bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-39. P-ERK ASSOCIATION WITH OVERALL SURVIVAL IN RECURRENT GBM PATIENTS TREATED WITH INTRACEREBRAL ADMINISTRATION OF PD-1 AND CTLA-4 BLOCKING ANTIBODIES
Authors: Arrieta Victor , Duerinck Johnny , Burdett Kirsten B , Geens Wietse , Schwarze Julia Katharina , Gould Andrew , Chen Li , McCord Matthew , Horbinski Craig , Zhang Hui , Stupp Roger , Neyns Bart , Sonabend Adam M 
Published: November 2022

Abstract

INTRODUCTION
Anti-PD-1 immunotherapy induces clinical responses in a subset of glioblastoma (GBM) patients. We previously reported that ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples is predictive of overall survival (OS) following adjuvant anti-PD-1 therapy in two independent cohorts of recurrent GBM patients.

METHODS
Following the Remark criteria for biomarker validation, we investigated p-ERK as a predictive of OS in 24 evaluable tumor samples of recurrent GBM patients from a clinical trial. These patients underwent intracerebral administration of immune checkpoint inhibitors as part of a phase I clinical trial where intracerebral administration of ipilimumab (10 mg) or ipilimumab (5 mg) and nivolumab (10 mg) followed by postsurgical intravenous nivolumab (10 mg) was evaluated (NCT03233152; Duerinck J, et al. JITC, 2021). We quantified cell density of p-ERK+ cells in tumor regions. For exploratory purposes, patients were divided in 3 groups (n=8 per group) bases on p-ERK cell density.

RESULTS
We observed an incremental OS with high p-ERK GBM patients exhibiting a median OS of 81.6 weeks (95% CI 33.86-NA), intermediate p-ERK median OS of 43.1 weeks (95% CI 33.14-NA), and low p-ERK group with a median OS of 19.3 weeks (95% CI 16.14-NA). A Cox proportional hazards model adjusted for age and IDH mutant status showed a trend for p-ERK association with favorable OS (HR= 0.77, 95% CI 0.6-=1.01, P=0.056).

CONCLUSIONS
While the number of patients analyzed is relatively small, this study suggests the potential predictive power of p-ERK in an independent prospective GBM cohort treated with an alternative and unique administration approach of immune checkpoint blockade.
BIOM-44. MAGNETIC RESONANCE IMAGING MAPPING OF BRAIN TUMOR BURDEN TO EVALUATE RESPONSE TO PULSED LOW-DOSE-RATE RADIOTHERAPY FOLLOWING RESECTION OF GLIOBLASTOMA MULTIFORME: A 4-PATIENT CASE SERIES
Authors: Amidon Ryan , Prah Melissa , Straza Michael , Santos-Pinheiro Fernando , Bovi Joseph , Schultz Christopher , Schmainda Kathleen 
Published: November 2022

Abstract

BACKGROUND
Pulsed low-dose-rate radiotherapy (pLDR) is an accepted reirradiation technique for recurrent glioma, but its upfront use, concurrent with temozolomide (TMZ) following resection of high-grade glioma is currently under investigation. Evaluating the response to upfront radiation can be challenging and there is limited data on expected rates of pseudoprogression with pLDR. Standard magnetic resonance imaging (MRI) has limitations in differentiating pseudoprogression from tumor progression, sometimes necessitating surgery for pathologic confirmation. Advanced MRI can be used to create fractional tumor burden (FTB) maps that spatially distinguish active tumor from treatment-related effect (pseudoprogression), perhaps providing a more reliable imaging biomarker in the absence of additional surgery.

METHODS
We performed a retrospective chart review to report the responses of four patients with glioblastoma to upfront pLDR and TMZ following resection. Each patient received advanced surveillance MRI and redo surgery. Tumor pathology included IDH-wild type (n = 4) and O6-methylguanine-DNA methyltransferase (MGMT) methylated (n = 1) tumors.

RESULTS
The median age of patients was 57.5 years (range 55-60 years) and all were male. One patient experienced mortality and another was transitioned to hospice. In all four cases, there were concerns of tumor progression in postcontrast MRI. Pathologic diagnosis revealed either treatment effect (n = 2) or tumor (n = 2). FTB maps were predominantly indicative of lesion volumes being comprised of treatment effect (n = 3) and tumor (n = 1). From the three FTB maps in the former category, the median fraction of the enhancing tumor volume comprised of vascular tumor was 6.4% (range 1.8-6.8%).

