bluuebunny/crossref_metadata_2025_split huggingface dataset:
ISIS-FXIRx, a Potent Antisense Inhibitor of Factor XI, Suppresses FXI Activity and Elevates Aptt without Increased Risk of Bleeding in Cynomolgus Monkeys Following 13 Weeks of Treatment
Authors: Younis Husam , Crosby Jeff R. , Zhao Chenguang , MacLeod Robert , Monia Brett P. , Henry Scott 
Published: October 2019

Abstract
Abstract 2255
Complications associated with increased bleeding risk are the main limitations with current anticoagulant therapy. Inhibition of factor XI (FXI), a component of the intrinsic coagulation pathway, has received considerable interest because of the potential to produce sufficient anticoagulant activity without bleeding. The objective of these studies were to characterize the efficacy and safety of ISIS-FXrx and to assess the bleeding risk associated with FXI depletion under experimental surgical settings in cynomolgus monkeys. ISIS-FXIRx was selected from a series of 2nd-generation (2'-O-methoxyethyl) antisense oligonucleotides (ASOs) targeted to FXI which were evaluated for both tolerability and efficacy in cynomolgus monkeys (25 mg/kg twice per week for 13 weeks, SC). ISIS-FXIRx emerged as the most efficacious among the FXI ASOs evaluated, producing marked reductions of FXI RNA in liver, and FXI protein and activity levelsin plasma with a good tolerability profile. A more extensive dose-response evaluation of ISIS-FXrx (4,8,12 and 40 mg/kg/wk, SC) was conducted over a 13-week treatment period in cynomolgus monkeys to further assess tolerability and activity. ISIS-FXIRx produced a dose-dependent reduction in plasma FXI activity (>80% at 4 weeks of treatment at 40 mg/kg) with a concomitant increase in aPTT (33%). No effects on PT, platelets and no evidence of bleeding were observed after 13 weeks of treatment with ISIS-FXrx. ASO treatment was well tolerated at all doses tested and only produced changes typical for this chemical class of ASOs (e.g., basophilic granules in multiple tissues due do drug accumulation). ISIS-FXIRx (20 mg/kg, SC for 6 weeks) was also evaluated for bleeding risk in two experimental surgical models in cynomolgus monkeys; a tail amputation model and gum laceration model. Enoxaparin (2 mg/kg), known to increase the risk of bleeding, produced a statistically significant (p<0.05) increase in bleeding time and blood volume loss compared to saline control animals in both the tail amputation and the gum laceration models. Animals treated with ISIS-FXIRx displayed no increase in bleeding parameters compared to control animals. These results further support the conclusion that targeting FXI is an effective and safe strategy for development of novel antithrombotic agents with minimal increase in bleeding risk. ISIS-FXIRx is currently under evaluation in Phase 1 studies.

Disclosures:
Younis: Isis Pharmaceuticals, Inc.: Employment. Crosby:Isis Pharmaceuticals: Employment. Zhao:Isis Pharmaceuticals: Employment. MacLeod:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment. Henry:Isis Pharmaceuticals, Inc.: Employment.
Detection of Continuous Flow Left Ventricular Assist Device -Associated Acquired Von Willebrand Factor (VWF) Abnormality by An Automated Immunoturbidimetric VWF Activity Assay
Authors: He Rong , Crow Sheri , Joyce Lyle D. , Milano Carmelo , Heit John A. , Chen Dong 
Published: October 2019

Abstract
Abstract 2273

Background:
Continuous flow left ventricular assist device (CF-LVAD) recipients have high tendency of post-surgical gastrointestinal (GI) bleeding. We previously described the loss of high molecular weight VWF multimers (HMWM), due to either an accelerated clearance or enhanced cleavage of the HMWM, in most CF-LVAD recipients (Ann Thorac Surg. 90:1263–9). However, besides the tedious plasma VWF multimer analysis, neither VWF ristocetin cofactor nor collagen binding activity assay provides sufficient sensitivity for detecting such an acquired VWF abnormality (AVWA). In this study, we examined a new automated latex particle-enhanced immunoturbidimetric VWF activity assay (VWF:Lx) for its ability of detecting CF-LVAD-AVWA. We also analyzed the VWF pro-peptide (VWF:pp) to explored the potential mechanism of CF-LVAD-AVWA.

