tbuckley/cabot-search huggingface dataset:
INNV-36. A METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY MAY PROLONG SURVIVAL FOR PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR
Authors: Irene Slavc, Andreas Peyrl, Monika Chocholous, Amedeo Azizi, Dominik Reisinger, Lisa Mayr, Johannes Gojo, Thomas Czech
Journal: Neuro-Oncology (2018)

Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 32 patients with recurrent medulloblastoma and ATRT treated with an antiangiogenic combination therapy. PATIENTS AND From 11/2006 to 02/2018, 32 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (14 first, 6 multiple recurrences) and 12 with recurrent ATRT (6 first, 6 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and aqueous or liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 3 (1–12) years for ATRT. As of 05/2018, 10/20 patients with medulloblastoma are alive, eight in CR, six off therapy for 96, 79, 77, 34, 12, and 4 months. 5-year-OS is 54.5 ± 11.2% and 5-year-EFS is 25.0 ± 9.7%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy. 6/12 patients with ATRT are alive and in CR for 123, 90, 45, 9, 6 and 3 months after start of antiangiogenic therapy, the first three off therapy. OS for the whole cohort was 47.7 ± 16.6% at 3 years and 31.8 ± 17.1% at 5-years with a median OS of 22.8 months (KI 0.0–66.8). Therapy was generally well tolerated and toxicities were manageable. The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.
PDTM-08. ROLE OF miR-212 AS A TUMOR SUPPRESSOR GENE IN NON-SHH/WNT MEDULLOBLASTOMA
Authors: Naveen Perumal, Ranjana Kanchan, Mohd Nasser, Surinder Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is divided into four subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Among them, haploinsufficiency of chromosome 17p13.3 is most commonly seen in Group 3 and 4 tumors, which are concurrently associated with the poorest prognosis. Recent studies have revealed the importance of microRNAs (miRNAs) in regulating posttranscriptional gene expression in MB tumorigenesis. In this study, we sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the development of non-SHH/WNT medulloblastoma. RNA expression analysis showed significantly reduced expression of miR-212 in MB tumor cell lines and in ex vivo non-SHH/WNT MB tumor samples (n=16). To further elucidate its putative tumor suppressor role, miR-212 was over-expressed in non-SHH/WNT tumor cell line, HDMB03, followed by functional assays of tumor cell behavior. In these studies, significantly reduced cell proliferation, colony formation, migration and invasion were noted. Additionally, reduced levels of pAKT, a marker of cell proliferation, was confirmed in miR-212-overexpressing HDMB03 cells. Subsequent cell cycle analysis revealed increased G0/G1 cell cycle arrest with a concurrent reduction in the corresponding cell cycle regulatory proteins, i.e. CDK6 and cyclinD1. Myc amplification, which is facilitated by phosphorylation of serine-62 (p-c-Myc-S62), is a characteristic feature of Group 3 medulloblastoma and a marker of poor prognosis. Decreased levels of p-c-Myc-S62 (active form favoring proliferation) with a complimentary increase in p-c-Myc-T58 (inactive form favoring apoptosis) results in degradation of c-Myc protein and cellular apoptosis, a trend recapitulated in miR-212-overexpressing HDMB03 cells. In addition, the pro-apoptotic binding partners of c-Myc, i.e. Bin-1 and P19ARF, were noted to be upregulated in miR-212 over-expressed HDMB03 cells, further favoring apoptosis. That c-myc may also serve as a target of miR-212 is currently being studied. These results substantiate miR-212 as a tumor suppressor gene in non-SHH/WNT medulloblastoma.
TMOD-11. IMAGING BASED INVASION METRIC PREDICTIVE OF RESPONSE TO ABT414 IN ORTHOTOPIC EGFRviii AMPLIFIED PATIENT DERIVED XENOGRAFTS
Authors: Susan Christine Massey, Bianca Marin, Andrea Hawkins-Daarud, Lisa Paulson, Lauren Kasle, Pamela Jackson, Ann Mladek, Jann Sarkaria, Kristin Swanson
Journal: Neuro-Oncology (2018)

