tbuckley/cabot-search huggingface dataset:
EXTH-32. TRANSGENIC EXPRESSION OF IL15 IMPROVES THE EFFICACY OF CAR T CELLS IN AN IMMUNE COMPETENT GLIOBLASTOMA MODEL
Authors: Katarzyna Pituch, Markella Zannikou, Liliana Ilut, Christopher Chen, Maciej Lesniak, Stephen Gottschalk, Giedre Krenciute, Irina Balyasnikova
Journal: Neuro-Oncology (2018)

Malignant gliomas (MG) are the most common and difficult-to-treat adult brain tumors. The outstanding efficacy of chimeric antigen receptor (CAR)-modified T cells against hematological malignancies gives hope that they can be programmed to target and eradicate solid tumors like MG. We recently demonstrated that murine CAR.CD28.ζ T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2) have antitumor activity in two syngeneic models of MG in comparison to control animals. However, the majority of tumors recurred. The goal of this project was now to explore if transgenic expression of IL15 improves their anti-glioma activity. We generated a retroviral vector encoding murine IL13Rα2-CAR.CD28.ζ, a 2A peptide, and secretable IL15 (IL13Rα2-CAR.IL15), and a control vector encoding a non-functional CAR (IL13Rα2-CAR.Δ), a 2A peptide, and IL15 (IL13Rα2-CAR.Δ.IL15). Murine CAR T cells were generated by activating and transducing murine CD3+ T cells with retroviral particles. The effector function of IL13Rα2-CAR, IL13Rα2-CAR.Δ, IL13Rα2-CAR.IL15, and CAR.Δ.IL15 were compared in vitro and in vivo. Only CAR T cells expressing functional CARs killed IL13Rα2+ GL261 (GL261-IL13Rα2) glioma cells. In addition, only IL13Rα2-CAR.IL15 and IL13Rα2-CAR.Δ.IL15 T cells secreted IL15 as judged by ELISA. In vivo, GL261-IL13Rα2 glioma-bearing mice treated with a single i.t. dose of IL13Rα2-CAR.IL15 T cells had a significant improved survival in comparison to mice treated with IL13Rα2-CAR T cells. This therapeutic benefit was antigen-specific since CAR.Δ.IL15 T-cells did not improve animals’ survival. Our data demonstrates that IL13Rα2-CAR.IL15 T cells have greater antitumor activity in vivo than IL13Rα2-CAR T cells in an immune competent glioma model. Thus, 2nd genetic modifications have the potential to improve current CAR T-cell therapy approaches for MG.
Inhibition of skeletal metastasis in prostate cancer growth by S-adenosylmethionine (SAM) and methyl binding domain protein 2 (MBD2) knockdown.
Authors: Nicholas Shukeir, Moshe Szyf, Shafaat Rabbani
Journal: Cancer Research (2007)

1167  During prostate cancer progression high levels of expression of growth factors and proteases play an important role in tumor growth, invasion and skeletal metastasis; often seen in patients with late stage hormone refractory prostate cancer (HRPC). Urokinase (uPA) plays an important role due to its ability to breakdown extracellular matrix to facilitate tumor invasion and metastasis. We hypothesized that global demethylation, a common epigenomic process, co-activates prometastatic genes in metastatic cancer. Studies carried out in our laboratory have shown the differential expression of uPA in human prostate cancer cells representing early (LnCAP) and late stage (PC-3) disease due to total demethylation of the uPA promoter in PC-3 cells. In the current study, we aim to evaluate the effect of changing the methylation status of the uPA promoter in PC-3 cells and its effect on tumor growth and skeletal metastasis. Towards these goals, PC-3 cells were treated with different doses of the universal methylating agent SAM or transfected with MBD2 antisense oligonucleotides (AS). The inactive homologue of SAM (SAH) and scrambled oligonucleotides (S) were used as control. Treatment of PC-3 cells with SAM or MBD2 knockdown resulted in a dose dependent inhibition in the levels of uPA mRNA expression resulting in a significant decrease in tumor cell invasive capacity. Additional genes involved in tumor progression including MMP-2 and VEGF were also downregulated. No change was observed in the levels of expression of genes known to be partially or fully methylated in HRPC such as GSTP1 and androgen receptor (AR). For in vivo studies, male Balb c nu/nu mice were inoculated with control and experimental cells via subcutaneous route or directly into tibia. Animals receiving cells treated with SAM and AS oligo developed tumors of significantly smaller volume (70%) compared to animals receiving untreated or S oligo transfected cells. In other studies, all animals inoculated with control cells into tibia developed skeletal lesions while animals injected with experimental cells either failed (90%) to develop or developed (10%) lesions of markedly smaller area as determined by X-ray using Faxitron, micro CT and bone histomormphometric analysis.  	Analysis of affiymetrix microarray of control, SAM and MBD2 treated PC-3 cells showed a significant reduction in the levels of expression of genes coding several factors and their receptors which are involved in tumor growth and skeletal metastasis. Change in the levels of expression of these genes was confirmed and the role of DNA methylation established by bisulfite sequencing. Results from these studies will elucidate the role of DNA demethyaltion in prostate cancer progression and its propensity to metastasize to skeleton which will help in developing new diagnostic, prognostic and therapeutic strategies for patients with HRPC.
RTHP-05. NON-OPERATIVE TREATMENT OF NON-GERMINOMATOUS GERM CELL TUMORS OF THE PINEAL REGION
Authors: Juan Lee, Lin Bo Cai, Mingyao Lai
Journal: Neuro-Oncology (2018)

