bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transplantation of Peripheral Blood Cells As Compared with Bone Marrow From HLA-Identical Related Donors Is Associated with Superior Long-Term Outcomes
Authors: Mielcarek Marco , Storer Barry , Martin Paul J. , Negrin Robert S , Forman Stephen J. , Flowers Mary E.D. , Inamoto Yoshihiro , Chauncey Thomas , Storb Rainer , Appelbaum Frederick R. , Bensinger William I 
Published: October 2019

Abstract
Abstract 319
Between 1996 and 1999, 172 patients (median age, 42; range, 12–55 years) with hematologic malignancies were randomly assigned to receive either bone marrow (BM) or G-CSF-mobilized peripheral blood stem cells (PBSC) from HLA-identical siblings after myeloablative conditioning. Early results of this 3-institution study (Bensinger et al., NEJM; Vol. 344, No .3, 2001) showed that the use of PBSC, compared with BM, was associated with significantly superior rates of 2-year overall and disease-free survival. To assess the long-term impact of evolving chronic graft-versus-host disease (GVHD) on outcomes, we analyzed follow-up data from all participating patients.
Our follow-up analysis showed sustained protection against recurrent malignancy associated with the use of PBSC compared with BM (Figure 1). The estimated 10-year probability of relapse was 20% with PBSC and 32% with BM (adjusted hazard ratio [HR] for BM versus PBSC, 2.22; 95% confidence interval [CI], 1.2–4.1; p=0.01). In contrast to the earlier analysis, the hazard of overall mortality for all patients was not significantly different between the two groups. However, there was a trend toward superior overall survival associated with use of PBSC, which was attributable to increased mortality with use of BM in the subgroup of patients with high-risk cancers (n=80; HR, 1.42; 95% CI, 0.8–2.5; p=0.21). The 2-year cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment was 48% with PBSC and 37% with BM (HR, 0.86; 95% CI, 0.5–1.4; p=0.55). We found no evidence that the use of PBSC prolonged the duration of systemic immunosuppressive treatment among patients with chronic GVHD (HR, 1.21; 95% CI, 0.6–2.6; p=0.64). In conclusion, among patients who had hematologic malignancies treated with myeloablative conditioning and hematopoietic cell transplantation from HLA-identical sibling donors, the use of PBSC conferred greater long-term protection against recurrent malignancy than BM without causing excess chronic GVHD-related mortality.

Disclosures:
No relevant conflicts of interest to declare.
Different Patterns of Myocardial Iron Overload by T2* Cardiovascular MR As Markers of Risk for Cardiac Complication in Thalassemia Major,
Authors: Meloni Antonella , Pepe Pasquale , Keilberg Petra , Favilli Brunella , Positano Vincenzo , Capra Marcello , Caruso Vincenzo , Cianciulli Paolo , Filosa Aldo , Zuccarelli Angelo , De Franceschi Lucia , Lombardi Massimo , Pepe Alessia 
Published: October 2019

Abstract
Abstract 3190

Introduction:
Cardiac complications mainly related to myocardial iron overload (MIO) remain the main cause of morbidity and mortality in thalassemia major (TM). Thalassemia cardiomyopathy is treatable and partly reversible if appropriate chelation therapy is instituted in time. The validated multislice multiecho T2* Cardiovascular Magnetic Resonance (CMR) technique has permitted to quantify segmental and global myocardial iron burden detecting different patterns of iron overload. The aim of this study was to verify the risk of cardiac complications related to different patterns of MIO in a large cohort of TM patients.

Methods:
We considered 812 TM patients for who CMR and cardiac data were collected in a central data base. Three short-axis views (basal, medium, apical) of the left ventricle were acquired using a multislice multiecho T2* sequence. Using a previously validated software the 16 segmental T2* values and the mean global heart T2* value were provided. A conservative cut off of 20 ms was considered the limit of normal for the segmental and global T2* values.

Results:
We identified 4 groups of patients: group I (17%) with homogeneous MIO (all segments with T2*<20 ms), group II (12%) with heterogeneous MIO (some segments with T2*<20 ms and others with T2*≥20 ms) and global heart T2*<20 ms; group III (29%) with heterogeneous MIO and global heart T2*≥20 ms; group IV (42%) with no MIO (all segments with T2*≥20 ms). The clinically relevant findings in the 4 groups are summarized in Table 1. The percentage of patients with cardiac complications was significantly different in the 4 groups (P<0.0001). In particular, the percentage of patients with heart failure was significantly different in the 4 groups (P<0.0001). No significant differences were found among groups in the percentage of arrhythmias and pulmonary hypertension. Odds Ratio for cardiac complications was 1.7 (1.0–2.7 OR 95% CI; P=0.041) for patients with homogeneous MIO versus patients with no MIO. Odds Ratio for heart failure was 2.3 (1.3–4.2 OR 95% CI; P=0.004) for patients with homogeneous MIO versus patients with no MIO and 2.2 (1.1–4.2 OR 95% CI; P=0.020) for patients with heterogeneous MIO and global heart T2*<20 ms versus patients with no MIO.