Design:
As part of an on-going prospective multicenter study, pre- and post-CF-LVAD implantation (7, 30 days and 5–7 months) blood samples were collected from 15 LVAD recipients (median age 52 years; 10 male and 5 female; 2008∼2009). Plasma VWF antigen (VWF:Ag), VWF:Lx activity, VWF:pp/Ag ratios were measured; and plasma VWF multimer analyses were performed on all available plasma samples. Standard statistical analyses were employed.

Result:
Loss of VWF HMWM was observed in 3 patients prior to CF-LVAD implantation and virtually all patients after surgery. VWF:Ag, VWF:Lx or VWF:pp/Ag ratios of the pre- and post-implantation samples were not significantly different (P> 0.1). However, VWF:Lx/Ag ratios of the post-implantation samples were significantly decreased (P<0.05). At a cut off of 0.8, the VWF:Lx/Ag ratio has a 90% sensitivity and specificity for detecting AVWA.

Conclusions:
VWF:Lx/Ag ratio has excellent sensitivity and specificity in detecting CF-LVAD-AVWA, and its impact on predicting post-surgical bleeding tendency in CF-LVAD recipients is being investigated. The distinct CF-LVAD-AVWA is most likely caused by enhanced cleavage, rather than clearance, of the HMWM.

Disclosures:
No relevant conflicts of interest to declare.
Is Deep-Vein Thrombosis Always the Origin of Pulmonary Embolism? Imaging of Veins with a Total-Body Direct Thrombus MRI Technique
Authors: van Langevelde Kirsten , Srámek Alexandr , Vincken Patrice W.J. , van Rooden Jan-Kees , Rosendaal Frits R. , Cannegieter Suzanne C. 
Published: October 2019

Abstract
Abstract 2297

Introduction
Pulmonary embolism (PE) is thought to originate from embolisation of a deep-vein thrombosis (DVT), resulting in two clinical manifestations of one disease: venous thrombosis. However, in up to 50% of patients with PE, no DVT is found with ultrasound. A new technique in diagnosing DVT is ‘MR Direct Thrombus Imaging’ (MRDTI), using methaemoglobin in the thrombus as endogenous contrast. We performed total body MRIs to visualize thrombi from calf veins to subclavian veins, to assess the origin of PE.

Methods
Consecutive patients with a first PE diagnosed by Multi Detector CT scan are included. All patients undergo a 1.5 T MRDTI scan. In addition, blood is sampled for determination of genetic risk factors: the Factor V Leiden (FVL) and prothrombin G20210A (FII) mutations.

Results
99 patients have been enrolled in the study. In 44/99 (44%) a thrombus was identified on MR images. Most thrombi originated from the left side of the body (27/44). The upper leg was involved most often (22/44), with thrombi extending into the calf in 16 of these patients. Other thrombi were present in the pelvic veins (4/44), and deep calf veins alone (12/44). 6 patients had merely thrombophlebitis. The FVL mutation was present in 14% (95% CI 6–27) of patients with a thrombus on MRI, and in 7% (95% CI 3–18) of patients without a thrombus. For FII, the prevalence in the group with a DVT on MRI was 2% (95% CI 0.4–12) and without a DVT 4% (95% CI 1–13).

Conclusion
In less than half of PE patients a thrombus can be found with total body MRI. When thrombi were present, they were mainly found in the upper leg, extending into the calf veins. Interestingly, 27% of PEs with a thrombus on MRI was related to isolated calf vein thrombosis and 14% to thrombophlebitis. In PE patients with no thrombus on MRI, a local origin of PE, a thrombus from cardiac origin or complete embolisation needs to be considered.
Supported by Netherlands Heart Foundation grant number 2009B050

Disclosures:
No relevant conflicts of interest to declare.
Venous Thromboembolism (VTE) in Patients with Hematologic and Non-Hematologic Malignancies: Incidence and Risk Factors for Recurrent VTE
Authors: Vadhan-Raj Saroj , Zhou Xiao , Shah Jatin J , Benjamin Robert S , Gladish Gregory 
Published: October 2019

