tbuckley/cabot-search huggingface dataset:
ACTR-31. PHASE 1 STUDY OF AG-881, AN INHIBITOR OF MUTANT IDH1 AND IDH2: RESULTS FROM THE RECURRENT/PROGRESSIVE GLIOMA POPULATION
Authors: Ingo Mellinghoff, Marta Penas-Prado, Katherine Peters, Timothy Cloughesy, Howard Burris, Elizabeth Maher, Filip Janku, Gregory Cote, Macarena De La Fuente, Jennifer Clarke, Lori Steelman, Kha Le, Huansheng Xu, Alison Sonderfan, Diana Hummel, Steven Schoenfeld, Katharine Yen, Shuchi Pandya, Patrick Wen
Journal: Neuro-Oncology (2018)

INTRODUCTION: Isocitrate dehydrogenase 1 and 2 mutations (mIDH1/2) occur in >70% of low-grade gliomas and secondary glioblastomas, and lead to genetic and epigenetic dysregulation, promoting tumorigenesis. AG-881 is an oral, potent, brain-penetrant inhibitor of mIDH1/2 under phase 1 clinical evaluation in gliomas and other solid tumors. Here we present clinical data from the glioma population. Patients with recurrent/progressive mIDH1/2 glioma received AG-881 daily in continuous 28-day cycles. A Bayesian model was used for dose escalation. Dose-limiting toxicity (DLT) definition: Grade 3 AG-881-related adverse event (AE) in Cycle 1 or by sponsor designation. Blood samples were collected for pharmacokinetic (PK)/pharmacodynamic (PD) evaluations. MRI response every 8 weeks by RANO and RANO-LGG criteria. As of 28Mar2018, 52 patients with glioma had received AG-881 and 17 (32.7%) remained on treatment. Grade 2/3 = 90.4%; median age = 42.5 years; IDH1/2: 48/3; median no. prior therapies = 2 (range 1–6). Five initial dose levels tested: 25mg (n=6), 50mg (n=5), 100mg (n=10), 200mg (n=14), and 300mg (n=5). To confirm safety and PK, a 10mg dose level was tested (n=6) and 6 additional patients enrolled in the 50mg cohort. Common (>20%) AEs across glioma patients regardless of attribution: ALT increased (44.2%), AST increased (38.5%), headache (34.6%), fatigue (30.8%), nausea (26.9%), seizure (21.2%). Five patients experienced DLTs at 100mg: Grade 2 ALT/AST that resolved to Grade 1 with dose modification (n=4) or discontinuation (n=1). Among the evaluable glioma population: 2% minor response, 75% stable disease, 21% progressive disease, and 2% missing as best overall response. CONCLUSION: Maximum tolerated dose/recommended phase 2 dose was not reached by Bayesian model; clinical team recommendation was to proceed with doses <100mg in patients with glioma. The 10mg and 50mg doses are being explored in an ongoing perioperative glioma study. Updated safety, PK, and imaging response analyses will be presented.
Targeting CD45 with an Amanitin Antibody-Drug Conjugate Effectively Depletes Human HSCs and Immune Cells for Transplant Conditioning
Authors: Rahul Palchaudhuri, Bradley R Pearse, Jennifer L Proctor, Sharon L. Hyzy, Sharon Aslanian, Sean M McDonough, Ganapathy Sarma, Melissa L. Brooks, Anjali Bhat, Danielle Ladwig, Molly A McShea, Nathan M Kallen, Qing Li, Rajiv Panwar, Junia Dushime, Pranoti Sawant, Hillary L Adams, Patrick C. Falahee, Tahirih L Lamothe, Andrew D Gabros, Lena Kien, Geoff Gillard, Charlotte F McDonagh, Anthony E. Boitano, Michael P. Cooke
Journal: Blood (2018)
Pharmacologic Exhaustion of Suppressor Cells with Tasquinimod Enhances Bacterial Clearance during Tuberculosis
Authors: Shashank Gupta, Stefanie Krug, Supriya Pokkali, Tomas Leanderson, John T. Isaacs, Geetha Srikrishna, William R. Bishai
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