CONCLUSION
This case series provides insight into response to upfront pLDR and TMZ following resection of glioblastoma and demonstrates the capacity for FTB mapping to spatially distinguish tumor progression from treatment effect in this patient population.
BIOM-46. EXPLORING CLINICAL AND PATHOLOGIC CHARACTERISTICS IN GLIOBLASTOMA LONG -TERM SURVIVORS (LTS) VERSUS SHORT-TERM SURVIVORS (STS)
Authors: Briceno Nicole , Abdullaev Zied , Vera Elizabeth , Komlodi-Pasztor Edina , Choi Anna , Christ Alexa , Grajkowska Ewa , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Kunst Tricia , Evans Karen , Mentges Kelly , Wu Jing , Polskin Lily , Papanicolau-Sengos Antonios , Quezado Martha , Aldape Kenneth , Gilbert Mark , Armstrong Terri 
Published: November 2022

Abstract
Glioblastoma (GBM) has a median survival of less than 18 months with infrequent long-term survival (LTS). Reports on LTS to date have not identified distinct molecular or clinical/imaging characteristic in long ( &gt;3 years) versus short (&lt; 3 year) survivors. We identified IDH wildtype GBM patients living ≥ 3 years post diagnosis (LTS, Nf25) and a control cohort (STS, Nf76) from our Natural History Study. Available tissue was analyzed with targeted panel sequencing (Nf25) and methylation analysis (Nf21) for classification, MGMT promoter (MGMTp) status and copy number changes. Median survival and age for LTS and STS was 54mo and 48yrs, and 16mo and 56yrs, respectively. LTS were more likely to be female (2.8x) or have a GTR (2.9x) but 83% less likely to be white. MGMTp was 10x more likely to be methylated in LTS tumors (95% CI [2.6, 39.6]), yet was unmethylated in 17%. LTS were 63% and 90% less likely to have TERTp or EGFR amplification (95% CI [0.14, 0.97] and [0.04, 0.29]). Core pathway review showed 21% of LTS had at least one alteration in p53, RB and RTK/PI3K with RTK/PI3K the most common (46%) . Methylation classifier identified 74% as GBM (STS=96%) with most the RTK II subtype (53%; STS=41%) and despite classic histologic features, indicated a non-GBM diagnosis in three cases (14%).Although uncommon, there are LTS with molecularly confirmed GBM. Remarkably, not all had MGMTp methylation, were young or had extensive tumor resection. Clinical estimates of outcome in GBM patients should consider the possibility of long-term survival even with established poor prognostic factors. Imaging characteristics in a subset of these cases are reported in a separate abstract. Additional interrogation of tumor from LTS may uncover additional determinants of response and outcomes.
BIOM-48. HOXD12 IS AN INDEPENDENTLY PROGNOSTIC AGE-ASSOCIATED INDICATOR FOR POOR SURVIVAL IN OLIGODENDROGLIOMA
Authors: Nuechterlein Nicholas , Cimino Sadie , Arora Sonali , Shapiro Linda , Holland Eric , Gilbert Mark , Cimino Patrick 
Published: November 2022

Abstract

BACKGROUND
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has variable outcomes that are strongly influenced by patient age. This study aimed to discover novel molecular biomarkers that may characterize an aggressive subgroup of oligodendroglioma that is associated with, but independently prognostic of patient age.

METHODS
Differential gene expression analysis, gene ontology analysis, and gene set enrichment analysis were conducted on TCGA RNA-seq data (N=169) to identify genes and pathways that differ significantly between older and younger patients. Genes whose expression was associated with age and survival in multivariate analyses were further studied using DNA methylation (N=171). The prognostic value of their expression and methylation profiles was then compared to known genomic biomarkers, radiographic features, and histopathologic features. RNA-seq and DNA methylation validation data were obtained from the CGGA (N=44) and a cohort published by Capper et al. (N=144), respectively.

RESULTS
Highly activated pathways in older oligodendrogliomas were linked to developmental transcription factors. Overexpression of HOXD12 was associated with patient age and survival in the TCGA (FDR&lt; 0.01, FDR=1e-5) and the CGGA (p=0.03, p&lt; 1e-3). Hypermethylation of HOXD12 was associated with age, tumor grade, and survival in the TCGA (p&lt; 1e-5, p&lt; 0.001, p&lt; 1e-3) and with age and tumor grade in Capper et al. (p&lt; 0.02, p=0.001). In the TCGA, HOXD12 hypermethylation and overexpression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, and MYC activation as well as mitotic figures, Ki-67 index, microvascular proliferation, and necrosis. HOXD12 overexpression was also independently prognostic of T1-post contrast enhancement, whole tumor volume, and peritumoral edema volume. We developed a risk-stratification nomogram predicting 5- and 10-year overall survival using patient age, HOXD12 methylation, and WHO grade.