Abstract
Abstract 2303
The incidence of VTE and risk for recurrence is known to be higher in patients (pt) with malignancy than in other patients. However, the exact incidence and risk factors predictive of recurrent VTE in patients with hematologic malignancies (Hem) and solid tumors (ST) are not well defined. A retrospective study was conducted to evaluate the incidence of VTE and the recurrent events during one year period at MD Anderson Cancer Center. The medical records of all patients with VTE confirmed by the radiologic studies in 2006 were reviewed. The data were collected for the incidence and type of VTE, the recurrent events during a one year follow-up from the time of primary event, and the risk factors for recurrent events, including, the pt demographics, diagnosis, prior history of VTE, transfusions, use of erythropoiesis-stimulating agents, and the laboratory parameters at the time of the index VTE event. Cox proportional hazard models were established to determine the independent predictive factors for recurrent VTE. There were 24,806 unique patients (each patient counted once) in active treatment at the Cancer Center between January 2006 and December 2006. Of the 980 pts diagnosed with VTE (480 DVT, 477 PE, and 23 DVT/PE) during this period, there were 770 ST, 208 Hem, and 2 benign conditions. The incidence of VTE was higher in Hem pts than in ST pts [208/3603 (6%) vs. 770/20212 (4%), p<0.0001]. Among Hem pts, the incidence was significantly higher in myeloma as compared to lymphoma and leukemia (9%, 6%, and 4%, respectively, p<0.0001). The proportion of VTE pts with PE was significantly higher among ST pts compared with Hem pts (55% vs 37%, p<0.0001). The incidence of recurrent VTE, as defined by any new event or progression of the index event, was 14% (140/978 pts) during one year follow-up period, and it was not different for Hem (16%) vs. ST (14%). Among Hem pts, the recurrence was higher for myeloma (19%) than lymphoma (16%) and leukemia (13%). Majority of the recurrent events (100/140, 71%) were seen during the initial 3 month period from the index event. The independent risk factors for recurrent VTE during 3 months, 6 months and 1 year were summarized in the following table:3 months6 months1 yearRisk factorsHazard ratio (95% CI)PHazard ratio (95% CI)PHazard ratio (95%CI)PPE vs. non-PE1.86 (1.20–2.88)0.0051.67 (1.12–2.42)0.0061.74 (1.20–2.51)0.003Age (<60 vs. ≥60 years)2.05 (1.34–3.15)0.0011.55 (1.08–2.23)0.0171.62 (1.14–2.32)0.008Men vs. women1.70 (1.10–2.63)0.0181.44 (0.994–2.07)0.054PE, pulmonary embolism; CI, confidence interval.

Conclusions:
The incidence of VTE is higher in Hem pts, especially in myeloma. Younger age (<60 years) and PE are independent risk factors predictive of recurrence during 3 month, 6 month and 1 year period.

Disclosures:
No relevant conflicts of interest to declare.
Thrombosomes Show Dose-Dependent Increase in Thrombus Formation in a Model of Deep Arterial Injury
Authors: Joshi Nikhil Vilas , Raftis Jennifer , Lucking AJ , Tandon Narendra , Fitzpatrick M , Feuerstein Giora , Newby David E 
Published: October 2019

Abstract
Abstract 2319

Introduction
Thrombosomes are novel lyophilized human platelet derivatives that retain a number of key platelet structural and functional properties. Building on preliminary in vitro studies, we here sought to investigate whether Thrombosomes, suspended in platelet free plasma (PFP), would enhance and be incorporated in thrombus generated under flow conditions within a validated and well-characterised model of deep arterial injury.

