bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of the EBMT Risk Score for Patients with Hematologic Malignancies Receiving Allogeneic Hematopoietic Stem Cell Transplant in a Transplant Center in Colombia over 20 Years
Authors: Abello Virginia , Rosales Carmen , Rosales Manuel , Figueroa Javier , Cordoba Iris , Borda Molina Andres Armando , Pedraza Enrique , Esguerra Herman , Villamizar Liceth 
Published: October 2019

Abstract
INTRODUCCION
EMBT the risk score has been validated in several studies in different types of diseases and modalities of transplantation. The conditions of the patients and the resources available in Latin America are different from those of European centers, so we consider important to validate this scale in our own patients.
METHODS
EBMT risk scale was validated in 965 of 1176 (750 autologous, allogeneic 426) transplanted from 1993 to 2014; that had all the information available and were not lost to follow up. Kaplan-Meier survival curves and log-rank test (p <0.05) were used to estimate the one (OS1) and three (OS3) probabilities of overall survival according to risk groups.
RESULTS
The mean age was 39.8 (SD 15.5). The median follow-up was 363 days (range: 179-1096) for the whole group. Most frequent diagnoses were Non-hodgkins lymphoma (314: 26.7%) and multiple myeloma (262: 22.22%). 96.3% transplants were performed using peripheral blood stem cells. Most donors were identical siblings; only 19.5% (n = 79) were transplanted before 2004.
81.9% of transplanted patients had 2-4 points on EBMT risk score. Upon analysis it became clear that at 1 and 3 years, two groups were defined: Low (0-3 points) and high (4-7), with a significant difference in overall survival for AML (1 year: p = <0.00; 3 years: p = <0.00) and ALL (1 year: p = 0.04; 3 years: p = 0.01). In NHL 4 risk groups remain significantly different in regards to 1 and 3 years overall survival (1 year: p = 0.04; 3 years: p = 0.02). In patients with diagnosis of MDS EBMT was predictive of survival only significant at one year (p = 0.01).
The EBMT score did to delineate risk groups patients with MM, LH, ASMO, or CML in this group.
CONCLUSION
EBMT score was validated in patients with hematologic malignancies transplanted in a center in Colombia, to our knowledge this is the first validation of this risk score in Latin America.

Disclosures
No relevant conflicts of interest to declare.
PLGA-PLL-Peg-Tf-Based Targeted Nanoparticles Drug Delivery System Enhance Antitumor Efficacy Via Intrinsic Apoptosis Pathway
Authors: Bao Wen , Liu Ran , Chen Baoan , Wang Fei , Zhang Haijun , Xia Guohua , Wu Xue , Zhao Kun , Li Xiaoyu 
Published: October 2019

Abstract
Chemotherapy offers a systemic cancer treatment; however, it is limited in clinical administration due to its serious side effects. In cancer medicine, the use of nanoparticles (NPs) drug delivery system (DDS) can sustainedly release anticancer drug at the specific site and reduce the incidence of toxicity in normal tissues. In the present study, we aimed to evaluate the benefit of a novel chemotherapeutic DDS and its underlying mechanisms. Daunorubicin (DNR) was loaded into poly (lactic-co-glycolic acid) (PLGA)-poly-L-lysine (PLL)-polyethylene glycol (PEG)-transferrin (Tf) NPs to construct DNR-PLGA-PLL-PEG-Tf-NPs (DNR-loaded NPs) as a DDS. After incubating with PLGA-PLL-PEG-Tf-NPs, DNR, and DNR-loaded NPs, the leukemia K562 cells were collected and the intracellular concentration of DNR was detected by flow cytometry, respectively. Furthermore, the effect of drugs on the growth of tumors in K562 xenografts was observed and the relevant toxicity of therapeutic drugs on organs was investigated in vivo. Meanwhile, cell apoptosis in the excised xenografts was measured by transferase-mediated dUTP nick-end labeling assay, and the expression of apoptosis-related proteins, including Bcl-2, Bax, Caspase-9, Caspase-3, and cleaved-PARP, was determined by Western blotting analysis. Results showed that DNR-loaded NPs increased intracellular concentration of DNR in K562 cells in vitro and induced a remarkable improvement in anticancer activity in the xenografts in vivo. The expression of Bcl-2 protein was downregulated and that of Bax, Caspase-9, Caspase-3, and cleaved-PARP proteins were obviously upregulated in the DNR-loaded NPs group than that in other ones. Interestingly, pathological assessment showed no apparent damage to the main organs. In summary, the results obtained from this study showed that the novel NPs DDS could improve the efficacy of DNR in the treatment of leukemia and induce apoptosis via intrinsic pathway. Thus, it can be inferred that the new drug delivery may be a useful clinical tool.