Conclusions:
Homogeneous MIO predicts a significantly higher risk to develop cardiac complications, especially heart failure, suggesting an intensive chelation therapy in this group of patients.

Disclosures:
No relevant conflicts of interest to declare.
Correlation of NT-ProBNP Levels and Cardiac Iron Concentration in Patients with Transfusion-Dependent Thalassemia Major,
Authors: Kattamis Antonios , Apostolakou Filia , Delaporta Polyxeni , Papassotiriou Ioannis 
Published: October 2019

Abstract
Abstract 3192

Background:
Iron-induced cardiotoxicity remains the leading cause of morbidity and mortality in patients with transfusion-dependent thalassemia major (TM). Heart failure in these patients, which may be reversible but has a poor prognosis, is characterized by myocardial iron deposition-related early diastolic dysfunction. N-terminal-proBNP (amino-terminal) (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic left ventricular (LV) dysfunction.
Patients and Methods: In this study, we prospectively evaluated plasma NT-proBNP levels determined on the Roche cobas e411immunoassay analyzer using electrochemiluminescence technique in 187 adult patients aged 19–54 years with TM. Possible correlations with the proposed recently cardiac iron concentration [Fe] based on an equation derived from heart T2* assessment by MRI: [Fe] = 45.0 × [T2*]−1.22 with [Fe] in milligrams per gram dry weight and T2* in milliseconds (Carpenter et al Circulation 2011;123;1519–1528) were explored.

Results:
143 patients had low cardiac hemosiderosis, defined as [Fe] < 1.1 mg/g dry weight, corresponding to T2*>20 milliseconds and 44 patients with high cardiac hemosiderosis, defined as [Fe] >1.2 mg/g dry weight. The main results of the study showed that: a) NT-proBNP levels were markedly increased in thalassemic patients (152.2 26.4 pg/mL, ranged from 6.0 – 1336.0 pg/mL compared to normal control levels 40.1 19.7 pg/mL, p<0.001, b) NT-proBNP levels were significantly higher in high cardiac hemosiderosis patients compared to low cardiac hemosiderosis patients (185.1 78.2 vs 128.9 20.2 pg/mL, p<0.05), c) NT-proBNP levels correlated with [Fe] values (r= 0.387, p<0.001). This correlation was significant in patients with high cardiac hemosiderosis (r= 0.520, p<0.001), but not in patients with low cardiac hemosiderosis (p>0.1), and d) no significant correlation was found between NT-proBNP levels and left ventricular ejection fraction (LVEF) values, (p>0.3).

Conclusions:
Our study demonstrate for first time the significant association of NT-proBNP levels and cardiac iron concentration in patients with TM linking blood chemistry and imaging techniques. Multicenter studies of these parameters during iron chelation therapies are needed to validate their association and further exploit its clinical use.

Disclosures:
Kattamis: Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Wording to add.
The Timing of Acute Renal Failure Strongly Affects Survival of Immunoglobulin Light Chain (AL) Amyloidosis Patients Undergoing Autologous Stem Cell Transplantation,
Authors: Leung Nelson , Kumar Shaji , Dispenzieri Angela , Lacy Martha Q , Buadi Francis K , Hayman Suzanne R , Dingli David , Hogan William J , Gastineau Dennis A. , Glavey Siobhan V , Gertz Morie A 
Published: October 2019