Methods
PFP was obtained by centrifuging citrated whole blood from six healthy non-smoking volunteers and filtering with a 0.22μm filter. Thrombosomes were suspended in 60 mL of PFP to generate final concentrations of 20 and 200 × 106Thrombosomes /mL. Immediately prior to use, 1.2 mL of 1M CaCl2 was added to permit fibrin generation. Thrombus formation was assessed using the Badimon Chamber at low (212 s−1) and high (1690 s−1) shear rates with porcine aortic tunica media as the thrombogenic substrate. Total thrombus area and platelet-rich area were measured histomorphometrically using conventional and immunohistochemical staining respectively. Fluorescent labeled Thrombosomes were added to the extracorporeal circuit in the Badimon chamber to study the ex vivo thrombus generation in the whole blood. Electron microscopy of Thrombosomes and platelets was undertaken.

Results
Thrombosomes contributed towards thrombus formation in whole human blood as evidenced by incorporation of fluorescent-labeled Thrombosomes into the thrombus. Immunohistochemical staining of the glycoprotein IIb/IIIa receptor confirmed incorporation of Thrombosomes into the thrombus. In the high shear chamber, mean thrombus area increased in a dose-dependent manner following the addition of Thrombosomes (704 μm2 [95% CI, 224 – 1184 μm2], 1511 μm2 [95% CI, 687 – 2336 μm2] and 2378 μm2 [95% CI, 1567 – 3189 μm2] for PFP and Thrombosomes at concentrations of 20 and 200 × 106/mL respectively [P= 0.003]). In the low shear chamber, total thrombus area for the PFP was 4962 μm2 (95% CI, 2489 – 7434 μm2). The addition of Thrombosomes at concentrations of 20 and 200 × 106/mL led to a numerical increase in mean thrombus area to 6170 μm2 (95% CI, 3944 – 8397 μm2) and 7504 μm2 (95% CI, 3864 – 11144 μm2) respectively, although this was not statistically significant (P= 0.2969).

Conclusions
Thrombosomes suspended in PFP and exposed to injured arterial tissue under physiologically relevant flow conditions are incorporated into thrombus and enhance thrombus formation in a dose dependent manner. These findings act as impetus to undertake clinical studies of this rehydrated, lyophilized infusible hemostatic platelet product.

Disclosures:
Fitzpatrick: Cellphire Inc.: Employment, Equity Ownership. Feuerstein:Cellphire: Consultancy. Newby:Cellphire: Research Funding.
A MiR-142-3p/EGR2 Feedback Circuitry In Human CSF-1 Driven Differentiation of Monocytes Into Macrophages
Authors: Lagrange Brice , Droin Nathalie , Aucagne Romain , Paggetti Jérôme , Largeot Anne , Solary Eric , Delva Laurent , Bastie Jean-Noel 
Published: October 2019

Abstract
Abstract 2366
Colony-stimulating factor-1 (CSF-1 or M-CSF) triggers the differentiation of human peripheral blood monocytes into macrophages through and integrated cytokine/transcription factors circuitry. Using microarray profiling to explore the role of microRNAs (miRNAs) in this molecular circuitry, we identified the down-regulation of miR-142-3p in human macrophages obtained from CSF-1-treated monocytes. We show that miR-142-3p is a repressor of the transcription factor EGR2 (Early Growth Response 2) through direct 3'UTR interactions. Interestingly, EGR2 binds the promoter of the pre-miR-142-3p gene to negatively regulate its expression, identifying a self-regulatory feedback loop. Enforced expression of miR-142-3p in primary human monocytes as well as decreased expression of miR-142-3p observed in monocytes from patients with a chronic myelomonocytic leukemia further assess the link between miR-142-3p and EGR2 expression in these cells. A chemical inhibition of the Src kinase family prevents the regulation loop induced by CSF-1. Thus, our study uncovers an EGR2/miR-142-3p circuitry which regulates CSF-1 driven differentiation of human monocytes into macrophages.

