sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG-sites 74–98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents.

METHODS
Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection was assessed by the Sanger-sequencing approach. Methylation of CpG-sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine/thymine peak > 50%. The total number of methylated CpG-sites was correlated with outcome using proportional hazards models. In a subset of 34 patients, a correlation between individual CpG-site methylation and MGMT mRNA-expression was performed.

RESULTS
Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6months, respectively. The cumulative total number of methylated loci within the CpG-sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p< 0.001). Furthermore, a linear coherence between the total number of methylated CpG-sites 74–98 and survival parameters could be observed. Moreover, low number of methylated CpG-sites was observed in tumor specimen with a high mRNA-expression and vice versa (Spearman-correlation-coefficient: -0.62).

CONCLUSION
Our data suggest a strong linear coherence between outcome and the total number of methylated CpG-sites 74–98, thus an up-front analysis of the individual GpC-site methylation status prior to initiation of alkylating chemotherapy might help improving treatment response in GBM patients.
PATH-05. RAPID SIMULTANEOUS IDH MUTATION AND MGMT METHYLATION STATUS ASSESSMENT IN GLIOMA PATIENTS USING CRISPR-Cas9-TARGETED NANOPORE SEQUENCING
Authors: Wongsurawat Thidathip , Jejaroenpun Piroon , DeLoose Annick , Ussery David , Alkam Duah , Day J D , Nookaew Intawat , Rodriguez Analiz 
Published: November 2019

Abstract
Molecular classification of diffuse glioma enables more-precise diagnosis, prognosis, and treatment decisions. Currently, combination of two molecular markers, isocitrate dehydrogenase 1 and 2 (IDH1/ IDH2) gene mutation information and O6-Methylguanine-DNA-methyltranferase (MGMT) methylation status, are the main prognostic biomarkers of newly diagnosed diffuse gliomas. Furthermore, an accurate interpretation of MGMT-promoter methylation status is essential to determining which patients benefit from temozolomide (TMZ) therapy. The presence of an IDH mutation can be easily tested by PCR or next generation sequencing. However, there remains controversy with the identification of MGMT-promoter methylation status since there exists variable degrees of methylation and no clear consensus on cutoff values for “methylated” or “unmethylated” have been defined. To be best suited for routine clinical setting and research use, the optimal test should be reproducible, readily available, and timely. Therefore, we explored the feasibility of single-molecule nanopore third generation sequencing technology to comprehensively assess both mutation and methylation status simultaneously. This technology allows methylation detection directly from the native DNA sequence without requiring bisulfite treatment which reduces processing time. To specifically study IDH1, IDH2, and MGMT-promoter loci, we combined the CRISPR-Cas9 system to cut desired DNA fragments in a non–amplification dependent fashion. In addition, a data analysis pipeline was developed to quantitatively detect methylation. We applied our approach on human DNA controls, glioma cell lines and 4 patient brain tumor samples and were enabled to assess mutation and methylation status of targeted loci within 1.5 days. The promise of CRISPR-Cas9-targeted nanopore sequencing in accelerating and improving the molecular diagnostics of diffuse glioma will be illustrated in this meeting. These efforts are in line with improving precision medicine and can be applied to all cancer types.
PATH-09. MGMT PROMOTER METHYLATION IS A STRONG PROGNOSTIC FACTOR FOR SURVIVAL AFTER PROGRESSION IN HIGH GRADE GLIOMAS
Authors: Liu Yanwei , Li Yanong , Qiu Xiaoguang 
Published: November 2019

