tbuckley/cabot-search huggingface dataset:
DIPG-25. GENETIC ALTERATIONS TARGETING THE MAPK PATHWAY CONFERS PRECLINICAL SENSITIVITY TO TRAMETINIB IN A CO-CLINICAL TRIAL IN DIPG
Authors: Elisa Izquierdo, Diana Carvalho, Jessica Boult, Alan Mackay, Sara Temelso, Valeria Molinari, Mark Stubbs, Rosemary Burke, Sarita Depani, Patricia O’Hare, Simon Robinson, Michael Hubank, Darren Hargrave, Chris Jones
Journal: Neuro-Oncology (2019)

The survival of children with DIPG remains dismal, and new treatments are desperately needed. The development of patient-specific in vitro and in vivo models represents one such opportunity, however the time taken to establish such models and the rapid disease progression has been thought to limit the utility of such an approach. We sought to explore a co-clinical trial model for DIPG patients enrolled in an ongoing biopsy-stratified study in order to identify rational therapeutic options with individualised preclinical evidence as to their efficacy. To date we have established novel patient-derived in vitro cultures from biopsy specimens of 11 patients, in both 2D (laminin matrix) and 3D (neurosphere) conditions, as well as orthotopic xenografts in vivo, with a high concordance in their molecular profile compared to the original tumour specimen (methylation BeadArray, exome, RNA sequencing). Cells were screened against a series of common and bespoke FDA-approved drugs based upon previous evidence in DIPG and/or the specific molecular alterations found in the patient sample. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 23-312nM) in samples which harboured genetic alterations targeting the MAPK pathway, specifically the non-canonical BRAF_G469V mutation and those affecting PIK3R1(N564D, H450E_VF_ins), with assessment of tumour volume in vivo by MRI. Allelic imbalance of PIK3R1_N564D by stochastic selection was observed in two independent cultures from the same patient showing a greater response to trametinib (6.4-fold) as well as a decreased sensitivity to dasatinib in the mutant-enriched culture (38-fold). RNAseq of the cultures revealed differential gene expression associated with hypoxia and interferon signalling linked to drug sensitivity. These data show the feasibility in generating patient-specific, testable hypotheses that may be clinically translated in a subset of patients, and we are currently exploring parallel resistance modelling to further inform novel treatment strategies at tumour progression.
BSTM-03. INCREASING ANTI-TUMOR T CELL ACTIVATION, VELOCITY, AND MIGRATION TO BRAIN STEM GLIOMA USING HEMATOPOIETIC STEM AND PROGENITOR CELLS
Authors: Catherine Flores, Cameron Morley, Ginger Moore, Thomas Angelini, Duane Mitchell
Journal: Neuro-Oncology (2019)

INTRODUCTION: The survival benefit of adoptive cellular therapy is significantly enhanced by concomitant transfer of bone marrow derived hematopoietic stem cells (HSC) with tumor-reactive T cells in two preclinical models of brain stem glioma (BSG), OB1 (wildtype H3.3), and K2 (H3.3K27M mutation). Using a novel method of 3D printing to fabricate microtumors using BSG cells, we interrogate tumor microenvironment and directly demonstrate that the presence of HSC-derived cells in the microenvironment increases T cell velocity and migration to tumor, and increased tumor cell death. In addition, longitudinal studies in a 3D system allows us to determine properties of tumor cells that escape T cell killing, and differences between T cells that infiltrate tumor bed and those that remain in the peritumoral area. METHODS: We employ an in vitro system using of BSG cells that are 3D printed into a liquid-like solid. Tumor-reactive T cells are generated against BSG cells and printed at distances from the 3D tumoroid to allow migration and T cell patterning studies. Cells retain function and viability in this system for greater than 30 days. Gene expression is used to validate cell properties. RESULTS: We found that HSCs are required for T cell infiltration to orthotopic brain stem glioma in vivo. In our in vitro 3D models of BSG, tumor-reactive T cell velocity of migration and infiltration was significantly increased in the presence of HSCs. Interrogation of T cells that remained adjacent to tumor but did not infiltrate revealed down regulation of chemokines required for migration. In the meantime, tumor cells that escaped T cell killing showed downregulation of MHC-I molecules on their cell surface. These studies are unique in that we are capable of studying biological properties of tumor-reactive T cells that are challenging in vivo.
Abstract 19660: Scoring System to Predict Major Bleeding Complications in Atrial Fibrillation Patients With Oral Anticoagulant After Drug-eluting Stent Implantation
Authors: Norihiro Kobayashi, Yoshiaki Ito, Keisuke Hirano, Masahiro Yamawaki, Motoharu Araki, Toshiya Muramatsu
Journal: Circulation (2015)

