bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of Relapse and Impact of Immunomodulation Based On Quantitative RT-PCR of Insertion/Deletion Polymorphism for Chimerism Analysis in Acute Leukemia
Authors: Jacque Nathalie , Nguyen Stephanie , Golmard Jean Louis , Garnier Alice , Uzunov Madalina , Leblond Veronique , Vernant Jean Paul , Bories Dominique , Dhedin Nathalie 
Published: October 2019

Abstract
Abstract 1966
Detection of increasing mixed chimerism (IMC) using standard PCR is correlated with relapse after allogeneic stem cell transplantation (allo-SCT) for acute lymphoblastic and myeloid leukemias (AL); however, it is not known whether using a very sensitive method such as quantitative real time PCR of insertion/deletion polymorphism (indel-qPCR) would be of benefit. Here, we studied whether this technique is useful for predicting relapse after transplant for AL, and whether an immunomodulation (IM) based on the detection of IMC would improve outcome. Eighty-nine transplants were included, with a median follow-up of 30 months for the survivors (range 4–86). The 3-year overall survival (OS) was 57.4% (95% CI: 48.1–66.7%). Twenty-one patients relapsed, leading to a 3-year incidence of relapse of 28.9%. An IMC was defined by an increasing of patient's DNA rate of 1 log when it was under 0.1% and an increasing of at least 0.1% beyond this threshold. Among the 57 transplants presented IMC, 21 relapsed, whereas none of the 32 patients with stable or decreasing chimerism relapsed. By multivariate analysis, the detection of IMC and the disease status at transplant were strongly associated with relapse (p=0.0002; HR: 27.6, 95%CI: 3–246 and p=0.0037; HR: 3.4 95%CI: 1.4–8.2, respectively). After the detection of one IMC (n=57), an IM was performed in 27 patients, consisted in withdrawal of immunosuppressive drugs for all, and followed by donor lymphocyte infusion (DLI) in 2. For these 27 patients, the 1 and 3-year relapse rate was 15.7%, versus 57.6% in the 30 other patients (p=0.0007). After IM, 2 patients developed acute graft versus host disease (GVHD) (grade 2 and grade 4) and died of infection. Both of them had received DLI. Four patients presented extensive chronic GVHD and two of them died. Altogether, the 3-year overall survival was 68.3% after IM versus 42.6% without any immunological intervention (p=0.02). These results suggest that chimerism analysis using indel-qPCR is a useful tool to early detect and prevent relapse after allo-SCT for AL.

Disclosures:
No relevant conflicts of interest to declare.
Autologous Stem Cell Transplantation with Yttriumm-90-Ibritumomab Tiuxetan (Zevalin) Plus BEAM Conditioning in Patients with Refractory Non-Hodgkin Diffuse Large B-Cell Lymphoma: Results of a Prospective, Multicenter, Phase II Clinical Trial
Authors: Briones Javier , Novelli Silvana , Marco Jose Antonio Garcia , Tomas Jose Francisco , Bernal Teresa , Grande Carlos , Canales Miguel , Torres Antonio , Moraleda José M. , Panizo Carlos , Palmero Fernanda , Jarque Isidro , Hernandez Miguel , Barca Eva Gonzalez , Lopez Dulce , Caballero Dolores 
Published: October 2019

Abstract
Abstract 1978

Background:
Autologous stem cell transplantation (ASCT) is the treatment of choice for patients with relapsed diffuse large B-cell lymphoma (DLBCL). However, in the rituximab era, patients with persistent disease receiving ASCT have a very poor outcome. Recent studies including radioimmunotherapy as part of the conditioning treatment suggest an improved outcome for this group of patients.

Methods:
We have evaluated, in a prospective phase 2 study, the safety and efficacy of yttriumm-90-ibritumomab tiuxetan (Zevalin) combined with standard BEAM in refractory DLBCL patients. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. Patients' response was evaluated with PET-CT according to 2007 Cheson's revised response criteria.

