tbuckley/cabot-search huggingface dataset:
PDTM-44. INTRACRANIAL EPENDYMOMA: DEVELOPING PRECLINICAL MODELS AND IDENTIFYING NOVEL TREATMENTS
Authors: Ashleigh Lester, Sylvia Chung, Shane Whittaker, Robert Rapkins, Kerrie McDonald
Journal: Neuro-Oncology (2018)

Clinical trials have not identified any effective chemotherapeutic treatments for intracranial ependymomas. This failure is partially explained by the recent identification of 6 molecularly distinct intracranial subgroups. Whilst subgroup specific preclinical investigations and treatments are required, these investigations have been hampered by the rarity of the tumours, failure to identify driver mutations for 5 of the subgroups, and difficulties establishing appropriate models. This study aims to establish patient derived cell lines, brain slice co-culture models and patient derived mouse models of intracranial ependymomas and utilise these models to identify and test novel subgroup specific drug treatments. METHODS/ Two patient-derived intracranial ependymoma cultures have been successfully established in neurobasal and serum free media, as adherent cells and neurospheres. Whole genome methylation sequencing and immunohistochemistry are being used to characterise the cultures. Brain slice co-culture models have been successfully created, with tumour cells growing on 200µM slices of brain from neo-natal mice. Cells dissociated from patient tumour tissue and matched low passage cultures have been injected intracranially into 25 mice, with evidence of tumours in three of the mice induced with cells from the first patient tumour. A screen of 111 approved drugs on ependymoma suspension cultures, has identified 4 drugs, including Bortezomib and Ponatinib, for further investigation in the established models. Patient-derived ependymoma cells can be successfully cultured as adherent cells, neurospheres, and in co-culture models. Subgrouping the samples, screening them against approved drugs, and testing potential drugs in patient-derived models is an effective mechanism for identifying candidate drugs for subgroups of these rare tumours.
CMET-06. DISTANT BRAIN FAILURE AND SALVAGE FREE SURVIVAL FOR RADIOSURGERY-TREATED MELANOMA BRAIN METASTASES IN THE ERA OF CHECKPOINT INHIBITOR IMMUNOTHERAPY
Authors: Steven Nguyen, Andrew Keller, Luke Pearson, Sean All, Hanisha Patel, Naren Ramakrishna
Journal: Neuro-Oncology (2018)

We evaluated median time-to-distant brain failure (DBF), and salvage-free survival from distant brain failure (DBF-SFS) in melanoma brain metastases (MBM) patients who received stereotactic radiosurgery (SRS) and checkpoint inhibitor treatment. An IRB-approved retrospective evaluation of 68 MBM patients with 229 metastases treated with SRS between 11/2008 and 2/2017 with at least one post-SRS brain MRI. Time-to-DBF was the interval between initial SRS to MRI revealing any new brain metastases. DBF-SFS was defined as the interval from initial SRS to MRI revealing brain metastases requiring salvage treatment. Survival analysis was performed using Kaplan-Meier estimates and Cox regression. Overall median time-to-DBF was 4.34 months. Median time-to-DBF for patients who received PD-1 inhibitors (5.43mo), ipilimumab without PD-1 inhibitors (3.95mo), and no immunotherapy (3.30mo) were not significantly different (p=0.28). Median overall survival of non-immunotherapy patients was 3.29 months and all DBF occurred within 4 months in this subgroup. Patients with active extracranial primary disease had significantly worse median time-to-DBF (3.58mo) than those without active primary disease (9.90mo) (HR 3.25, p< 0.01). Overall median DBF-SFS was 4.50 months. Median DBF-SFS for patients who received PD-1 inhibitors (9.21mo), ipilimumab without PD-1 inhibitors (5.44mo), and no immunotherapy (4.50mo) were not significantly different. Multivariate analysis confirmed a significantly worse DBF-SFS for patients with > 2 SRS-treated metastases (2.30mo) versus 1–2 metastases (9.21mo), (HR 10.22, p< 0.01). Patients treated in 2014 or later demonstrated significantly longer DBF-SFS (median not reached) vs those treated prior to 2014 (4.34mo) (HR 0.01,p=0.01). CONCLUSIONS: Our study demonstrated improving DBF-SFS rates for patients treated since 2014 compared to those treated earlier. Our study does find that patients with active extracranial disease and > 2 initial metastases have higher rates of DBF and DBF-SFS.
IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System
Authors: Cristina Puig-Saus, Giulia Parisi, Angel Garcia-Diaz, Paige E. Krystofinski, Salemiz Sandoval, Ruixue Zhang, Ameya S. Champhekar, James McCabe, Gardenia C. Cheung-Lau, Nhat A. Truong, Agustin Vega-Crespo, Marie Desiles S. Komenan, Jia Pang, Mignonette H. Macabali, Justin D. Saco, Jeffrey L. Goodwin, Brad Bolon, Christopher S. Seet, Amelie Montel-Hagen, Gay M. Crooks, Roger P. Hollis, Beatriz Campo-Fernandez, Daniela Bischof, Kenneth Cornetta, Eric H. Gschweng, Celia Adelson, Alexander Nguyen, Lili Yang, Owen N. Witte, David Baltimore, Begonya Comin-Anduix, Donald B. Kohn, Xiaoyan Wang, Paula Cabrera, Paula J. Kaplan-Lefko, Beata Berent-Maoz, Antoni Ribas
Journal: Clinical Cancer Research (2018)

To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application.HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use.TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality.Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.
Effect of Foster Care Intervention on Trajectories of General and Specific Psychopathology Among Children With Histories of Institutional Rearing
Authors: Mark Wade, Nathan A. Fox, Charles H. Zeanah, Charles A. Nelson
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> It is unclear whether early institutional rearing is associated with more problematic trajectories of psychopathology from childhood to adolescence and whether assignment to foster care mitigates this risk. <h3>Objectives</h3> To examine trajectories of latent psychopathology factors—general (P), internalizing (INT), and externalizing (EXT)—among children reared in institutions and to evaluate whether randomization to foster care is associated with reductions in psychopathology from middle childhood through adolescence. <h3>Design, Setting, and Participants</h3> This longitudinal, intent-to-treat randomized clinical trial was conducted in Bucharest, Romania, where children residing in 6 institutions underwent baseline testing and were then randomly assigned to a care as usual group (CAUG) or a foster care group (FCG). A matched sample of a never-institutionalized group (NIG) was recruited to serve as a comparison group. The study commenced in April 2001, and the most recent (age 16 years) follow-up started in January 2015 and is ongoing. <h3>Intervention</h3> Institutionally reared children randomized to high-quality foster homes. <h3>Main Outcomes and Measures</h3> Psychopathology was measured using the MacArthur Health and Behavior Questionnaire. Teachers and/or caregivers reported on symptoms of psychopathology in several domains. <h3>Results</h3> A total of 220 children (50.0% female; 119 ever institutionalized) were included in the analysis at the mean ages of 8, 12, and 16 years. A latent bifactor model with general (P) and specific internalizing (INT) and externalizing (EXT) factors offered a good fit to the data. At age 8 years, CAUG (mean, 0.41; 95% CI, 0.17-0.67) and FCG (mean, 0.30; 95% CI, 0.04-0.53) had higher P than NIG (mean, −0.40; 95% CI, −0.56 to −0.18). By age 16 years, FCG (mean, 0.07; 95% CI, −0.18 to 0.29) had lower P than CAUG (mean, 0.37; 95% CI, 0.13-0.60). This effect was likely driven by modest declines in P from age 8 years to age 16 years among FCG (slope, −0.12; 95% CI, −0.26 to 0.04) compared with CAUG, who remained stably high over this period (slope, −0.02; 95% CI, −0.19 to 0.14). Moreover, CAUG and FCG showed increasing divergence in EXT over time, such that FCG (mean, −0.30; 95% CI, −0.58 to −0.02) had fewer problems than CAUG (mean, 0.05; 95% CI, −0.25 to 0.36) by age 16 years. No INT differences were observed. <h3>Conclusions and Relevance</h3> Institutionalization increases transdiagnostic vulnerability to psychopathology from childhood to adolescence, a period of significant social and biological change. Early assignment to foster care partially mitigates this risk, thus highlighting the importance of social enrichment in buffering the effects of severe early neglect on trajectories of psychopathology. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT00747396
Abstract 15144: LCZ696 Improves Lipid Mobilization From Adipose Tissue: A Randomized, Double-blind, Active-controlled, Parallel-group Study in Obese Hypertensive Patients
Authors: Jens Jordan, Rudi Stinkes, Thomas Jax, Stefan Engeli, Sven Haufe, Ellen Blaak, Macus May, Bas Havekes, Christoph Schindler, Diego Albrecht, Parasar Pal, Nicolaaes Schaper, Birgitta van der Kolk, Uwe Tegtbur, Tim Heise, Gijs Goossens, Thomas Langenickel
