bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Impact of CD25 Expression of Leukemic Blasts on Subsequent Transplant Outcomes in Patients with Refractory or Relapsed Acute Myeloid Leukemia
Authors: Ikegawa Shuntaro , Doki Noriko , Yamamoto Keita , Hino Yutaro , Harada Kaito , Shingai Naoki , Watanabe Ken , Senoo Yasushi , Igarashi Aiko , Najima Yuho , Kobayashi Takeshi , Kakihana Kazuhiko , Sakamaki Hisashi , Ohashi Kazuteru 
Published: November 2019

Abstract
Introduction: We have recently reported that the evaluation CD25 expression on leukemic blasts at the time of disease onset could be an alternative non-molecular tool for predicting transplant outcomes in patients with cytogenetically intermediate acute myeloid leukemia (AML). We herein focus on patients with refractory or relapsed AML and examine the clinical correlation of the surface CD25 expression measured by flow cytometry at the time of transplantation and subsequent transplant outcomes.
Patients and methods: A total of 60 AML samples with primary induction failure (n = 32), first relapse (n = 23) or second relapse (n = 5) were analyzed by means of flow cytometric CD25 antigen expression on leukemic blasts at the time of transplantation. Survival outcomes were compared with regard to the CD25 expression. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meiyer. Factors associated with at least borderline significance (p< 0.10) on univariate analyses were subjected to multivariate analysis using backward stepwise proportional hazard modeling. Multivariate analysis was performed using the Cox proportional hazards regression model.
Results: CD25 antigen expression (>10%) on leukemic blasts was observed in 24 patients (40%). There was no significant difference between CD25 positive and negative groups in terms of clinical characteristics including cytogenetic risk, WHO classification, marrow or peripheral blasts % at transplantation, comorbidity, conditioning regimen, donor source or interval between diagnosis and transplantation. Although more early relapse cases within 180 days were observed in the CD25 positive group (p = 0.01), cumulative incidence of relapse, non-relapse mortality, acute or chronic graft-versus-host disease were not different between 2 groups. However, there was a significant difference in OS or PFS between 2 groups: 2-years OS; 8.3% vs. 34.0%, p=0.004 (Fig 1A), 2-years PFS; 8.3% vs. 26.3%, p=0.003 (Fig 1B). Moreover, multivariate analysis showed that CD25 expression was an independent adverse factor for OS (hazard ratio: 2.01, 95% confidence interval: 1.10-3.67, p = 0.02).
Conclusion: Our cohorts with total 60 patients with refractory or relapsed AML showed that CD25 endowed these patients with an adverse prognostic impact, which might not be overcome even by transplantation. AML patients with residual CD25+ blasts at the time of transplantation might require additional therapy before or after transplantation for better survival. However, our small experience clearly desires larger series patients for evaluating the real impact of CD25 expression.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Race-Based Differences in Routine Cytogenetic Profiles of Patients with Multiple Myeloma
Authors: Blue Brandon Jamaal , Sanfilippo Kristen M. , Ganti Arun , Gumbel Jason , O'Brian Katiuscia , Luo Suhong , Carson Ken R 
Published: November 2019

Abstract
Background: Multiple myeloma (MM) is a common hematologic malignancy for which standard therapy does not offer a cure. Incidence of MM in African-Americans is twice that of Caucasians, suggesting differences in either environmental or genetic risk factors. Historically, black patients have also had a slightly better prognosis than white patients, suggesting racial differences in prognostic factors such as cytogenetics. Since metaphase cytogenetic profiles are routinely collected in MM patients, we sought to determine if race-based differences in cytogenetics exist, using data from the Veterans Health Administration (VHA) cancer registry.
Methods: Using CPT codes, 88271-88275, 88291, 88299, 88365, 83896, 88237, 88261-88264, 88280, 88283, and 88285, we identified 988 patients with MM diagnosed between 1998 and 2009, who also had standard metaphase cytogenetic analysis performed on a bone marrow specimen at the time of diagnosis (228 Black and 585 White) . Fisher’s exact test was used to assess for race-based differences in the following cytogenetic abnormalities: 13q deletion, Hypodiploidy, Hyperdiploidy, and translocations involving chromosome 14.
Results: Among the 988 patients in the cohort, normal cytogenetic profiles, isolated Y chromosome deletion, or no mitotic activity were observed in 704(71%) patients. Translocations involving the immunoglobulin heavy chain (chromosome 14) (n=4) were uncommonly observed on routine cytogenetics, such that no statistical conclusions could be drawn. Hyperdiploidy was noted in 13/228(5.7%) of the black and 45/585(7.7%) of the white patients (p=0.32). Similarly 13q deletions were detected in 8/228(3.5%) black patients, and 21/585(3.6%) of the white patients (p=0.96). Hypodiploidy was also not significantly different in black 4/228(1.8%) and white patients 12/585(2.0%).
Conclusion: This is the largest study of race-based differences in MM cyogenetics presented to date. We found no significant race-based differences in standard metaphase cytogenetics. Future studies should focus on determining if race-based differences can be discovered using fluorescent in situ hybridization (FISH) or molecular testing not available for this retrospective study. Our study adds to this growing body of evidence suggesting that metaphase cytogenetic differences are not a significant factor in MM outcome disparities.