Results:
Patients with a median age of 53 years (range, 25–67) received Zevalin at a fixed dose of 0.4mCi/kg (maximum dose 32 mCi) 14 days prior to standard BEAM. Histology included de novo DLBCL (22) and transformed DLBCL (8). Patients received a median of 3 (range, 2–6) prior therapies before ASCT. All patients had active disease at the time of ASCT, with 25 patients considered to be chemorefractory to the last treatment. Median CD34+ cell dose infused was 3.9 × 106/kg (range, 2–18.3). All patients engrafted. Median time to neutrophil recovery (>500/μl) was 11 days (9–21), and to platelet recovery (>20.000/μl) was 13 days (11–35). Overall response at day +100 was 70% (95% CI, 53.6–86.4) with 60% (95% CI, 42.5–77.5) complete responses. Eleven patients have died. One due to a cerebral hemorrhage before ASCT and 1 due to sepsis immediately post-transplant. Seven patients died of disease progression, and 2 patients died due to late complications: bacterial sepsis and secondary acute leukemia. One patient developed a myelodysplastic syndrome (refractory anemia with excess blasts-2) 33 months after TASP, while being in CR of its lymphoma. After a median follow-up of 22.7 months for alive patients (range, 12.2–39.0), 2-year overall and progression-free survival is 65% (95% CI, 47.8–82.8) and 63% (95% CI, 45.5–80.4), respectively.

Conclusion:
ASCT with conditioning including Zevalin radioimmunotheray plus BEAM is safe, and results in a very high response rate with promising survival in this very poor prognosis group of refractory DLBCL patients.

Disclosures:
No relevant conflicts of interest to declare.
Glycine Supplementation – A Novel Therapeutic Strategy for Congenital Sideroblastic Anemia.
Authors: Berman Jason N , Fernandez-Murray Pedro , Nasrallah Gheyath , Dufay Noelia , Fernandez Conrad V , Jarrar Ameer , Coombs Andrew J , McMaster Christopher 
Published: October 2019

Abstract
Abstract 2087
Congenital sideroblastic anemias (CSA) are inherited diseases, characterized by ineffective haematopoiesis, typically severe microcytic anemia and bone marrow sideroblasts representing excess iron deposition in the mitochondria of the erythroid precursors. More than 40% of CSA cases are attributed to mutations in the X-linked gene ALAS2. ALAS2 encodes the mitochondrial enzyme aminolevulinic acid synthase-2, which utilizes glycine to form 5-aminolevulinic acid (5-ALA), a crucial precursor in heme synthesis. Another gene, SLC25A38, has recently been implicated in the abnormal heme development noted in CSA. The function of the SLC25A38 protein product is uncertain, although it is thought to be an erythroid specific mitochondrial carrier family protein, transporting glycine across mitochondrial membranes. We employed yeast and zebrafish model systems in parallel to evaluate the absence of SLC25A38 or ALAS2 on heme synthesis in vivo and identify potential therapeutic strategies. HEM1 (ALAS2 homologue) mutant yeast were completely unable to make heme, whereas heme synthesis was significantly reduced in YDL119c (SLC25A38 homologue) mutant yeast. To monitor heme synthesis, we utilized a beta-galactosidase reporter linked to Pcyc1, which is only active following binding of the yeast Hap1 transcription activator in the presence of heme. Both HEM1 and YDL119c mutant yeast showed no beta-galactosidase activity, however activity in the YDL119c mutant was returned to 30% with the addition of 5-ALA and to 40% following treatment with glycine. Microarray studies of untreated and glycine treated YDL119c mutant yeast revealed increased expression of genes required to synthesize vitamin B6, a cofactor for the Hem1 enzyme in yeast and humans. Morpholino (MO)-mediated knockdown of the zebrafish homologues of SLC25A38 (slc25a38a and slc25a38b) or alas2 correlated with decreased hemoglobin levels by o-dianisidine staining and increased embryonic malformation and mortality. 5-ALA treatment either by addition to the egg water or by injection into the yolk failed to restore hemoglobinization in alas2 morphant embryos. By contrast, the addition of glycine to the egg water resulted in upregulation of hemoglobin to near normal levels in the majority of slc25a38a/b double morphant embryos. Our study demonstrates conserved heme synthesis pathways through evolution across species and further supports the contention that SLC25A38 functions as a glycine transporter. Most significantly, glycine supplementation emerged as an effective therapeutic strategy to restore heme synthesis in CSA caused by SLC25A38 deficiency, providing the rationale to support use of glycine in a clinical trial that is under development for these patients.