Disclosures
No relevant conflicts of interest to declare.
Overuse of DVT Prophylaxis in Medical Inpatients
Authors: Deng Jing , Thomas Lisa , Li Huijing , Varughesekutty Elvin , Shi Qi , Sambharia Meenakshi , Musto Kevin , Petal Gaurav , Gordon Erin , Ruparella Sudeep , Bansal Rajiv 
Published: October 2019

Abstract
Introduction: Unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH), is commonly used with mechanical prophylaxis as an anticoagulant to reduce the risk for venous thromboembolism (VTE). However, overuse of these prophylaxes can increase the risk of bleeding, heparin-induced thrombocytopenia (HIT) and associated medical cost.
PURPOSE: The aim of this study is to determine the incidence of DVT prophylaxis among hospitalized nonsurgical patients in a community medical center. To evaluate the use of the prophylaxes as described above, the investigators collected data on medical inpatients and addressed how to avoid overuse.
Method: A retrospective inpatient chart review of 100 general internal medicine patients analyzed data using Padua Prediction Score as the risk estimate for deep venous thrombosis (DVT). High risk for VTE was defined by a cumulative score >=4 and low risk was a score <4. Only patients at increased risk for DVT but not at high risk for bleeding qualified for heparin treatment.
Results: A total of 100 patients were surveyed. 54/100 (54%) patients had low risk of DVT with score < 4, and of those 29/54 (53.7%) patients received DVT prophylaxis with SCDs and/or heparin, and 17/54 (31.5%) patients were treated with heparin. All 46 patients with score >= 4 were treated with DVT prophylaxis of which 10 patients were only treated with heparin and 36 patients were given both mechanical and chemical prophylaxis. Collectively, 53.7% of the patients received treatment with DVT prophylaxis (p < 0.001, Chi-Square test).
Discussion:
In hospital settings, physicians want to avoid DVT or PE so they tend to consider patients as being at moderate risk for DVT without using any method of DVT risk assessment. This leads to unnecessary overuse of DVT prophylaxis on patients and may increase the risk of bleeding and injury.
Conclusion:
Our data suggests that there DVT prophylaxis including UFH and LMWH was over prescribed among patients with who had marginal risk for DVT in hospitalized nonsurgical patients in a community medical center.
Clinical implications:
To avoid the overuse of DVT prophylaxis, physicians need to follow guidelines. Education and inclusion of the guidelines in EHRs of information on VTE risk assessment for hospitalized medical patients upon admission may reduce unneeded DVT prophylaxis and the risk of bleeding and costs associated with additional care needs.

Disclosures
No relevant conflicts of interest to declare.
All-Cause Health Care Resource Utilization in Individuals with Sickle Cell Disease
Authors: Rajpura Jigar , Thomas Joseph 
Published: October 2019