CONCLUSIONS
HOXD12 overexpression and hypermethylation are associated with an aggressive subtype of oligodendroglioma and may serve as superior prognostic biomarkers than previously reported genomic, radiographic, and histopathologic features.
BIOM-52. DIAGNOSTIC POTENTIAL OF EXTRACELLULAR VESICLES IN MENINGIOMA PATIENTS
Authors: Ricklefs Franz , Maire Cecile , Wollmann Kathrin , Dührsen Lasse , Fita Krystian , Sahm Felix , Herold-Mende Christel , von Deimling Andreas , Fuh Marceline , Schlüter Hartmut , Westphal Manfred , Lamszus Katrin 
Published: November 2022

Abstract
Standard monitoring after meningioma resection relies on serial MRI examinations, which are time-consuming, expensive and provide no information on molecular alterations that may indicate progression towards a more aggressive tumor. Extracellular vesicles (EVs) secreted by tumor cells play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. We investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic and proteomic alterations of original tumors. EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis. We found that the levels of circulating EVs were significantly elevated in meningioma patients compared to healthy individuals, and that plasma EV concentrations correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection (Simpson grade). Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in nearly all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins such as desmoplakin that could potentially be utilized to enrich meningioma EVs from biofluids. In conclusion, elevated EV levels in meningioma patient plasma may aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.
BIOM-54. ANALYTICAL VALIDATION OF A TARGETED GENE EXPRESSION BIOMARKER PREDICTING MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: Chen William , Lucas Calixto-Hope , Choudhury Abrar , Vasudevan Harish , Magill Stephen , Raleigh David 
Published: November 2022

Abstract

BACKGROUND
Improvements in meningioma risk stratification are needed to guide postoperative management. We previously developed and externally validated a targeted gene expression biomarker predicting meningioma outcomes and radiotherapy response using fresh frozen meningiomas. Here, we present the analytical validity, test-retest and cross-platform reproducibility, intra-tumor heterogeneity, and formalin fixed paraffin embedded (FFPE) concordance for this biomarker.

METHODS
Matched FFPE and fresh frozen samples from 50 meningiomas underwent RNA extraction for concordance testing using a custom Nanostring gene expression panel comprised of 34 meningioma genes and 7 housekeeping genes. Matched Nanostring gene expression profiling and RNA-sequencing was available from 173 fresh frozen meningiomas. Nanostring batch, machine, and technician variability was tested on 10 FFPE meningiomas using 2 independent batches of biomarker reagents that were processed at 2 independent laboratories. To study intra-tumor heterogeneity, 68 spatially distinct meningioma biopsies obtained under stereotactic guidance from 13 tumors were analyzed using the Nanostring gene expression biomarker.

RESULTS
Matched FFPE and fresh frozen meningioma samples (N=50) demonstrated high gene expression concordance (Pearson R=0.89, F-test P&lt; 2.2e-16) and risk score concordance (R=0.78, F-test P&lt; 1.8e-11, residual standard error 0.12). The biomarker achieved high performance on FFPE samples (local freedom from recurrence [LFFR] c-index 0.75±SEM 0.05, 5y LFFR AUC 0.84, 95% interval 0.67-0.96). Test-retest concordance on FFPE samples (N=10) across independent reagent batches, machines, and technicians was high (gene expression concordance: R=0.97; risk score concordance R=0.94). Transcript counts were concordant across Nanostring and RNA sequencing approaches (N=173 frozen samples, R=0.90). Stereotactic intra-operative sampling (N=68 samples from 13 patients) revealed low levels of intra-tumor heterogeneity (median inter-quartile risk score within tumor: 0.10±0.01).