Journal: Circulation (2015)

LCZ696 simultaneously inhibits neprilysin, thereby augmenting natriuretic peptide (NP) availability, and blocks AT 1 -receptors. NPs released during exercise promote lipid mobilization and oxidation. Therefore, we investigated whether LCZ696 treatment augments lipid mobilization and oxidation at rest and during exercise. In this double-blind study, 98 patients with mild-to-moderate hypertension and abdominal adiposity were randomized to LCZ696 400 mg or amlodipine (AML) 10 mg once daily for 8 weeks. At baseline and week 8, abdominal subcutaneous adipose tissue lipolysis (microdialysis), whole-body lipolysis (glycerol tracer kinetics), and substrate oxidation and energy expenditure (indirect calorimetry) were assessed at rest and during exercise (60 min cycling at approximately 50% of peakVO 2 ). LCZ696 and AML groups had comparable baseline characteristics with regards to age, blood pressure and body mass index (LCZ696 32.6±4.6 kg/m 2 , AML 33.3±4.4 kg/m 2 ). Abdominal subcutaneous adipose tissue lipolysis at rest was increased with LCZ696 compared to AML (interstitial glycerol concentrations at week 8; 80.5 μmol/L vs. 64.0 μmol/L; p=0.020). The apparent exercise-induced increase in adipose tissue lipolysis was more pronounced with LCZ696 compared to AML at 15 and 30 min of exercise (interstitial glycerol concentrations at week 8; 15 min exercise: 153.1 μmol/L vs. 128.8 μmol/L, p=0.014; 30 min exercise: 187.63 μmol/L vs. 149.19 μmol/L, p=0.010). However, whole-body lipolysis at rest and during exercise was not significantly different between groups. While respiratory quotient increased with exercise in both treatment groups, energy expenditure and substrate oxidation at rest and during exercise did not differ between treatments. In conclusion, 8 weeks of treatment with LCZ696 vs. AML increased lipid mobilization from abdominal subcutaneous adipose tissue at rest and during physical exercise in obese, hypertensive patients, while whole-body lipolysis and lipid oxidation remained unchanged. This study therefore suggests an improvement in lipid mobilization with LCZ696 and supports a central role of NPs in the crosstalk between human cardiovascular and metabolic regulation.
SURG-25. INTRAMEDULLARY SPINAL CORD TUMOURS – A SINGLE UNITED KINGDOM CENTRE TEN-YEAR ANALYSIS
Authors: Oliver Richards, Edward Goacher, Christopher Derham
Journal: Neuro-Oncology (2018)

Intramedullary spinal cord tumours are relatively rare tumours of the central nervous system. Surgical outcomes are affected by many variables, including pre-operative neurological function, tumour histology and extent of resection. Emphasis remains on surgical treatment due to the limited adjunctive therapeutic options and poor drug penetration. To identify clinically relevant predictors of progression free survival by retrospectively analysing the anatomical location, pre- and post-operative function and histology in intramedullary spinal cord tumours from a single United Kingdown neurosurgical centre over 10 years. METHOD: 49 patients were identified from a surgical database. Variables collected included pre-and post-operative Frankel Grade and Modified McCormick Scale assessments, tumour histology, extent of resection and length of follow up. Chi-Squared, Kaplan-Mier Survival and Mann-Whitney U-Tests were completed. Ependymoma, Haemangioblastoma and Pilocytic Astrocytoma were the commonest tumour histologies. In total 21 different histological tumours were identified in the series. There was a statistically significant relationship between identification of the tumour plane and extent of resection (p<0.01), along with the extent of resection and recurrence (p<0.01). Compared to the other histological subtypes, ependymoma’s demonstrated a significantly greater extent of resection (p=0.02). There was a significant relationship between the grade of tumour and progression free survival (p<0.01). We did not find a significant relationship between pre- and post-operative neurological function and survival. Tumour plane and the extent of tumour resection are significant determinants of progression free survival. Ependymoma, whilst being the commonest histology in our series were also the most resectable. Whilst complete resection reduces the rate of recurrence, tumour grade is the most important predictor of outcome.