Abstract
Introduction
Clinical manifestations of Sickle Cell Disease (SCD) range from frequent fatigue and anemia to severe complications involving multiple organs. We estimated all cause health care resource utilization in individuals with SCD as compared to individuals without SCD.
Methods
Data from the Truven multi-state Medicaid claims database were used for all analyses. Sample inclusion criteria was being enrolled in covered health plan from January 1, 2012 through December 31, 2012. A cohort of individuals with SCD was identified based on having at least one inpatient or two or more outpatient claims with ICD-9-CM codes for sickle-cell thalassemia without crisis (282.41), sickle-cell thalassemia with crisis (282.42), Sickle-cell disease, unspecified (282.60), Sickle-cell-S disease without crisis (282.61), Sickle-Cell-S disease with crisis (282.62), Sickle-cell-C disease without crisis (282.63), Sickle-cell-C disease with crisis (282.64), other sickle-cell disease without crisis (282.68), or other sickle-cell disease with crisis (282.69). From the continuously enrolled individuals, a cohort of individuals without SCD was identified by matching individuals with SCD one-to-one on age, gender, and ethnicity. Means and 95 percent confidence intervals were calculated for, number of hospitalizations, hospital days, long term care visits, long term care days, emergency room visits, and outpatient visits. Wilcoxon Mann-Whitney test was employed to assess differences in health care resource utilizations in individuals with and without SCD.
Results
Among 5,136,748 individuals covered in the study period, 8,652 individuals with SCD were identified and matched to 8,652 individuals without SCD. Majorities of the study sample were black (74%), female (54%), and under 24 years old (64%). Mean annual hospitalizations among individuals with SCD were 1.39 (95 percent C.I.: 1.3 to 1.4, <0.001) as compared to 0.10 (95 percent C.I.: 0.09 to 0.1, p<0.001) hospitalizations in persons without SCD. Mean annual outpatient visits in individuals with SCD were 24.7 (95 percent C.I.: 23.9 to 25.5, p<0.001) as compared to 14.18 (95 percent C.I.: 13.4 to 14.9, p<0.001) outpatient visits in persons without SCD, and, mean annual emergency room visits in individuals with SCD were 3.71 (95 percent C.I.: 3.5 to 3.9, p<0.001) as compared to 0.89 (95 percent C.I.: 0.8 to 0.9, p<0.001) emergency room visits in persons without SCD.
Conclusions
SCD was associated with higher annual hospitalizations, hospital days, outpatient visits and emergency room visits as compared to individuals without SCD.

Disclosures
Rajpura: Pfizer Inc.: Research Funding. Thomas:Pfizer Inc.: Research Funding.
Acute Myeloid Leukemia (AML): A Retrospective Claims Analysis of Resource Utilization and Expenditures
Authors: Irish William D , Ryan Michael , Gache Larry , Gunnarsson Candace , Bell Timothy , Shapiro Mark 
Published: October 2019

Abstract
Motivation/Objectives: The primary objective of this study was to estimate resource utilization and expenditures for de novo (dn) AML patients in a real world claims database.
Sponsorship Statement: This study was sponsored by Pfizer, Inc.
Methods: All AML patients with an ICD-9 diagnosis code of 205.00 (dn) and a record of a hospitalization within 14 days after their initial diagnosis between 1/1/2009 - 1/31/2015 were identified in the MarketScan Commercial, Medicaid, and Medicare supplemental databases. Patients also had to have a minimum of two instances of the AML diagnosis code and ≥6 mos of enrollment prior to their first AML diagnosis. Patient demographics, Charlson Comorbidity Index from the National Cancer Institute (CCI NCI), risk factors for AML, such as history of smoking and blood disorders, and key comorbid conditions were recorded. Age at initial diagnosis was grouped as follows: <18, 18-<50, 50-70 and >70 years. Healthcare utilization and expenditures (in 2014 dollars) were aggregated for dn patients from first line induction to remission. For the subset of patients that had a record of relapse and remission following induction, their healthcare utilization and expenditures were aggregated from the time of relapse to their second remission.
Results: Of the 1,671 patients meeting the inclusion criteria the mean (SD) age was 58.3 (16.7). Age at initial diagnosis by group was as follows: less than 18 years, 0.4%; 18 to 50 years, 26.5%; 50 to 70 years, 49.7%; and greater than 70 years, 23.5%. Male patients made up 51% of the cohort and mean (SD) CCI NCI score for all patients was 1.1 (1.6). Over 90% of patients had at least one risk factor for AML, with 88% of patients having a history of blood disorders. Mean healthcare expenditures for patients who achieved remission (n=703) were $208,431 (SD $153,144). A subset of patients (n=145) had a record of a second treatment period defined as days from their first record of relapse to their second remission. During this second treatment period, mean healthcare expenditures were $127,953 (SD $175,020); 61.4% were admitted to the hospital for an average of 16.8 hospital days; and 22.8% had at least one ER visit.
Conclusions: Treating AML patients poses a significant healthcare burden, both during de novo and relapse. With people living longer, the number of cases of AML are expected to increase in the future.