CONCLUSIONS
We demonstrate analytical reproducibility and robustness of a gene expression biomarker predicting meningioma outcomes and radiotherapy responses in FFPE and frozen samples across multiple conditions and platforms.
BIOM-55. DE RITIS RATIO AS A NOVEL PROGNOSTIC BIOMARKER IN ATYPICAL MENINGIOMAS: A MULTI-INSTITUTIONAL STUDY
Authors: Chang Won Ick , Byun Hwa Kyung , Lee Joo Ho , Park Chul-Kee , Kim In Ah , Kim Chae-Yong , Chang Jong Hee , Kang Seok-Gu , Lee Sang Hyung , Kuranari Yuki , Tamura Ryota , Toda Masahiro , Yoon Hong In , Wee Chan Woo 
Published: November 2022

Abstract

PURPOSE
To investigate the impact of prognostic serum biomarkers in newly diagnosed surgically resected intracranial atypical meningiomas.

METHODS
This multi-institutional study included 523 grade 2 (according to the 4th edition of WHO Classification of Tumors of the Central Nervous System) patients who underwent resection between 1998–2018. The baseline characteristics and serum laboratory data within one week after surgery were obtained for analyses investigating the association with progression/recurrence (P/R) rate or progression-free survival (PFS). Optimal cut-offs were calculated for each serum marker using the maxstat package of R. Nomograms were developed based on the multivariate analyses of statistically significant prognosticators.

RESULTS
Among 523 patients, 454 patients were included in the multivariate analysis for P/R rate excluding patients with incomplete histopathologic or laboratory data. On multivariable analysis, tumor size &gt;5 cm (HR, 2.18; 95% CI, 1.49–3.19) and subtotal resection (HR, 3.60; 95% CI, 2.37-5.47) were associated with higher P/R rate, whereas adjuvant radiotherapy (HR, 0.32; 95% CI, 0.20-0.53) and postoperative platelet &gt;137 x 103/μL (HR, 0.58; 95% CI, 0.39-0.86) were associated with lower P/R rate. Interestingly, postoperative De Ritis Ratio (aspartate aminotransferase/alanine aminotransferase) &gt;2 proved to be an adverse prognosticator (HR, 1.87; 95% CI, 1.15-3.05). Similarly, patients with De Ritis ratio &gt;2 showed inferior PFS (HR, 1.87; 95% CI, 1.23-2.84). In the subgroup of patients who received adjuvant radiotherapy, tumor size &gt;5 cm and postoperative neutrophil-to-lymphocyte ratio &gt;21 were the only prognosticators and were associated with higher P/R rate. On the other hand, postoperative De Ritis ratio &gt;2 remained to be an adverse prognosticator in patients who did not receive radiotherapy.

CONCLUSION
Postoperative De Ritis Ratio was unrevealed as a novel serum prognosticator in newly diagnosed atypical meningiomas. Further studies are warranted to validate its clinical significance and biological background.
BIOM-58. ROLE OF CD79B Y196 MUTATION IN PCNSL AS A POTENT PREDICTIVE MARKER FOR FAVORABLE RESPONSE TO R-MPV TREATMENT AND DEVELOPMENT OF RAPID ALL-IN-ONE GENOTYPING SYSTEM FOR MOLECULAR MARKERS OF PCNSL
Authors: Yamaguchi Junya , Ohka Fumiharu , Lushun Chalise , Motomura Kazuya , Aoki Kosuke , Takeuchi Kazuhito , Nagata Yuichi , Ito Satoshi , Mizutani Nobuhiko , Ohno Masasuke , Suzaki Noriyuki , Takasu Syuntaro , Seki Yukio , Tanahashi Kuniaki , Hirano Masaki , Shimizu Hiroyuki , Kitano Yotaro , Maeda Sachi , Yamazaki Shintaro , Wakabayashi Toshihiko , Kondo Yutaka , Saito Ryuta 
Published: November 2022

Abstract
Although high-dose methotrexate (HD-MTX)-based chemotherapy, such as rituximab, HD-MTX, procarbazine and vincristine (R-MPV) regimen, has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), predictive factors for response to R-MPV have not yet been investigated. Then, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. 47 and 21 patients with PCNSL treated with R-MPV and HD-MTX respectively were included, and correlation of their MYD88 and CD79B status with prognosis was analyzed. R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). Among the 47 patients, 36 harbored MYD88 L265P or CD79B Y196 mutations. While the MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (P &lt; 0.05). However, the association of the CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that the CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. This system enabled the detection of these genetic mutations in a small amount of biopsy samples within 90 min. In conclusion, we revealed that the CD79B Y196 mutation is associated with a good response to R-MPV, and the rapid and accurate genotyping system for MYD88 L265P and CD79B Y196 mutations that we developed in this study will enable reliable rapid molecular diagnosis and early prediction of response to R-MPV, which might help to determine the best treatment strategy for PCNSL.
BIOM-61. SYSTEMATIC REVIEW OF BIOLOGIC CORRELATES OF FRAILTY IN SOLID TUMORS: IMPLICATIONS FOR BRAIN TUMORS
Authors: Sass Dilorom (Delia) , Streck Brennan , Cooper Diane , Guida Jennifer , Armstrong Terri 
Published: November 2022

