bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel, Potent and Selective JAK2 Inhibitors.
Authors: Radimerski Thomas , Baffert Fabienne , Regnier Catherine H. , De Pover Alain , Pissot Carole , Gerspacher Marc , Brueggen Josef , Tavares Gisele , Blasco Francesca , Ledieu David , Nolan Lynda , Ruetz Stephan , Chene Patrick , Erdmann Dirk , Drueckes Peter , Furet Pascal , Lang Marc , Trappe Joerg , Vangrevelinghe Eric , Wartmann Markus , Hofmann Francesco 
Published: October 2019

Abstract
Abstract 3777
Poster Board III-713
The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and from primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative disorders and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild type enzymes by novel small molecule inhibitors, which act in an ATP-competitive manner. The profile of a lead compound from this class will be presented that displays more than twenty-fold selectivity towards JAK2 within the JAK family, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, the inhibitor exhibited good oral bioavailability and is efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model as well as polycythemia and extramedullary erythropoiesis in mouse and rat models.

Disclosures:
Radimerski: Novartis: Employment, Equity Ownership. Baffert:Novartis: Employment. Regnier:Novartis: Employment. De Pover:Novartis: Employment. Pissot:Novartis: Employment. Gerspacher:Novartis: Employment. Brueggen:Novartis: Employment. Tavares:Novartis: Employment. Blasco:Novartis: Employment. Ledieu:Novartis: Employment. Nolan:Novartis: Employment. Ruetz:Novartis: Employment. Chene:Novartis: Employment. Erdmann:Novartis: Employment. Drueckes:Novartis: Employment. Furet:Novartis: Employment. Lang:Novartis: Employment. Trappe:Novartis: Employment. Vangrevelinghe:Novartis: Employment. Wartmann:Novartis: Employment. Hofmann:Novartis: Employment.
Thrombin Generation in Pediatric Patients Treated with L-asparaginase.
Authors: Tousovska Katerina , Zapletal Ondrej , Vytiskova Sona , Slanska Martina , Ruzickova Petra , Sterba Jaroslav 
Published: October 2019

Abstract
Abstract 3983
Poster Board III-919

Introduction
Treatment with L-asparaginase is associated with an disturbance of coagulation cascade. Increased thrombin generation is the most frequently cited coagulation anomaly associated with L-asparaginase treatment. Until now, almost all studies aimed on estimation of thrombin generation, have used circulating procoagulant markers such are thrombin/antithrombin complexes(TAT),D dimers(DD),prothrombin fragments (F1,F2).Calibrated automated thrombogram (CAT) allows the precise estimation of the whole amount of thrombin generated in vivo at present time. We show the first data on thrombin generation measured by CAT among pediatric patients with acute lymphoblastic leukemia treated with L-asparaginase.

Patients and methods
Thrombin generation was measured in platelet poor plasma of 18 patients (age 7-17years) by means of CAT. Samples were obtained at pre-defined time points during the induction and reinduction phase of protocol ALL-IC BFM 2000. We simultaneously checked the APTT,PT,AT III,fibrinogen and DD from each blood sample. Detailed patientsx data were collected prospectively.

Results
We collected 22 series of CAT measurements from 18 patients. The average endogenous thrombin potential (ETP) value was 1237,64±334,49nM/min during protocol I(PI) and 892,31±405,03 during protocol II resp.III(PII/III) (p .000013). Maximum ETP was reached on day 24 in PI (1310,15±256,3nM/min) and on day 15 in PII/III (978,20±262,30 nM/ min). The average ETP value in 20 healthy controls was 1218,12±129,00 nM/min. Three patients developed deep venous thrombosis (DVT) during the study period, all of them on PI. Their average ETP value on the last measurement before thrombosis was 1510,54±78,6 nM/min. Four patient had an infection gr. III/IV, according WHO, during the study period. Their average ETP value after the infection was 1711,43±106,0 nM/min. Two of those four patient developed DVT within 5 resp.8 days after the first sign of infection. Fibrinogen level <1g/l was detected in 19 samples out of 104. From those 19 samples with fibrinogen < 1,0,the ETP value from the same sample was normal in 14 cases and low in 5 cases. There were no bleeding episodes in that time.