Disclosures
Irish: Pfizer Inc: Consultancy; Alexion: Consultancy; BMS: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Astellas: Consultancy. Ryan:Pfizer Inc: Consultancy. Gache:Pfizer Inc: Consultancy. Gunnarsson:Pfizer Inc: Consultancy. Bell:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment.
Neutrophil DREAM Is a Novel Regulator for Beta2 Integrin Function through NF-Kappab Signaling and Modulates Neutrophil Recruitment during Vascular Inflammation
Authors: Barazia Andrew , Li Jing , Kim Kyungho , Tiruppathi Chinnaswamy , Cho Jaehyung 
Published: October 2019

Abstract
The interaction between neutrophils and activated endothelial cells (ECs) is critical for the pathogenesis of vascular inflammation. However, it remains poorly understood how the cell-cell interactions are regulated under inflammatory conditions. Using intravital microscopy in mice lacking DREAM (downstream regulatory element antagonist modulator), a member of the neuronal Ca2+ sensors and a transcriptional repressor, we have found that DREAM plays an important role in neutrophil rolling and adhesion to the TNF-α-inflamed cremaster muscle venules. Studies with DREAM bone marrow chimeras revealed that both hematopoietic and EC DREAM are important for neutrophil recruitment. We found that neutrophils lacking DREAM exhibit reduced αMβ2 surface expression and decrease fibrinogen binding following stimulation with TNF-α, but not fMLF, implying the role for neutrophil DREAM in regulating β2 integrin function through a specific signaling pathway. Since recent studies demonstrated the important role of endothelial cell DREAM in NF-κB signaling, we further examined whether neutrophil DREAM regulates NF-κB signaling. Indeed, the protein expression of A20 (an inhibitor of NF-κB signaling) and p65 (a key subunit of the NF-κB complex) was significantly up- and down-regulated, respectively, in DREAM-deficient neutrophils, compared to WT neutrophils. Moreover, DREAM deletion impaired the phosphorylation of IKKa/β following TNF-a-stimulation, suggesting the role of neutrophil DREAM in NF-κB signaling. Consistently, we found that the transcription of the NF-κB target genes, such as IL-1β, TNF-α, and IL-6, was inhibited by DREAM deletion. Taken together, our results provide evidence that neutrophil DREAM is a novel regulator for β2 integrin function through NF-κB signaling and could be a therapeutic target for treatment of inflammatory disease.

Disclosures
No relevant conflicts of interest to declare.
Preclinical Evaluation of RA101495, a Potent Cyclic Peptide Inhibitor of C5 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria
Authors: Ricardo Alonso , Arata Michelle , DeMarco Steven , Dhamnaskar Ketki , Hammer Robert , Fridkis-Hareli Masha , Rajagopal Vaishnavi , Seyb Kathleen , Tang Guo-Qing , Tobe Sylvia , Treco Douglas 
Published: October 2019