Disclosures:
McMaster: DeNovaMed: Equity Ownership.
Differential Targeting of Signaling Pathways to Selectively Expand Mouse Regulatory T Cells While Inhibiting Conventional T Cells.
Authors: Satake Atsushi , Schmidt Amanda M , Archambault Angela , Wu Gregory F , Kambayashi Taku 
Published: October 2019

Abstract
Abstract 2158
Regulatory T cells (Tregs) are suppressive T cells with therapeutic potential for ameliorating T cell-mediated diseases. Thus, there has been great interest in revealing the mechanisms by which Tregs proliferate. Recently, we reported that TCR signaling is partially dispensable for Treg proliferation in vivo when exogenous IL-2 is administered. Based on this data, we hypothesized that when given in conjunction with IL-2, pharmacological inhibition of TCR signaling might allow Tregs to expand while simultaneously inhibiting conventional T cell (Tconv) proliferation.
Using mutant mice with defective TCR-mediated PLCγ activation, we found that the activation of PLCγ is dispensable for IL-2-mediated Treg proliferation. In contrast, costimulation-derived mTOR signaling was required for IL-2-induced Treg proliferation. We next used Cyclosporine A (CSA; calcineurin inhibitor) and rapamycin (mTOR inhibitor) to differentially target these signaling pathways. Consistent with our hypothesis, while both CSA and rapamycin suppressed antigen-specific Tconv proliferation, only CSA permitted IL-2-induced Treg expansion in vitro and in vivo. Rapamycin, however, did increase the overall Treg:Tconv ratio due to its negative effects on Tconv survival.
Given that CSA inhibited antigen-specific Tconv proliferation while maintaining IL-2-induced Treg expansion, we hypothesized that the combination of CSA and IL-2 would be beneficial for attenuating T cell-mediated disease. Indeed, CSA synergized with IL-2 in protection against experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Surprisingly, however, the administration of CSA blocked whereas rapamycin augmented the beneficial effect of IL-2 in graft-versus-host disease (GVHD). These differences potentially results from the overt TCR stimulation that Tregs would receive in the allogeneic (GVHD) vs. syngeneic (EAE) environment. Moreover, inducible Treg (iTreg) generation from allogeneic MHC-stimulated naïve Tconvs contributes greatly to the Treg pool during GVHD. This was consistent with our data showing that rapamycin promotes iTreg generation and allows TCR-enhanced Treg proliferation, whereas CSA inhibited both of these processes. Thus, depending on the disease setting, the signaling pathways contributing to expansion of the Treg pool need to be carefully considered and specifically targeted to increase the Treg:Tconv ratio in treatment of T cell-mediated disorders.

Disclosures:
No relevant conflicts of interest to declare.
Dysregulation of Inflammatory and Hemostatic Markers in Sepsis Associated Disseminated Intravascular Coagulation.
Authors: Fareed Jawed , Hoppensteadt Debra , Cunanan Josephine , Mosier Michael , Osawa Yutaka , Kaul Inder 
Published: October 2019