Disclosures
Carson: Spectrum Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.
Analyzing Survival Trends in Multiple Myeloma Patients in Pre and Post-Bortezomib Era Using the SEER Database
Authors: Manikkam Umakanthan Jayadev , Uprety Dipesh , Kasireddy Vineela 
Published: November 2019

Abstract
Background: Bortezomib is an antineoplastic agent that acts through protease inhibition. Since, its approval in 2003 by U.S. Food and Drug administration, it has been used religiously for multiple myeloma. There is no current population based study that assesses the survival benefit in multiple myeloma from bortezomib. We conducted a population based study to evaluate the relative survival rates in multiple myeloma patients in pre and post-Bortezomib era in the United States.
Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) 18 registry database to compare five-year relative survival rates (RS) among multiple myeloma patients. The study arms were categorized by gender (male and female), race (Caucasians and African-Americans) and age (20-59, ≥60 years). The RS were compared between pre-bortezomib era (1991-2002) and post-bortezomib era (2004-2011). The survival rate accompanied standard errors and the statistical significance was defined as p value <0.05.
Results: The database comprised of 57,328 patients. The RS have improved significantly during post-bortezomib era in all cohorts under consideration. There was no significant difference in survival rate between male and female and between the African American and Caucasian. However, the relative survival was much better with the young adult (20-59 years) as compared to adult ≥60 years. The table detailing the relative survival is given below.
Conclusion: The Primary treatment protocols for Multiple Myeloma have changed dramatically since the approval of Bortezomib in 2003. Other novel agents introduced in the last decade include thalidomide, Lenalidomide and liposomal doxorubicin that are used in conjunction with Bortezomib. Survival trends continue to improve and we believe this modest improvement in survival rate is mainly due to the introduction of Bortezomib and other novel agents. The next challenge is to find new drugs which would prevent relapses and further prolong survival. Abstract 2639. Table.Study armSubclass of cohortsPre-bortezomib era (1991-2002)Post- bortezomib era (2004-2011)Z scoreP ValueNRS (%)Relative Standard Error (SE) (%)NRS (%)Relative Standard Error (SE) (%) GenderMale13,06634.60.517,76546.10.615.904<0.0001Female11,58032.10.514,91743.70.614.765<0.0001 RaceCaucasian18,83632.90.423,98145.00.519.259<0.0001African American4,27434.70.86,39145.10.98.488<0.0001 Age group20-596,35848.10.69,43960.20.712.920<0.0001>=6018,28827.80.423,24338.40.516.606<0.0001
Total: male and female: 1991-2002; 24,646, RS 33.4%; SE 0.3%; 2004-2011; 32,682, RS 45.0%, SE 0.4%; Z score 21.766, P value <0.0001.

