bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulation of Inflammatory and Hemostatic Markers In Disseminated Intravascular Coagulation.
Authors: Hoppensteadt Debra , Cunanan Josephine , Sadeghi Nasiredin , Kaul Inder , Fareed Jawed 
Published: October 2019

Abstract
Abstract 3656
Disseminated intravascular coagulation (DIC) represents a complex polypathologic syndrome where marked alterations in the hemostatic system are manifested. As a result several inflammatory mediators are upregulated through multiple mechanisms. The upregulation of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO) and c reactive protein (CRP), and circulating levels of hemostatic markers including protein C inhibitor (PCI), plasminogen activator inhibitor 1 (PAI-1), prothrombin fragment1.2 (F1.2), thrombin antithrombin complex (TAT), antithrombin (AT), activated protein C (APC) and protein C (Pr C) were evaluated in the baseline samples of an initial cohort of provisionally diagnosed DIC and sepsis patients enrolled in an ongoing clinical trial designed to assess the safety and efficacy of r-thrombomodulin (ART-123) (n=100). The control group consisted of normal male and female volunteers (n=30). Commercially available ELISA methods were used to measure the various mediators. Marked deviations in the circulating levels of these markers, as compared to controls, were noted as shown in the following table. Compared with normal volunteers, patients showed a 5–10 fold increase in the circulating level of most inflammatory markers, with the exception of PCT, IL-6 and CRP, where the increase was over 50 fold. PCI, Pr C and AT exhibited slight decreases. Wide individual variations were obvious. These results clearly indicate that inflammation, thrombin generation, impairment of fibrinolysis and impairment of endogenous anticoagulants play a key role in the pathogenesis of DIC.
Marker Normal Human Volunteers (n=30) DIC with Sepsis Patients (n=100) Fold Change PCT (ng/ml) 0.1 ± 0.04 (0.01) 18.7 ± 31.2 (3.1) 187× Increase C5a (ng/ml) 6.7 ± 1.7 (0.5) 15.5.7 ± 14.9 (1.5) 2× Increase PCI (% NHP) 138.9 ± 71.1 (8.8) 106.9 ± 33.4 (7.1) 1.3× Decrease IL-6 (pg/ml) 2.5 ± 1.2 (0.3) 522.5 ± 881.5 (88.2) 210× Increase IL-10 (pg/ml) 9.8 ± 5.23 (1.7) 46.9 ± 73.3 (8.8) 5× Increase MPO (ng/ml) 15.1 ± 10.1 (2.7) 111.4 ± 74.9 (7.5) 7× Increase PAI-1 (ng/ml) 31.7 ± 8.9 (3.1) 130.2 ± 178.1 (22.1) 4× Increase F1.2 (pM) 108.6 ± 46.2 (12.3) 473.7 ± 320.2 (32.0) 4× Increase TAT (ng/ml) 4.4 ± 1.1 (0.3) 17.0 ± 30.8 (3.1) 5× Increase AT (% NHP) 94.2 ± 10.3 (2.7) 80.4 ± 30.7 (3.1) 1.2× Decrease APC (ratio) 2.23 ± 0.3 (0.1) 2.48 ± 0.4 (0.04) 1.1× Increase CRP (ug/ml) 0.5 ± 1.1 (0.3) 38.4 ± 3.9 (0.4) 76× Increase Pr. C (% NHP) 78.3 ± 13.3 (3.6) 41.3 ± 17.4 (1.7) 2× Decrease

Disclosures:
Kaul: Artisan Pharma: Employment.
Incidence of Venous Thromboembolism In Korea: From Health Insurance Review and Assessment Service Database.
Authors: Jang Moon , Bang Soo-Mee , Oh Doyeun 
Published: October 2019

Abstract
Abstract 3676

Background:
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a major health concern with an annual incidence of 70 to 113 cases per 100,000 Caucasians. Although historically lower than in Caucasians, its incidence among Asians is anticipated to increase rapidly with widespread Westernization of diet and lifestyle.

