bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-26. WHOLE GENOME SEQUENCING OF AN OSSEOUS METASTASIS DURING CHECKPOINT-CONTROLLED INTRACRANIAL GLIOBLASTOMA REVEALS NEW INSIGHTS INTO POTENTIAL MECHANISMS OF IMMUNE ESCAPE
Authors: Mohme Malte , Maire Cecile , Schliffke Simon , Joosse Simon , Alawi Malik , Lamszus Katrin , Westphal Manfred 
Published: November 2019

Abstract
Glioblastoma (GBM) has a devastating prognosis and recent advances in the treatment of a variety of cancer entities, e.g. through checkpoint inhibition, could so far not be translated into improved outcome in newly-diagnosed GBM. Characterizing rare cases of peripheral metastases which succeeded in overcoming immune control, can help to understand the mechanisms of immune escape. Here we describe the first reported case of a detailed genetic and immunological characterization of a peripheral bone metastasis from a GBM which was controlled intracranially by anti-PD1 checkpoint inhibition We performed whole genome sequencing (WGS) of the primary- and recurrent tumor, as well as the bone metastasis. Genomic data was analyzed for copy number variations and mutational profiles. In addition, immune monitoring with flow cytometric phenotyping and next-generation sequencing of the peripheral T-cell repertoire was used. A 70-year old patient developed multiple osseous metastases in the spine, while his IDHwt GBM recurrence was immunologically controlled with checkpoint inhibition. Biopsy confirmed peripheral GBM metastases. Immunophenotyping reflected the effective activation of the peripheral T-cell response, with, however, simultaneous upregulation of regulatory T-cells during disease progression. WGS sequencing demonstrated a distinct molecular profile of the GBM metastasis, with amplifications in chromosome 3 and 9, as well as genomic loss on chromosomes 4, 10 and 11. The peripheral metastasis was distinguished by mutations in mismatch repair genes, such as MSH4 and MLH1, associated with a hypermutated phenotype. Among the mutated genes we found potential candidates involved in immune escape of circulating tumor cells. This case represents a unique opportunity to analyze potential mechanisms of GBM-mediated immune escape during immune activation with anti-PD1 checkpoint therapy. It highlights the fact, that although an effective, disinhibited immune response can control the cranial GBM disease, hypermutated tumor clones can evade the tumor-specific T-cell response and disseminate to distant organs.
RARE-29. AZD8055 ENHANCES IN VIVO EFFICACY OF AFATINIB IN CHORDOMAS
Authors: Zhao Tianna , Siu I-Mei , Williamson Tara , Zhang Haoyu , Ji Chenchen , Burger Peter , Cottone Lucia , Flanagan Adrienne , Hann Christine , Gallia Gary 
Published: November 2019

Abstract

INTRODUCTION
Chordomas are rare, locally aggressive bone tumors that arise in cranial base, mobile spine, and sacrum. Currently, there are no FDA-approved therapies for chordoma patients, thus there is a high unmet need to develop effective treatments. In this study, we aim to evaluate the anti-tumor efficacy of small molecule inhibitors that target crucial oncogenic pathways in chordoma, as single agents or in combination, to identify novel therapies with the greatest translation potential.

METHODS
A panel of small molecule compounds that had exhibited in vitro efficacy against human chordoma cell lines or target known chordoma drivers was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and their efficacy was further evaluated using chordoma cell lines and xenograft models.

RESULTS
The in vivo activity of compounds identified in a NIH Chemical Genomics Center screen utilizing chordoma cell lines, together with inhibitors of c-MET and PDGFR, were evaluated in PDX models of chordoma that were previously described or recently established for this study. Inhibitors of EGFR (BIBX1382, erlotinib and afatinib), c-MET (crizotinib) or mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, co-inhibition of EGFR and mTOR also synergistically suppressed tumor growth in vivo, showing improved disease control.