TMIC-06. DEFICIENCY OF miRNA-146a-5p CONTRIBUTES TO TRANSFORMATION OF GLIOMA-DERIVED MESENCHYMAL STROMAL/STEM CELLS VIA TARGETING HNRNPD
Authors: Jun Dong
Journal: Neuro-Oncology (2018)

Although malignant transformation of tumor stroma cells has been reported previously, its relevant mechanisms still kept largely unknown. In this study, we established three intracerebral xenograft tumor models byde novo transplanting glioma initiating cells and glioblastoma surgical specimens into cerebral cortex of the enhanced green fluorescent protein (EGFP) transgenic nude mice and chimeric nude mice. With dual color tracing techniques, which based on transfection of tumor cells with red fluorescent protein(RFP) and host cells bearing EGFP, three EGFP-expressing host bone marrow derived mesenchymal stromal cells (MSCs) were sorted from different intracerebral xenograft models, showing characteristics of immortality and malignant growth pattern. High-throughput RNA-sequencing of these cells results showed up-regulation of 19 miRNAs, and down-regulation of 24 miRNAs, respectively. MiRNA-146a-5p was one of the downregulated miRNAs, and overexpression of it can reverse malignant phenotype of transformed MSCs. Double-luciferase assay showed that miRNA-146a-5p directly acted on oncogene HNRNPD which was overexpressed in cancerous MSCs. SiRNA targeting HNRNPD could efficiently inhibit the proliferation of transformed cells and arrest the cell cycle at G2/M phase, and increase the apoptosis of cells. In summary, deficiency of miRNA-146a-5p contributes to the malignant transformation of host bone marrow derived mesenchymal stromal cells in the intracerebral xenograft tumors by overexpressing the tumorigenesis gene, HNRNPD.
EPID-01. ASSOCIATIONS OF TIMING OF ADJUVANT THERAPIES, RADIATION FRACTIONS AND RADIATION DOSES WITH GLIOBLASTOMA SURVIVAL: A RETROSPECTIVE COHORT ANALYSIS USING THE NATIONAL CANCER DATABASE AND SEER-MEDICARE DATABASE
Authors: Ping Zhu, Xianglin Du, Yoshua Esquenazi, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2018)

Few studies investigated the association between the timing of initiating adjuvant therapies and survival in glioblastoma (GBM) patients.A total of 20511 and 4435 eligible GBM patients were derived from the National Cancer Database (NCDB) and the Surveillance, Epidemiology and End Results (SEER) -Medicare dataset, respectively (NCDB: 2005(NCDB: -2014;; SEER-Medicare: 2004-2013).Times to starting adjuvant treatment were calculated as the days from the date of diagnosis to the initiation of adjuvant treatment [radiation therapy (RT), chemotherapy, or concurrent chemoradiation (CRT)] and categorized into quartiles (Q1: 0-21; Q2: 22-30; Q3: 31-39; Q4: ≥40, days).Kaplan-Meier method and Cox proportional hazards regression were applied for survival analysis.Multivariate logistic regression was performed to compare differences in treatment patterns, delayed treatment, and secondary outcomes.The patients underwent biopsy obtained significant survival benefit by having adjuvant treatment during Q2 and Q3 [NCDB: HR: Q1 (Ref.),Q2: 0.88, Q3: 0.86, Q4: 0.91; SEER-Medicare: Q1 (Ref.),Q2: 0.87, Q3: 0.86, Q4: 0.89].For the patients with craniotomy, initiation of adjuvant treatment during Q2 and Q3 had significantly reduced risk of death [NCDB: HR: Q1 (Ref.),Q2: 0.95, Q3: 0.94, Q4: 1.03; SEER-Medicare: Q1 (Ref.),Q2: 0.98, Q3: 0.96, Q4: 1.00].Furthermore, patients received more RT fractions [comparing to 10-29 fractions, 30-33 fractions: HR: 0.62 (biopsy), 0.62 (resection); ≥34 fractions: HR: 0.53 (biopsy), 0.62 (resection)] and higher-dose RT [comparing to 34-46 Gy, 50-60 Gy: HR: 0.91 (biopsy), 0.95 (resection); ≥ 60 Gy: HR: 0.77 (biopsy), 0.88 (resection)] experienced significantly survival benefit in both biopsy and resection groups.A similar analysis was performed in SEER-Medicare dataset as validation set and the findings remained consistent.The impact of time to adjuvant treatment on GBM survival varied by surgery procedures.Having adjuvant treatment immediately may not guarantee a significant survival benefit.More RT fractions and higher-dose RT are associated with better survival.