the radiology department.This, arguably, limits the optimization of respiratory support during neonatal intensive care with existing monitoring tools focusing on ventilation alone.A further strength of this case report is the lack of any adjunctive respiratory support during the measurements.EIT demonstrated an almost complete lack of tidal ventilation in the left lung.EIT has been repeatedly shown to be able to differentiate single-lung ventilation in animal and human reports (5).Interestingly, EIT detected some residual tidal ventilation that clinicians would not have seen without the EIT recordings.The pulmonary artery infarct likely occurred after the pseudoglandular period and airway development.The residual ventilation likely represents bronchial tidal air movement and collateral ventilation via pores of Kohn.This suggests that EIT is able to image complex ventilation patterns within the lung at a resolution not currently possible within a bedside tool.EIT holds potential in monitoring ventilation and perfusion development in conditions characterized by unilateral lung differences and altered pulmonary blood flow, such as congenital diaphragmatic hernia and after cardiac surgery, over longer time periods.To date, the use of EIT to measure lung perfusion has been limited to human observations in which the perfusion state was not known (2) or animal models with selective occlusion of a single pulmonary artery and injection of an electrical impedance contrast agent (3).Our data support the preclinical data demonstrating the ability of EIT to selectively measure lung perfusion.The clear differentiation between the heartbeat-related signals within the left and right lung suggests that the cardiac-domain impedance measures within the anatomical regions of the chest containing lung are not exclusively due to heart movement being transmitted through lung regions.Conclusions.This case report describes the first report of EIT to measure perfusion and ventilation patterns in a newborn with a known loss of both in a single lung.EIT was able to demonstrate the perfusion and ventilation defects found on static radiological imaging.Importantly, EIT recordings within the heart-rate domain were independent of heart movement and at a respiratory resolution able to identify small areas of tidal ventilation.This suggests that EIT may hold promise as the first tool able to dynamically measure ventilation-perfusion matching over time in infants.
Human and computational models of atopic dermatitis: A review and perspectives by an expert panel of the International Eczema Council
Authors: Kilian Eyerich, Sara J. Brown, Bethany E. Perez White, Reiko J. Tanaka, Robert Bissonette, Sandipan Dhar, Thomas Bieber, Dirk J. Hijnen, Emma Guttman-Yassky, Alan Irvine, Jacob P. Thyssen, Christian Vestergaard, Thomas Werfel, Andreas Wollenberg, Amy S. Paller, Nick J. Reynolds
Journal: Journal of Allergy and Clinical Immunology (2018)

Atopic dermatitis (AD) is a prevalent disease worldwide and is associated with systemic comorbidities representing a significant burden on patients, their families, and society. Therapeutic options for AD remain limited, in part because of a lack of well-characterized animal models. There has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico to better define pathophysiologic mechanisms and identify novel therapeutic targets and biomarkers that predict therapeutic response. This review critically appraises a range of models, including genetic mutations relevant to AD, experimental challenge of human skin in vivo, tissue culture models, integration of "omics" data sets, and development of predictive computational models. Although no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways, and therapeutic target identification through each approach. Recent developments in computational analysis, including application of machine learning and a systems approach to data integration and predictive modeling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development, and precision medicine. Such predictive modeling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD.