To retrospectively summarize the therapeutic effect of conventional radiotherapy combined with stereotactic radiosurgery (SRS) boosts in patients with NGGCTs of the pineal region, and explore an optimal non-operative treatment for improving patient’s prognosis by increasing the radiotherapy dose of local focus dose. NGGCTs of the pineal region treated in our hospital from 2008 to 2017 were retrospectively analyzed. Inclusive criteria: AFP (+) and/or HCG (+); the focus was located in the pineal region and cerebrospinal fluid implantation metastasis was excluded; postoperative image confirmed that the tumor was completely excised. The whole central nervous system radiotherapy combined with local conformal radiotherapy and SRS were performed in treatment group, and surgery as a salvage treatment was conducted when disease progression was confirmed. The patients in control group were treated with surgery combined with the whole central nervous system radiotherapy and local conformal radiotherapy. All patients received 6–8 courses of BEP regimen. A total of 26 patients were selected in this study, with a median age of 15 years (6–30 years). There were 17 cases in treatment group and 9 cases in control group. After being followed-up to 2018, 4 cases were lost and the median followed-up time was 35 months (8–100 months). For all 26 patients, the 3y-PFS and 3y-OS were 82.6% and 89.7%, respectively. During the follow-up period, disease progression was identified in 5 cases in treatment group (29.4%), 2 of which were treated with salvage surgery, with a 3y-PFS of 74.9% in treatment group. Two patients in treatment group were dead, with a 3y-OS of 85.6% in treatment group. No statistical differences were found in PFS and OS (P=0.119, 0.345). Conventional radiotherapy combined with local conformal radiotherapy and SRS boosts for NGGCTs of the pineal region is proved to be feasible.
Baclofen for the treatment of alcohol use disorder: the Cagliari Statement
Authors: Roberta Agabio, Julia MA Sinclair, Giovanni Addolorato, Henri-Jean Aubin, Esther M Beraha, Fabio Caputo, Jonathan D Chick, Patrick de La Selle, Nicolas Franchitto, James C Garbutt, Paul S Haber, Mathis Heydtmann, Philippe Jaury, Anne R Lingford-Hughes, Kirsten C Morley, Christian A Müller, Lynn Owens, Adam Pastor, Louise M Paterson, Fanny Pélissier, Benjamin Rolland, Amanda Stafford, Andrew Thompson, Wim van den Brink, Renaud de Beaurepaire, Lorenzo Leggio
Journal: The Lancet Psychiatry (2018)
EXTH-63. EFFICIENT ADCC-MEDIATED KILLING OF MALIGNANT MENINGIOMA CELLS USING AVELUMAB AND AN ENGINEERED HIGH AVIDITY NATURAL KILLER CELL LINE, haNK
Authors: Amber Giles, Shuyu Hao, Rika Fuji, Michelle Padget, Hua Song, Wei Zhang, Xiaoyu Cao, Jinkyu Jung, Yang Liu, Randy Jensen, John Lee, Patrick Soon Shiong, David Gillespie, Jeffrey Schlom, Mark Gilbert, Chunzhang Yang, James Hodge, Deric Park
Journal: Neuro-Oncology (2018)