Abstract
Abstract 4120

Introduction:
Autologous stem cell transplantation (ASCT) remains an effective treatment for immunoglobulin light chain (AL) amyloidosis but its high treatment related mortality is a concern. The development of acute renal failure can strongly affect the survival of these patients. This study looks at the impact of the timing of dialysis initiation on the overall survival (OS). Methods: AL patients who underwent ASCT from 3/96 to 1/10 were selected. Patients were placed into 4 groups: I - never dialyzed, II - initiated dialysis prior to ASCT, III - dialysis began within 30 days of ASCT and IV - dialysis was started after 30 days of ASCT. Results: Four hundred and ten patients were selected for study and 75 (18.3%) received dialysis. Baseline characteristics are listed in Table 1. In univariate analysis, serum creatinine (Scr) and b-2 microglobulin (b2m) were associated with dialysis post-ASCT. Both became non-significant in the multivariate model suggesting they are co-dependent. Dialysis had a strong influence on survival, p < 0.001 (Fig 1). This was most evident when dialysis was started after ASCT (group III (p = 0.003) and IV (p = 0.004)), but not before (II, p = 0.19).To explore the interactions of dialysis with cardiac biomarkers in their relationship with OS, cardiac troponins T (cTnT) and N terminal-pro-brain natriuretic peptide (NT-pro-BNP) were analyzed with timing of dialysis in a proportional hazard model. Timing of dialysis (p < 0.001), cTnT (p = 0.03) and NT-pro-BNP (p = 0.03) all were associated with OS. Using Receiver Operator Characteristic (ROC) curves, best cut points were chosen for cTnT (0.01 ng/ml) and NT-pro-BNP (1350 pg/ml) for survival. When treated as categorical variables, the proportional hazard model found that only NT-pro-BNP (p = 0.002) and timing of dialysis (p < 0.001) were independent predictors of OS but cTnT had loss its significance (p = 0.07). Using Kaplan Meier method, dialysis was a significant risk factor in patients with low cTnT and both high and low NT-pro-BNP (p < 0.001) but not in patients with elevated cTnT (p = 0.25). Discussion: The timing of acute renal failure strongly affects the OS of AL patients undergoing ASCT. In our study, patients who started dialysis prior to ASCT did not have an inferior OS compared to patients who never needed dialysis. On the other hand, starting dialysis after ASCT significantly shortened OS. The timing of dialysis was an independent predictor of OS even when combined with cardiac biomarkers. NT-pro-BNP appears to be the stronger marker when timing of dialysis is considered in the multivariate analysis.

Disclosures:
No relevant conflicts of interest to declare.
Allogeneic Cytokine-Induced Killer Cells Kill Dendritic Cells Efficiently Resulting in Less Graft-Versus-Host Disease
Authors: Mase Shintaro , Maeba Hideaki , Kuroda Rie , Araki Raita , Fujiki Toshihiro , Yagita Hideo , Yachie Akihiro , Koizumi Shoichi , Nishimura Ryosei 
Published: October 2019

Abstract
Abstract 4308
Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. The mechanism of suppression of GVHD after allogeneic bone marrow transplantation is, in part, due to the abundant production of IFN-gamma from the CIK cells, which has protective effect against GVHD. We have also demonstrated that allogeneic CIK cells displayed a significant lower acquisition of homing molecules, required for the entry of inflamed and GVHD target organs (a4b7, CCR9, E-selectin, CXCR3, and CCR5) and a higher susceptibility to apoptosis compared to allogeneic splenocytes. There also might be some causes other than we mentioned above. Host residual dendritic cells (DCs) have a crucial role for initiating GVHD reaction, because they present recipient alloantigens to donor T cells, which finally attack on recipient tissues. Murine alloreactive NK cells, even when infused in large numbers, do not cause GVHD in the mouse by killing recipient DCs. Similarly, it remains a possibility that the reduced GVHD in CIK cells receiving mice was due to the elimination of residual host DCs by CIK cells. To test this, DCs generated from bone marrow cells with the addition of GM-CSF were used for 51Cr release cytotoxicity assays as target cells. Although autologous CIK cells (Balb/c) had relatively strong killing activity against DCs (Balb/c), allogeneic CIK cells (B6) had much more killing activity even from at a 5:1 effector-target ratio as shown below. Allogeneic CD8+ cells did not show any killing activity against DCs. In addition, killing activity against DCs did not changed with/without adding NKG2D blocking antibody, suggesting that other mechanisms to undergo cell lysis should exist in CIK cells in addition to NKG2D/NKG2D ligand system, which are mainly involved in tumor eradication. To further evaluate whether allogeneic CIK cells kill host DCs in vivo, lethally irradiated Balb/c recipients were given BM (B6) with CIK cells or splenocytes to compare the percent of residual host-typed DCs in the spleen five days after bone marrow transplantation. Percent of host-typed DCs tended to be lower in the mice receiving alllogeneic CIK cells compared with those receiving fresh splenocytes or BM alone. In conclusion, allogeneic CIK cells caused less GVHD due in part to elimination of host DCs.