Background: We aimed to introduce scoring system to predict major bleeding complications after triple antithrombotic therapy (TAT) in patients with atrial fibrillation (AF) and drug-eluting stent (DES) implantation. Methods: Between April 2007 and December 2011, 119 patients with AF and DES implantation were enrolled in this study. All of these patients received oral anticoagulant therapy and dual antiplatelet therapy (DAPT). We investigated the incidence of major bleeding complications including intracranial and gastrointestinal bleeding. Each variables which seem to be associated with major bleeding complications were analyzed using the univariate logistic regression model. All variables tested in univariate analysis with p&lt;0.10 were included in multivariate logistic regression model. The scores for each variables were transformed from regression coefficients and computed in a total score. Results: The mean follow-up period was 43.6 ± 25.5 month. The incidence of major bleeding was 17.6%. In multivariate analysis, age &gt; 75 (OR 3.67, 95%CI 1.01-13.3, p = 0.048), continuation of DAPT (OR 7.85, 95%CI 1.50-41.2, p = 0.015), INR &gt; 2.2 (OR 9.19, 95%CI 2.65-31.9, p &lt; 0.001) were predictors of major bleeding complications. Each item’s score ranged from 0 to 2 and the total score ranged from 0 to 5. The area under the receiver operating characteristics curve revealed that there was 82.8% accuracy in the total scores predicting the likelihood of major bleeding complications. The rate of major bleeding complications was 2.3% in low-risk group (scores 0-1), 20.0% in moderate-risk group (scores 2-3), and 53.3% in high-risk group (scores 4-5) (p&lt;0.001). Conclusions: This scoring system is useful for the risk stratification of major bleeding complications in AF patients with TAT after DES implantation.
DA-R-EPOCH in Post Transplant Lymphoproliferative Disorders (PTLD) and EBV-Positive High Grade B-Cell Lymphomas with Rearrangements of MYC and BCL2 (HGBL)
Authors: Patrick D. Ford, Alexandra E. Kovach, John P. Greer, David S. Morgan, Mahsa Sharifi Talbott, Nishitha Reddy
Journal: Blood (2016)
Subgroup Analysis From the RE-DUAL PCI Trial : Dual Antithrombotic Therapy With Dabigatran in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention
Authors: Jonas Oldgren, Philippe-Gabriel Steg, Stefan H. Hohnloser, Gregory Y. Lip, Stephen G. Ellis, Takeshi Kimura, Matias Nordaby, Jurrien M. ten Berg, Deepak L. Bhatt, Christopher P. Cannon, Eva Kleine
Journal: Circulation (2017)