Conclusions
Thrombin generation is preserved in majority of patients treated with L-asparaginase in accordance with ALL-IC BFM 2000 protocol, despite the associated hypofibrinogenemia. Patients on induction treatment generate significantly more thrombin than patients on reinduction treatment. Our results show the sharp increase in ETP right after the infection with risk of DVT. Our data should be proved on larger group of patients.

Disclosures:
No relevant conflicts of interest to declare.
Subsegmental Pulmonary Embolism Diagnosed by Computed Tomography: Incidence and Clinical Implications. A Systematic Review and Meta-Analysis of the Management Outcome Studies.
Authors: Carrier Marc , Righini Marc , Wells Phil , Perrier Arnaud , Anderson David , Rodger Marc , Le Gal Gregoire 
Published: October 2019

Abstract
Abstract 4002
Poster Board III-938

Background
Multiple-detectors CTPA appears to have a higher sensitivity for PE as compared to single-detector CTPA. In particular, multiple-detectors CTPA allows better visualization of segmental and subsegmental pulmonary arteries, hence the proportion of patients with suspected PE in whom isolated subsegmental thrombus are reported might be higher using multiple-detectors CTPA.
The clinical significance of subsegmental PE is unknown. In the PIOPED study, PE limited to subsegmental pulmonary arteries were most prevalent among patients with low-probability ventilation/perfusion (V/Q) scans. Patients with non diagnostic (low or intermediate probability) V/Q scans can be safely managed without anticoagulation. Nonetheless, patients with isolated subsegmental PE detected on CTPA are more commonly receiving anticoagulation than not.

Purpose
To determine whether multiple-detectors CTPA increases the proportion of PE diagnosis limited to subsegmental arteries and to assess the safety of diagnostic strategies based on CTPA.
Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews.

Study Selection
Twenty four articles met all the inclusions criteria (21 prospective cohort studies; 3 randomized controlled trials).

Data extraction
Two reviewers independently extracted data onto standardized forms.

Data Synthesis
A total of 2674 patients with suspected PE were included in the analyses. Of these, 1140 and 1534 patients underwent a single and multiple-detectors CTPA respectively.

Conclusion
The use of multiple-detectors CTPA in diagnostic strategies for PE appears to increase the proportion of patients diagnosed with subsegmental PE with comparable outcomes in patients with negative tests. This suggests that patients with subsegmental PE appear to not require anticoagulation.

Disclosures:
Rodger: Biomerieux: Research Funding; Boehringer Ingelheim: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Leo Pharma: Research Funding; Bayer: Research Funding; GTC Therapeutics: Research Funding.
Minimal Risidual Disease monitoring in Childhood Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia: Preliminary Results of JPLSG Ph+ALL04.
Authors: Kawasaki Hirohide , Adachi Souichi , Ohara Akira , Kikuta Atsushi , Sato Atsushi , Takahashi Hiroyuki , Chin Motoaki , Tsuchida Masahiro , Hamamoto Kazuko , Matsumoto Kouichi , Yagi Keiko , Yabe Hiromasa , Yoshida Makoto , Watanabe Tsutomu , Manabe Atsushi 
Published: October 2019

