bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNAR-01. CHROMOTHRIPSIS, ONE MAJOR GENETIC INSTABILITY FACTOR IN GLIOBLASTOMA, IS RARE IN IDH-MUTANT GLIOMAS
Authors: Sourty Baptiste , La Basset ëtitia , Garcion Emmanuel , Rousseau Audrey 
Published: November 2022

Abstract

INTRODUCTION
Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas, and IDH-wildtype glioblastomas (GBM). GBM display genomic instability, which is favored by two genetic events leading to massive chromosomal alterations: chromothripsis (CT) and whole-genome duplication (WGD). Those events are scarcely described in IDH-mutant gliomas. The better prognosis of IDH-mutant gliomas may be in part related to their greater genomic stability compared to GBM.

METHODS
Pangenomic profiles of 301 adult diffuse gliomas were analyzed at initial diagnosis by SNP arrays, including 196 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 oligodendrogliomas). We further analyzed 16 IDH-mutant recurrent gliomas (11 astrocytomas and 5 oligodendrogliomas). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using Kaplan-Meier method and categorical variables using Chi2 test.

RESULTS
At initial diagnosis, 37 GBM (18.8%) displayed CT (mainly affecting chromosomes 12, 9 and 7) versus five IDH-mutant gliomas (4.8%) (p = 0.0007). The latter were all high-grade astrocytomas. No oligodendroglioma or grade 2 astrocytoma displayed CT. There was a trend towards higher occurrence of CT in GBM versus high-grade IDH-mutant astrocytomas (p = 0.0589). WGD was detected at initial diagnosis in 18 GBM (9.2%) and 9 IDH-mutant gliomas (of any subtype and grade; 8.6%). Over 75% of chromosomal losses occurred after WGD. Neither CT nor WGD was associated with overall survival in GBM. At recurrence, one grade 4 IDH-mutant astrocytoma displayed CT and another one, WGD with CT.

CONCLUSION
CT is rare in IDH-mutant gliomas compared to GBM. The absence of CT in oligodendrogliomas and grade 2 astrocytomas may contribute to their greater genomic stability and better prognosis. CT occurrence in high-grade IDH-mutant astrocytomas may underlie aggressive biological behavior. WGD is a rare early event occurring equally in IDH-mutant gliomas and GBM.
DNAR-04. BOTH P53 CODON 72 ARG/ARG AND PRO/ARG GENOTYPES IN GLIOBLASTOMA MULTIFORME PATIENTS HAVE A BETTER PROGNOSIS IN BEVACIZUMAB TREATMENT
Authors: Shen Chiung-Chyi 
Published: November 2022

Abstract

BACKGROUND
In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival but it has failed to improve overall survival (OS) in controlled trials. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients.

METHODS
The polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis.

RESULTS
We found that among these GBM patients, the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone.

CONCLUSIONS
This pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patientsaccording to bevacizumab sensitivity.
DNAR-07. BET PROTEIN INHIBITION SENSITIZES GLIOBLASTOMA CELLS TO TEMOZOLOMIDE TREATMENT BY ATTENUATING MGMT EXPRESSION
Authors: Tancredi Alessandro , Gusyatiner Olga , Bady Pierre , Buri Michelle , Lomazzi Rémy , Chiesi Davide , Hegi Monika 
Published: November 2022

Abstract
Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of identifying rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres. This identified 6 distinct expression patterns. To uncover emerging actionable vulnerabilities that can be targeted with a second drug, we extracted the significantly disturbed DNA Damage Response genes. Among the constantly downregulated candidates was the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a known resistance factor for alkylating agent therapy in glioblastoma. BETi not only reduced MGMT expression in GBM cell lines, but also inhibited its induction, typically observed upon temozolomide treatment. To determine the potential clinical relevance, we evaluated the specificity of the effect on MGMT expression and MGMT mediated treatment resistance to temozolomide. BETi-mediated attenuation of MGMT expression was associated with reduction of BRD4- and Pol II-binding at the MGMT promoter. On the functional level, we demonstrated that ectopic expression of MGMT under an unrelated promoter was not affected by BETi, while under the same conditions, pharmacologic inhibition of MGMT restored the sensitivity to temozolomide, reflected in an increased level of gammaH2AX. Importantly, members of the mismatch repair pathway, required for sensitivity to unrepaired O6G-lesions, namely MSH6 and MSH2, were only transiently affected by BETi. Taken together, the addition of BET-inhibitors to the current standard of care, comprising temozolomide treatment, may improve the outcome of the 50% of patients whose GBM exert an unmethylated MGMT promoter.
DNAR-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON HIGH GRADE GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASKFORCE
Authors: Negm Logine , Nobre Liana , Bennett Julie , Chung Jiil , Fernandez Nick , Johnson Monique , Aronson Melyssa , Zhang Cindy , Komosa Martin , Bianchi Vanessa , Stengs Lucie , Lim-Fat Mary Jane , Keith Julia , Tsang Derek , Gao Andrew , Munoz David , Nguyen Lananh , Das Sunit , Levine Adrian , Das Anirban , Hawkins Cynthia , Tabori Uri 
Published: November 2022