CONCLUSION
Single inhibition of EGFR, c-MET or mTOR suppresses chordoma growth both in vitro and in vivo. Co-inhibition of EGFR and mTOR synergistically inhibits chordoma growth in a range of preclinical models. The insights gained from our study provide a novel combination therapeutic strategy for patients with chordoma.
RARE-40. OUTCOMES AFTER PROTON THERAPY FOR SKULL-BASE CHORDOMA: A PROSPECTIVE STUDY
Authors: Holtzman Adam , Rotondo Ronny , Rutenberg Michael , Indelicato Daniel , Rao Dinesh , Louis Debbie , Morris Christopher , Mendenhall William 
Published: November 2019

Abstract
We evaluated treatment outcomes following definitive or adjuvant high-dose, image-guided proton therapy in 91 patients with skull-base chordoma enrolled on a prospective outcomes tracking protocol and treated between February 2007 and February 2018. The median age was 53 years (range, 22–78 years). Patients received passively scattered 3-dimensional conformal proton therapy to a median dose of 73.8 GyRBE (range, 69.6–75.6 GyRBE). Two patients received a component of intensity-modulated radiotherapy. Seventy percent (n=64) were men and 30% (n=27) were woman. Eighty-two percent (n=75) of patients had macroscopic disease at the time of radiotherapy; 18% (n=16) had undergone a macroscopic gross total resection. Overall survival, cause-specific survival, local control, and RT-related grade 3 toxicity-free survival were calculated. Proton therapy-related toxicities were scored using CTCAE v4.0. With a median follow-up of 3.7 years (range, 0.2–10 years), 26 patients experienced disease recurrence, including 26 local, 0 regional, and 1 distant recurrence. The median time to local progression was 2.2 years (range, 0.4–7.0 years). At the time of last follow-up, 66 patients were alive (56 with no evidence of disease progression) and 25 were deceased (18 with disease progression). There were no acute grade 3 toxicities related to the radiation therapy. The 4-year actuarial rates of overall survival, cause-specific survival, local control, and radiation therapy-related grade 3 toxicity-free survival were 83%, 87%, 76% and 83%, respectively. Definitive or adjuvant high-dose passively scattered 3-dimensional conformal proton therapy for skull-base chordoma provides acceptable local control, comparing favorably to historic photon data, with no acute grade ≥3 radiation-related toxicity and an acceptable rate of grade ≥3 late toxicity. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities.
RARE-42. INCIDENCE AND BEHAVIOR OF CENTRAL NERVOUS SYSTEM INVOLVEMENT IN PATIENTS WITH HODGKIN’S LYMPHOMA
Authors: Eduardo Silva Correia Carlos , Malani Rachna , DeAngelis Lisa , Moskowitz Alison 
Published: November 2019

Abstract

INTRODUCTION
Central nervous system (CNS) involvement from Hodgkin’s Lymphoma (HL) is rare, with a reported incidence of 0.07–0.5%. There is a paucity of data regarding its natural history and management.

METHODS
In this retrospective single-institution review, we analyzed all adult patients with HL for CNS involvement (parenchymal or meningeal), who were evaluated at Memorial Sloan Kettering Cancer Center from January 2008 until December 2018.

RESULTS
A total of 3478 patients with HL were identified, and CNS involvement was found in 10 patients (0.3%). All patients were symptomatic from CNS disease. Four patients had a synchronous presentation. The other 6 patients had a median time from systemic diagnosis to CNS involvement of 8 years (2.5–14). Two patients had radiographic evidence of leptomeningeal disease, however 4 had positive cerebrospinal fluid (CSF) cytology. At time of CNS involvement, 2 patients had confirmed transformation to Non-Hodgkin-Lymphoma on biopsy. 2 patients had EBV-positive HL. One patient died before treatment. Five patients received high-dose methotrexate (HD-MTX) for CNS disease. Of these patients, 1 died during treatment, 2 had partial responses, and 2 had complete response of both systemic and CNS disease; to date they are in remission. Three patients had varied responses to immunotherapy and cytotoxic chemotherapy. Removal of an immunosuppressive agent resolved disease in one EBV-positive patient. Median overall survival (OS) from diagnosis of HL was 10.6 years (1.1–21.2), and OS from time to CNS involvement was 6 years (0.2–15).

CONCLUSION
The median time from diagnosis to CNS involvement, and OS from time of CNS involvement are higher than previously reported, which may be related to newer therapies for systemic disease. Neuroimaging should be used in conjunction with CSF for diagnostic accuracy. HD-MTX can be used to treat CNS and refractory systemic disease, as historically used for the latter.
RARE-53. THE ROLE OF RADIATION AND CHEMOTHERAPY IN ADULT PATIENTS WITH HIGH-GRADE BRAINSTEM GLIOMAS
Authors: Kerezoudis Panagiotis , Lu Victor , Alvi Mohammed , Goyal Anshit , Bydon Mohamad , Kizilbash Sani , Burns Terry 
Published: November 2019

Abstract

BACKGROUND
High-grade gliomas (HGGs) of the brainstem represent a rarer subtype of central nervous system tumors compared to their supratentorial counterpart. Predictors of survival and patterns of care have not yet been established on a national, multi-institutional scale.