Meningiomas are the most common primary brain tumor. Standard of care includes surgery and radiation therapy. There are no known effective medical therapies for recurrent meningioma, particularly for WHO grades II and III. As such, novel therapeutic approaches are desperately needed. PD-L1 is highly expressed in malignant meningioma, including the cell lines we tested, creating a potential target for ADCC-mediated killing. Therefore, we investigated the ability of avelumab, a PD-L1-specific antibody, to direct NK-mediated ADCC against malignant meningioma cells using healthy donor NK cells and the engineered NK cell line, haNK. PD-L1 expression was assayed by flow cytometry and Western blotting in five human malignant meningioma cell lines. Avelumab-targeted ADCC was measured with healthy donor NK and haNK cells. Efficacy of avelumab+haNK was determined in vivo against meningioma implanted subcutaneously and orthotopically in a skull-base intracranial model. PD-L1 was deleted from tumor cells using CRISPR knockout to test specificity of the target. Avelumab directed healthy donor NK and haNK cells to mediate ADCC against all five meningioma cell lines in vitro. ADCC was enhanced by using NK cells with a high-avidity Fc receptor, haNK cells, or by upregulating PD-L1 in target cells. Avelumab+haNK significantly extended survival in mice bearing orthotopic meningioma and subcutaneous tumors. Conversely, killing (and survival benefit) was abrogated against cells in which PD-L1 was deleted. No toxicity was noted in pre-clinical models. We demonstrate that avelumab can target meningioma for ADCC by healthy donor NK cells, and killing is significantly enhanced with haNKs. haNK cells have demonstrated safety in humans, and avelumab has shown promising clinical activity in a variety of solid tumors. These data support the design of a clinical trial targeting PD-L1 with avelumab and haNK cells, potentially offering a novel immunotherapeutic approach for patients with malignant meningioma.
ACTR-45. PHASE 0/2 STUDY OF RIBOCICLIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: An-Chi Tien, Xun Bao, Alanna Derogatis, Seongho Kim, Shwetal Mehta, Jing Li, Nader Sanai
Journal: Neuro-Oncology (2018)

CDK4/6-dependent cell-cycle regulation is disrupted in 78% of glioblastoma patients. We conducted a Phase 0/2 clinical trial (NCT02933736) of ribociclib, a selective CDK4/6-inhibitor, to examine the plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD) of recurrent glioblastoma. Eligible patients with intact RB expression and CDKN2A deletion or CDK4/6 amplification were enrolled into the Phase 0 component to receive ribociclib (900mg daily) for 5 days prior to tumor resection. Plasma, tumor, and CSF samples were collected to determine drug concentrations using validated LC-MS/MS methods. PD effects, including RB and FoxM1 phosphorylation, were compared to archival tissue. Patients with favorable PK and PD outcomes were transitioned into the Phase 2 component. Twelve patients were enrolled into three presurgical time-escalation groups (2-hours, 8-hours, 24-hours). Ribociclib penetrated both enhancing and non-enhancing regions of the tumor. In non-enhancing tissue, median unbound brain-to-plasma ratio was 1.78 and median ribociclib concentration was 0.54 nmol/mL, exceeding the in vitro IC50 for CDK4/6 (0.04 nmol/mL). Suppression of G1-to-S phase was inferred by a decrease in RB phosphorylation (p<0.01) and cell proliferation (p<0.05). Six patients (50%) were graduated to the Phase 2 component and demonstrated a median progression-free survival of 9.7 weeks (95% CI, 6.3 to 40 weeks). Tissue samples from re-resection following Phase 2 study identified mTOR pathway upregulation as a candidate resistance mechanism to ribociclib monotherapy. CONCLUSION: Ribociclib penetrates the tumor-brain barrier, achieving pharmacologically-active concentrations in human glioblastoma and suppressing tumor proliferation. Phase 2 study results suggest ribociclib is ineffective as a monotherapy, but analysis of ribociclib-resistant tumors identified the addition of an mTOR inhibitor as a dual-drug strategy for recurrent glioblastoma.
SURG-06. LASER ABLATION FOR BRAIN METASTASES: SAFETY AND PRELIMINARY OUTCOMES FROM THE LASER ABLATION OF ABNORMAL NEUROLOGICAL TISSUE USING ROBOTIC NEUROBLATE SYSTEM (LAANTERN) REGISTRY
Authors: Ashwin Kamath, Stephen Tatter, Peter Fecci, Clark Chen, Veronica Chiang, Ganesh Rao, Alireza Mohammadi, Kevin Judy, Melvin Field, Joseph Neimat, Eric Leuthardt, Albert Kim
Journal: Neuro-Oncology (2018)