Disclosures:
No relevant conflicts of interest to declare.
HSP70 Inhibitor, YK5, Ablates Blast, Progenitor and Stem Cell Populations in Primary Acute Myelogenous Leukemia Cells
Authors: Rico Juan Felipe , Sharma Krishan K. , Kang Yanlong , Taldone Tony , Patel Hardik , Brennan Sarah , Zong Hongliang , Becker Michael W. , Roboz Gail J. , Chiosis Gabriela , Guzman Monica L. 
Published: October 2019

Abstract
Abstract 2493
Prognosis for acute myelogenous leukemia (AML) with traditional chemotherapeutic agents remains poor, most patients relapse and die of their disease. Studies have shown that AML can be originated and maintained by leukemia stem cells (LSCs) and that a high percentage of phenotypically-defined LSCs correlate to especially poor prognosis. Thus, novel therapies that can eliminate LSCs are needed. Upregulation of HSP70 has been described in human cancer cells and is often associated with chemoresistance and poor prognosis. Therefore, HSP70 represents a novel target for cancer therapy. Due to this, we tested a novel inhibitor of tumor-HSP70, YK5, and found that it can induce potent cell death in AML cells including progenitor and stem cell populations with minimal effects in normal hematopoietic cells.
Fifteen primary AML patient samples were treated with YK5 in varying concentrations for 48 hours to determine the LD50 of YK5. The viability of these samples was determined by multiparameter flow cytometry using cell surface markers to distinguish, lymphocytes, blasts, progenitor and stem cell populations in conjunction with Annexin V and 7AAD. Mean LD50 for all samples tested was 4.5μM (CI 95% 2.239–6.853). Three of these samples had very low LD50s below 2.5μM and only one sample demonstrated relative resistance with a LD50 that was greater than 15μM. Notably, progenitor and stem cell populations were also targeted while normal remaining lymphocytes were spared. Furthermore, we found that LSCs in a subset of patient samples treated with YK5 exhibited higher sensitivity to the compound when compared to blast cells. Importantly, treatment of primary AML samples with 5μM YK5 resulted in a 63% decrease in colony forming ability when compared to untreated control (N=5), suggesting that YK5 can impair malignant progenitors. In contrast, normal CD34+ cord blood cells after treatment with 5μM YK5 for 48hrs exhibited a viability of 57% (N=3). Xenotransplant assays are currently ongoing to determine the ability of YK5 to inhibit LSC function. Treatment with YK5 resulted in a decrease in phosphorylation of STAT5, determined by flow cytometry. Taken together, HSP70 inhibition is a promising potential treatment for AML and has the potential to eradicate leukemic stem and progenitor cells while sparing normal hematopoietic cells. Thus, targeting HSP70 in AML appears to hold great promise.
*JFR and KKS contributed equally to this project

Disclosures:
Roboz: EpiCept: Consultancy; ChemGenex: Consultancy; Celgene: Consultancy; Boehringer Ingelheim: Consultancy.
Comparison of Short-Term Outcomes Between CSTIBES02 and ALL Ph08 Trials for Young Patients with Philadephia Chromosome-Positive ALL (Ph+ALL) Differing In Imatinib Dose and Amount of Chemotherapy Before Stem Cell Transplantation
Authors: Ribera Josep-Maria , Garcia Olga , Montesinos Pau , Barrios Manuel , Oriol Albert , Brunet Salut , Gonzalez Jose , Esteve Jordi , Tormo Mar , Potro Eloy Del , Moreno Maria-José , Fernández-Abellán Pascual , Hernández-Rivas Jesú S. M.a , Barba Pere , Sarrá Josep , Abella Eugènia , Bernal Maria-Teresa , Llorente Andreu , Amigo Maria-Luz , Lavilla Esperanza , Bravo Pilar , Sanz Miguel-Angel , Feliu Evarist 
Published: October 2019

Abstract
Abstract 2582

Background and objectives.
Concurrent imatinib and chemotherapy followed by allogeneic stem cell transplantation (SCT) is the most used treatment for young patients with Ph+ALL. However, the amount of chemotherapy before SCT is not well established. The Spanish PETHEMA Group conducted two consecutive protocols (CSTIBES02 -Haematologica 2010; 95: 87–95- and ALL Ph08) differing in the imatinib dose (400 mg/d vs. 600 mg/d) and the amount of chemotherapy (two consolidation cycles vs. one consolidation cycle) before SCT. The short –term outcomes are herein compared.