Abstract
Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation and aggressive cancers that are resistant to chemoradiation yet sensitive to immunotherapy. MMRD mutations can occur somatically or be inherited as a part of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD). Although MMRD affects children, adolescents and young adults (CAYA, ages 0-40) with gliomas, its prevalence and impact of germline inheritance is unknown. Given that high microsatellite instability (MSI) is a key characteristic of MMRD, we previously developed a robust low-coverage whole genome-based tool to quantify MSI, which allows for accurate MMRD detection. We are therefore performing a large-scale MMRD screen of CAYA high grade gliomas (HGGs) and utilizing data from the International Replication Repair Deficiency Consortium (IRRDC) to determine the impact of germline mutations in MMRD gliomas. Ongoing data on 346 HGGs from CAYA patients reveals that MMRD is identified in 6% of HGGs and is not present in tumors with pediatric type alterations. Moreover, of MMRD tumors with IDH1 mutations, none harbor 1p/19q co-deletions. Of patients with available information, all are diagnosed with Lynch Syndrome (69%) or CMMRD (31%), with all Lynch Syndrome diagnoses occurring in patients above 18 years of age. Complementary data from the IRRDC on 113 MMRD patients with gliomas reveal that the median age of glioma is 9.7 and 17.5 years in CMMRD and Lynch Syndrome, respectively (p &lt; 0.001). Strikingly, CMMRD gliomas are enriched for secondary polymerase mutations (60%, p &lt; 0.001) and exhibit ultra-hypermutation, while MMRD gliomas with Lynch Syndrome are enriched for IDH1 mutations (32%, p &lt; 0.025) and harbor a lower mutational burden. Our data reveal a high prevalence of MMRD in CAYA HGGs with alarming impact of germline predisposition. These data can support universal screening for MMRD in high grade glioma diagnostics and identify patients for precision therapeutics.
DNAR-12. COMBINING TUMOUR TREATING FIELDS WITH THERAPEUTIC DNA DAMAGE RESPONSE INHIBITORS TO INCREASE POTENCY IN HIGH-GRADE GLIOBLASTOMAS USING CLINICALLY RELEVANT EX-VIVO GLIOMA STEM CELL MODELS
Authors: Vanderlinden Aurelie , Rominiyi Ola , Collis Spencer , Jones Callum , Myers Katie , McGarrity - Cottrell Connor 
Published: November 2022