Abstract
High grade gliomas (HGGs: anaplastic gliomas and GBM) are the most lethal type of primary brain tumor. Maximal resection and postoperative concurrent chemoradiotherapy, and followed with adjuvant chemotherapy is the standard treatment. But patients with HGGs have a relapse rapidly and short survival. Studies have identified many clinical characteristics and biomarkers were associated with progression free survival (PFS) and over survival (OS). However, there has not yet a comprehensive study on the effects of these factors to survival after the first progression (SAP). 319 patients with HGGs were conducted maximum resection followed by radiotherapy and/or temozolomide chemotherapy and have been confirmed the first progression. Clinical characteristics, biomarkers (IDH1/2 mutation, MGMT promoter methylation, LOH1p/19q, TP53 mutation, EGFR amplification, Ki-67 expression) and clinical interventions (extent of resection, chemoradiotherapy, operation after progression) were analyzed in accordance with SAP. The 1-year SAP was 14.2% (median SAP: 5.1 months). Significant prognostic factors of improved SAP were tumor grade, MGMT promoter methylation and Ki-67 expression in univariate analysis (p< 0.05). Further multivariate analysis showed that MGMT promoter methylation and Ki-67 expression were independently prognostic markers for SAP (p< 0.05). In our data, HGGs could be divided into low, intermediate and high risk groups for SAP by MGMT promoter methylation and Ki-67 expression. However, analysis of 308 patients with GBM from The Cancer Genome Atlas (TCGA) found that MGMT promoter methylation is the only prognostic marker for SAP in multivariate analysis (p< 0.05). Consequently, MGMT promoter methylation is independently prognostic marker for SAP in patients with HGGs. MGMT promoter methylation, combined with Ki-67 expression, might establish a risk model for SAP and this stratification may aid in treatment strategy selection and clinical prognosis evaluation in HGGs.
PATH-10. RELATIONSHIP BETWEEN CYTOGENETIC COMPLEXITY AND PERITUMORAL EDEMA IN HIGH-GRADE ASTROCYTOMA
Authors: Su Sung Kyoung , Song Young-Jin , Han Jin-Yeong , Kim Ki-Uk 
Published: November 2019

Abstract
The purpose of the study is to reveal the association of cytogenetic complexity and peritumoral edema volume (PTEV) and its prognostic significance in high-grade astrocytoma patients by culturing patient tumor cells. Twenty-seven high-grade astrocytoma patients were divided into three groups according to karyotype complexity: normal, non-complex karyotype (NCK), and complex karyotype (CK). Endothelial growth factor receptor (EGFR) amplification was detected by FISH, and its association with chromosome 7 abnormalities was analyzed. Mean PTEV of each group was compared by ANOVA to evaluate the relationship between PTEV and cytogenetic complexity. The PTEV of patients in normal (n=6), NCK (n=8), and CK (n=13) groups were 24.52±17.73, 34.26±35.04, and 86.31±48.7 cm3, respectively (P=0.005). Ten out of 11 patients with EGFR amplification showed abnormalities in chromosome 7. The mean PTEV of EGFR-amplified and non-amplified groups were 80.4±53.7 and 41.3±37.9 cm3, respectively (P=0.035). The average survival of patients with PTEV less than 90 cm3 was 30.52±26.11 months, while in patients with PTEVs over or equal to 90 cm3, it was 10.83±5.53 months (P=0.007). The results show an association of complex karyotype with the PTEV of high-grade astrocytoma. EGFR amplification plays a significant role in the formation of peritumoral edema, causing PTEV to increase, which is related with survival. This implies that cytogenetic karyotype can be applied as a prognostic factor.
PATH-16. HISTOPATHOLOGICAL EPENDYMOMA VARIANTS ARE ASSOCIATED WITH DISTINCT CLINICAL PARAMETERS AND DNA METHYLATION PATTERNS
Authors: Neumann Julia E , Spohn Michael , Obrecht Denise , Mynarek Martin , Thomas Christian , Hasselblatt Martin , Dorostkar Mario M , Wefers Annika K , Frank Stephan , Monoranu Camelia-Maria , Koch Arend , Witt Hendrik , Kool Marcel , Rutkowski Stefan , Glatzel Markus , Schüller Ulrich 
Published: November 2019

Abstract
According to the current WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas and RELA-fusion positive ependymoma (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e. the clear-cell, papillary, and tanycytic ependymoma. In parallel to this WHO classification scheme, DNA methylation patterns can distinguish nine distinct molecular ependymoma subgroups, some of which tightly overlap with certain histopathological subgroups, e.g. subependyomas or myxopapillary ependymomas. Since very little is known about the molecular background of histological classic ependymoma variants, we analyzed histomorphology, clinical parameters and global DNA methylation patterns of diagnosed tanycytic ependymomas (n=12), clear-cell ependymomas (n=14) and papillary ependymomas (n=19). Surprisingly, up to 42% of these variants did not match to ependymomas using a previously published DNA methylation-based classifier for brain tumors. Among the tumors with a match to one of the nine known ependymoma methylation classes, tanycytic ependymomas were predominantly located in the spine, but showed diverse molecular methylation patterns. Most clear-cell ependymomas showed a common histomorphology, were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas showed a “papillary”, “trabecular” or “pseudo-papillary” growth pattern. Interestingly, a true papillary growth pattern was strongly associated with the molecular class B of posterior fossa ependymoma (PFB), but tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Our results show that the diagnosis of classic histological ependymoma variants can be challenging. While clear-cell and papillary ependymomas harbor common molecular features, tanycytic ependymoma may not represent a molecularly distinct subgroup.
PATH-17. HYPERPROGRESSIVE DISEASE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS TREATED WITH IMMUNE CHECKPOINT INHIBITORS OR CYTOTOXIC THERAPIES
Authors: Donovan Laura , Gedailovich Samuel , Joanta-Gomez Adela , Lassman Andrew , Iwamoto Fabio 
Published: November 2019