Methods:
This population-based study investigated the incidence of VTE in Korea. The National Health Insurance (NHI) is the only public medical insurance system operated by the Ministry of Health and Welfare in Korea. All Korean are required to possess NHI service. Health Insurance Review and Assessment Service (HIRA) is a government-affiliated organization to build an accurate claims review and quality assessment system for the NHI. Using the Korean HIRA database, VTE patients from 2004 to 2008 were retrospectively identified by both diagnostic codes and medication codes for drugs used in initial treatment of VTE.

Results:
The respective age- and sex-adjusted annual incidences of VTE, DVT alone, and PE (with or without DVT) per 100,000 individuals increased significantly from 8.83, 3.91, and 3.74 in 2004 to 13.8, 5.31, and 7.01 in 2008 (P = 0.0001) with successive increments each year. The annual incidence of VTE, DVT alone, and PE (with or without DVT) for both men and women steadily increased over time (Fig 1). Specifically, the annual incidence of PE (with or without DVT) for both sexes significantly increased during the last 2 years studied (2007 to 2008). All three annual incidences also increased steadily with age (P = 0.0001 for all) particularly among those over 60 years old.

Conclusions:
This represents the largest epidemiologic study which demonstrate the lower incidence of VTE and increasing incidence of VTE in Korean population.

Disclosures:
No relevant conflicts of interest to declare.
Duration of Corticosteroid Tapering as First Line Treatment In Idiopathic Thrombocytopenic Purpura.
Authors: Lam Selay , Hsia Cyrus C. 
Published: October 2019

Abstract
Abstract 3688

Background:
Idiopathic Thrombocytopenic Purpura (ITP) is a relatively common benign hematologic disorder. Management of ITP is difficult as many treatment regimens present risks that may pose more harm than the disease itself. Typically, corticosteroid is used as first line treatment, but there is currently no evidence-based guideline to direct the optimal duration of therapy.

Objective:
To investigate the effectiveness and relative safety of various lengths of corticosteroid therapy.

Methods:
In a retrospective cohort study, charts of all ITP patients seen in the general hematology clinic at the London Health Sciences Centre (LHSC) from January 1, 2004 to December 31, 2009 were reviewed.

Results
: A total of 312 patients with ITP were reviewed. 128 of the patients (52 male, 76 female), age range 4–94 at time of diagnosis, required corticosteroid treatment. Of those, 35 patients were treated with short term steroid regimen (< 8 weeks); 32 patients had 8–16 weeks of therapy, and 64 patients received long term steroid tapering regimen (>16 weeks). Based on results, 63%, 56% and 39% of patients achieved complete response in each group respectively. The follow-up duration from diagnosis ranged from 1 month to 29 years (with median of 1 year).
Interestingly, the same proportion of patients experienced side effects as a result of steroid use in all groups. However, frequency of serious complications such as avascular necrosis and infections, occurred at a higher rate in the long term therapy group (9%) compared to 0% in short term therapy group.

Conclusions:
Rapid corticosteroid taper is as effective as a slow corticosteroid taper and has less serious side effects.

Disclosures:
No relevant conflicts of interest to declare.
Kinetics of Engraftment and Graft Versus Host Disease After Cotransplantation of Ex Vivo Expanded and Unexpanded Cord Blood Units In Immunodeficient Mice.
Authors: Ong Li Ming , Fan Xiubo , Chu Pak Yan , Gay Florence , Ang Justina , Li Zhihong , Chen Jianzhu , Lim SaiKiang , Bunte Ralph , Hwang William 
Published: October 2019