Disclosures
No relevant conflicts of interest to declare.
Collapse of Ribosome Biogenesis Induces Rapid Erythroblast Differentiation
Authors: Raimbault Anna , Floquet Celia , Guyot Boris , Cuhadar Ulku , Kosmider Olivier , Morle Francois , Mayeux Patrick , Fontenay Michaela 
Published: November 2019

Abstract
Genetic insults of ribosomal protein (RP) genes including heterozygous mutations in Diamond Blackfan Anemia (DBA) or RPS14 haploinsufficiency in acquired 5q- syndrome selectively impair erythropoiesis suggesting that the integrity of ribosome biogenesis (RB) is fully required for the production of 10e11erythrocytes per day in humans. Defective RB consecutive to RPL5, RPL11 mutation or RPS14 deletion is thought to induce cell cycle arrest and a various degree of apoptosis in erythroblasts (EB). However, recent data showed that, loss of RPL5/RPL11neither induces apoptosis nor arrests cell cycle, but hampers the progression through the G1 phase, in primary fibroblasts. Furthermore, RB coordinates cell cycle to cell growth for the maintenance of constant cell size. In this work, we investigate the role of RB in erythroid cell differentiation and cell size regulation.
We first analyzed the renewal of ribosome during in vitro differentiation of human EB derived from cytapheresis CD34+ cells and mouse erythroblasts derived from mouse fetal liver by a pulsed SILAC (Stable Isotopic Labeling by Amino acids in Culture cell) riboproteomic assay. Ribosome biogenesis dramatically decreases with the disappearance of proEB and basophilic EB and the onset of poly- and ortho-chromatophilic EB. Importantly, inhibition of RNA polI by CX-5461 in proEB forced them to enter the final maturation steps with an increase of glycophorin A (GPA) expression. To study the effect of RPS14 heterozygous deletion on RB, UT7/EPO cell line was infected by a lentivirus containing an inducible GFP-shRNA RPS14. After a 48-h treatment with doxycyclin, Rps14 protein expression was reduced by half and sorted GFP-positive cells had an altered ribosome profile devoid of 40S small subunit or 80S entire particle. Consistently, RB inhibition induced a cell size reduction. Second, we compared RB level in cells responsive to SCF+EPO or EPO alone. RB was optimal when EB responded to SCF+EPO and this was correlated with cell size being higher in SCF+EPO-responsive cells compared to EPO-responsive cells. Both cytokines additively activate the cell growth regulator, p70S6K1. Third, inhibition of p70S6K1 by rapamycin, or a specific chemical S6K1 inhibitor significantly reduced RB as shown by a 50% decrease of ribosome renewal in pulsed-SILAC. Inhibition of RB by rapamycin led to a size reduction and to GPA acquisition, which are the features of erythroid cell differentiation.
Our data shows that the collapse of RB due to the loss of c-Kit and reduced activation of p70S6K1 is a key step for cell growth inhibition and induction of terminal differentiation in human or mouse erythroblasts.

Disclosures
No relevant conflicts of interest to declare.
Sphingosine 1-Phosphate Induces Erythrocytes Sickling in Sickle Cell Disease By Promoting Hemoglobin S Aggregation
Authors: Zhang Yujin , Berka Vladimir , Song Anren , Kellems Rodney E , Xia Yang 
Published: November 2019

Abstract
Sickle cell disease (SCD) is a genetic hemolytic disease with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was identified a century ago, we still lack effective mechanism-based therapies to treat this disease. Our recent study showed inhibition of sphingosine kinase 1 (Sphk1, the enzyme that produces S1P) significantly decreased S1P level in sickle erythrocytes, attenuated sickling cells. We also found sickling was induced by high concentration (10µM) but not low concentration (0.5 µM) of S1P, which indicates S1P induced sickling is independent of its receptors. However, the mechanism of S1P inducing sickling in SCD is unknown. Because sickling is induced by formation of polymers of deoxygenated sickle hemoglobin, we hypothesized that S1P functions intracellularly to induce sickling by directly promoting polymerization of deoxygenated HbS. To test this possibility, we determined the effects of S1P on deoxy-HbS polymerization using temperature jump method. We found that 5µM S1P began to induce aggregation of deoxy-HbS (0.25mM) with shorter delay time at 17.65 ± 0.57min compared to HbS treated with solvent (methanol) which with delay time at 19.28 ± 0.17 min. Moroever, S1P at 10µM induced deoxy-HbS aggregation with further decreased delay time at 15.71 ± 0.38 min, clearly demonstrating a dose-dependent effect. Thus, this study indicates that S1P at concentrations higher than 5µM dramatically and specifically accelerated HbS aggregation. Next, we found that aggregation amplitude (ΔA) of deoxy-HbS was significantly increased by S1P at a concentration of 5µM and was further elevated at 10mM of S1P. indicating that S1P enhanced polymerization ability of deoxy-HbS in a dosage-dependent manner. Finally, we detected the effect of S1P on deaggregation of aggregated deoxy-HbS. We found that S1P significantly reduced temperature drop-mediated unaggregated HbS and this effect was in a dosage dependent manner. In order to test whether anti-sickling drug can increase delay time of Hb S aggregation, we chose 5-HMF that was reported anti-sickling. We found 5-HMF significantly increased delay time of HbS. Taken together, we demonstrated that S1P induces HbS polymerization via three mechanisms: 1) Accelerating polymerization of HbS by shortening temperature jump-mediated delay time; 2) enhancing the aggregate formation during temperature jumping; and 3) reducing deaggregation ability during temperature dropping. Thus, this study strongly supports our in vivo animal, in vitro cellular and functional evidence that S1P contributes to sickling by promoting polymerization.