Abstract

BACKGROUND
Hyperprogressive disease (HPD), defined as a ≥ 2-fold increase in tumor growth rate (TGR) compared to baseline following initiation of immune checkpoint inhibitors (ICI), has been described in solid tumors but is not well explored high grade gliomas (HGG). We investigated the rate of HPD in HGG patients receiving ICIs for first or second recurrence compared to those treated with non-immunotherapy agents.

METHODS
Patients with HGG receiving ICIs for 1st or 2nd recurrence compared to a controls receiving other therapies at first progression. Prior or concurrent bevacizumab or anti-VEGFR were exclusionary due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment.

RESULTS
49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients receiving ICIs and 20/22 patients in the control group were evaluable in the analysis. The ICI group included 60% men (15/25) and 80% (20/25) had a diagnosis of primary GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of primary GBM. 28% (7/25) of patients met criteria for HPD in the ICI group compared to 4/20 controls (20%). Median OS in patients with primary GBM was 26mo in the ICI group vs. 15.9mo in controls. Median survival past progression in patients with primary GBM receiving ICI for 1st recurrence (13/25) was 12mo vs. 10.6mo in controls. 40% of patients in both groups had next generation sequencing (5/7 with HPD in ICI and 2/4 in control). EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in HPD (71% vs. 33.3%).

CONCLUSION
HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies.
PATH-21. CLINICAL UTILITY OF DNA METHYLATION PROFILING FOR DIAGNOSIS OF CHALLENGING CENTRAL NERVOUS SYSTEM TUMORS: THE TORONTO EXPERIENCE
Authors: Karimi Shirin , Zuccato Jeffrey , Mamatjan Yasin , Mansouri Sheila , Suppiah Suganth , Nassiri Farshad , Diamandis Phedias , Munoz David , Aldape Kenneth , Zadeh Gelareh 
Published: November 2019

Abstract
The update on the WHO classification of central nervous system (CNS) tumors incorporated molecular signatures for a more accurate diagnosis. Recently, DKFZ has demonstrated the utility of DNA methylation profiling(MP) for molecular classification of CNS tumors. We performed a prospective clinical study over the last three years to evaluate the clinical utility ofDNA MP on FFPE samples of 66 challenging CNS tumor cases using online DKFZ classifier. Eleven samples were excluded due to low tumor DNA content or low calibration(predictive) scores(CS)< 0.3.DNA MP confirmed the original pathology diagnoses in 15(27%)cases. The integrated molecular diagnoses were changed in 38/55(70%) including establishment of a new diagnostic entity, change in molecular signature and subtyping. TheWHO grades were changed in 16(27%) of the tumors; about two-thirds resulted in upgrading. We detected non-canonical IDH mutations in 9 diffuse gliomas and the CNV plots revealed false positive FISH results for 1p/19q co-deletion in two diffuse gliomas. The CNV plots contributed to the final diagnosis in 40(72%) patients. The molecular subtypes of medulloblastoma, ependymoma and glioblastoma subclasses were determined in 36(65%) cases. Seventy-five percent of cases with confirmation of initial diagnosis or change in molecular diagnosis had CS > 0.5, among which 51% had a CS >0.9. The median and range CS of cases with new diagnostic entity and confirmed cases were 0.86(0.37–0.99) and 0.98(0.42–0.99), respectably. Furthermore, we detected higher CS in IDH-mutant gliomas in comparison to glioblastoma IDH-wild type(P=0.04). We also observed lower CS in mesenchymal glioblastoma in comparison to other subclasses. The MGMT promoter methylation was determined in 17/20(85%) glioblastoma cases. While the DKFZ group established CS of 0.9 as a cut-off for matching to methylation classes, our findings suggest lower threshold values in challenging CNS tumor cases. Our experience indicates clinical utility of MP of challenging CNS tumors as a reliable ancillary diagnostic tool in routine neuropathology practice.
PATH-39. DNA MISMATCH REPAIR ENZYME IMMUNOHISTOCHEMISTRY IS A RAPID, EFFECTIVE SCREENING TEST FOR HYPERMUTATED GLIOMAS
Authors: McCord Matthew , Steffens Alicia , Kam Kwok-Ling , Javier Rodrigo , McCortney Kathleen , Horbinski Craig 
Published: November 2019