Abstract
Abstract 3722
Ex vivo expansion of cord blood (CB) hematopoietic stem cells (HSCs) and cotransplantation of two CB units can enhance applicability of CB transplants to adult patients. This is the first study on cotransplantation of ex vivo expanded and unexpanded human CB units in immunodeficient mice, simulating conditions for ex vivo CB expansion clinical trials.
CB units were cultured in serum-free medium supplemented with Stem Cell Factor, Flt-3 ligand, Thrombopoietin and Insulin Growth Factor Binding Protein-2 with mesenchymal stromal co-culture. Cotransplantation of unexpanded and expanded CB cells was achieved by tail vein injection into forty-five sublethally irradiated nonobese diabetic SCID-IL2γ−/− (NSG) mice. Submandibular bleeding was performed monthly and mice were sacrificed 4 months following transplantation to analyze for human hematopoietic engraftment.
CB expansion yielded 40-fold expansion of CD34+ cells and 18-fold expansion of HSCs based on limiting dilution analysis of NSG engraftment. Mice receiving expanded grafts had 4.30% human cell repopulation, compared to 0.92% in mice receiving only unexpanded grafts at equivalent starting cell doses (p = 0.07). Ex vivo expanded grafts with lower initiating cell doses also had equivalent engraftment to unexpanded grafts with higher cell dose (8.0% vs 7.9%, p= 0.93). However, the unexpanded graft, richer in T-cells, predominated in final donor chimerism.
Ex vivo expansion resulted in enhanced CB engraftment at equivalent starting cell doses, even though the unexpanded graft predominated in long-term hematopoiesis. The expanded graft with increased stem/progenitor cells enhanced initial engraftment despite eventual rejection by the unexpanded graft.

Disclosures:
No relevant conflicts of interest to declare.
G-CSF as Secondary Prophylaxis of Febrile Neutropenia In the Management of Advanced-Stage Hodgkin Lymphoma Treated with ABVD Chemotherapy: A Decision Analysis.
Authors: Graczyk Joanna , Cheung Matthew , Buckstein Rena , Chan Kelvin 
Published: October 2019

Abstract
Abstract 3831

Background:
ABVD is the standard treatment for advanced stage Hodgkin Lymphoma (HL) with rates of complete remission achieved in the majority of patients treated. Current practice guidelines (American Society of Clinical Oncology, Smith TJ et al. JCO 2008) recommend the use of granulocyte colony stimulating factor (G-CSF) in secondary prophylaxis despite lack of a survival benefit and potential toxicities, including bleomycin pulmonary toxicity (BPT). Recently, small retrospective series and expert opinion (Horning S, ASH Education Program Book 2007) advocate for the omission of G-CSF, although this approach has not been prospectively studied. The purpose of this study was to perform a decision analysis that compared the life expectancy and quality-adjusted life expectancy of advanced-stage HL managed with and without secondary prophylactic G-CSF.

Methods:
We constructed a decision-analytic model to compare the strategy of secondary prophylaxis with G-CSF to a strategy of no G-CSF with severe neutropenia for a hypothetical cohort of 40 year-old patients with clinical stage IIB to IV Hodgkin Lymphoma treated with 8 cycles of ABVD chemotherapy. Markov models were used to simulate a 2-year clinical course of patients. Baseline probability estimates were derived from a systematic review of relevant published studies. Utilities for various health states were derived from expert opinion. One-way sensitivity analysis was performed on key variables such as severe neutropenia, febrile neutropenia and bleomycin pulmonary toxicity, as well as the utilites associated with these health states.

Results:
The life expectancy was 1.858 years for the G-CSF strategy and 1.875 years for no G-CSF, yielding a net expected benefit of 0.017 years for no G-CSF use in severe neutropenia. The quality-adjusted life expectancy was 1.371 years for the G-CSF strategy and 1.408 years for no G-CSF with a net expected benefit for no G-CSF of 0.037 QALYs. On microsimulation (10,000 trials), 96% of the simulations showed that the no G-CSF strategy is preferred to the use of G-CSF. This analysis was not sensitive to the odds ratio of lung toxicity with G-CSF, the hazard ratios of febrile neutropenia and severe neutropenia, the probability of death from febrile neutropenia, or the utilities associated with bleomycin pulmonary toxicity, hospitalization for febrile neutropenia and musculoskeletal pain from G-CSF.

Conclusions:
While the difference between the two strategies is small, our model predicted that for a 40 year-old patient with advanced-stage Hodgkin Lymphoma treated with ABVD chemotherapy, the strategy of avoiding use of G-CSF with severe neutropenia is preferred. This finding is robust across a wide range of sensitivity analyses.