Failed trials involving targeted therapies face a daunting task of understanding whether the root cause was inadequate targeting, resistance, or insufficient delivery to the tumor. Previous work with a bio-mathematical model has shown the prognostic value of an imaging based invasion metric, D/ρ (mm2/yr), which is linearly correlated with the extent of tumor burden beyond the imaging abnormality. As this extent likely impacts the definition of sufficient drug delivery, we investigated whether this metric is able to predict response to ABT-414, an antibody drug conjugate targeting EGFR. Preclinical experiments: After initial screening in vitro and in flank, the efficacy of ABT-414 was evaluated for three patient derived cell lines (PDXs), GBM6, GBM12, and GBM39, implanted orthotopically. All three showed strong response to ABT-414 in the previous experiments. In the orthotopic setting, GBM39 was very sensitive to therapy (> 155 days benefit), GBM12 was moderately sensitive (15–30 days benefit), and GBM6 was resistant to therapy (no benefit). Invasion Index: D/ρ was calculated for each cell line based on the original patients’ pre-treatment T1-weighted with Gd contrast and FLAIR MRIs. We then analyzed whether D/ρ was correlated with the observed response to ABT-414. GBM6 had the highest D/ρ = 4.7 (greatest proportion of tumor cells invaded beyond the imaging abnormality), GBM12 was in the middle with D/ρ = 1.7, and GBM39 had the lowest D/ρ = 0.9. This perfectly (inversely) correlates with the response patterns. GBM6 showed no response, GBM12 had a moderate response, and GBM39 showed the greatest response to ABT-414. Our results suggest that the imaging based tumor invasion metric, D/ρ, is inversely correlated with tumor response to ABT-414. This supports our hypothesis that drugs with low BBB permeability will be more beneficial for tumors with little tumor burden beyond the imaging abnormality.
CSIG-38. ROBO2 SIGNALING IN INVASION OF GLIOBLASTOMA
Authors: Amber Kerstetter-Fogle, Harris Peggy, Jill Barnholtz-Sloan, Marta Couce, Andrew Sloan
Journal: Neuro-Oncology (2018)

Glioblastoma accounts for 54.3% of newly diagnosed glioma in the United States each year. Rapid growth and invasion confers a devastating phenotype with very limited treatment options at recurrence. Numerous studies of the molecular alterations in GBM have been conducted but few have completely characterized the invasiveness characteristic of GBM. The roundabout (Robo) family of transmembrane receptors and their Slit protein ligands, have been demonstrated to be involved in neuronal migration and outgrowth during CNS development and implicated in various cancers. We hypothesize that Slit-Robo pathway may be involved in GBM cell invasion. We reviewed numerous databases and analyzed protein and RNA from GBM samples. Analysis of the NCI Rembrandt database indicated poorer survival among glioma patients with a greater than two-fold overexpression of the Robo2 gene (17.1 months versus 37.4 months; p=1.42E-4). GBM tumor was identified prospectively on pre-operative MRI and sampled using stereotactic image-guided resection from various regions within the tumor. In tissue samples from 6 GBM and 3 control patients, indicted a 2.5 fold difference in the expression of Robo2 protein. Quantitative PCR and Western blot confirmed a 101- fold increase in mRNA expression. Knockdown of the mRNA using siRNA directed against Robo2 in U87 cells resulted in survival advantage (65.5 days versus 52.5 days; p=0.011). These data suggest a complex and heterogenous tumor microenvironment and implicates Robo axis signaling in GBM as a potential therapeutic target.
CD33/CD3-bispecific T-cell engaging (BiTE®) antibody construct targets monocytic AML myeloid-derived suppressor cells
Authors: Regina Jitschin, Domenica Saul, Martina Braun, Sehmus Tohumeken, Simon Völkl, Roman Kischel, Michael Lutteropp, Cedric Dos Santos, Andreas Mackensen, Dimitrios Mougiakakos
Journal: Journal for ImmunoTherapy of Cancer (2018)