METHODS
The National Cancer Database was queried for adult cases surgically diagnosed with brainstem high-grade glioma. An array of patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Predictors of survival were investigated using multivariable Cox proportional hazards regression analysis adjusting for age, insurance status, Charlson comorbidity score, tumor grade, tumor size and type of treatment.

RESULTS
A total of 422 patients (median 51 years, 60% males) were analyzed. Two hundred eighty one received postoperative radiation with chemotherapy (66.6%), thirty-nine had radiation alone (9.2%), while the remaining had no adjuvant treatment (24.2%). Median radiation dosage was 54Gy. Overall median survival was 9.8 months (95% CI 8.8–12). Survival was significantly longer (p< .001) in the chemotherapy+radiation group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no adjuvant treatment (median:1.8 months, 95% CI 1.4–4). In multivariable analysis, increasing age (HR 1.87, 95% CI 1.47–2.37, p< .001) was associated with worse survival, whereas radiation with chemotherapy (HR 0.67, 95% CI 0.46–0.98, p=0.038) were associated with lower hazards of death compared to radiation alone. In subgroup analysis, the effect of adjuvant chemotherapy with radiation remained significant for grade IV (HR 0.46, 95% CI 0.28–0.76, p=0.003), but not for grade III tumors (HR 0.87, 95% CI 0.48–1.58, p=0.65).

CONCLUSION
Findings of the present analysis demonstrate the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should aim on identifying specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.
RARE-56. RECURRENCE PATTERN AND SURVIVAL FOR RELAPSED INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS: A SINGLE-INSTITUTION EXPERIENCE
Authors: Wen Lei , Zhou Zhaoming , Li Juan , Zhou Cheng , Lai Mingyao , Cai Linbo 
Published: November 2019

Abstract

PURPOSE
Intracranial non-germinomatous germ cell tumors (NGGCTs) have lower overall survival than germinoma because higher recurrence usually occurs after first line therapy in NGGCTs.

METHODS
Between January 2003 and December 2017, 23 patients with clinically or pathologically diagnosed recurrent NGGCTs after first line therapy were reviewed at our institution. Data of first line treatment, salvage treatment, clinicopathological features and survival were collected and analyzed.

RESULTS
First line therapy including craniospinal irradiation (CSI) in 15 patients, surgery in 3 patients, Gamma knife in 2 patients, chemotherapy in 2 patients and whole brain radiotherapy (WBRT) in 1 patient. The median time to recurrence was 13.8 months (5.8 to 89.2). With reference to the distribution of relapsed lesions, there were 8 patients within the primary site, 6 with distant intracranially, 1 ventricularly, 5 in spinal cords, 1 with dual sites in both primary site and intracranially, and 1 patient evidenced only serologically positive. Three patients did not receive further treatment and was lost during follow-up. Of the other patients, 16 patients received salvage chemotherapy with or without surgery, 4 received CSI or radiosurgery. After median follow up of 54 months, 7 patients died of disease progression. The 4-year overall survival rate after recurrence was 55.4%.

CONCLUSION
Protracted follow-up is recommended because late recurrence is not uncommon. Primary tumor site and distant intracranial are the most prevalent relapsed location. Patients who relapsed could benefited from salvage chemotherapy.
STEM-05. NEURAL G0: A NOVEL QUIESCENT-LIKE STATE IN PROLIFERATING HUMAN NEURAL STEM AND GLIOBLASTOMA TUMOR CELLS
Authors: Feldman Heather , Arora Sonali , Hoellerbauer Pia , Pollard Steven , Patel Anoop , Plaisier Christopher , Paddison Patrick 
Published: November 2019