Disclosures:
No relevant conflicts of interest to declare.
Mesenchymal Stem Cells Express the Surface Receptor Calreticulin (cC1qR) and Complement C1q Chemoattracts Them.
Authors: Qiu Yuanyuan , Marquez-Curtis Leah A. , Janowska-Wieczorek Anna 
Published: October 2019

Abstract
Abstract 3855
Complement cleavage fragments play an important role in the trafficking of hematopoietic stem/progenitor cells as reported by us (Blood 2003;101:3784; Exp Hematol 2010;38:321; Transfusion Sept 2010), as well as of mesenchymal stem cells (MSC) as reported by others (J Immunol 2009;182:3827). Because MSC have a great potential for tissue regeneration and cellular therapies, in this study we investigated the mechanisms of migration of MSC to injured sites. As complement cascade is activated upon tissue injury we examined whether complement component 1 subcomponent q (C1q), the initiator of the classical pathway of complement activation, plays a role in the migration of MSC, and which C1q receptors (CR1, gC1qR, calreticulin (cC1qR), CD93) are expressed on MSC and could be involved in their migration. We previously reported that matrix metalloproteinases (MMPs), especially membrane type 1 (MT1)-MMP and MMP-2, regulate the migration of MSC (Stem Cells, 2006, 24:1254); therefore in this study we examined the effects of C1q on MMP expression and migration of MSC. Human MSC isolated from cord blood and bone marrow were maintained for 3–6 passages and characterized by adipocyte and osteoblast differentiation. We used chemoinvasion across the reconstituted basement membrane Matrigel to evaluate the migration of MSC, RT-PCR and flow cytometry to determine the expression of C1q receptors and, upon stimulation with C1q, zymography and Western blot to examine the expression of MMPs and ERK1/2 and PI3K/Akt signaling pathways. We found that MSC were chemoattracted by a C1q gradient in a dose-dependent manner, and MSC expressed transcripts for gC1qR, CD93 and cC1qR, but only calreticulin protein was detected on the surface of MSC. Specific antibody against calreticulin (anti-cC1qR antibody) inhibited the trans-Matrigel chemoinvasion of MSC towards C1q. Moreover, stimulation of MSC with C1q (10 μ g/mL) increased MT1-MMP expression, but no changes in MMP-2 secretion were observed. Trans-Matrigel migration of MSC towards C1q was also reduced by the MT1-MMP inhibitor EGCG. Further, the ERK1/2 inhibitor PD98059 and the PI3K inhibitor Ly294002 decreased the chemoinvasion of MSC towards C1q. In conclusion, this study indicates that: 1) C1q exerts chemoattractant activity towards MSC through its surface receptor calreticulin; 2) MT1-MMP regulates the C1q-induced trans-Matrigel migration of MSC; and 3) both the ERK1/2 and PI3K/Akt signaling pathways are involved in this process. These findings demonstrate a broader regulatory role for C1q, which functions as a chemotactic factor for MSC through its binding to surface calreticulin, and suggest a newly-found mechanism for the migration of MSC which may be important for its clinical use.

Disclosures:
No relevant conflicts of interest to declare.
Distribution of Bim Determines MCL-1 Dependence or Co-Dependence on BCL-xL/BCL-2 In Multiple Myeloma
Authors: Boise Lawrence H. , Morales Alejo A , Kurtoglu Metin , Matulis Shannon M , Markovitz Rebecca , Lee Kelvin P , Lonial Sagar 
Published: October 2019