Abstract

BACKGROUND
Cancer and cancer treatments contribute to accelerated aging and frailty, which is present in over 50% of adult cancer survivors and increases vulnerability to poor outcomes. Biomarkers of frailty would allow for early identification and timely interventions. The purpose of this review is to synthesize the current literature examining biomarkers of frailty across solid tumor patients, including primary brain tumors (PBT).

METHODS
The systematic review was conducted using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. PubMed, Web of Science, and Embase, were searched by the medical librarian (D.C.) of all reports from the inception to December 08, 2021. Inclusion criteria were: a) English language, b) biomarkers of aging hallmarks, c) association between biomarkers and frailty. Studies were limited to human solid tumors. Two reviewers (D.S. and B.P.S.) independently screened titles, abstracts, and full-text articles using Covidence platform with conflict resolution by the third researcher (T.S.A.). Included studies were independently evaluated for quality assessment using NIH tools for Observational Cohort, Cross-Sectional and Case-Control studies.

RESULTS
In total, 915 reports were screened and 15 full-text articles were included for the review. Studies were most commonly in breast tumors with no PBTs identified. Most were cross-sectional using small sample sizes. Fried, Balducci, and Leuven Oncogeriatric Frailty tools and cytokines (i.e. Interleukin-6 and C-reactive protein) were commonly used. Increased inflammatory response was the prevalent identified mechanism. Threats to internal validity of the studies were the use of unvalidated cut-off scores or modification of existing tools in about 50% of studies. Only six studies were rated as good using quality assessment ratings.

CONCLUSIONS
Varied use of frailty measures and nonspecific blood biomarkers limited conclusions for mechanisms of frailty in cancer survivors. There are missed opportunities in neuro-oncology; inclusion of frailty assessment and biomarkers is instrumental to advancing science in PBTs.
BIOM-66. MULTIPARAMETRIC QUALITIES OF PLASMA EXTRACELLULAR VESICLES AS NOVEL DIAGNOSTIC BIOMARKERS FOR GLIOBLASTOMA
Authors: Aibaidula Abudumijiti(Zack) , Fain Cori , Garcia Luz Cumba , Jung Miyeon , Johnson Aaron , Parney Ian 
Published: November 2022

Abstract
INTRODUCTION: Plasma extracellular vesicles (EVs) have been shown as a promising source for biomarker identification in glioblastoma (GBM) and could help differential diagnosis, treatment evaluation and tumor progression monitoring. These EVs are enriched in molecular signatures indicative of their cell origins, giving an indication of the key players in this pathology. In this project, we aimed to identify diagnostic biomarkers for GBM plasma EVs and their cells of origin. METHODS: Plasma EV samples were prepared following the MIFlowCyt-EV guideline of the International Society for Extracellular Vesicles, then stained for EV markers (CD9/CD63/CD81) and markers indicative of cell origins (CD31/CD45/CD41a/CD11b). Actin phalloidin was used as a negative marker. Stained plasma samples were analyzed using a Cytek Aurora flow cytometer. Percentages of different EV subpopulations were analyzed and compared between GBM and normal donor (ND) plasma EVs (reference group). Further clustering analysis was performed on EV events by t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) analysis. The predictive value of multiparametric qualities derived from the reference group was tested in blinded test group samples. RESULTS: Percentages of CD9, CD81, and CD11b positive EVs were higher in GBM patient plasma, while ND plasma had more CD41a positive EVs. GBM plasma EVs had unique multiparametric signatures compared to ND plasma EVs based on t-SNE and FlowSOM analysis. Our analysis also identified 15 distinct EV subpopulations which differed in size and various surface marker expression levels. Eight of these subpopulations were enriched for GBM EVs, while three were enriched for ND EVs. Our method of multiparametric analysis demonstrates high sensitivity and specificity in predicting disease status in human samples. CONCLUSIONS: GBM plasma EVs have a unique surface marker expression profile and distinct EV subpopulations compared to ND plasma EVs. Multiparametric signatures show promise as potential diagnostic markers of GBM.