CBMT-08. COMPARISON OF THREE METABOLIC PET RADIOTRACERS IN GLIOBLASTOMA: CELL CULTURE AND ANIMAL STUDIES
Authors: Corinne Beinat, Chirag Patel, Surya Murty, Tom Haywood, Jun Hyung Park, Yuanyang Xie, Sanjiv Gambhir
Journal: Neuro-Oncology (2018)

INTRODUCTION: Positron emission tomography (PET) is a non-invasive imaging modality used to visualize and define tumors based on their molecular characteristics and may play an important role in diagnosis and response assessment in glioblastoma patients. We have reported [18F]DASA-23 as a novel radiotracer for the measurement of aberrantly-expressed pyruvate kinase M2 (PKM2) in glioblastoma. PKM2 represents an attractive target for PET imaging due to lack of expression in the healthy brain and key role in the glycolytic reprogramming of glioblastoma. We compared the uptake dynamics and in vivo performance of [18F]DASA-23 to that of established radiotracers ([18F]FDG and [18F]FDOPA). Human U87 glioblastoma cells were studied for the uptake experiments and were also orthotopically implanted into nude mice (N=4) for in vivo microPET/CT dynamic imaging with the three radiotracers. Finally, a separate cohort of mice (N=6) was evaluated with [18F]DASA-23 microPET/CT before and one week post-initiation of vehicle or temozolomide chemotherapy (70 mg/kg, oral, 5 days per 28-day cycle). Data are reported as mean±SD. The cellular uptake at 60 minutes post-addition of radioactivity was 10.5 ± 0.5 %uptake/mg protein for [18F]DASA-23, which was significantly greater than that of [18F]FDG (1.94 ± 0.1, p<0.0001) and [18F]FDOPA (1.2 ± 0.1, p<0.0001). In the animal imaging studies at 30 minutes post-injection of radioactivity, [18F]DASA-23 clearly delineated the tumors from the surrounding healthy brain tissue and had a significantly higher tumor-to-brain ratio compared to that of [18F]FDG and [18F]FDOPA (4.1 ± 0.4 vs. 1.2 ± 0.2 [p=0.0005] and 2.6 ± 0.2 [p<0.0001], respectively). In another cohort of mice, the percent change in the [18F]DASA-23 tumor-to-brain ratio from pre-treatment to one week post-treatment was significantly reduced in the temozolomide compared to the vehicle group (p=0.004). These studies highlight the benefit of PET imaging with [18F]DASA-23 over other radiotracers ([18F]FDG and [18F]FDOPA) and suggest the potential to detect early response to temozolomide therapy with [18F]DASA-23.
DDIS-01. THE ANTIBODY-DRUG CONJUGATE ABT-414 DEMONSTRATES SINGLE-AGENT ANTI-CANCER ACTIVITY ACROSS A PANEL OF GBM PATIENT-DERIVED XENOGRAFTS
Authors: Bianca Marin, Ann Mladek, Danielle Burgenske, Lihong He, Zeng Hu, Katrina Bakken, Brett Carlson, Mark Schroeder, Jann Sarkaria
Journal: Neuro-Oncology (2018)

ABT-414 is a novel antibody-drug conjugate (ADC) of monomethyl auristatin F (MMAF), a microtubule destabilizing agent, and an anti-EGFR antibody (ABT-806). ABT-414 has demonstrated promising efficacy in clinical trials against newly diagnosed and recurrent glioblastoma (GBM), but little is known about mechanisms of sensitivity and resistance to the drug. The efficacy of ABT-414 was evaluated in vitro across a panel of nine EGFR-amplified GBM patient-derived xenografts (PDXs). Six lines responded to therapy, with the EGFR vIII mutant lines (GBM6, GBM39, GBM76, GBM108) being more sensitive (IC50 ~0.01 ug/mL) than point mutant (GBM12) or wild-type (GBM84) amplified lines (IC50 ~0.5 ug/mL). In contrast, GBM26 (point mutant), GBM46 (vII mutant) and GBM59 (vIII mutant) were non-responsive (IC50 > 10 ug/mL). Further testing revealed that these latter three lines were also resistant to MMAE, a cell-permeable analog of MMAF, which suggests intrinsic resistance to the toxin. In the responsive lines, ABT-414 was further tested in tumors implanted in heterotopic and orthotopic locations using tumor volume measurements and/or bioluminescent imaging (BLI). In flank, GBM6, GBM39, GBM76 and GBM108 were all highly sensitive to therapy, with complete tumor regression observed in all mice extending beyond 200, 250, 130 and 50 days, respectively. Intracranial GBM39 tumors were also highly responsive, with continuous suppression of BLI signal to background, and a survival benefit greater than 155 days. In contrast, GBM6 was resistant to therapy, without detectable impact on tumor growth and a difference in median survival of 5 ± 10 days. GBM76 was intermediately sensitive, with an extension in median survival of 20 ± 10 days. In summary, the majority of EGFR amplified lines tested are sensitive to ABT-414 in vitro and as flank tumors, but efficacy in treatment of orthotopic tumors is more limited. We hypothesize this effect may be related to heterogeneity of drug delivery.