Abstract
Abstract 2223
Disseminated intravascular coagulation (DIC) represents a complex pathophysiologic syndrome where marked alterations in the hemostatic system are manifested. As a result several inflammatory mediators are up regulated through multiple mechanisms. The up regulation of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO), C reactive protein (CRP), and circulating levels of hemostatic markers including protein C inhibitor (PCI), plasminogen activator inhibitor 1 (PAI-1), and protein C (Pr C) were evaluated in 758 subjects enrolled in a randomized, double-blind, placebo-controlled, Phase-2B study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in subjects with sepsis and suspected DIC. Thirty healthy male and female volunteers served as the control group. 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 controls, subjects in DIC showed an increase in the circulating levels of most inflammatory markers. The levels of PCT, IL-6 and CRP, where considerably higher in the DIC subjects whereas PCI, Pr C and AT exhibited slight decreases. Wide individual variations were present. The PAI-1 levels were also increased in the DIC subjects. These results are tabulated below. These results clearly indicate that inflammation and impairment of fibrinolysis play a key role in the pathogenesis of DIC
Parameter Nomal (NHP Mean+SEM) DIC (Baseline Mean+SEM) % Change Protein C (% Ag) 82.5 ± 13.6 47.6 ± 23.7 −42.2% Functional Protein C (%) 83.4 ± 13.2 46.2 ± 29.8 −44.6% PCI (% Inhibition) 130.0 ± 24.6 79.4 ± 105.5 −38.9% PAI-1 (ng/ml) 35.4 ± 10.8 140.6 ± 165.6 297.1% CRP (ug/ml) 2.6 ± 0.4 48.0 ± 14.2 1736.9% C5a (ng/ml) 9.2 ± 3.2 17.2 ± 13.3 85.1% IL-6 (pg/ml) 9.3 ± 3.7 620.3 ± 1883.4 6583.9% IL-10 (pg/ml) 13.9 ± 13.1 130.2 ± 118.6 836.1% MPO (ng/ml) 16.0 ± 4.2 108.1 ± 68.6 574.6% PCT (ng/ml) 0.2 ± 0.13 21.9 ± 43.3 14514.5%

Disclosures:
Osawa: Asahi Kasei Pharma America Corporation: Employment. Kaul:Asahi Kasei Pharma America Corporation: Employment.
Protein Z Deficiency in Patients with Bleeding History. Is It a Coagulopathy?.
Authors: Bergmann Frauke , Czwalinna Andreas , Groening Arndt 
Published: October 2019

Abstract
Abstract 2227

Introduction:
Protein Z (PZ) is a vitamin K-dependent protein. In hemostasis PZ has two functions: together with Factor Xa it forms an inhibiting complex with the PZ- dependent protease-inhibitor and it enhances binding of Thrombin to phospholipid surfaces. Therefore, low PZ levels may induce thrombosis or bleeding.
The latter has been questioned by Vasse 2008 and in 1995 Kemkes-Matthes reported in 58% of patients (pts) with a bleeding history PZ deficiency as the only abnormality.

Aim of the study:
To evaluate if low PZ levels are associated with a bleeding tendency, we reviewed data of pts referred to or laboratory. PZ determination is part of our diagnostic work up, including whole blood count, PT, PTT, VWF/FVIII-complex, FXIII and platelet function studies.

Material and Methods:
Over a 1 year period we investigated PZ level in 173 pts. PZ concentration was determined by ELISA (Asserachrom Protein Z; Diagnostica Stago), a sandwich immunoassay using a mouse monoclonal antibody against PZ, normal range 1600 – 3300 μg/l, mean 2600 μg/l published by Miletich. Our normal range obtained by 62 donors 990–2490, mean 1740μg/l (+/− 2SD). PZ <1000μg/l is considered to be abnormal.

Results:
In 75/173 (43%) pts with a bleeding history (e.g. postoperative hemorrhage, epistaxis, menorrhagia) no coagulation abnormality was detected. In 41/98 (42%) low PZ level was the only abnormality (mean PZ 642, range 195–994). 57/98 (58%) were diagnosed with vWD n=17; platelet function disorders n=10 or ASA/drugs causing platelet dysfunction n=20, others n=10. In 21/57 (37%) low PZ level was detected additionally (mean PZ 699μg/l; range 219–949) and in the remaining 36/57 (mean PZ 1689; range 1036–2842).