Subgroup Analysis From the RE-DUAL PCI Trial : Dual Antithrombotic Therapy With Dabigatran in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention
Carfilzomib-Lenalidomide-Dexamethasone (KRd) Induction-Autologous Transplant (ASCT)-Krd Consolidation Vs KRd 12 Cycles Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Induction-ASCT-KCd Consolidation: Analysis of the Randomized Forte Trial in Newly Diagnosed Multiple Myeloma (NDMM)
Authors: Francesca Gay, Chiara Cerrato, Delia Rota Scalabrini, Monica Galli, Angelo Belotti, Elena Zamagni, Antonio Ledda, Mariella Grasso, Emanuele Angelucci, Anna Marina Liberati, Patrizia Tosi, Francesco Pisani, Stefano Spada, Ombretta Annibali, Anna Baraldi, Paola Omedé, Piero Galieni, Rita Rizzi, Norbert Pescosta, Sonia Ronconi, Donatella Vincelli, Anna Maria Cafro, Massimo Offidani, Antonio Palumbo, Pellegrino Musto, Michele Cavo, Mario Boccadoro
Journal: Blood (2018)
P130 Peficitinib targets synovial fibroblasts in rheumatoid arthritis
Authors: M Diller, R Hasseli, M-L Hülser, I Aykara, S Rehart, U Müller-Ladner, E Neumann
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> Tofacitinib and baricitinib are the first approved Janus kinase inhibitors (JAKi) in Europe for treatment of rheumatoid arthritis (RA). Other JAKi differing in the inhibition profile of the four isoforms JAK1, JAK2, JAK3 and TYK2 are currently examined in clinical trials. Especially filgotinib, inhibiting mainly JAK1/2, and the panJAKi peficitinib are well tolerated up to doses causing C<sub>max</sub> values higher than 1 µM. However, less is known about the effect of JAKi in RA on synovial fibroblasts (RASF) activated by IL-1β. RASF contribute to the growing pannus and develop an aggressive cartilage-destructive phenotype. <h3>Objectives</h3> The aim of the study was to examine the effect of JAKi on activated RASF and further characterize the most effective inhibitor. <h3>Methods</h3> Isolated human RASF were pretreated with JAKi for 2 hour and then stimulated with IL-1β and JAKi with/without soluble IL-6 receptor (sIL-6R). IL-6 and MMP-3 were measured in supernatants by ELISA. Stimulation with oncostatin M served as control. The proliferation of RASF was detected using a BrdU-incorporation assay. The effect of peficitinib on RASF migration was investigated by cell culture inserts using a FCS gradient. For adhesion assays, RASF were treated with JAKi, detached and seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified by counting crystal violet stained cells. Cell viability, cytotoxicity and apoptosis were measured using commercially available assays. <h3>Results</h3> Addition of the sIL-6R caused an additional release of IL-6 in RASF treated with IL-1β compared to IL-1β alone. This release was fully blocked by tofacitinib at 0.5 and 1 µM (both p&lt;0.01). However, tofacitinib was not able to reduce the IL-6 release of IL-1β activated RASF without sIL-6R. In contrast, peficitinib attenuated the IL-6 levels by 62% at 5 µM (p&lt;0.001, n=7) and by 24% at 1 µM. Filgotinib resulted in a reduction of 30% at 5 µM only (p&lt;0.05). The MMP-3 release was reduced by peficitinib (88%, p&lt;0.001) at 5 µM. Peficitinib was the only JAKi able to reduce the proliferation of activated RASF by 23% at 1 µM (p&lt;0.05). Furthermore, peficitinib at 1 and 5 µM decreased the migration of RASF by 38% and 92% (p&lt;0.001, n=4). Peficitinib up to 5 µM did not act cytotoxic on RASF even after 48 hour. <h3>Conclusions</h3> JAKi suppress the inflammatory response induced by transsignaling of IL-6 in RASF. Peficitinib appears to be superior to other JAKi in suppressing the IL-1β induced response and the proliferation of activated RASF. Thus, patients suffering specifically from severe synovial proliferation could benefit from treatment with peficitinib. <h3>Disclosure of Interest</h3> None declared.
Microbial therapeutics: New opportunities for drug delivery
Authors: Miguel Jimenez, Robert Langer, Giovanni Traverso
Journal: The Journal of Experimental Medicine (2019)

With &amp;gt;40 clinical trials underway, we are nearing the first FDA-approved live microbial therapeutic. Here, Giovanni Traverso, MIT and Harvard Medical School Assistant Professor, and colleagues Miguel Jimenez and Institute Professor Robert Langer from MIT discuss the significant challenges of administering live microorganisms to patients and the opportunities for drug delivery of these new complex therapeutics.
Reply to Jagtap et al.
Authors: Vincent Huberty, Jacques Deviere
Journal: Endoscopy (2019)

Letter to: Endoscopic gastric reduction with an endoluminal suturing device: a multicenter prospective trial with 1-year follow-upEndoscopy 2018; 50(12): 1156-1162DOI: 10.1055/a-0630-1224 Letter to: Revision surgery after endoscopic sutured gastroplastyEndoscopy 2019; 51(05): 495-495DOI: 10.1055/a-0826-4606
THER-12. NOVEL IRON-TARGETED THERAPY IS HIGHLY EFFECTIVE IN TREATMENT-RESISTANT HIGH-GRADE GLIOMA IN VIVO
Authors: Mona Al-Gizawiy, Robert Wujek, Melissa Prah, Jeffrey Knipstein, Hisham Alhajala, Ninh Doan, Salvatore Molino, Shama Mirza, Christopher Chitambar, Kathleen Schmainda
Journal: Neuro-Oncology (2019)