IMMU-41. IDO1 INCREASES Treg RECRUITMENT INDEPENDENT OF TRYPTOPHAN METABOLISM IN A MODEL OF GLIOBLASTOMA
Authors: Lijie Zhai, Jun Qian, Erik Ladomersky, Kristen Lauing, Denise Scholtens, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) patients with high intratumoral IDO1 mRNA levels have an associated decrease in survival (Zhai et al., 2017; CCR). IDO1 is an immunosuppressive mediator that metabolizes tryptophan (Trp), and through its associated enzyme activity, has long been recognized to increase immunosuppressive CD4+CD25+FoxP3+ Tregs. Accordingly, we previously showed that the genetic knockdown of IDO1 in murine glioma cells, suppresses intratumoral Treg recruitment and increases animal subject survival. Unexpectedly, however, IDO1 knockdown has no effect on intratumoral Trp metabolism (Zhai et al., 2017; BBI). Further surprisingly, we recently demonstrated that, although IDO1 overexpression increases Treg levels in brain tumors, the pharmacological inhibition of IDO1 metabolism has no effect on Treg accumulation (Ladomersky et al., 2018; CCR). These novel data led us to question the requirement for IDO1 enzyme activity to regulate Tregs in malignant glioma. Lentiviral vectors encoding: (i) vector control-, (ii) wild-type (WT)-, or (iii) enzyme-null-IDO1, were created by site-directed mutagenesis in a plasmid containing WT, murine, IDO1-GFP cDNA. IDO1-deficient glioma cells from transgenic mice [(ERT2)GFAP→Cre;pTENfl/fl;p53fl/fl;Rbfl/fl;IDO1-/-] were transduced with the modified plasmids. RT-PCR, Western blotting and HPLC confirmed IDO1 expression and enzyme activity, in vitro. Syngeneic IDO1-/- mice were intracranially-engrafted with 2 × 105 modified glioma cells and studied for intratumoral Treg levels. The substitution of IDO1 histidine 350, to an alanine (H350A), decreases IDO1 enzyme activity by 90%. Syngeneic mice with intracranial, IDO1 enzyme null (H350A) glioma, have similar intratumoral Treg levels as IDO1 WT glioma, at 25% and 26%, respectively, and is significantly increased as compared to the 5.8% Tregs in vector control glioma (P=0.015). Our data challenge current dogma explaining how IDO1 causes Treg accumulation, and are in-line with the recent IDO1 enzyme inhibitor-focused Phase III clinical trial failure [NCT02752074]. We are now focused on revealing the mechanism underlying IDO1-mediated immunosuppression in malignant glioma.
Abstract 16800: Influence of Triggering Events on the Manifestation and Clinical Course of Takotsubo Cardiomyopathy
Authors: Birke Schneider, Anastasios Athanasiadis, Wolfgang Pistner, Johannes Schwab, Uta Gottwald, Tobias Müller-Honold, Wolfgang Toepel, Ralph Schoeller, Christian Wegner, Udo Sechtem
Journal: Circulation (2013)

Purpose: Takotsubo cardiomyopathy (TTC), an acute form of heart failure, is often preceded by stressful events. In a large registry we evaluated the influence of triggering events on the manifestation of TTC. Methods: From 37 hospitals, 324 pts (296f, 28m, age 68±12) were included in the registry according to established TTC criteria. All pts were asked if a stressful event preceded TTC onset. Results: A trigger was identified in 77%. Emotional stress was reported by 117 (36%), physical stress by 104 (31%) and a combination of both stress modalities felt to be equal by 29 pts (9%). In 74 pts (23%) no trigger was identified. The 4 groups were compared by analysis of variance. Age was not different. Physical stress was more frequent in males (57% vs 30%, p=0.005), emotional stress or no identifiable trigger were more prevalent in women. Pts with emotional stress as compared with physical, both or no stress more frequently complained about angina (94% vs 57% vs 59% vs 64%, p<0.0001) and less frequently about...
