bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACase Of Asymptomatic Pediatric Chronic MyelogenousLeukemia With Hyperleukocytosis
Authors: Berger David A , Jaiyesimi Ishmael , Khandhar Paras 
Published: October 2019

Abstract

Introduction
Chronic Myeloid Leukemia (CML) represents 3% of pediatric leukemias. The natural history and molecular biology of pediatric CML is the same as those of older patients with CML. 95% of pediatric CML presents in asymptomatic chronic phase and the rest diagnosed in accelerated or in blast crisis stage. It is reported that patients with pediatric CML have higher white blood cell (WBC) counts and thereby have higher incidence of symptomatic leukostasis compared to adults. Sparse literature exists on particular triggers for treatment with leukapheresis (LA). We present a case of asymptomatic hyperleukocytosis (HL) secondary to pediatric CML and a brief discussion of treatment in this emergency.

Objective
To report a rare case of asymptomatic pediatric CML with HL.

Case Summary
A 9-year-old Caucasian male presented to his pediatrician on the outpatient basis for well child care and was found to have a WBC of > 200,000 and then was admitted to the Pediatric Intensive Care Unit for further management. Upon arrival in the PICU, pt was found to have splenomegaly (down 4-5 cm from the costal margin) and hepatomegaly (2 cm down from costal margin). CBC revealed hemoglobin of 7.4 g/dL, platelet of 883 bil/L and a total white blood cell count (WBC) of 302.7 bil/L. A differential on the WBC revealed 43.9 basophils, 24.2 blasts, and 6.1 promyelocytes. Flow cytometry showed prominent myeloid population with 5% CD34 positive myeloblasts and a prominent basophil population, consistent with morphological expression of CML. The cytogenetic analysis revealed a t(9,22)(q34;q11) translocation consistent with a Philadelphia chromosome. Pediatric Leukaphresis (LA) for cytoreduction was not available at our facility, thus he was transferred.

Discussion
The HL in this patient is a direct result of his pediatric CML. The decision regarding need for cytoreduction with LA has been described in the literature for symptomatic children, but no case has been reported of when to perform LA when no symptoms of leukostasis are present.

Conclusions
In this case, it was discovered that the trigger(s) to perform LA is vague in the literature, as well as controversial in practice especially with well appearing children with the potential for a swift precarious demise. Further studies and meta-analyses to uncover the proper triggers for LA are warranted.

Disclosures:
No relevant conflicts of interest to declare.
Application Of The Revised International Prognostic Scoring System In Korean Patients With MDS and Clinical Significance Of Clonal Evolution
Authors: Park Jae Hyeon , Park Si Nae , Kwon Jiseok , Im Kyongok , Kim Jung Ah , Choi Qute , Kim Seon Young , Hwang Sang Mee , Kim Inho , Yoon Sung-Soo , Park Seonyang , Lee Dong Soon 
Published: October 2019

Abstract

Introduction
The International Prognostic Scoring System (IPSS) was recently revised (IPSS-R). IPSS-R was developed using a large cohort of patients received supportive therapy, so we validated the new prognostic score system in Korean patients. IPSS-R emphasizes initial cytogenetic abnormalities, but the risk of clonal evolution is not well identified in follow up of MDS patients.

Methods
Data of 88 MDS patients were collected retrospectively and verified by chart review. And we also collected cytogenetic analysis results performed with bone marrow study.

Results
By IPSS-R cytogenetic scoring system, 2 (2.3%), 41 (46.6%), 22 (25.0%), 5 (5.7%), and 18 (20.5%) patients were classified as very good, good, intermediate, poor, and very poor, respectively. According IPSS, 5 (5.7%), 50 (56.8%), 19 (21.6%), and 14 (15.9%) patients were classified as low, intermediate-1, intermediate-2, and high, respectively. According to IPSS-R, 2 (2.3%), 13 (14.8%), 28 (31.8%), 25(28.4%), and 20 (22.7%) patients were reclassified as very low, low, intermediate, high, and very high, respectively. Median 3 years overall survival of patients intermediate, high and very high IPSS-R are 36 (95%CI 34-39), 32 (95%CI 8 – 56), and 13 (95%CI 6-21), respectively (P = 0.004). Clonal evolutions were occurred in 22 patients and they were classified by IPSS-R cytogenetic scoring system: 11 (50.0%) good, 8 (36.4%) intermediate, 1 (4.5%) poor, 2 (9.1%) very poor. Prior clonal evolution was considered as except concurrent occurrence of clonal evolution and acute myeloid leukemia (AML) transformation. These 17 patients have significant correlation with AML transformation (P = 0.010) and mortality (P = 0.021).