Disclosures
No relevant conflicts of interest to declare.
Reversibility of Iron Loading in Transferrin-Deficient Mice
Authors: Bartnikas Thomas Benedict 
Published: November 2019

An abundant serum metal-binding protein, transferrin is a critical factor in mammalian iron homeostasis. As transferrin is essential for iron delivery for erythropoiesis, transferrin-deficient patients and mice develop anemia but also a paradoxical systemic iron overload. Iron overload results from deficiency in hepcidin, a peptide hormone synthesized largely by the liver that inhibits dietary iron absorption and macrophage iron efflux. Using transferrin-deficient mice, we have previously shown that transferrin deficiency leads to hepcidin deficiency via two mechanisms. First, the anemia and/or hypoxia that results from inadequate iron delivery to bone marrow actively suppresses hepcidin expression by the liver. Second, transferrin directly stimulates hepcidin expression by the liver independently of transferrin's role in erythropoiesis; this second mechanism is dependent upon hemojuvelin, a bone morphogenetic protein coreceptor essential for hepcidin expression that is mutated in juvenile hemochromatosis. Here we present data examining the reversibility of iron loading in transferrin deficiency. Measurement of tissue metal levels in adult transferrin-deficient mice demonstrated progressive and systemic iron loading yet minimal to moderate changes in levels of other metals. Treatment of adult transferrin-deficient mice with exogenous transferrin normalized red cell parameters and hepcidin levels and reduced iron load in most organs. To further investigate the reduced tissue iron burden in transferrin-treated mice, we employed iron-loaded cell lines to demonstrate that cellular iron efflux can be stimulated by transferrin and that this efflux is specific to iron but not manganese or zinc. Current studies focus on two goals. First, we are determining if the reduction in tissue iron load represents solely a redistribution of iron stores to the erythron or additionally excretion of iron via urine and/or feces by measuring whole body iron levels in mice before and after transferrin treatment. Second, we are identifying transporters required for mobilization of iron stores using expression profiling of known and putative iron transporters in mouse tissues and validating the role of transporters of interest using our cell culture model. Results of these studies and their implications will be presented.

Disclosures
No relevant conflicts of interest to declare.
Identifying Iron Overload in Pediatric Oncology Patients
Authors: Giamanco Nicole , Warwick Anne B. , Crouch Gary 
Published: November 2019