Abstract
High-grade gliomas are the most common and aggressive type of primary brain cancer. Despite maximal surgical resection, followed by chemotherapy and radiotherapy, overall survival for patients remains between 10-16 months, with limited improvement in survival rates over the last 40 years. This highlights an urgent unmet clinical need to develop more effective therapeutic interventions for these devastating tumours.Tumour-Treating Fields (TTFields), which deliver low-intensity (1–3V/cm) intermediate-frequency (100–300kHz) alternating electric fields to localised tumour sites, represents an exciting new clinically-approved fourth modality for the treatment of high-grade gliomas, with randomised clinical trial evidence supporting improved overall survival (20.9 vs 16.0 months). Whilst TTFields are primarily thought to mediate their anti-cancer effects by disrupting mitotic tubulin dimer alignment leading to abnormal chromosomal segregation and mitotic cell death, recent data suggests that TTFields may also attenuate DNA damage repair efficiency and replication fork dynamics. We therefore hypothesised that combining TTFields with therapeutic DNA damage response inhibitors (DDRi), to develop next generation multimodal therapy regimes, would enhance TTFields potency in glioma cells either alone, or in combination with current standard-of-care chemoradiotherapy. To assess this, we employed clinically-relevant patient-derived primary glioma stem cell (GSC) models that represent both inter-patient and intra-tumoural heterogeneity, including unique ex-vivo models of post-surgical residual disease. We show that combining TTFields with radiation and clinically approved PARP inhibitor therapy leads to significantly increased amounts of DNA damage with concurrent decreased clonogenic survival in GSCs. Furthermore, we have shown similar impressive potency when TTFields treatments are combined with ATR inhibitors that are currently being assessed in various global clinical trials for other cancers. Overall, these exciting findings support further assessment of TTFields and DDRi combinations to underpin future clinical trials combining TTFields with clinically approved DDRi to improve outcomes for patients with currently incurable high-grade gliomas.
DDEL-12. QUADRUPLE CARBON DOT NANO MODEL FOR ENHANCED TUMOR TARGETING AND DUAL DRUG DELIVERY FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Graham Regina , Cilinger Emel Kirbas , Hettiarachchi Sajini , Zhou Yiqun , Ferreira Braulio , Leblanc Roger , Vanni Steven 
Published: November 2022

Abstract
High-grade gliomas remain among the most lethal neoplasms. Nanotechnology aims to Improve drug targeting and efficacy. Here we developed a quadruple nano-model (QNM) that specifically targets pediatric high-grade glioma cells and delivers chemotherapies to the cell nucleus. This carbon dot based QNM were fabricated by covalently attaching two drugs (epirubicin and temozolomide) and two targeting peptides. ShPep-1 peptide binds to the IL-13Rα2 receptors allowing for cellular import while lnPep-1h peptide delivers the DNA damaging drugs to the nucleus. Despite demonstrating the lowest measurable drug content (23.3%), the dual peptide linked QNM induced significantly greater cell death than single peptide linked conjugates suggesting enhanced cell uptake. Greatest effect was observed in glioblastoma (SJ-GBM2) and diffuse intrinsic pontine glioma (NP53) cells with IC50s of approximately 60 nM, 3-6-fold lower than single peptide conjugates. Imaging studies using FITC-conjugated carbon dots confirmed the dual peptide conjugate demonstrated greatest cellular uptake and nuclear localization.
DDDR-32. A NEW IMMUNOMODULATORY FUNCTION OF PYRIDO-PYRIMIDINE DERIVATIVES TO IMPAIR METASTATIC GROUP 3 MEDULLOBLASTOMA IN VIVO
Authors: Zollo Massimo , Asadzadeh Fatemeh , Ferrucci Veronica , De Antonellis Pasqualino , Bibbò Francesca , Siciliano Roberto , Sorice Carmen , Criscuolo Giuseppina , Filiz Dalim Kardelen , Tecik Melisa , Amente Stefano , Saccà Carmen Daniela , Gorini Francesca , Pedone Emilia , Diana Donatella , Pirone Luciano , Fattorusso Roberto , Navas Luigi , Donofrio Vittoria , Errico Maria Elena , Spennato Pietro , De Martino Lucia , Quaglietta Lucia , Tirone Felice , Cinalli Giuseppe 
Published: November 2022

Abstract
Medulloblastoma (MB) is an embryonal tumor of the cerebellum constituting ~ 20% of pediatric brain tumors. To date, four MB molecular groups (further stratified in twelve subtypes) have been described. Among them, Groups 3 and Group 4 MB have the poorest prognosis due to their high metastatic potential. Recently, we have reported a metastatic axis driven by Prune1 overexpression in MB Group3 characterized by canonical TGF-β signaling enhancement and epithelial-mesenchymal transition. Here, we have developed a new not toxic pyrido-pyrimidine derivative with the ability to impair Prune-1-driven-axis, thus ameliorating the survival rate of a murine model of metastatic MB Group3 characterized by overexpression of human Prune1 gene in the cerebellum (under the control of MATH1 promoter). Of importance, this small molecule also is showing immunomodulatory functions thus inhibiting the conversion of tumor-infiltrating T lymphocytes (TILs) to immunosuppressive regulatory T cells (Tregs) in vivo via impairing the secretion of inflammatory cytokines from MB cells. Furthermore, this molecule can also act synergistically with the currently used modified-intensity chemotherapy (e.g. in PNET5 use of Vincristine) or potential in the combination with epigenetics drugs (e.g., LSD1/KDM1A inhibitors). Altogether these results are of importance for future targeted therapies of high-risk metastatic MB. Acknowledgments: We thank for funding support: the Italian Association for Cancer Research (AIRC) Grant IG no. 22129 (M.Z.) and Lazio Innova Grant n. 85-2017-14785 (FT; MZ)
EPID-10. SEIZURE CONTROL BY BEVACIZUMAB IN GLIOBLASTOMA PATIENTS
Authors: Hertler Caroline , Seystahl Katharina , Le Rhun Emilie , Wirsching Georg , Roth Patrick , Weller Michael , Gramatzki Dorothee 
Published: November 2022