Acute myeloid leukemia (AML) is the most common acute leukemia amongst adults with a 5-year overall survival lower than 30%. Emerging evidence suggest that immune alterations favor leukemogenesis and/or AML relapse thereby negatively impacting disease outcome. Over the last years myeloid derived suppressor cells (MDSCs) have been gaining momentum in the field of cancer research. MDSCs are a heterogeneous cell population morphologically resembling either monocytes or granulocytes and sharing some key features including myeloid origin, aberrant (immature) phenotype, and immunosuppressive activity. Increasing evidence suggests that accumulating MDSCs are involved in hampering anti-tumor immune responses and immune-based therapies. Here, we demonstrate increased frequencies of CD14<sup>+</sup> monocytic MDSCs in newly diagnosed AML that co-express CD33 but lack HLA-DR (HLA-DR<sup>lo</sup>). AML-blasts induce HLA-DR<sup>lo</sup> cells from healthy donor-derived monocytes in vitro that suppress T-cells and express indoleamine-2,3-dioxygenase (IDO). We investigated whether a CD33/CD3-bispecific BiTE® antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33<sup>+</sup> MDSCs. In fact, T-cells eliminate IDO<sup>+</sup>CD33<sup>+</sup> MDSCs in the presence of AMG 330. Depletion of total CD14<sup>+</sup> cells (including MDSCs) in peripheral blood mononuclear cells from AML patients did not enhance AMG 330-triggered T-cell activation and expansion, but boosted AML-blast lysis. This finding was corroborated in experiments showing that adding MDSCs into co-cultures of T- and AML-cells reduced AML-blast killing, while IDO inhibition promotes AMG 330-mediated clearance of AML-blasts. Taken together, our results suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell-mediated cytotoxicity against AML-blasts but also against CD33<sup>+</sup> MDSCs, suggesting that it is worth exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy.
RTHP-14. TUMOR-TREATING FIELDS FOR GLIOBLASTOMA: NUMERICAL SIMULATION EXPLORES SUB-CELLULAR MECHANISMS
Authors: Kristen Carlson, Nirmal Paudel, Socrates Dokos, Jack Tuszynski
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) 100–500 kHz electric fields at ~1–4 V/cm exert an anti-mitotic effect on cancer cells. Our goal is to uncover TTFields mechanism by numerically modeling their effects on sub-cellular structures, notably microtubules (MTs). We built a geometrically accurate finite element model in COMSOL Multiphysics (tm) of the MT and its micro-environment as a layered 27 nm-diameter cylinder: the inner lumen; 13 helical strands of alpha-beta tubulin dimers; C-termini; counter-ion layer; and an outer non-conductive Bjerrum layer. Modeling current density induced in each layer by TTFields for MTs varying in length from 1 10 µm showed that MTs act as electrical shunts conducting electric current within them. The resulting strongest current flows through the counter-ion layer surrounding the C-termini and energy density in this layer exceeds the level likely to disrupt the motor protein kinesin walk along the C-termini. The energy density is highest predicted at 1e-20 Joules when both the field and the MTs are aligned with the cell axis, in accord with in vitro experiments. A second mechanism predicted by our model is disruption of the foot of kinesin, released from its C-terminus contact by ATP (1e-19 Joules). The final phase of the walk is driven by thermal buffeting of the forward foot randomly positioning it near enough to the C-terminus for electrostatic forces to bind it. A stall force ~1e-19 - 1e-16 N from TTFields would prevent diffusion and disrupt the kinesin walk. Our modeling predicts that TTFields in cytosol induce electric currents along MTs that are strong enough to disrupt key cellular functions such as the kinesin walk and C-termini transitions, which are crucial for motor protein transport. Hence, TTFields disrupt the most delicate mechanisms involved in the carefully-orchestrated succession of steps in mitosis.
Abstract 17314: Human Mesenchymal Stem Cell Therapy Reverses Sugen/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice
Authors: Allan K Alencar, Guilherme C Montes, Luiza V Mendes, Ananssa M Silva, Tadeu L Montagnoli, Maria F Toledo, Aline G Fraga, Pedro M Pimentel-Coelho, Valéria M Cunha, Rosália Mendes-Otero, Roberto T Sudo, Gisele Zapata-Sudo
Journal: Circulation (2017)

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive increase in pulmonary vascular resistance and right ventricular (RV) failure. This work evaluated the therapy with ...
CBMT-25. ANTI-TUMOR EFFECT OF VEGF INHIBITOR PLUS KETOGENIC DIET THERAPY FOR GLIOBLASTOMA
Authors: Masahiro Maeyama, Takashi Sasayama, Kazuhiro Tanaka, Yasuhiro Irino, Masamitsu Nishihara, Hirotomo Tanaka, Satoshi Nakamizo, Eiji Kohmura
Journal: Neuro-Oncology (2018)