ACTR-10. A RANDOMIZED, PHASE I/II TRIAL OF IXAZOMIB IN COMBINATION WITH STANDARD THERAPY FOR UPFRONT TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED MGMT METHYLATED GLIOBLASTOMA (GBM) STUDY DESIGN
Authors: Xiao-Tang Kong, Albert Lai, Jose A Carrillo, Dan Beverly Fu, Frank Meyskens, Daniela A Bota
Journal: Neuro-Oncology (2018)

OBJECTIVE: To investigate the toxicity, tolerability and efficacy of the combination of ixazomib and standard chemoradiation therapy for newly diagnosed MGMT methylated GBM patients. GBM is the most aggressive primary malignant brain tumor. Standard therapy with temozolomide and radiotherapy after the surgery offers limited overall survival (OS). The median OS in patients with MGMT methylation is still less than 2 years. Our recent phase II clinical trial found that the addition of bortezomib, a proteasome inhibitor, to the standard therapy, offered mild survival benefit (19 months) for the entire group of GBM patients. However, significant improvement of OS and progression free survival (PFS) were found in the MGMT methylated patients when compared to MGMT unmethylated patients (OS: 49.4 vs 15.6 months, p=0.0002; PFS: 24.7 vs 5.1 months, p=0.00004) [Kong et al. Int J Radiation Oncology Biol Phys 2018]. Ixazomib is a newer generation of proteasome inhibitor and has demonstrated similar selectivity and potency to bortezomib in biochemical and cell-based assays. While bortezomib can be administered via injection, ixazomib is taken orally, which is more convenient. HYPOTHESIS: Adding ixazomib to standard therapy improve the survival of the patients with newly diagnosed MGMT-methylated GBM compared to standard therapy. STUDY DESIGN: This is a randomized, active controlled, open label phase I/II study of Ixazomib plus standard therapy versus standard therapy. Primary and secondary endpoints are PFS, 12, 24, 36 and 48 month survival rates and response duration. The study consists of two parts: In part I, the maximum tolerated dose (MTD) is decided by using 3 + 3 design with dose limiting toxicity (DLT) method. In part II, randomize the patients to the combination therapy or the standard therapy arm. Safety will be assessed by CTCAE V4.03. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.
THU0176 The effect of methotrexate on gastrointestinal symptoms in patients with rheumatoid arthritis
Authors: S. Asai, K. Nagai, T. Kojima, N. Takahashi, N. Ishiguro
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Methotrexate (MTX) can cause gastrointestinal (GI) symptom in patients with rheumatoid arthritis (RA); however, it is uncertain how much dose of MTX affects GI symptoms. RA patients may receive various drugs besides MTX. NSAIDs are known to be a risk factor for GI disorders, and folic acid has been reported to reduce GI side effects of MTX. Moreover, obesity is a risk factor for reflux. Therefore, it is necessary to evaluate comprehensively the causes of GI symptoms in RA patients. <h3>Objectives</h3> To compare prevalence of GI symptoms for the patients with RA treated with low and high dose MTX, and investigate factors associated with GI symptoms. <h3>Methods</h3> A total of 529 patients with RA treated with MTX were included in this cross-sectional study. GI Symptom Rating Scale (GSRS) was used to evaluate GI symptoms. The GSRS has five subscales (Reflux, Abdominal pain, Indigestion, Diarrhoea and Constipation) and a seven-point graded Likert-type scale. Symptomatic was defined as a score of ≥2 on GSRS subscale. Patients were divided into two categories according to their MTX dosage: low dose (≤8 mg/week) and high dose (&gt;8 mg/week). Prevalence was compared by two groups with the chi-square test, and factors associated with GI symptoms were assessed with multivariate logistic regression analysis. <h3>Results</h3> Patient characteristics are shown in table 1. Of all patients, 313 (59%) received low dose MTX at a mean (SD) dose of 6.2 (1.7) mg/week, whereas 216 (41%) received high dose MTX at a mean (SD) dose of 11.8 (1.8) mg/week. Relative to patients receiving low dose MTX, those receiving high dose MTX had a higher prevalence of reflux (24% vs 32%, p=0.047) and abdominal pain (18% vs 28%, p=0.008) (figure 1). Multivariate analysis revealed that higher dose MTX was independently associated reflux (OR: 1.62, 95% CI: 1.07–2.43) and abdominal pain (OR: 1.70, 95% CI: 1.12–2.59) (table 2). The odds ratio of reflux or abdominal pain in patients receiving high dose MTX was similar to that in patient receiving NSAIDs. <h3>Conclusions</h3> MTX more than 8 mg/week is associated with upper GI symptoms as much as NSAIDs in Japanese patients with RA. <h3>Disclosure of Interest</h3> None declared