Abstract
Background. Intensive therapy for childhood cancer is possible in large part due to improvements in supportive care that are currently available. Blood product transfusions, including red blood cell transfusions, are supportive care measures which are important in the tolerability of this therapy, and are frequently used in the majority of patients receiving therapy for childhood cancer. Although it is well recognized that frequent red blood cell transfusions in pediatric hematological disorders, such as sickle cell disease and thalassemia major, lead to iron overload and its complications (ie, organ dysfunction), pediatric oncology patients receiving numerous red blood cell transfusions are not routinely screened or evaluated for risk of iron overload or its consequences. This study was done to identify pediatric oncology patients with iron overload in a general pediatric hematology/oncology clinic.
Methods. A retrospective blood bank records review was performed of pediatric hematology/oncology patients treated in our clinic in the last 10 years (2003-2013) to identify those patients receiving >10 packed red blood cell (PRBC) transfusions. These patients’ medical records were reviewed to determine which patients had been assessed for iron overload with a serum ferritin level. If a serum ferritin was obtained and the result was >1000 ug/L, records were reviewed to determine if patients received therapy for iron overload.
Results. For the time period 2003-2013, blood bank records were screened on 144 patients. Fifty patients (34.7%) were identified as receiving >10 PRBC transfusions. Of these patients, 22 (44%; M/F = 12/10; age range = 2-23 y/o) were patients who had received therapy or were on active therapy for childhood cancer; 14 with leukemia (5 AML, 9 ALL), 8 with solid tumors (5 sarcomas, 1 hepatoblastoma, 1 lymphoma). Of these 22 patients, 6 (27%) patients had a serum ferritin level that was obtained and the remaining 16 (73%) had not. All the patients (100%) with a serum ferritin result had a serum ferritin level >1000 ug/L (range 1048-22021). Only one patient (off-therapy sarcoma patient, serum ferritin =1788 ug/L) was on therapy for iron overload (Exjade and phlebotomy).
Conclusions. Pediatric oncology patients receiving numerous PRBC transfusions are at risk for iron overload. Routine risk screening and assessment for iron overload should be accomplished in all pediatric oncology patients as part of their off therapy follow-up management. For those identified as having iron overload, appropriate therapy should be considered as indicated.

Disclosures
No relevant conflicts of interest to declare.
Left Ventricular Global Function Index and Left Ventricular Mass Volume Ratio By CMR: Relation with Heart Failure in Thalassemia Major Patients
Authors: Meloni Antonella , De Franceschi Lucia , Maddaloni Domenico , Carollo Sabrina , Sarli Roberto , Cosmi Carlo , Ruffo Giovan Battista , Neri Maria Giovanna , Resta Maria Chiara , Vallone Antonino , Positano Vincenzo , Pepe Alessia 
Published: November 2019

Abstract
Introduction: Recently two novels indicators of left ventricular (LV) performance assessed by Cardiovascular Magnetic Resonance (CMR) have been introduced: the LV global function index (LVGFI) and the LV mass/volume ratio (LVMVR). The LVGFI combines LV stroke volume, end-systolic and end diastolic volumes, as well as LV mass, integrating structural as well as mechanical behaviour. Elevated LVMVR is indicative of concentric remodelling. A LVGFI <37% and a LVMVR>1 were shown to be associated with the occurrence of cardiovascular events in no-thalassemic populations.
This retrospective cohort study aimed to systematically evaluate in a large historical cohort of thalassemia major (TM) in the CMR era whether the LVGFI and the LVMVR were associated with a higher risk of heart failure.
Methods: We considered 812 TM patients (391 M, 30.4±8.6 years), consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. LVGFI and LVMRI were quantitatively evaluated by SSFP cine images. The T2* value in all the 16 cardiac segments was evaluated and a global heart T2* value <20 ms was considered indicative of myocardial iron overload (MIO).
Results: Eighty (9.9%) patients had a LVGFI<37% and, compared to the patients with a normal LVGFI, they showed a significant higher frequency of heart failure (43.8% vs 4.2%; P<0.0001). Patients with a LVGFI<37% had a significant higher risk of heart failure (odds-ratio-OR=17.59, 95%CI=9.95-21.09; P=<0.001). The risk remained significant also adjusting for the presence of MIO (OR=15.54, 95%CI=8.05-26.27; P=<0.001).
Thirty (3.7%) patients had a LVMVR≥1% and, compared to the patients with a normal LVMRI, they showed a significant higher frequency of heart failure (20.0% vs 7.7%; P=0.015). Patients with a LVMVR≥1% had a significant higher risk of heart failure (OR=3.01, 95%CI=1.18-7.64; P=0.021). The risk remained significant also adjusting for the presence of MIO (OR=3.44, 95%CI=1.31-9.01; P=0.012).
In a multivariate model including LVGFI, LVMVR and heart iron, the significant predictors of heart failure were a LVGFI<37% (OR=14.05, 95%CI=7.66-25.77; P=<0.001) and a global heart T2*<20 ms (OR=1.94, 95%CI=1.08-3.47; P=0.026).
Conclusions: In TM patients a LVGFI<37% was associated with an higher risk of heart failure, independent by the presence of MIO. A widespread program using CMR exploiting its multi-parametric potential can have considerable power for the early identification and treatment of patients at risk for heart failure.

Disclosures
No relevant conflicts of interest to declare.