Abstract
Abstract 4116
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) is very rare and poor prognostic condition in children. Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted first nationwide clinical trial for Ph+ALL in children (Ph+ALL04). Ph+ALL04 consists of five therapy phases; Induction phase (five drugs induction), Intensification phase (high-dose CA and BFM Ib), Re-induction phase (four drugs re-induction), Imatinib mono-therapy phase, and hematopoietic stem cell transplantation phase (VP+CY+TBI condioning). Before and after each phase, BCR-ABL minimal residual disease (MRD) was monitored by the real-time PCR method. During the period 2004-08, 44 patients were enrolled in the Ph+ALL04 study. Out of 44 patients, five were resistant to Induction Phase and did not achieve CR. Their levels of BCR-ABL transcript at diagnosis were significantly higher than that of patients achieved CR after Induction phase. After Induction phase, 39 patients achieved CR, and seven of 39 patients also achieved MRD negative. After Intensification phase, two patients relapsed. Thirty-four patients were still in CR, and 10 patients also achieved MRD negative after Intensification phase. One patient relapsed after Re-induction phase and three patients relapsed after Imatinib mono-therapy phase. Thirteen patients were MRD negative before Imatinib mono-therapy phase, and 14 patients were MRD negative after Imatinib mono-therapy phase. Before Hematopoietic stem cell transplantation phase, 14 patients were MRD negative. Twenty-six patients received hematopoietic stem cell transplantation. Out of 26 patients, three relapsed after hematopoietic cell transplantation. Twenty-three patients continued to be in CR and MRD negative for median 2 years after hematopoietic stem cell transplantation. In conclusion, amount of BCR-ABL transcript is a possible predictor for achieving remission after induction therapy in Ph+ALL children. MRD detection during therapy is confirmed the important prognostic indicator in the context of the intensive chemotherapy and hematopoietic stem cell transplantation in Ph+ALL children.

Disclosures:
No relevant conflicts of interest to declare.
Decitabine Can Induce Complete Cytogenetic Responses When Used as Initial Therapy in Older AML Patients.
Authors: Cashen Amanda F 
Published: October 2019

Abstract 4123

Background
The incidence of acute myeloid leukemia (AML) increases with advancing age. At present, there are limited treatment options available for older patients because of lack of efficacy and increased toxicity. In a previously reported Phase II AML trial (n = 55), older patients not previously treated for AML experienced an overall response rate of 25% with decitabine (Cashen et al. Blood 2008). Response rate was similar in patients with poor or intermediate cytogenetic risk at baseline. In addition, 5 (15%) of the 34 patients who had cytogenetic abnormalities at baseline achieved a complete cytogenetic response in this trial. As older AML patients are more likely to present with unfavorable cytogenetic profiles, it was of interest to review the patient characteristics and describe the responses of the 5 patients who had a complete cytogenetic response.

Methods
The patients for this analysis were from a multicenter, Phase II study. In this study, patients over the age of 60 with AML (>20% bone marrow blasts) and no prior therapy for AML were treated with decitabine, 20 mg/m2 IV for 5 consecutive days of a 28-day cycle until disease progression or unacceptable adverse event. Cytogenetic profile was assessed at screening and after every cycle, beginning with cycle 2.

Results
The 5 patients (2 males, 3 females; 5 white; 2 M1, 1 each for M2, M6, and M7) with a complete cytogenetic response had baseline characteristics that are associated with high risk. Three were >70 yrs of age, and all 5 had AML secondary to prior therapy (n=2) or MDS (n=3). Four patients had poor-risk cytogenetics: 2 pts with -7, -5q, and ≥ 3 abnormalities and 2 pts with deletions of chromosome 5 and ≥ 3 abnormalities. One patient had intermediate-risk cytogenetics. The median baseline bone marrow myeloblast count was 33% (range 21 to 60). These patients were treated with a median 10 cycles (range 6 to 19) of decitabine. The median time to a complete cytogenetic response was 5 cycles (range 2.3 to 6). The median time to relapse from a complete cytogenetic response was 8.1 cycles (range 3.4 to 19.8). The overall median survival was 21.6 months (95% CI: 9.5, 24.7), which compares favorably to the median overall survival of the entire study cohort (21.6 months vs. 7.7 months, Cashen et al. Blood 2008).

Conclusions
Treatment with decitabine can induce complete and durable cytogenetic responses, even in older patients with high risk disease characteristics and poor risk cytogenetics. Patients who achieve a cytogenetic response may have a survival benefit. A presently ongoing Phase III survival trial with decitabine will help further characterize the effect of decitabine on cytogenetic responses in older AML patients.