BACKGROUND: Chemo- and radioresistance are characteristic features of post-treatment high-grade glioma (HGG). The cell populations responsible for this treatment-resistant phenotype are glioma stem cells (GSCs). These GSCs have a high requirement for iron which is essential for tumor cell viability. Intriguingly, the transferrin receptors that play a crucial role in iron uptake by both adult and pediatric astrocytomas exhibit a high affinity for gallium maltolate (GaM), a novel iron mimetic. Given the added commonality between adult and pediatric glioma stem cell signatures, especially post-treatment, we believe targeting treatment-resistant cell populations via their inherent iron metabolism is a viable approach to combat treatment-resistant HGG in adults and children. Here, we demonstrate the profound effects of GaM in a novel in vivo model of recurrent glioblastoma. METHODS: Irradiated human GBM cells (adult or pediatric) were stereotactically implanted into the right striatum of male athymic rats. Following confirmation of in vivo tumor growth by MRI at 9.4T, animals received GaM (50 mg/kg/day) in an oral preparation for voluntary ingestion. Tumor growth was monitored weekly by MRI, and lesion volume and associated advanced MRI parameter maps were determined using enhancing tumor ROIs. RESULTS: In a first set of animals, the mean weekly tumor growth rates of enhancing lesions were 65.8% and 156% in GaM-treated and control rats, respectively (p=0.002). Median disease-specific survival was 51 days in GaM-treated animals and 28 days in controls (p=0.004). Complete response was observed in 20% of the animals, with complete resolution of the disease confirmed histologically. A partial response was observed in 40% of the animals. Follow-up data is being collected in a second set of animals for verification and updated results will be discussed. CONCLUSION: We present compelling evidence that iron-targeted therapy using the novel iron mimetic GaM is highly effective in treatment-resistant HGG.
No Shortcuts to Safer Opioid Prescribing
Authors: Deborah Dowell, Tamara Haegerich, Roger Chou
Journal: New England Journal of Medicine (2019)

No Shortcuts to Safer Opioid Prescribing The CDC’s 2016 Guideline for Prescribing Opioids for Chronic Pain has largely been embraced by the medical and health policy communities. Unfortunately, some policies and practices purportedly derived from the guideline have been inconsistent with its recommendations.
SAT0221 Diagnostic value of serum and synovial procalcitonin (pct) in bacterial, crystal-associated and rheumatoid arthritis
Authors: J Sibilia, M Martinot, A Saraux, P Guggenbuhl, X Puechal, JF Maillefert, M Soubrier, G Coumaros, F Liote, FX Limbach
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Procalcitonin (PCT), the calcitonin peptide precursor, is a new specific marker of severe bacterial and fungal infections. PCT is not or slightly elevated in others inflammatory diseases. PCT measurements could help to differentiate bacterial arthritis to other forms of acute arthritis. <h3>Objectives</h3> To determine the interest of serum and synovial PCTfor the diagnosis of acute bacterial arthritis. <h3>Methods</h3> A one year prospective study (RR study group): sera and synovial fluid from 32 adults with acute arthritis were immediately frozen (-20°C) before treatment. for all patients, the diagnosis was confirmed by specific synovial analysis. PCT (N &lt; 0.5 mg) was measured by a specific and ultrasensitive immunoluminometric yesy (BRAHMS diagnostica, Berlin, Ger.) <h3>Results</h3> Results are expressed in median and range. Values are compared between septic group and crystal or rheumatoid group by Mann-Whitney test: **p &lt; 0.01; *p &lt; 0.05. <h3>Conclusion</h3> These results show that plasma PCT levels are higher in patients with septic arthritis, but PCT sensitivity remains unsufficient. However, in case of bacterial arthritis, PCT in association with CRP, could be of great interest for clinicians, as its increase is in favour of a bacterial origin. PCT is not present in all biological fluids. If synovial PCT does not seem to be helpful in clinical diagnosis, this study is, to our knowledge, the first to demonstrate PCT existence in synovial fluid.
Probability of cancer in lung nodules using sequential volumetric screening up to 12 months: the UKLS trial
Authors: Michael W Marcus, Stephen W Duffy, Anand Devaraj, Beverley A Green, Matthijs Oudkerk, David Baldwin, John Field
Journal: Thorax (2019)