Abstract

BACKGROUND
While gliomas with hypermutated DNA are resistant to alkylating agents like temozolomide, they may be especially responsive to immunotherapy, since they express abundant neoantigens on their cell surfaces. Screening for hypermutated gliomas is currently being done through next-generation sequencing (NGS) panels that cover large portions of tumor DNA, although this is costly and access to such testing is not universal. Since hypermutated gliomas typically contain inactivating mutations in one of the main DNA mismatch repair (MMR) proteins, and cancers with an MMR mutation usually show loss of normal MMR protein, we sought to determine the feasibility of rapidly screening for hypermutated gliomas with an MMR immunohistochemistry (IHC) panel that is already in widespread use for colorectal adenocarcinomas.

METHODS
Tumor mutation burden (TMB) was determined via NGS for 101 gliomas, including 64 GBMs, 24 grade II-III astrocytomas, 9 grade II-III oligodendrogliomas, and 4 grade I gliomas. IHC for MSH2, MSH6, MLH1, and PMS2 was performed and analyzed on all gliomas while blinded to mutation profile and TMB.

RESULTS
Seven of 101 gliomas (7%) showed loss of an MMR protein by IHC. All 7 had matching MMR gene mutations and were hypermutated (100%), defined as TMB >20 per megabase of DNA. Of the remaining 94 with intact MMR IHC, only one was hypermutated. That case had an inactivating splice region mutation in another gene involved in DNA repair, ATM, although ATM is not part of the IHC panel originally developed for colorectal cancer. Overall sensitivity and specificity of the current MMR IHC panel for hypermutated gliomas was therefore 88% and 100%, respectively.

CONCLUSION
The colorectal MMR IHC panel, available in virtually all clinical IHC labs, is also a good screening test for hypermutated gliomas. Expansion of the panel to include even more DNA repair proteins, like ATM, would enhance its utility.
PATH-40. PROFILING PLEOMORPHIC XANTHROASTROCYTOMA WITH DNA METHYLATION AND EXPLORING THE TUMOR IMMUNE CELL-TYPE COMPOSITION WITH METHYLATION-BASED DECONVOLUTION
Authors: Tang Karen , Kurland David , Vasudevaraja Varshini , Serrano Jonathan , Radmanesh Alireza , Snuderl Matija 
Published: November 2019

Abstract

INTRODUCTION
Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that commonly affects children and young adults. PXAs are typically characterized by tumor lymphocytic infiltration, but the significance of the tumor immune microenvironment has not yet been well-defined. In this study, we correlated DNA methylation profiling of PXAs with clinical outcome and explored the tumor microenvironment by analyzing inflammatory cell populations.

METHODS
We retrospectively analyzed 30 tumor samples, of which 21 tumor samples from 18 subjects had a diagnosis of PXA both by DNA methylation and by histology. MethylCIBERSORT was used to deconvolute PXA inflammatory cell populations and compare them with inflammatory cell populations in previously published cohorts of IDH wildtype glioblastoma and ganglioglioma samples.

RESULTS
Median age at diagnosis was 16 years (range 7–32). 3-year and 5-year overall survival (OS) was 73% and 71% respectively. CDKN2A/B deletion was noted in 15 out of 18 subjects (83%). 10 out of the 12 subjects (83%) that had testing for BRAFV600E showed the mutation. CDKN2A/B deletion and Trisomy 7 did not show any significant association with overall survival (p = 0.39 and p = 0.69). Decreased survival was observed in subjects with tumors lacking the BRAFV600E mutation (p = 0.03). PXAs were observed to have significantly increased CD8 T-cell epigenetic signatures compared to gangliogliomas (p = 0.0019) and significantly increased CD8 T-cell and CD19 B-cell signatures compared to IDH wildtype glioblastomas (p = 0.0011 and p = 0.0011).

CONCLUSION
This research suggests that PXAs have a distinct methylation profile that correlates with clinical outcome. PXAs show significant upregulation of CD8 T-cell epigenetic signatures compared to gangliogliomas and significant upregulation of CD8 T-cell and CD19 B-cell epigenetic signatures compared to IDH wildtype glioblastomas. This distinct characterization of immune cell-types in PXAs could have an impact on future development of immunotherapy.