Disclosures:
Cashen: Eisai, Inc.: Consultancy.
Analysis of the Coagulation Factor XII 46 C/T Polymorphism in a Pedigree and Related Literature Review.
Authors: Chang Da-Yu , Ouyang Jian , Zhou Rong-Fu , Shao Xiao-Yan 
Published: October 2019

Abstract
Abstract 4210

To detect the gene mutation of a pedigree with coagulation factor XII (FXII) deficiency.

Methods
The peripheral blood samples were collected from the proband and his parents, and the plasma FXII:C were determined. All the exons and exon-intron boundries of F12 gene were amplified with PCR and sequenced directly.

Results
The activity of FXII were 52.5%, 78.6% and 89% for the proband, his father and mother, respectively. Direct sequencing suggested that the proband was 46 T/T genotype in exon1, while both his parents were 46 C/T genotype in the same alle. No other base change was detected in F12 gene.

Conclusion
The 46 T/T polymorphism of F12 gene might be the cause of FXII:C deficiency for the propositus.

Disclosures:
No relevant conflicts of interest to declare.
CD200 Is Preferentially Expressed in CD138 dim Multiple Myeloma Cells: Implications for a Myeloma Stem Cell Subpopulation with Potential Immune-Resistance.
Authors: Chen Xiaochuan , Stein Rhona , Goldenberg David M. 
Published: October 2019

Abstract
Abstract 4877

Introduction
The CD138negCD20+ cell population has been suggested as the putative multiple myeloma (MM) cancer stem cells, both in MM cell lines and in patient specimens. CD200 is an immunosuppressive membrane glycoprotein reported to be co-expressed with other stem-cell markers in prostate, breast, brain, and colon cancers. Also, CD200 is a negative prognostic factor for MM. It remains unknown whether CD200 is expressed in the CD138negCD20+ MM cell population, the putative MM cancer stem cells. Here we addressed this question by assessing CD200 expression in different subpopulations of MM cells according to their CD138 expression levels.

Methods
Two MM cell lines (RPMI8226 and NCI-H929) were co-stained with FITC-labeled anti-CD200, PE-labeled anti-CD20, and APC-labeled anti-CD138 antibodies for multicolor flow cytometry analysis. The cells were gated into 4 subpopulations (h1>h2>h3>h4 corresponding to CD138 expression levels: high>dim>low>negative). In each gated cell population, CD200 expression was assessed, and the CD200+ and CD200neg cell subpopulations were further gated for analysis of their CD20 expression levels.

Results
In the RPMI 8226 cell line, the distribution of gated h1, h2, h3, and h4 populations was 87.51%, 5.86%, 5.26%, and 1.29%, respectively. In the h2 (CD138dim) population, 22.88% of the cells were CD200+. In contrast, CD200 was expressed at much lower levels in the other three populations, ranging from 7.28% (h1), 6.65% (h3), to 0.48% (h4). In CD200+ cells from the gated h1, h2, h3, and h4 population, CD20+ cells were 19.50%, 23.03%, 27.67%, and 18.75%, respectively, while in the CD200neg cells, CD20+ cells were 20.79%, 22.50%, 25.08%, and 28.02%, respectively. In the NCI-H929 cell line, 18.59% of the cells in the h2 population were CD200+, whereas only 1.61%, 1.69%, and 0.47% of the cells in the h1, h3, and h4 populations were CD200+. In each population, there were more CD20+ cells in CD200+ cells than in CD200neg cells, which were 24.52% vs 0.04% (h1), 41.94% vs 11.34% (h2), 11.11% vs 3.06% (h3), and 50.00% vs 2.25% (h4), respectively.

Conclusions
These results demonstrate that the immunosuppressive molecule CD200 is preferentially expressed in a CD138dim subpopulation of multiple myeloma cells. Depending on cell line, the putative myeloma stem cell marker CD20 is either preferentially, or not preferentially, expressed in the CD200+ cells, suggesting that an immune-resistant subpopulation of MM stem cells might exist, which may have important implications for designing immunotherapeutic approaches to treat this disease.