Disclosures:
No relevant conflicts of interest to declare.
Successful Unrelated Bone Marrow Transplantation for Three patients with Amegakaryocytic Thrombocytopenia with Radio-Ulnar Synostosis (CTRUS) in Japan
Authors: Ohtsuka Yoshitoshi 
Published: October 2019

Abstract 4510

Objectives:
Amegakaryocytic thrombocytopenia with radio-ulnar synostosis (CTRUS) is a rare inherited bone marrow failure syndrome that has the potential to progress to pancytopenia that behaves like TAR.The diagnosis of CTRUS is made later when pronation-supination of the forearm is discovered to be restricted. Hox 11a was reported to be abnormal in the initial cases but at least 1 other case did not have this abnormality. Hematopoietic stem-cell transplantation (HSCT) is presently the only curative treatment approach. We used a reduced intensity transplantation regimen in CTRUS patient with aplastic anemia.We reported two cases of CTRUS who underwent successful unrelated bone marrow transplantation.

Methods:
Conditioning regimen consisted of Flu, ATG, CY, and TLI (300cGy). For GVHD prophylaxis, all received FK506 and short course MTX. The number of transplanted nucleated cells were 6.35, 6.8, 5.8 ×108/kg. All patients underwent an alternative donor SCT. The each age at transplant for patients were 8, 18,11 months.

Results:
The patients had rapid and durable engraftment at day +13, +16, +23 with minimal complications.No regimen related toxicity were observed, and no viral re-activation (CMV, EBV, VZV) were seen. Each patients developed acute GVHD involving skin only (grade I - II).One of three patients developed chronic GVHD (skin only limited type). All patients are alive and transfusion independent with each follow-up time of 61, 56, 33 months.

Conclusions:
Allo-BMT from an unrelated donor is a curative and suitable approach for patients with amegakaryocytic thrombocytopenia with radio-ulnar synostosis (CTRUS), reduced intensity conditioning might be a feasible approach to stem-cell transplantation in patients who do not have a sibling donor. In our three cases, the mutation in exon 2 of HOXA11 gene was not found, which may suggest that these cases are possibly a subtype of this syndrome.Careful clinical course watching is required if another complications or the disease relapse will occur again.

Disclosures:
No relevant conflicts of interest to declare.
Reversal of Multidrug Resistance by Magnetic Fe3O4 Nanoparticle Loading Daunorubicin and Bromotetrandrine in Nude Mice Bearing Leukemia Tumor Xenografts
Authors: Ren Yan-Yan , Chen Bao-An , Cai Xiao-hui , Liu Ran , Wu Wei-wei 
Published: October 2019

Abstract
Abstract 5013

PURPOSE:
This paper was to study the reverse effect of magnetic Fe3O4 nanoparticle loading daunorubicin and bromotetrandrine(Fe3O4-MNPs/DNR/BrTet) with the conduction of alternating magnetic field in nude mice bearing K562/A02 xenografts, and to provide theoretic evidence for the clinical application of malignancies as a new treatment.

METHODS:
20 BALB/c nude mice with equivalent different gender, which were age-matched (four weeks of age) and weight-matched (16-22g), were randomly divided to 5 groups. The subclone of K562/A02 cells was inoculated subcutaneously into the oxter of all athymic nude mice. Group 1 each mouse was given 0.9% normal saline 0.2ml/once; Group 2, DNR 1mg/kg and BrTet 1mg/kg; Group 3, DNR 1mg/ml and BrTet 10mg/kg; Group 4, Fe3O4-MNPs 10.5mg/kg; Group 5, Fe3O4-MNPs/DNR/BrTet 12.5mg/kg(DNR: BrTet: Fe3O4-MNPs=1:1:10.5). After being delivered in an alternating magnetic field for 40minutes, the incidence of growth characteristics of mice, and volume of tumor were observed for 14 days. At the 14th day, the mice were sacrificed by cervical dislocation to detect all tumors by weight measuring, Hematoxylin and eosin staining, Western-blot and so on.

RESULTS:
The average tumors' weight and volume was much less in Group 4 and 5 than others, there were significantly different (P<0.05). The results of hematoxylin and eosin staining showed that obvious necrosis area was observed in Group 4 and Group 5, and there was less necrosis in the Group 3 compared with the other groups. The Western-blot showed the expression of caspase-3 and bax in Group 4 and 5 increased two times than other groups, while the expression of bcl-2 decreased to half of others.