Abstract
Single cell (sc) genomic technologies are rapidly transforming our understanding of cellular states in normal and diseased tissues. Here, we applied scRNA-seq to cultures of proliferating human neural stem cells (NSCs) to better understand the relationship between cell cycle dynamics and developmental gene expression. This analysis revealed both conventional cell cycle states (S, G2, M) and novel G1 and G0-like states. Of note, we identified a Neural G0 phase representing a subpopulation enriched for expression of genes associated with adult quiescent NSCs, including CLU, HOPX, ID3, OLIG2, PTN, SYT11, S100B, SOX9, PTPRZ1, and TTYH1. Remarkably, by applying our hNSC cell cycle phase classifier to human glioblastoma (GBM) tumors, we found that Neural G0 subpopulations as a prominent tumor-specific cellular subclass of GBM tumors, which, similar to NSCs, does not overlap with proliferative cell cycle phases. We further identified modulators of Neural G0 via CRISPR-Cas9 screens, revealing highly significant enrichment for tumor suppressor genes associated with brain tumors. In depth analysis of five of these Neural G0 modulatory genes, including CREBBP, NF2, PTPN14, TAOK1, or TP53, revealed that they promote compartmentalization of G0/G1 phase and expression of genes associated with Neural G0. Our results suggest that Neural G0 is a dynamic cell state in mammalian NSCs, that a subset of GBM cells maintain and is modulated by genes commonly found altered in GBM.
STEM-06. TISSUE FACTOR SIGNALING IN GLIOBLASTOMA TUMOR-INITIATING CELLS
Authors: Tran Anh , Unruh Dusten , Mirkov Snezana , Horbinski Craig 
Published: November 2019

Abstract
Glioblastoma (GBM) is an aggressive form of brain cancer with few treatment options, characterized by over-activation of receptor tyrosine kinases (RTKs). Brain tumor-initiating cells (BTICs) is a subpopulation of cells in GBM which have the unique capacity to self-renew, facilitating recurrence. Tissue Factor (TF), normally involved in blood coagulation, is elevated in GBM and strongly correlates with more aggressive behavior. We hypothesize that TF promotes malignant behavior in glioblastoma by activating protease-activated receptor 2 (PAR2), leading to RTK stimulation and the maintenance of brain tumor-initiating cells. Therefore, our approaches are to determine: the mechanisms by which TF-PAR2 stimulates RTK signaling in GBM; the role of RTKs in mediating TF-induced BTIC maintenance in GBM, and the effect of blocking TF signaling on RTK-based therapies against GBM. Our data indicate that TF can activate multiple classes of tumor-promoting RTKs, and sustains cell proliferation through its main receptor, PAR2, even in the presence of an RTK inhibitor. We also found that TF suppression impairs the BTIC phenotype in high TF-expressing, RTK-driven GBM. This project will advance our understanding of how TF promotes malignant behavior, identify a powerful means by which cancers can resist RTK inhibitors currently in clinical use, and demonstrate the therapeutic potential of blocking TF-PAR2 signaling in cancer.
STEM-11. CD146/MCAM REGULATES MESENCHYMAL PROPERTIES, STEMNESS, RADIO-RESISTANCE AND YAP ACTIVITY IN GLIOBLASTOMA
Authors: Liang Yuan-Ke , Voshart Daniëlle , den Dunnen Wilfred , Barazzuol Lara , Kruyt Frank 
Published: November 2019

Abstract
Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemoradiotherapy resistance resulting in recurrences and poor prognosis. In this study we examined if the cell adhesion molecule CD146/ MCAM is contributing to the malignant properties of GBM, as it is known to have multiple protumorigenic functions in other tumor types. TCGA GBM database analyses revealed enhanced levels of CD146 in GBM compared to normal brain. A panel of patient-derived GBM spheroids, enriched for GBM stem cells (GSC), displayed variable and modest expression of CD146 that was strongly enhanced by cell adherence mediated by serum differentiation or ECM-coating. TGF-β-induced mesenchymal transition in U87 cells was accompanied by induction of CD146 expression, whereas ectopic overexpression of CD146/GFP in GG16 spheroids increased mesenchymal marker expression and cell invasion. Conversely, CRISPR/Cas9-generated CD146 knockouts in GSC23 spheroids led to reduced mesenchymal marker expression and invasion. These results were confirmed by applying embryonic stem cell-derived brain organoids as models to study invasion. Hence, GBM spheroid - brain organoid fusions demonstrated a stimulatory function of CD146 on invasion. Moreover, stem cell marker expression and clonogenic assays showed that CD146 increases the stem cell potential of GBM cells. The CD146 ectopic overexpression and knockout models also demonstrated involvement of CD146 in resistance to radiation that could be mechanistically linked with CD146-dependent suppression of p53 accumulation and activation of NF-kB. Interestingly, exploration of additional mechanisms potentially involved in CD146 functioning, led to the discovery that the oncogenic protein Yes-associated protein (YAP) is also regulated by CD146. Together, our findings demonstrate the importance of CD146 in controlling tumor aggressiveness and radioresistance in GBM cells.
STEM-15. RADIATION-INDUCED MODULATION OF NEURODEVELOPMENTAL PATHWAYS IN CLASSICAL GLIOMA STEM CELLS
Authors: Lo Cascio Costanza , Luna Melendez Ernesto , McNamara James , Schultz Robert , Tien An-Chi , Plaisier Christopher , Mehta Shwetal 
Published: November 2019