Disclosures
Goldenberg: Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Oncogenic RAS Enables DNA Damage- and p53-Dependent Differentiation of Acute Myeloid Leukemia Cells in Response to Chemotherapy.
Authors: Meyer Mona , Rübsamen Daniela , Slany Robert K. , Illmer Thomas , Stabla Kathleen , Roth Petra , Stiewe Thorsten , Eilers Martin , Neubauer Andreas 
Published: October 2019

Abstract
Abstract 5040

Introduction
Acute myeloid leukemia (AML) is a clonal disease originating from myeloid progenitor cells with a heterogeneous genetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequently observed in AML, and patients with RAS mutations benefit most from high-dose cytarabine as postremission therapy (Neubauer et al., J Clin Oncol 2008). The molecular reason for this phenomenon is not well understood.

Methods
We used bone marrow cells expressing a conditional MLL-ENL-ER oncogene to investigate the interaction of oncogenic RAS and chemotherapeutic agents. In addition, we used primary human inversion 16 positive AML samples with or without oncogenic RAS mutations to corroborate our findings.

Results
There was no difference in cell cycle kinetics, apoptosis or cellular senescence in MLL-ENL cell expressing control vector vs. MLL-ENL cells expressing oncogenic RAS in response to cytarabine treatment. However, we observed an increased activation of DNA damage checkpoints in MLL-ENL-cells expressing oncogenic RAS after incubation with chemotherapeutic agents. This resulted in an Atm/r as well as p53-dependent genetic program causing dramatically reduction of clonogenicity in MLL-ENL cells expressing oncogenic RAS due to induction of myeloid differentiation. Co-expression of dominant – negative p53 completely abolished this differentiation resulting in the rescue of the clonogic potential. Activation of p53 as a result of inhibition of Mdm2-mediated degradation of p53 further enhances this myeloid differentiation. Of note, in primary AML cases, oncogenic RAS also was associated with a more differentiated phenotype.

Conclusions
The data can explain the beneficial effects observed in AML patients with oncogenic RAS mutations treated with high dosages of cytarabine and suggest that induction of p53-dependent differentiation, e.g. by interfering with Mdm2-mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy since stronger acitvation of p53 by oncogenic RAS and chemotherapeutic agents cause the differentiation of hematopoietic stem cells to more differentiated progenitors. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiation of tumor-initiating cells.

Disclosures
No relevant conflicts of interest to declare.
Antiphosplipid Antibodies and Thrombosis in Cancer Patients.
Authors: Jajeh Ahmad 
Published: October 2019

Abstract 5071
Antiphospholipid antibodies,Abs are common in hospitalized patients,particularly with cancer and acquired human virus immunodeficieny HIV/AIDS. The role of antiphospholipid antibodies in deep vein thrombosis DVT, pulmonary embolism PE and thrombocytopenia is underestimated in clinical practice. The matter is also complicated by many other confounding factors affecting the interpretation of the result for lupus anticoagulant LAC; a coagulation/qualitative test and ELISA test for anticardiolipin antibodies(quantitative). Anticoagulation therapy, presence of antithrombin antibodies, coagulation factors deficiency, the lag time between collection of blood and testing, reagent used and the dilution are all contributing to the accuracy of results. In this study all patients with cancer and thrombosis, thrombocytopenia with coagulopathy not related to coumadin or disseminated intravascular coagulopathy or coagulation factors deficiency were tested for antiphospholipid antibodies. A total of three hundred patients over a year period were randomly selected. All patients were consulted for hematological evaluation. Fifty patients had thrombotic events. this include DVT with or without PE. Eighty percent had cancer. Twenty percent had other problems including HIV infection or AIDS. Female:male ratio is 1:1. Fifty percent were LAC positive with moderately to high titers for phospholipid antibodies. Thirty percent were LAC borderline with discordant results for ELISA anticardiolipin antibodies IgG and IgM. All patients had negative workup for other hypercoagulability panel. This study was done at a single institution with limited internal bias regarding ordering physician. In conclusion: This study indicates the impact of antiphospholipid antibodies in the pathophysiology of thrombosis. Larger prospective multicenter trials needed to confirm this fact.

Disclosures
No relevant conflicts of interest to declare.