Background Estimation of the clinical probability of malignancy in patients with pulmonary nodules will facilitate early diagnosis, determine optimum patient management strategies and reduce overall costs. Methods Data from the UK Lung Cancer Screening trial were analysed. Multivariable logistic regression models were used to identify independent predictors and to develop a parsimonious model to estimate the probability of lung cancer in lung nodules detected at baseline and at 3-month and 12-month repeat screening. Results Of 1994 participants who underwent CT scan, 1013 participants had a total of 5063 lung nodules and 52 (2.6%) of the participants developed lung cancer during a median follow-up of 4 years. Covariates that predict lung cancer in our model included female gender, asthma, bronchitis, asbestos exposure, history of cancer, early and late onset of family history of lung cancer, smoking duration, FVC, nodule type (pure ground-glass and part-solid) and volume as measured by semiautomated volumetry. The final model incorporating all predictors had excellent discrimination: area under the receiver operating characteristic curve (AUC 0.885, 95% CI 0.880 to 0.889). Internal validation suggested that the model will discriminate well when applied to new data (optimism-corrected AUC 0.882, 95% CI 0.848 to 0.907). The risk model had a good calibration (goodness-of-fit χ[8] 8.13, p=0.42). Conclusions Our model may be used in estimating the probability of lung cancer in nodules detected at baseline and at 3 months and 12 months from baseline, allowing more efficient stratification of follow-up in population-based lung cancer screening programmes. Trial registration number 78513845.
MEDU-38. A CASE SERIES OF CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYER ROSETTES TREATED WITH A MODIFIED IRS-III CHEMOTHERAPY BACKBONE
Authors: Derek Hanson, Susan Chi, David Ziegler
Journal: Neuro-Oncology (2019)

Embryonal tumor with multilayer rosettes (ETMR) is a rare and highly-aggressive CNS neoplasm which occurs almost exclusively in young children and is associated with an extremely poor prognosis. The tumor is characterized by the presence of C19MC amplification in the majority of cases and all specimens demonstrate overexpression of LIN28. To date no large clinical investigations have been conducted to determine the optimal therapy for these tumors and patients have been treated according to a variety of regimens. Historical data suggests that extensive surgical resection, radiotherapy, and high-dose chemotherapy are not sufficient treatment in the vast majority of cases. As such, it is imperative that the known biology of these tumors be taken into consideration and that additional therapies targeting underlying oncogenic mechanisms in ETMR are incorporated into any investigational regimen. The Dana-Farber modified IRS-III protocol has demonstrated success in the treatment of children with atypical teratoid rhabdoid tumor. This regimen includes many agents found to be effective in the recent German drug screen using the ETMR BT183 cell line, including doxorubicin and actinomycin D. To date, four children with ETMR have been treated with IRS-III chemotherapy, three of which have progression-free survival of >2 years. Based on these encouraging outcomes, a phase II multi-center study with an IRS-III-based consensus therapy approach is proposed. In addition, an international registry of children diagnosed with ETMR has been formed. The goals of the registry include obtaining survival data for this rare population, evaluating therapeutic response to the consensus therapy and procuring patient tumor tissue for use in preclinical modeling to further develop new biology-based therapies. Difluoromethylornithine (DFMO) as a biologic maintenance agent targeting the LIN28/let-7 axis is also being developed and will be available to registry participants at the completion of their up-front therapy.
TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the <i>Aicda</i> superenhancer
Authors: Chan-Wang J. Lio, Vipul Shukla, Daniela Samaniego-Castruita, Edahi González-Avalos, Abhijit Chakraborty, Xiaojing Yue, David G. Schatz, Ferhat Ay, Anjana Rao
Journal: Science Immunology (2019)

TET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Here, we report a close correspondence between 5hmC-marked regions, chromatin accessibility and enhancer activity in B cells, and a strong enrichment for consensus binding motifs for basic region-leucine zipper (bZIP) transcription factors at TET-responsive genomic regions. Functionally, Tet2 and Tet3 regulate class switch recombination (CSR) in murine B cells by enhancing expression of
Systemic miRNA delivery by nontoxic nanoscale coordination polymers limits epithelial-to-mesenchymal transition and suppresses liver metastases of colorectal cancer
Authors: Christina Chan, Nining Guo, Xiaopin Duan, Wenbo Han, Lai Xue, Darren Bryan, Sean C. Wightman, Nikolai N. Khodarev, Ralph R. Weichselbaum, Wenbin Lin
Journal: Biomaterials (2019)
Concurrent Metastatic Pheochromocytomas and Lung Adenocarcinoma on 18F-FDG and 68Ga-DOTATATE PET/CT Images
Authors: Zhaoting Cheng, Sijuan Zou, Shuang Song, Xiaohua Zhu
Journal: Clinical Nuclear Medicine (2019)

Abstract Both 18 F-FDG and 68 Ga-DOTATATE PET/CT are used in the evaluation of pheochromocytomas. We reported 18 F-FDG and 68 Ga-DOTATATE PET/CT findings in a 60-year-old man who had recurrent metastatic pheochromocytoma coexisting with lung adenocarcinoma. The metastatic pheochromocytoma showed increased activity on both 18 F-FDG and 68 Ga-DOTATATE PET/CT, whereas the lung adenocarcinoma lesion showed no obvious DOTATATE activity.