Abstract
Regulation of the terminal phase of the complement component pathway is a clinically validated approach for the therapeutic treatment of complement disorders. Inhibition of complement activation at the C5 level with the monoclonal antibody eculizumab has successfully been used for the treatment of rare disorders such as PNH and aHUS. However, even in these settings there remains a continued unmet need primarily due to need for intravenous administration, lack of activity in patients with C5 mutations and lack of universal access.
Ra Pharmaceuticals has developed a macrocyclic synthetic peptide, RA101495, which binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative or lectin pathways. In vitro studies also demonstrated that RA101495 is capable of preventing MAC assembly after thrombin mediated complement activation and is a potent disruptor of the interaction in between C5b and C6.
Inhibition of complement activity was evaluated in cynomolgus monkeys following single- and multi-dose subcutaneous (SC) administration. RA101495 exhibited high SC bioavailability and low, single doses fully inhibited complement-mediated hemolytic activity (>95%). Repeat dosing was well tolerated in monkeys and rats at high multiples of the projected human therapeutic dose and resulted in sustained and predictable inhibition of complement activity.
RA101495 fully inhibited the hemolysis of erythrocytes from PNH patients after activation of the alternative pathway. The synthetic peptide offers a novel therapeutic approach for inhibiting C5 for the treatment of disorders caused by or associated with complement dysregulation. As a product designed for convenient self-administration, RA101495 should provide an attractive option over monoclonal antibody therapy for patients with PNH and aHUS, including those with C5 polymorphisms and other complement disorders, especially those associated with hypercoagulable states.

Disclosures
Ricardo: Ra Pharmaceuticals: Employment. Arata:Ra Pharmaceuticals: Employment. DeMarco:Ra Pharmaceuticals: Employment. Dhamnaskar:Ra Pharmaceuticals: Employment. Hammer:Ra Pharmaceuticals: Employment. Fridkis-Hareli:Ra Pharmaceuticals: Consultancy. Rajagopal:Ra Pharmaceuticals: Employment. Seyb:Ra Pharmaceuticals: Employment. Tang:Ra Pharmaceuticals: Employment. Tobe:Ra Pharmaceuticals: Employment. Treco:Ra Pharmaceuticals: Employment.
Association Between Serum Ferritin and Liver Iron Concentration with Cardiac Iron in Pediatric Thalassemia Major Patients
Authors: Pepe Alessia , Meloni Antonella , Casale Maddalena , Neri Maria Giovanna , Bitti Pier Paolo , Macchi Silvia , Giugno Giovanni Roberto , De Franceschi Lucia , Missere Massimiliano , Toia Patrizia , Positano Vincenzo , Filosa Aldo 
Published: October 2019

Abstract

Introduction: Recently, the ability of LIC (liver iron concentration) and serum ferritin in predicting myocardial iron overload (MIO) has been challenged by magnetic Resonance Imaging (MRI) monitoring which demonstrated no or weak correlation between serum ferritin or LIC and MIO. Anyway, the role of this traditional markers could result particularly useful in pediatric population, where MRI assessment is difficult to carry out, because of early age, scarce collaboration or limited availability. So, we derived objective thresholds for these markers for predicting cardiac T2*<20 ms in pediatric patients.
Methods: From the 2171 patients with hemoglobinopathies enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we retrospectively selected 107 paediatric patients with thalassemia major (TM) (61 boys, median age 14.4 years). MIO was assessed using a multislice multiecho T2* approach. Hepatic T2* values were assessed in a homogeneous tissue area and converted into LIC.
Results: Twenty-three patients (21.5%) showed an abnormal global heart T2* value and none of them was under 7.9 years of age.
Serum ferritin was negatively correlated with global heart T2* values (r=-0.425; P<0.0001). Using ROC curve analysis, a serum ferritin of 2000 ng/ml was found to be the best threshold for discriminating the presence of cardiac iron with an area under the curve (AUC) of 0.733 (P=0.001) (Figure 1A) (Sensitivity= 0.73 and Specificity=0.65). Odds ratio (OR) for global heart T2* values<20 ms was 4.9 (1.7-13.8 95%CI; P=0.003) for serum ferritin levels ≥2000 ng/ml.
There was a significant negative correlation between global heart and MRI LIC values (P=-0.436; P<0.0001). Using ROC curve analysis, a LIC≥14 mg/g/dw was found to be the best threshold for discriminating the presence of MIO in children with an AUC of 0.817 (P<0.0001) (Figure 1B) (Sensitivity= 0.74 and Specificity=0.85 ). OR for abnormal global heart T2* values was 30.08 (3.58-252.68 95%CI; P=0.002) for patient with MRI LIC≥14 mg/g/dw versus patients with normal MRI LIC.
Conclusion: A weak connection between serum ferritin levels or hepatic iron and cardiac iron was demonstrated in our pediatric population. Anyway, MRI LIC≥14 mg/g/dw and serum ferritin levels≥2000 ng/ml were found to be significant risk factors for a global heart T2* value <20 ms in TM children.
Figure 1. Figure 1.