MNGI-03. PATIENT PARAMETERS ASSOCIATED WITH TUMOR GROWTH IN INCIDENTAL MENINGIOMA
Authors: David Kamson, Carlen Yuen, Laura Castillo-Saavedra, Andrew Wilmington, Matthew Walker, Ryan Merrell
Journal: Neuro-Oncology (2018)

Meningiomas are the most common primary intracranial tumors. Obesity or nulliparity are established risk factors for the development of these tumors. While radiographic tumor characteristics have been shown to be predictive of future tumor growth as demonstrated by the Asan Intracranial Meningioma Scoring System (AIMSS) [1], the relation of patient characteristics with tumor growth has been largely unexplored. The present study aims to evaluate a set of patient characteristics for predicting tumor growth and to assess whether these may provide information in addition to radiographic data for the prediction of progression free survival (PFS). Ninety-two treatment-naïve patients with incidental meningiomas (mean±SD age 62 ± 14y; 73F) were enrolled with at least 2 contrast-enhanced MRIs acquired in a state ≥0.5y apart (mean: 4.3 MRIs/patient; mean follow-up time 4.5 ± 3.8y). Age, height, BMI, sex were recorded for all patient, and parity available for 32 patients. Two-dimensional tumor growth rate(TGR, mm2/mo) calculated for all patients, while the AIMSS score was recorded for 81 patients. PFS was established as per the RANO criteria, defining progression as ≥25% increase in size. Age had a weak positive (r=0.21), while height had a weak inverse correlation (r=-0.19) with TGR (p Our preliminary data suggests that population data such as age, sex, height and BMI may have a value independent of radiographic characteristics to predict progression in incidental meningioma. Of these parameters, BMI is a modifiable risk factor. Weight loss could be evaluated as a potential intervention to slow down meningioma growth. [1] Lee, EJ, et al. Journal of neurosurgery 127.5 (2017): 971–980.
ACTR-65. INTRATHECAL PEMETREXED FOR PATIENTS WITH RECURRENT LEPTOMENINGEAL METASTASIS FROM LUNG ADENOCARCINOMA: A PHASE I CLINICAL TRIAL (IPRLM,NCT03101579)
Authors: Zhenyu Pan, Guozi Yang, Lihua Dong, Pengxiang Gao, Tongchao Jiang, Zhuo Wang
Journal: Neuro-Oncology (2018)

To determine toxicities, maximally tolerated dose (MTD), and potential antitumor activity of intrathecal pemetrexed (IP). MATERIAL AND Pulmonary adenocarcinoma patients with recurrent or progressive leptomeningeal metastases (LM) after intrathecal chemotherapy and other LM-related therapy were included. IP doses escalated from 10 mg to 15 mg, and even 20 mg. Protocol schema of IP was twice per week for 2 weeks (induction therapy), followed by once per week for 2–4 weeks (consolidation therapy). The primary endpoints were MTD and safety. The secondary endpoint was efficacy. Plasma and cerebrospinal fluid (CSF) samples were collected and analyzed for drug concentration. Nine patients (male: 3; female: 6; age: 37–71 years; median: 55) were enrolled between March 2017 and March 2018. All cases received total 50 times of IP (2–8 times, median: 6). Incidence of >grade III adverse events was 50%, including 4 cases with hematological toxicities and 2 with radiculitis. One patient received 15 mg IP dose expired due to hematological toxicities. Then protocol was revised. The dose was decreased to 10 mg. B12 and folic acid supplementation was indispensable. Three more cases were enrolled subsequently. No case showed severe hematological toxicities. Total clinical response rate was 80%. For the cohort of 10 mg dose, clinical response rate was 88%. All cases were followed up until May 1, 2018. Six cases died from cancer or related complications. No acute or subacute CNS toxicity was observed. The median overall survival was 2.5 (0.3–12) months from enrollment of this study. Pemetrexed was not cumulative in CSF. Times of plasma concentration peak were 6 h in 3 cases, 9 h in 1 case, and 12 h in 1 case after IP. CONCLUSION: Pemetrexed is suitable for intrathecal use. A dose of 10 mg shows well safety and high clinical response rate, which is worth for subsequent trials.
Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study
Authors: Mirjam Stahl, Mark O. Wielpütz, Isabell Ricklefs, Christian Dopfer, Sandra Barth, Anne Schlegtendal, Simon Y. Graeber, Olaf Sommerburg, Gesa Diekmann, Johannes Hüsing, Cordula Koerner-Rettberg, Lutz Nährlich, Anna-Maria Dittrich, Matthias V. Kopp, Marcus A. Mall
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. Objectives: To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures. Methods: In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (n = 21) or 0.9% IS (n = 21) for 52 weeks. Measurements and Main Results: Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (P = 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (-0.6) than in those treated with IS (-0.1; P < 0.05). In addition, weight gain was improved in infants with CF treated with HS (P < 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group. Conclusions: Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).