Conclusion:
Surprisingly, in 24% of pts with a bleeding history the only abnormality was PZ deficiency. Therefore, we consider PZ determination a useful parameter in patients with a bleeding history after ruling out more common disorders. Low PZ levels may cause a coagulopathy in some pts.

Disclosures:
No relevant conflicts of interest to declare.
Risk Factors for Inpatient Acute Venous Thromboembolism (VTE) Despite Thromboprophylaxis.
Authors: Wang Tzu-Fei , Wong Catherine A , Milligan Paul , Thoelke Mark S , Woeltje Keith F , Gage Brian F 
Published: October 2019

Abstract
Abstract 2248

Background:
Venous thromboembolism (VTE) is the most common preventable cause of morbidity and mortality in the hospital. Adequate thromboprophylaxis has reduced the rate of hospital-acquired VTE by 50–70%; however, some inpatients still develop VTE despite thromboprophylaxis. Predictors associated with thromboprophylaxis failure are undefined.

Objectives:
We aimed to identify risk factors for VTE despite use of inpatient thromboprophylaxis.

Patients/Methods:
We used a case-control study to determine independent predictors of inpatient VTE. We matched 94 cases discharged from the BJC HealthCare system from January 1st, 2010 to May 31st, 2011who developed in-hospital VTE despite thromboprophylaxis (including either pharmacological or mechanical prophylaxis or both) to 272 controls without VTE. Matching was done by hospital, age, and date of discharge. Two thirds of the sample was used as derivation model, while one third was used for validation. We used multivariate conditional logistic regression on the derivation sample to develop a VTE prediction model and validated the model. We repeated conditional logistic regression on the pooled data.

Results:
Age and sex were well-matched. Mean age was 62.8 years-old in the VTE group and 63.2 years-old in the no-VTE group. Forty-three percent were female in the VTE group, while 49% were female in the no-VTE group. Using conditional logistic regression model in the pooled data, we identified five independent risk factors for in-hospital VTE: hospitalization for cranial surgery (Odds ratio [OR] 16.1, 95% confidence interval [CI] 3.2–80.4, p<0.001), hospitalization in a critical care unit (OR 3.0, 95% CI 1.5–5.9, p=0.002), admission leukocyte count > 13 × 103/mm3(OR 2.7, 95% CI 1.4–5.1, p=0.003), presence of an indwelling central venous catheter (OR 2.5, 95% CI 1.3–4.7, p=0.007), and admission from a long-term care facility (OR 2.1, 95% CI 1.0–4.2, p=0.04).

Conclusions:
In the hospital setting, we derived and validated five risk factors associated with the development of VTE despite thromboprophylaxis. Clinicians should be vigilant for VTE in these patients and ensure that they have aggressive VTE prophylaxis.

Disclosures:
No relevant conflicts of interest to declare.
Obesity Is a Risk Factor for Recurrent Venous Thrombosis in Young and Middle-Aged Women. Results From Tehs-Follow up, a Nested Cohort Study On 1394 Women with VTE.
Authors: Ljungqvist Maria , Sonnevi Kristina , Bergendal Annica , Holmstrom Margareta , Kieler Helle , Larfars Gerd 
Published: October 2019

Abstract
Abstract 2250

Introduction:
Venous thromboembolism (VTE) is a multifactorial disease with a high risk of recurrence. The risk of recurrence is highest during the first year with an incidence of 10–15%, thereafter recurrence occurs in 3 to 5 % per year. The risk of recurrence is associated with age, gender and whether the first VTE was provoked by a transient risk factor or not. Obesity increases the risk of a first event of VTE but its role for a recurrent event is unclear.