Abstract
The current standard-of-care treatment for GBM is ineffective and fails to significantly prolong survival. Following exposure to aggressive multimodal treatment, GBMs have been shown to frequently shift their biological features upon recurrence, acquiring a more resistant phenotype. However, the temporal dynamics and molecular mechanisms that facilitate GBM recurrence are poorly understood. The objective of our study was to assess the acute response to ionizing radiation in glioma stem cells (GSCs) from the Classical subtype of GBM in vitro and in vivo. We find that Classical GSCs rapidly undergo dramatic molecular and cellular changes in response to single and fractionated doses of ionizing radiation, resulting in a heterogeneous cell population. Ionizing radiation causes a transient decrease in the expression of key stemness genes (e.g., SOX2) followed by drastic morphological changes and a concomitant significant increase in the levels of key cell fate markers expressed in adult quiescent neural stem cells. Radiation-induced alteration of SOX2 levels in Classical GSCs is dependent on intact p53 signaling. GSCs previously exposed to radiation are more radio-resistant upon re-treatment compared to their naïve, untreated counterparts – suggesting that the aforementioned phenotypic shift to a quiescent neural stem cell phenotype promotes treatment resistance. Our results suggest that cell-intrinsic factors dictate how GSCs respond to radiation, and that Classical GSCs are neurodevelopmentally predisposed to shift towards an astrocytic/neural stem cell identity in response to cellular stress.
STEM-16. DUAL INHIBITION OF PROTEIN ARGININE METHYLTRANSFERASE 5 AND PROTEIN PHOSPHATASE 2A ENHANCES THE ANTI-TUMOR EFFICACY IN PRIMARY GLIOBLASTOMA NEUROSPHERES
Authors: Sur Hannah , Gangaplara Arunakumar , Wang Xiang , Ray-Chaudhury Abhik , Zhuang Zhengping , Kumar Sachin , Heiss John , Young Yoo Ji , Kaur Balveen , Kumar Banasavadi-Siddegowda Yeshavanth 
Published: November 2019

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most common malignant primary brain tumor and has a heterogeneous tumor cell population. The median survival of GBM patients is less than two years with current multi-model therapy of maximal surgical resection followed by chemotherapy, radiation and tumor treating fields. Protein Arginine Methyltransferase 5 (PRMT5) regulates cellular functions through symmetric di-methylation of arginine residues of histone and non-histone proteins. Our recent findings show that PRMT5 is overexpressed in GBM; its inhibition causes apoptosis and senescence of mature and immature GBM tumor cells respectively. Protein Phosphatase 2A (PP2A), a serine-threonine phosphatase, is associated with senescent tumor cells that contribute to therapy resistance; LB100 is a first-in-class small molecule inhibitor of PP2A that can sensitize tumor cells that are chemo- and radiation-therapy resistant. In this study, using patient-derived primary GBM neurospheres (GBMNS), we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition.

METHODS
Patient-derived primary GBM neurospheres transfected with PRMT5 target-specific siRNA were treated with LB100 and subjected to in vitro assays such as proliferation assay, cell cycle analysis, cytotoxicity assay, PP2A activity and western blot.

RESULTS
LB100 treatment significantly reduced the viability of PRMT5-depleted GBM cells as compared to PRMT5 intact cells. LB100 caused G1 cell cycle arrest through inactivation of Rb protein; this effect is further enhanced in combination with PRMT5-depletion. Combination therapy also increased the expression of phospho-MLKL; Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100 indicating that necroptosis caused the enhanced cytotoxicity in combination therapy. We also found that PRMT5-depletion increased the PP2A activity in GBM neurospheres.

CONCLUSION
Combining the PRMT5 inhibition and PP2A inhibition produced greater antitumor effects than with PRMT5 inhibition alone.