Laser Interstitial Thermal Therapy (LITT) is a novel technology that offers a minimally invasive option for brain metastases. The current understanding of LITT in this context is limited by small sample size or to single center experiences. Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN) is a registry designed to address these limitations. We present the preliminary experience with regard to safety, procedural data, and preliminary outcomes of LITT for brain metastases. LAANTERN is an ongoing registry that collects data on patients treated with the NeuroBlate® system. Data presented here include procedural data, complications, and survival. Fifty-one brain metastases in 50 patients (33 male, 17 female) were treated with LITT. Mean age was 58.3 ± 13.4 years (range 25–80 years). 48 patients (96%) had prior treatment(s) to the target lesion, including surgery, chemotherapy, and radiation. 49 lesions (96.1%) were treated with a single trajectory, and 2 (3.9%) were treated with two trajectories. Location of lesions were frontal lobe (26, 51%), followed by parietal (10, 19.6%) and temporal (9, 17.6%) lobes. Average lesion volume was 2.9 ± 3.2cm3. Volumetric data was available for 48 patients; of these, 40 (83%) had 91–100% ablation coverage based on physician determination; eight (16.7%) had 51–90% ablation coverage. The 91–100% group had a death rate of 18.9%; the 51–90% group had a death rate of 37.5% (p=0.35). Adverse events occurred in 5 (10%) patients within 30 days of procedure. There were no mortalities in this timeframe. Median follow up was 6 months; median overall survival has not yet been reached. Kaplan-Meier survival estimates at 1, 6, and 12 months were 90%, 76%, and 71%, respectively. Preliminary results from the LAANTERN registry demonstrate an acceptable safety profile, procedural efficacy, and satisfactory outcomes of LITT in carefully selected patients with brain metastases.
Abstract 01: Dispatching Lay Rescuers Through a Smartphone Application is Associated With Increased Bystander Defibrillation in Out-of-Hospital Cardiac Arrest
Authors: Linn Andelius, Carolina Malta Hansen, Freddy Lippert, Lena Karlsson, Christian Torp-Pedersen, Gunnar Gislason, Fredrik Folke
Journal: Circulation (2018)

Introduction: Survival after out-of-hospital cardiac arrest (OHCA) is dependent on early defibrillation. To increase bystander defibrillation in OHCAs, a first-responder program dispatching lay rescuers (Heart Runners) through a smartphone application (Heart Runner-app) was implemented in the Capital Region of Denmark. We investigated the proportion of Heart Runners arriving prior to the Emergency Medical Services (EMS) and rates of bystander defibrillation. Methods: The Capital Region of Denmark comprises 1.8 mil. inhabitants and 19,048 Heart Runners were registered. In cases of suspected OHCA, the Heart Runner-app was activated by the Emergency Medical Dispatch Center. Up to 20 Heart Runners &lt; 1.8 km from the OHCA were dispatched to either start cardiopulmonary resuscitation (CPR) or to retrieve and use a publicly accessible automated external defibrillator (AED). Through an electronic survey, Heart Runners reported if they arrived before EMS and if they applied an AED. OHCAs where at least one Heart Runner arrived before EMS were compared with OHCAs where EMS arrived first. All OHCAs from September 2017 to May 2018, where Heart Runners had been dispatched, were included. Results: Of 399 EMS treated OHCAs, 78% (n=313/399) had a matching survey. A Heart Runner arrived before EMS in 47% (n=147/313) of the cases, and applied an AED in 41% (n=61/147) of these cases. Rate of bystander defibrillation was 2.5-fold higher compared to cases where the EMS arrived first (Table 1). Conclusions: By activation of the Heart Runner-app, Heart Runners arrived prior to EMS in nearly half of all the OHCA cases. Bystander defibrillation rate was significantly higher when Heart Runners arrived prior to EMS.
EPID-07. RELATIONSHIP BETWEEN COGNITION, SPEED OF PRESENTATION AND SEMANTIC VERBAL FLUENCY TEST IN PATIENTS WITH NEW INTRA-CEREBRAL TUMORS
Authors: Karolis Zienius, Paul Brennan, Yoav Ben-Shlomo, Mio Ozawa, Edna Keeney, David Weller, William Hamilton, William Hollingworth, Robin Grant
Journal: Neuro-Oncology (2018)