Abstract
Seizures are a frequent symptom in patients with glioblastoma and bear a relevant impact on quality of life. Likewise, anti-epileptic treatment may affect patients’ well-being due to side effects. Here, we assessed whether owing to relieve from edema and intracranial pressure, treatment with bevacizumab for recurrent glioblastoma might contribute to seizure control.We retrospectively analyzed clinical data of adult patients with glioblastoma who were treated with bevacizumab versus a non-bevacizumab-containing regimen for first recurrence of glioblastoma in the Canton of Zurich between 2010 and 2014 and assessed occurrence and dynamics of seizures before and after first recurrence. Categorical and continuous variables were compared by the Chi-square and the Mann-Whitney U test, respectively. Associations of clinical parameters and seizures were analyzed by binary logistic regression.We identified 55 patients with glioblastoma who had received bevacizumab and 61 patients that received a non-bevacizumab-containing regimen at first recurrence. Seizures were noted in 42 of 111 patients (37.8%) during the 12 weeks preceding tumor recurrence. In the non-bevacizumab group, 23 patients (39.0%) still suffered from seizures 3 months after recurrence whereas only 4 patients (7.7%) in the bevacizumab group experienced seizures (p &lt; 0.001). Multivariable binary logistic regression analyses, including sex, age, performance status, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and first-line treatment confirmed bevacizumab to be inversely associated with seizures in the 12 weeks after first recurrence (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06-0.94, p = 0.009).Bevacizumab may contribute to a reduction in seizure frequency in patients with recurrent glioblastoma.
EPCO-18. UNSUPERVISED MACHINE LEARNING ON TUMOR IMMUNE TRANSCRIPTOMIC DATA REVEALS DISTINCT IMMUNOLOGIC SUBTYPES OF GLIOBLASTOMA
Authors: Haddad Alexander F , Chen Jia Shu , Perera Sudheesha , Reddy Anvith , Ambati Vardhaan , Aghi Manish 
Published: November 2022

Abstract
Glioblastoma (GBM) has demonstrated a limited therapeutic response to single-agent immunotherapies, highlighting the need for a better understanding of GBM tumor immune phenotypes to inform targeted immunologic treatments. To elucidate GBM immunologic phenotypes we performed unsupervised machine learning on microarray transcriptomic data from 815 newly diagnosed GBM patients. We utilized immune genes only and performed k-means clustering for k=2-10 with within-cluster sum of squares and silhouette methods used to identify the optimal number of clusters. Identified subtypes were further characterized using xCell to estimate the tumor infiltration of 64 immune and stromal cell types. Two primary immunologic subtypes were identified: subtype 1 (423 patients) and subtype 2 (392 patients). There was no difference in patient age (mean age 58 years) or gender between subtypes. Subtype 1 was primarily classical subtype GBMs (50.5%, p&lt; 0.001), while subtype 2 was composed of primarily mesenchymal subtype GBMs (74.2%). Relative to subtype 1, subtype 2 was characterized by high expression of immune checkpoint and co-stimulatory proteins, including CD86, OX40L, IDO1, and LAG3. Subtype 2 also had increased activation of immune genes associated with cytolytic activity and antigen processing. In addition, subtype 2 had increased infiltration of M2 macrophages, monocytes, dendritic cells, and neutrophils while subtype 1 had higher infiltration of CD8 naïve T cells. Multivariate logistic regression confirmed that subtype 2 was characterized by monocytes, M1 and M2 macrophages, neutrophils, and dendritic cells while subtype 1 was characterized by CD8 naïve T cells, regulatory T cells, and naive B cells. Subtype 2 had reduced progression-free survival, but there was no difference in overall survival between the two subtypes. In summary, unsupervised machine learning of GBM immune transcriptomic data identified two immune phenotypes, one of which was more immunologically active than the other, potentially informing future personalized immunotherapy treatments.
IMMU-02. STANDARDIZATION OF THERAPY AND MANUFACTURING USING TUMOR-ASSOCIATED ANTIGEN-STIMULATED AUTOLOGOUS DENDRITIC CELLS CO-CULTURED WITH CYTOKINE-INDUCED KILLER CELLS IN CANCER IMMUNOTHERAPY
Authors: Yen Chun-Ming , Fu Yun-Yen 
Published: November 2022