Methods:
We performed a nested cohort study and included 1394 women 18 to 64 years of age with a previous first episode of deep vein thrombosis (DVT) located in the leg or pelvis or with a pulmonary embolism (PE). All women had taken part in TEHS, a population based case-control study on risk factors for VTE. Information on risk factors was obtained by interviews and DNA-analyses immediately after the VTE and information of recurrent VTE was obtained from a follow-up questionnaire or from data recorded in the Swedish Patient Register. Only women who were not on continues anticoagulant treatment were included for assessment of recurrent VTE. Women with a BMI ≥ 30 were considered obese. Risks of recurrence were calculated in Cox regression models and are presented as hazard ratios (HRs) with 95% confidence intervals.

Results:
A total of 964 women (mean age 46 ± 13 years) with a median follow-up of 76 months accepted participation in the nested cohort study. The recurrence rate was 10.3% and 221 women (23%) were obese when diagnosed with their first VTE. At follow up 240 women (25%) were obese. The recurrence rate was higher in obese than in non-obese women (15.8% vs. 8.6%, p=0.002). The HR for recurrence was 1.9 (p=0.02, 95% CI 1.3–2.9) for obese women compared to non-obese. The HR was unchanged in a multivariate analysis, adjusting for age, index VTE (provoked or unprovoked by cast/surgery or hormonal treatment) and presence of factor V Leiden or prothrombin gene mutation.

Conclusion:
Obesity is a strong independent risk factor for recurrent VTE in women. Obese women with a first VTE might benefit from long time treatment with anticoagulants and consultation on weight reduction.

Disclosures:
No relevant conflicts of interest to declare.
Fondaparinux Versus Argatroban and Danaparoid for the Treatment of Suspected or Confirmed Heparin-Induced Thrombocytopenia: A Propensity Score Analysis.
Authors: Kang Matthew , Alahmadi Majed , Sawh Sonja , Kovacs Michael J. , Lazo-Langner Alejandro 
Published: October 2019

Abstract
Abstract 2262

Background:
Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy leading to platelet activation, thrombocytopenia and potentially thrombosis. Upon suspicion, current guidelines recommend heparin cessation and switching to a non-heparin anticoagulant such as argatroban or danaparoid. Fondaparinux could be potentially effective but information supporting its use is limited.

Methods:
We retrospectively evaluated 239 patients admitted to London Health Sciences Centre from January 10, 2004 to June 21, 2011 receiving a non-heparin anticoagulant (133 fondaparinux, 59 danaparoid, 47 argatroban) for suspected or confirmed HIT. Using logistic regression a propensity score was constructed based on age, gender, creatinine, 4T scores and comorbidities (assessed by the Charlson comorbidity index modified by Quan) and used to match 133 patients to 60 controls. Efficacy outcome was thrombosis or thrombosis-related death. Safety outcome was major bleeding. Group comparisons were done using χ2, Fisher's exact or Mann-Whitney tests. Survival analysis was conducted using the Kaplan-Meier method. Analyses were conducted in SPSS 20.0 and R 2.12.

Results:
Population characteristics are shown in Table 1. Well-balanced groups were obtained after matching. There were no differences in the proportion of thrombotic or bleeding events between control and fondaparinux groups (Table 2). Subgroup analyses comparing fondaparinux versus argatroban or danaparoid and unmatched analyses showed similar results. Sensitivity analysis stratified by propensity score quintiles showed no differences in either outcome. Survival analysis showed no differences in thrombosis or bleeding (Log-rank p = 0.415 and 0.779, respectively; Figure 1). Subgroup survival analysis for the 3 drugs independently found no difference in thrombotic events (Log-rank p=0.582) and a trend towards increased major bleeding in patients on argatroban (Log-rank p=0.068). In the fondaparinux group 60% of patients received prophylactic doses.

Conclusion:
Fondaparinux has similar effectiveness and safety as argatroban and danaparoid in patients with suspected HIT. Prophylactic fondaparinux doses seem to be effective if no indication for full anticoagulation exists.

Disclosures:
Off Label Use: Fondaparinux as a treatment option in heparin-induced thrombocytopenia. Lazo-Langner:Pfizer: Honoraria; LeoPharma: Honoraria.