INTRODUCTION: Malignant glioma cells depend on glucose as the main energy source. Cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary therapy for treatment of malignant gliomas. VEGF (vascular endothelial growth factor) inhibitor (bevacizumab) decreases blood supply to tumor and clinically used for glioblastoma treatment. Therefore, we examined anti-tumor effect of the combination of bevacizumab (Bev) and KD therapy using mouse model. U87MG cells were implanted into the right brain of nude mice. One week after the implantation, mice were randomized into four treatment groups: control group, KD group, Bev group, and combination group. KetoCal 4:1 was administered to the mice for KD. Bev (10mg/kg) was injected from tail vein twice a week. Metabolic and histological analysis of the tumor, and survival analysis of the mice were performed. 3-hydroxy-butyrate, one of the ketone bodies, was increased in the tumor of KD group, and principal component analysis (PCA) analysis demonstrate distinct clustering or a clear separation of the four groups. Histologically, density of neovascularization was more increased in the combination group, compared with control, and phospho-ERK expression and Ki-67 index were decreased in the combination group. There was no different in body weight between KD group and other groups, and there was no different in survival time between KD group and control median overall survival 26 days vs 23 days, p=0.11. However, Bev group had significant longer survival than control group median OS 40 days, p=0.0016, and the combination group had most longer survival time among four groups median OS 50 days, p=0.0015. Drastic metabolic remodeling in the tumor occurred in the combination of Bev and KD. This combination may be potentially useful for glioblastoma therapy.
A Combined Nomogram Model to Preoperatively Predict Histologic Grade in Pancreatic Neuroendocrine Tumors
Authors: Wenjie Liang, Pengfei Yang, Rui Huang, Lei Xu, Jiawei Wang, Weihai Liu, Lele Zhang, Dalong Wan, Qiang Huang, Yao Lu, Yu Kuang, Tianye Niu
Journal: Clinical Cancer Research (2018)

The purpose of this study is to develop and validate a nomogram model combing radiomics features and clinical characteristics to preoperatively differentiate grade 1 and grade 2/3 tumors in patients with pancreatic neuroendocrine tumors (pNET).Experimental Design: A total of 137 patients who underwent contrast-enhanced CT from two hospitals were included in this study. The patients from the second hospital (n = 51) were selected as an independent validation set. The arterial phase in contrast-enhanced CT was selected for radiomics feature extraction. The Mann-Whitney U test and least absolute shrinkage and selection operator regression were applied for feature selection and radiomics signature construction. A combined nomogram model was developed by incorporating the radiomics signature with clinical factors. The association between the nomogram model and the Ki-67 index and rate of nuclear mitosis were also investigated respectively. The utility of the proposed model was evaluated using the ROC, area under ROC curve (AUC), calibration curve, and decision curve analysis (DCA). The Kaplan-Meier (KM) analysis was used for survival analysis.An eight-feature-combined radiomics signature was constructed as a tumor grade predictor. The nomogram model combining the radiomics signature with clinical stage showed the best performance (training set: AUC = 0.907; validation set: AUC = 0.891). The calibration curve and DCA demonstrated the clinical usefulness of the proposed nomogram. A significant correlation was observed between the developed nomogram and Ki-67 index and rate of nuclear mitosis, respectively. The KM analysis showed a significant difference between the survival of predicted grade 1 and grade 2/3 groups (P = 0.002).The combined nomogram model developed could be useful in differentiating grade 1 and grade 2/3 tumor in patients with pNETs.
SP0159 Eular recommendations for the management of sjÖgren’s syndrome
Authors: S. Retamozo
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Sjögren's syndrome (SjS) is a systemic autoimmune disease that affects 0.1% of the European population and that presents with a wide spectrum of clinical manifestations. Primary SjS has no cure, and their therapeutic management has not changed significatively over the past decades. The current approach is still based upon symptomatic treatment of sicca symptomatology and broad-spectrum immunosuppression directed against systemic disease. In spite of the several therapeutic options available, there is insufficient information on their differential efficacy and safety, making that treatment decisions remain challenging in clinical practice. Over the last decade, research has centred on investigating more effective SS-targeted therapies, with the development of various randomised controlled trials (RCT) unfortunately with the absence of game-changing results. With these discouraging results, national efforst promoted by some scientific societies have led to the development of several sets of recommendations. The European League Against Rheumatism (EULAR) promoted and supported in 2010 an international collaborative study (EULAR SS Task Force) aimed at developing consensual disease activity indexes in SS. This work was very successful with the development of the first international specific scores for SjS (ESSPRI and ESSDAI), now widely used both in clinical and research settings. The wide consensus obtained on the development of the ESSDAI/ESSPRI scores provided an excellent opportunity to advance in the development of international recommendations for the therapeutic management of SS. Therefore, we continued the work of the Task Force with the development of evidence-, consensus-based official EULAR recommendations following the Delphi methodology, with the aim to provide physicians and patients with a rational therapeutic approach to SjS patients. <h3>Disclosure of Interest</h3> None declared
CADD-09. TARGETING Nrf2 ANTIOXIDATIVE PATHWAY AS A NOVEL THERAPEUTIC STRATEGY FOR <i>IDH1</i>-MUTATED CANCERS
Authors: Yang Liu, Yanxin Lu, Orieta Celiku, Aiguo Li, Chunzhang Yang
Journal: Neuro-Oncology (2018)

Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic abnormalities in lower grade glioma. Neomorphic enzyme activity of mutant IDH1/2 leads to the production of oncometabolite 2-hydroxyglutarate, accompanied with disruption of redox balance through aberrant NADP+/NADPH metabolism. The remarkable accumulation of reactive oxygen species (ROS) suggests distinctive metabolic stress and vulnerability in cancer cells, implying possible selective therapeutic approaches through targeting antioxitant pathways. We investigated the ROS homeostasis in IDH1 mutation transduced cells as well as patient derived IDH1-mutated brain tumor initiating cells (BTIC). The importance of antioxidant genes was confirmed through COX regression analysis from large cohort of IDH1-mutated lower grade glioma. Further, we investigated the involvement of Nrf2, the master transcriptional factor that regulates antioxidant enzymes in IDH1-mutated cells. Finally, we evaluated the therapeutic value of Nrf2 inhibitor in IDH1-mutated cancer in vitro and in vivo. We found that pathogenic IDH1 mutation leads to substantial reprogramming in ROS homeostasis, highlighted with prompted ROS generation and compensatory up-regulation of ROS scavenging genes. The expression of key ROS scavenging genes not only establishes resistance for cancer cells, but also predicts poor disease outcome in IDH1-mutated lower grade glioma. Further, IDH1-mutated glioma develop dependency on Nrf2-governed antioxidant pathway, which plays a key role in modulating glutamate/glutathione metabolism, ROS detoxification and cancer cell survival. Pharmacologic targeting Nrf2 not only led to ROS-derived cytotoxicity in IDH1-mutated cells, but also selectively suppressed IDH1-mutated xenograft growth in vivo. Our findings showed that Nrf2 antioxidant pathway plays a central role in the biology of IDH1-mutated glioma. Targeting Nrf2 antioxidant pathway showed promising tumor suppressing effect, suggesting novel therapeutic approaches for IDH1-mutated malignancies.
CBMT-14. EXPLOITING VULNERABILITIES OF THE MESENCHYMAL SUBTYPE OF GLIOMA STEM-LIKE CELLS TO ENDOPLASMIC RETICULUM STRESS
Authors: Alessandra Audia, Xing Guo, Arvid Das, Farah Mukheef, Siobhan Conroy, Krishna Bhat
Journal: Neuro-Oncology (2018)

Transcriptome profiling of glioma stem-like cells (GSCs) show differences in biological properties depending on their expression signature. Mesenchymal (MES) GSCs are generally associated with increased treatment resistance, thus it is important to identify essential molecules that promote their survival. Here, we discover the preferentially higher expression of the endoplasmic reticulum (ER) chaperone protein glucose-regulated protein 78 (GRP78) in the MES subtype of glioblastomas (GBMs) and derivative GSCs. MES GSCs showed lesser activated basal unfolded protein response (UPR) compared to its proneural (PN) counterparts. GRP78 knockdown in GSCs increased the basal level of UPR and enhanced tunicamycin induced apoptosis. GSCs expressing high levels of GRP78 concomitantly possess higher content of protein and lipid droplets (LDs). As shown by metabolomics studies we have performed in MES GSCs, silencing GRP78 stimulated biosynthesis of lipids that we hypothesize might protect MES GSCs from ER stress induced reactivation oxygen species (ROS) accumulation and apoptosis. In fact, concomitant treatment with simvastatin, a cholesterol inhibitor, induced apoptosis in cells with silenced GRP78 in vitro and significantly improved survival in vivo. Our study shows that higher GRP78 expression and lipid biosynthesis in MES GSC might act as protective mechanisms from ER and oxidative stress, which can be exploited for therapeutic targeting of the MES subtype of GSCs.