Abstract

BACKGROUND
The application of DC-CIK in the field of cancer immunotherapy has been shown to be an effective treatment. However, the cost of DC-CIK treatment is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are the main limitations.

METHODS
Our experiments used tumor lysate instead of tumor cell line as tumor-associated antigen source with DCs co-culture. We provide the most efficient method for obtaining autologous DC-CIK cells from peripheral blood. Flow cytometry was used to evaluate DCs activation, CBA assay was used to quantify cytokines secreted by CIK cells, and the antitumor activity of DC-CIK was evaluated in vitro by K562 cell line.

RESULTS
We demonstrate that the manufacturing process of employing frozen Peripheral Blood Mononuclear Cells (PBMCs) can balance patient’s comfort and economic benefits. DC-CIK can effectively upgrade the immunological specificity of CIK cells to tumors in the presence of tumor-associated antigen. In vitro experiments showed that when the number of DC: CIK cells was co-cultured in 1:20 ratio on the 14th day, the amount of cytokine secreted by CIK cells was the largest, and the anti-tumor immune effect was the most potent. When the number of CIK: K562 cells was in 25:1 ratio, the cytotoxic activity of CIK on K562 cells was the highest.

CONCLUSION
We developed an efficient activated fashion of DC:CIK, established the optimal ratio of DC-CIK immunologic activity and the best cytotoxic model of CIK to K562 cells.
IMMU-23. ELIMINATING MONOCYTE CHEMOATTRACTION INVOKES COMPENSATORY NEUTROPHIL INFLUX AND PRONEURAL TO MESENCHYMAL TRANSITION IN GLIOBLASTOMA
Authors: Chen Zhihong , Soni Nishant , Pinero Gonzalo , Giotti Bruno , Eddins Devon , Lindblad Katherine , Ross James , Tsankova Nadejda , Gutmann David , Lira Sergio , Lujambio Amaia , Ghosn Eliver , Tsankov Alexander , Hambardzumyan Dolores 
Published: November 2022

Abstract
Myeloid cells comprise the majority of immune cells in tumors, where their content and composition is determined by tumor type and driver mutation. While these cells are essential for shaping the tumor microenvironment, promoting tumor growth, and contributing to therapeutic resistance, targeting tumor-associated myeloid cells, including bone-marrow-derived monocytes and neutrophils, has not been successful in the clinics. Monocyte chemoattractant protein (MCP) family, comprising of Ccl2, Ccl7, Ccl8, Ccl12, are essential for monocytes trafficking to the tumor sites. To eliminate monocyte recruitment, we leveraged CRISPR/Cas-9 based gene editing tool to generate a mouse strain that is devoid of all MCP genes, which we termed quadruple MCP knockout (qMCP-/-). Using these mice in combination with genetically engineered mouse models (GEMM) of glioblastoma (GBM), we abolished tumor monocyte infiltration. Due to the functional redundancy of MCP family members, we show that targeting individual MCP genes leads to compensation by other MCPs. In contrast, when all MCPs are genetically deleted and monocyte recruitment is abolished, neutrophil infiltration ensues. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Remarkably, pharmacologic or genetic interventions that suppress both monocytes and neutrophil infiltration improve the survival of GBM-bearing mice. Taken together, our findings establish that specific subsets of myeloid cells can influence the dynamism of tumor microenvironment, and they emphasize the importance of targeting both monocytes and neutrophils simultaneously for effective GBM immunotherapy.