Patients and methods.
CSTIBES02 trial included 30 patients with a median age of 44 yr and ALL Ph08 includes 26 patients (median age 37 yr). The main clinical and biological features of the two series of patients are comparable. The initial induction chemotherapy schedule included VCR, DNR and PDN at the same doses in the two protocols, but in the CSTIBES02 mitoxantrone and ARA-C were administered on day 15 if >5% blast cells were present in bone marrow smear, whereas no change in the chemotherapy schedule was prescribed in the ALL Ph08 trial according to the percentage of blast cells on day 15. The first consolidation cycle included HD MTX, ID ARA-C, MP and teniposide in both protocols. Patients in CR were then submitted to SCT in ALL Ph08 study, whereas those included in CSTIBES02 received a second consolidation cycle before SCT. Imatinib was administered concurrently with chemotherapy from diagnosis (400 mg/d in CSTIBES02 trial and 600 mg/d in ALL Ph08 study).

Results.
The main short-term outcomes are compared in the table

Conclusion.
Despite non-significant improvement has been observed in ALL Ph08 protocol regarding CR attainment, molecular response after induction and consolidation, 2-yr EFS has been improved after the increase of imatinib dose and the decrease of amount of chemotherapy. Both decrease in relapse before SCT and TRM observed in the ALL Ph08 protocol are responsible for the better EFS.
Supported in part by grants RD06/0020/1056 from RTICC and P-EF-11 from FJC

Disclosures:
No relevant conflicts of interest to declare.
Adolescents and Young Adults with Acute Lymphoblastic Leukemia Have Better Outcomes When Treated with Pediatric-Inspired Regimens - Systematic Review and Meta-Analysis of Comparative Trials
Authors: Ram Ron , Wolach Ofir , Vidal Liat , Gafter-Gvili Anat , Shpilberg Ofer , Raanani Pia 
Published: October 2019

Abstract
Abstract 2591

Background:
Survival of adults with acute lymphoblastic leukemia (ALL) is inferior to pediatric patients. Therefore, strategies to improve long-term results in this population are warranted. Objectives: This study aims to evaluate the efficacy and safety of pediatric-inspired regimens given to adolescents and young adults (AYA) with ALL. Methods: Systematic review and meta-analysis of comparative trials of AYA patients with ALL given induction chemotherapy with either pediatric-inspired regimens or conventional adult chemotherapy was conducted. Cochrane Library, MEDLINE and conference proceedings were searched (up-to May, 2011). Outcomes assessed were: all-cause mortality, number of patients achieving complete remission after induction chemotherapy and toxicity of the regimen (evaluated by non-relapse mortality). Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Results: Our search yielded 11 trials, including 2489 patients. The age of AYA patients ranged between 10 and 57 years. Studies were published between the years 2003 and 2009. AYA patients given pediatric-inspired regimens had a statistically significant lower all cause mortality at 3 years (RR 0.58; 95% CI 0.51–0.79, 7 trials) beyond 3 years (RR 0.58; 95% CI 0.51–0.65, 8 trials) and at the end of study period (RR 0.59; 95% CI 0.52–0.66, 9 trials, Figure). Sensitivity analysis for all cause mortality including studies in which the two cohorts were well compared in either age or disease risk also showed decreased all cause mortality in patients given pediatric-inspired regimen (RR 0.53; 95% CI 0.41–0.70, I2=50%, 4 trials). However, this superiority in survival for pediatric-inspired regimens was not maintained when studies including only patients older than 20 years were analyzed (RR 0.49; 95% CI 0.23–1.06, I2=67%, 2 trials). Complete remission rate after induction chemotherapy was superior in patients given pediatric-inspired regimens when compared to patients given conventional adult chemotherapy (RR 1.05; 95% CI 1.01–1.10, I2=55%, 7 trials) with comparable non-relapse mortality in both groups (RR 0.53; 95% CI 0.19–1.48, I2=56%, 4 trials). Conclusions: For patients up to the age of 20 years, pediatric-inspired regimens are superior to conventional adult chemotherapy in terms of ACM and complete remission rate with similar non relapse mortality. Randomized controlled trials to further investigate the feasibility of this approach in adult ALL patients are warranted.

Disclosures:
No relevant conflicts of interest to declare.