Abstract
Abstract 4054
The inappropriate activation of oncogenes can result in the up-regulation of pro-apoptotic signals often in the form of BH3-only proteins such as Bim, Noxa or Puma. This renders cells dependent on anti-apoptotic proteins including BCL-2, BCL-xL and MCL-1. Thus cancer cells would be predicted to be more susceptible to inhibition of BCL-2 family proteins, prompting the development and testing of several small molecule inhibitors of this class of proteins. Multiple myeloma is a plasma cell malignancy of the bone marrow and like normal plasma cells, myeloma plasma cells express MCL-1. A search of gene expression profile data from normal plasma cells (n=22), MGUS plasma cells (n=12), plasma cells from patients with asymptomatic (smoldering) myeloma (n=44) or newly diagnosed multiple myeloma (n=538) revealed no significant difference in MCL-1 mRNA expression associated with progression of disease. We then determined MCL-1 dependence through the introduction of siRNA in 4 MM cell lines and consistent with previous findings using anti-sense oligonucleotides in additional lines, we demonstrated that all cell lines tested were MCL-1 dependent. However using the BCL-2/BCL-xL/BCL-w-selective inhibitor ABT-737 we found that 3 of the 6 MCL1-dependent cell lines tested were sensitive (IC50 for Annexin V-FITC positive at 24 hrs of 300 – 600 nM) and therefore also dependent on BCL-xL/BCL-2. Taken together this is the first formal demonstration that cells can be co-dependent on multiple Bcl-2 family members. We have previously reported that ABT-737 sensitivity, and what we now refer to as co-dependence on MCL-1 and BCL-xL/BCL-2, is determined by the distribution of BIM on the anti-apoptotic BCL-2 proteins in these cells. We have now expanded these findings to patient samples that displayed sensitivity to ABT-737 that is similar to what we have observed in the co-dependent cell line MM.1s. Consistent with these findings co-immunoprecipation revealed BIM binding predominantly to BCL-xL. Additionally we have now demonstrated that BIM binding is not simply controlled by the expression levels of BCL-xL or MCL-1 as enforced over-expression of each protein could alter the sensitivity of co-dependent cell lines to ABT-737 but did not alter the initial distribution of BIM amongst these proteins. These data suggest that additional factors regulate the association of BIM with anti-apoptotic BCL-2 proteins. These factors could include differences in cellular localization of these proteins as well as differences in post-translational modifications of either pro- or anti-apoptotic BCL-2 family proteins.

Disclosures:
Boise: University of Chicago: Patents & Royalties.
Primary Pulmonary MALT Lymphoma: Clinical Characteristics and Treatment Outcomes – Single Institution Experience
Authors: Nowakowski Grzegorz S. , Ristow Kay , Kurtin Paul , Allen Mark S , Micallef Ivana N , Colgan Joseph , Inwards David James , McPhail Ellen , Markovic Svetomir , Ansell Stephen M. , Porrata Luis , Johnston Patrick B , Thompson Carrie A , Witzig Thomas E. , Habermann Thomas M. 
Published: October 2019

Abstract
Abstract 4168

Background:
Primary Pulmonary MALT lymphoma represents 15–20% of Extranodal Marginal Zone Lymphomas of Mucosa Associated Lymphoid Tissue (MALT). In contrast to the more common gastric MALT lymphoma, natural history, prognosis and treatment outcomes for primary pulmonary MALT lymphoma are not well defined. Herein, we report a single institution experience.

Methods:
Consecutive patients with primary pulmonary MALT lymphoma registered in the Mayo Clinic Lymphoma Database, which includes all consenting patients with lymphoma seen at Mayo Clinic Rochester, were reviewed for clinical features, treatment outcome progression free survival (PFS) and overall survival (OS). The pathology for all patients was centrally reviewed by hematopathologist and the diagnoses were based on WHO lymphoma classification criteria. PFS and OS were assessed using the Kaplan–Meier method and the Cox proportional hazard model was used to assess the impact of variables on PFS and OS.