Patients with brain tumors often have subtle cognitive change, which may go unnoticed by patient and family doctor. This may result in delays in diagnosis. We studied the relationship between first and subsequent symptoms and semantic verbal fluency test (SVFT), a quick cognitive screening test. (Normal median SVFT for 60–79 age range who have 12 years of education = 17 animals; 10th percentile is 12 animals). Patients with new intrinsic brain tumors had structured patient interviews to determine first and subsequent symptoms. Patients were specifically asked about cognition. A cognitive screening test (SVFT – how many animals can you think of in a minute) was performed in patients as part of the Addenbrookes Cognitive Exam on admission. Symptoms were categorized into focal, non-focal, episodic attack or headache. 127 patients with cerebral brain tumors were assessed– glioma (n=94 HGG=79;LGG=15); metastasis (n= 28); primary CNS lymphoma (n=5). Mean age, 56.2, (SD 13.1): 55% male. 16 patients presented with a solitary symptom (episodic (9); focal (4); headache (3); non-focal (0)). As symptoms accumulated time to diagnosis increased “1 symptom” (med 23 days); “2 symptoms” (med 42 days) “>=3 symptoms” (med 44 days). Mean SVFT was lowest in HGG (mean 10.9) vs LGG (mean 15.7). Patient awareness of cognitive problems did not correlate with SVFT score (aware (n=50) mean 11.9 v unaware (n=77) mean 11.7)) Presentation with an isolated cognitive complaint is uncommon in cerebral brain tumors. Diagnosis becomes apparent when combined with headache or focal symptoms. Diagnosis becomes easier when multiple symptoms accumulate, but there are increasing delays. Many patients with headache also have asymptomatic cognitive problems on SVFT. Where there is a suspicion of cerebral problem e.g. headache suspicious of cancer, it is insufficient just to ask patients whether they have cognitive problems. SVFT may be a helpful red flag.
Preventive Migraine Drug Approved
Authors: Rebecca Voelker
Journal: JAMA (2018)

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STEM-02. DEVELOPING BRAIN METASTATIC TUMOR MODELS FOR TARGETED STEM CELL THERAPY
Authors: Yohei Kitamura, Susana Moleirinho, Wanlu Du, Clemens Reinshagen, Nada Attia, Khalid Shah
Journal: Neuro-Oncology (2018)

Metastatic brain tumors are the most commonly observed intracranial tumors, and 10–20% of adults with cancer develop brain metastasis. Characterizing clinically relevant brain metastasis models and exploring different delivery options to deliver drugs across blood brain barrier in such models are fundamental for the development of novel therapies for metastatic brain cancers. We have created imageable breast to brain metastasis tumor models using patient derived brain seeking triple negative breast cancer (TNBC) lines. We show a widespread distribution of micro- and macro-metastasis and the close association of tumor cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we assessed the EGFR and DR4/5 levels in TNBC and show that brain seeking TNBC have higher EGFR and DR5 levels than their primary counterparts. We also show that intracarotid artery injection of stem cells engineered to express optical imaging markers home to metastatic brain tumors. These findings provide useful models for testing treatments for metastatic brain tumors and also provide insights into the changes in gene expression in metastatic TNBC and means to deliver therapeutics to metastatic tumors in the brain.
COMP-23. ASSESSMENT OF PITUITARY ADENOMA CONSISTENCY AND VASCULARITY USING TEXTURE ANALYSIS OF CONVENTIONAL MRI
Authors: Moran Artzi, Ben Shofty, Alon Kashanian, Zvi Ram, Nir Shimony, Nataly Popovits, Tali Jonas-Kimchi, Rachel Grossman, Dafna Ben Bashat
Journal: Neuro-Oncology (2018)

Pituitary adenomas are the third most common primary brain tumor in adults, with an incidence of 73–94/100000 cases. Most adenomas can be effectively resected using endoscopic endonasal approach, yet in about 10% of cases the tumor may be fibrous requiring a more complex procedure. Preoperative assessment of pituitary adenoma consistency and vascularity is thus important for surgical planning and risk assessment. The aim of this study was to assess pituitary macroadenoma consistency and vascularity using texture analysis of conventional MRI. Retrospective analysis of pre-operative MRI data of 109 patients with pituitary adenoma was performed. Tumor consistency (hard vs soft) and vascularity (vascular vs avascular) were determined intraoperatively by the surgeon. Radiomics analysis was performed on T2-weighted (T2W) and post contrast T1-weighted (T1W+C) images, and apparent diffusion coefficient (ADC) maps (available in 57 patients). Fifteen features were extracted from the lesion area for each modality, including: mean, minimum, maximum, median, percentile 10,25,75,90, standard deviation, kurtosis, skewness, entropy, root mean square (RMS), and energy. Between group differences were tested using independent samples T-Test. Consistency: Significant group differences (p<0.05) were detected for T2W min and ADC mean, min, percentile 25,75 median and RMS values, with higher values detected for the soft tumors for all parameters, indicates lower tissue organization. Vascularity: Significant group differences (p<0.05) were detected for T2W min, T1W+C skewness and ADC mean, min, percentile 10,25,75,90 median RMS and energy values, with higher ADC and lower T2W and T1W+C values detected for the vascular tumors, indicating lower tissue organization and higher heterogeneity. Texture analysis of conventional MRI and particularly of ADC maps may assist in pre-operative assessment of hard and vascular pituitary adenoma, and may have important applications in the field of personalized medicine.