Disclosures
Pepe: Novartis: Speakers Bureau; ApoPharma Inc: Speakers Bureau; Chiesi: Speakers Bureau.
Heme Concentration As a Biomarker of Sickle Cell Disease Severity: Its Role in Steady-State and in Crisis Patients
Authors: Carvalho Magda Oliveira Seixas , Rocha Larissa Carneiro , Reis João Henrique Oliveira , Santos Théo de Araújo , do Nascimento Valma Maria Lopes , Carvalho Mauricio Batista , Luz Nívea Farias , Borges Valeria de Matos , Goncalves Marilda Souza 
Published: October 2019

Abstract
Background: Sickle cell disease (SCD) is a heredity group of anemia characterized by hemolysis, chronic inflammation, and vaso-occlusive/painful crisis. The heme is a product of erythrocytes' lyses and is increased in hemolytic diseases.
Objectives: To investigate associations between hematological/biochemistry biomarkers and total plasma heme levels between SCD patients groups (in crisis and in steady-state) and healthy controls. To identify molecules related to hemolysis, inflammation, hepatic dysfunction, renal and lipid metabolism.
Methods: We evaluated a total of 125 SCD steady-state patients, 22 SCD in crisis patients, and 32 healthy individuals age- and sex-matched with patients groups. Hematological analyses were performed by automatic cell counter, and hemoglobin profile by HPLC. Biochemistry analyses of inflammatory and infection markers, as well as lipid, hepatic, and kidney metabolism markers were investigated by immunochemistry assays. Plasma concentration of total free heme was measured by QuantiChrom Heme Assay Kit.
Results: SCD patients groups (steady state and crisis) had higher heme concentration when compared to healthy individuals (p < 0.0001). However, significant difference of heme level was not finding in the comparison between SCD in steady state and SCD crisis patients groups. Biomarkers analyses of steady-state SCD patients showed negative correlation between heme levels and: red blood cell (r = -0.36, p<0.0001); hematocrit (r = -0.38, p <0.0001); hemoglobin (r = -0.34, p <0.0001); and HDL-C (r = -0.42, p <0.0001). Heme level showed positive correlation with: platelets (r = 0.35, p <0.0001); lactic dehidrogenase (r = 0.40, p <0.0001); reticulocytes count (r = 0.19, p =0.04); monocytes count (r = 0.36, p <0.0001); HbS concentration (r = 0.54, p <0.0001); total proteins (r = 0.22, p =0.01); AST (r = 0.41, p <0.0001); ALT (r = 0.18, p= 0.04); serum iron (r =0.21, p =0.03); total cholesterol (r = 0.23, p =0.01); LDL-C (r = 0.22, p= 0.02); VLDL-C (r = 0.65, p <0.0001); and triglycerides (r = 0.63, p <0.0001). In steady state SCD patients there was no difference of clinical manifestations history and heme levels.
Conclusions: The finding of similar heme concentration between steady state and crisis SCD patients may be explained by the hyperhemolysis phenomenon, showing that even in steady-state, these patients continue to have hemolysis and generate heme and reactive oxygen species. It was also shown that high concentration of free heme increases hemolytic and inflammatory biomarkers, such as LDH, bilirubin's, reticulocytes count, and lipids, contributing to a severe clinical modulation of SCD.

Disclosures
No relevant conflicts of interest to declare.