Results:
Between December 1986 and June of 2009, ninety-seven patients with primary pulmonary MALT lymphoma were enrolled. The median age at diagnosis was 63 years (range 31–87). There were 43 (44%) males. The initial presentation was a unilateral pulmonary lesion (n=47, 48%), bilateral pulmonary lesions (n=41, 42%), and pulmonary lesion with intrathoracic lymphadenopathy (n= 4, 4%). Bone marrow involvement and presence of B symptoms were 4, 4% and 5, 5%, respectively. International Prognostic Index (IPI) was 0–1, 2–3 and 4–5 in 69, 25 and 1 patient(s) respectively. The median follow-up was 10.4 years. The estimated median OS was 13. 6 years and the median PFS was 5.5 years (Figure). In a multivariate analysis, age >60 (p=0.02) and ECOG PS>2 (p=0.01) were associated with shortened survival. The IPI and age adjusted IPI were not predictive of overall survival. The treatment outcomes for the most common treatment modalities are summarized in the Table below. The median PFS of the 38% of patients who had a complete surgical resection was excellent at 11.2 years; whereas for observed patients with residual disease after biopsy was 3.2 years. Only 8 patients received single agent rituximan with relatively low response rate.

Summary:
The prognosis of primary pulmonary MALT lymphoma is favorable, with a median survival of over 13 years. In patients with resectable disease, surgery alone is associated with excellent disease control. Further prospective studies are needed to define the optimal treatment of primary pulmonary MALT lymphoma.

Disclosures:
No relevant conflicts of interest to declare.
Fibrinogen γ' In the Budd-Chiari Syndrome: Results From a Multicenter Case-Control Study
Authors: Smalberg Jasper , Koehler Edith , Murad Sarwa Darwish , Plessier Aurelie , Garcia-Pagan Juan-Carlos , Seijó Susana , Langlet Philippe , Trebicka Jonel , Primignani Massimo , Maat Moniek De , Rijken Dick , Valla Dominique , Janssen Harry , Leebeek Frank 
Published: October 2019

Abstract
Abstract 4213
Primary Budd-Chiari syndrome (BCS) is a rare disorder characterized by thrombosis of the hepatic outflow tract anywhere from the level of the hepatic veins to the suprahepatic inferior vena cava. Thrombophilic factors or prothrombotic disorders are found in the majority of patients. However, in around 20% of primary BCS patients still no cause can be identified, which highlights the need to further explore the etiology of this disorder. The fibrinogen γ' variant is a thrombosis risk modifier and may thus contribute to BCS. The aim of this study was to determine the role of fibrinogen γ' levels and common variations in the fibrinogen γ gene (FGG) in the etiology of BCS. Patients were recruited from the EN-Vie cohort, consisting of 163 consecutive BCS patients, enrolled in nine European countries between October 2003 and October 2005. Plasma and/or DNA was available from 118 BCS patients (50 males and 68 females; median age 37.9) and 104 healthy controls (43 males and 61 females; median age 36.8). We measured fibrinogen γ' levels by ELISA and genotyped two haplotype-tagging single nucleotide polymorphisms (SNPs): rs2066865 (10034C>T) tagged FGG H2 and rs1049636 (9340T>C) tagged FGG H3. All statistical analyses were adjusted for differences in age and sex. Fibrinogen γ' (0.50 vs 0.42 g/l; p=0.02) and total fibrinogen levels (3.0 vs. 2.8 g/l, p=0.04) were significantly elevated in BCS patients compared to controls. Also the fibrinogen γ'/total fibrinogen ratio, which adjusts for a potential acute phase induced increase of fibrinogen, was significantly elevated in BCS patients (0.17 vs. 0.15; p=0.03). Logistic regression showed a significant association between an increasing fibrinogen γ'/total fibrinogen ratio and risk of BCS (p=0.03). FGG H2 (OR 0.97; 0.96–0.98) and H3 (OR 1.02; 1.01–1.03) were significantly associated with fibrinogen γ'/total fibrinogen ratios. FGG H2 (OR 0.96; 0.64–1.46) and H3 (OR 0.86; 0.62–1.21) were not associated with BCS. In conclusion, fibrinogen γ' levels and the fibrinogen γ'/total fibrinogen ratio are significantly elevated in BCS patients. Common FGG gene variations determine the fibrinogen γ'/total fibrinogen ratio in these patients. We did not observe an association between FGG gene variations and risk of BCS.
This study was carried out on behalf of the European Network for Vascular Disorders of the Liver (EN-Vie).

Disclosures:
No relevant conflicts of interest to declare.