CONCLUSION:
Fe3O4-MNPs/DNR/BrTet can reverse multidrug resistance efficiently in vivo through inducing apoptosis, which may be related to the upregulating of bax and downregulating of bcl-2. Moreover, our synthesized magnetic Fe3O4 nanoparticle may be as a high efficiency and security medicine carriers to treat malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Changes in Gene Expression Profiles in Patients with 5q- Syndrome Caused by Lenalidomide Treatment
Authors: Belickova Monika , Cermak Jaroslav , Vesela Jitka , Cechova Eliska , Zemanova Zuzana , Michalova Kyra , Dostalova Merkerova Michaela , Jonasova Anna 
Published: October 2019

Abstract
Abstract 5023
A direct effects of lenalidomide on gene expression in 5q- patients was studied using HumanRef-8 v2 Expression BeadChips (Illumina). Expression profiles of 6 patients (before treatment and at the time of the first erytroid response) and 6 healthy controls were investigated from CD14+ monocytes of peripheral blood. Differentially expressed genes were identified by Significance Analysis of Microarrays (SAM). Simultaneously, selected genes (TNF, JUN, IL1) were monitored in the course of treatment using Real-Time PCR with Taqman Gene Expression Assays.
A comparison of gene expression levels before and during lenalidomide treatment revealed 97 differentially expressed genes (FC >2; p<0.05) related to following biological processes: immune response (16 genes), inflammatory response (11 genes), response to bacteria (8 genes), anti-apoptosis (7 genes), regulation of MAP kinase activity (5 genes), oxygen transport (4 genes), and regulation of cell proliferation (11 genes). An overexpression of a number of cytokines (e.g. TNF, IL8, IL1B, CCL3L, CXCL2, and TNFAIP3) was detected in patients before treatment, after lenalidomide administration expression of the majority of the up-regulated cytokine genes decreased to the control baseline level. Detected overproduction of the cytokines in 5q- syndrome may lead to an increased apoptosis of hematopoietic progenitor cells and together with excessive oxidative stress may contribute to the damage the hematopoietic niche. In the same manner, untreated patients showed suppressed expression of two genes (CXCR4, CRTAP) which play an important role in the stem cell niche. After treatment, we detected increased expression of these genes. Both the observations might explain favorable effects of lenalidomide on the bone marrow stroma defect seen in 5q- syndrome. On the other hand, a substantial increase of the ARPC1B gene (an activator and a substrate of Aurora A) expression was detected after lenalidomide treatment. Since overexpression of Aurora A leads to polyploidy and chromosomal instability, ARPC1B might play a role in the disease progression observed in some patients treated with lenalidomide.
To conclude, described changes in genes expression may contribute to identification of the pathways affected by lenalidomide and to the explanation of some effects of this drug that have not been fully understood yet.
Supported by grants NS/9634 MZCR, UHKT2005 00023736, MSM0021620808 and COST EUGESMA

Disclosures:
No relevant conflicts of interest to declare.
The Clinical and Biologic Significance of Thrombocytosis in Myeloid Disorders
Authors: Zikria Jennifer , Galili Naomi , Tsai Wei Yann , Raza Azra 
Published: October 2019

Abstract
Abstract 5031

Purpose
Myelodysplastic syndromes (MDS) are typically characterized by peripheral blood cytopenias. However, some MDS is associated with thrombocytosis rather than thrombocytopenia. The prognostic significance of thrombocytosis is unknown. The purpose of this study was to compare the overall survival (OS) of MDS patient based on their platelet count.

Methods
We reviewed a prospective cohort of patients with myeloid disorders from 1994 to present. Out of the 1,654 unique patients, 102 had platelets > 450,000 (5.7%) throughout their disease; 88 had stable platelet counts, 6 had varying platelet counts, and 12 were excluded because of missing information.
OS of patients with thrombocytosis (>450,000 platelet count) was compared to FAB/WHO case matched patients with normal (100–450 platelet counts) and low platelet counts (<100 platelet count). OS was evaluated using unadjusted and adjusted Cox proportional hazard regression modeling with all-cause mortality as the dependent variable and demographic and clinical characteristics as independent variable; adjusted for IPSS risk group at first sample collection and age-adjusted mortality. The OS curves were constructed using Kaplan-Meier methods.

Results
The worst OS occurred in patients with unstable platelet counts, followed by thrombocytopenia, and then thrombocytosis. Thrombocytopenia was associated with a poorer prognosis than thrombocytosis, although not significantly worse. Patients with normal platelet counts had the best prognosis. Thrombocytosis significantly reduced OS compared to patients with normal platelet counts (HR 1.44, p= 0.04) using adjusted Cox analysis. Thrombocytopenia had significantly reduced OS compared to patient with normal platelet counts (HR 1.8, p=0.0002) using unadjusted Cox regression. Patients who had unstable platelet counts had significantly the worst OS (HR 5.7, p= 0.0009). Both older age at diagnosis and IPSS independently and significantly affected OS.

Conclusion
MDS patients with both thrombocytopenia and thrombocytosis have significantly decreased OS compared to normal platelet counts.{abspict}

Disclosures:
No relevant conflicts of interest to declare.