Conclusion
IPSS-R gives more refined prognostic discrimination and can be applicable in Korean MDS patients. In addition, the clonal evolution occurring during follow up should be considered as a risk factor of AML transformation and mortality.

Disclosures:
No relevant conflicts of interest to declare.
Utility Of Revised International Prognostic Scoring System (R-IPSS) To Predict Outcome Of Myelodysplastic Syndromes (MDS) Patients After Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)
Authors: Corrales-Yepez Maria Gabriela , Field Teresa , List Alan , Anasetti Claudio , Perkins Janelle , Al Ali Najla H , Mishra Asmita , Padron Eric , Lancet Jeffrey E , Kharfan-Dabaja Mohamed A. , Komrokji Rami S 
Published: October 2019

Abstract

Introduction
The R-IPSS at time of diagnosis was recently proposed and validated as a superior prognostic tool refining the original IPSS. The new model recognized further cytogenetic heterogeneity of the disease, and importance of the depth of cytopenia. The value of R-IPSS at time of AHSCT to predict post-transplant outcomes is not known. We examined the utility of R-IPSS prior to AHSCT in our cohort of MDS patients.

Methods
This was a retrospective study. We identified MDS patients who underwent AHSCT in our MDS database. Individual patient charts were reviewed. R-IPSS was calculated at time of transplant using data obtained from tests performed within 30 days of transplant. The R-IPSS karyotype was based on the new proposed 5 groups. The study main objective was to compare overall survival (OS) from time of AHSCT among R-IPSS groups and R-IPSS karyotype groups. Kaplan Meier estimates were used to calculate OS; log rank test was used to compare groups.

Results
Out of 1259 MDS patients in our database, 175 received AHSCT, and we excluded 65 patients who had AHSCT at any point after AML transformation. The median duration of follow up was 46 months (mo) (95% CI 39-53). Table-1 summarizes baseline characteristics of the cohort (n=110). All patients received a reduced intensity AHSCT using fludarabine and IV-busulfan. The rate of acute graft versus host disease (GVHD) II-IV was 68% and 72% for chronic GVHD. The median OS for the whole cohort was 22 mo (95% 10-33 mo.).
The IPSS at time of AHSCT did not predict OS. Based on R-IPSS, 24 pts (22%) were very low, 26 (24%), low, 16 (15%) intermediate, 21 (19%) high, and 23 (21%) were very high. The R-IPSS at time of AHSCT did not predict OS. The median OS was not reached, 14, 52, 20 and 23 mo for very low, low, int, high and very high respectively. (p= 0.1). The R-IPSS karyotype groups did predict OS. The median OS was 29 mo, 26 mo, 19 mo, and 9 mo for good, intermediate, poor and very poor karyotype risk groups respectively (p=0.047)
No other factors prior to AHSCT including age, myeloblasts percentage, Hemoglobin, platelets, treatment before AHSCT had impact on OS in univariate analysis.

Conclusions
IPSS and R-IPSS prior to AHSCT did not predict OS in our cohort of MDS patients. The R-IPSS karyotype group was the only statistically significant prognostic factor prior to AHSCT.

Disclosures:
List: Celgene: Membership on an entity’s Board of Directors or advisory committees.
Real-Life Efficacy Of Azacitidine In Myelodysplastic Syndromes According To IPSS Cytogenetic Profile
Authors: Breccia Massimo , Voso Maria Teresa , Maurillo Luca , Niscola Pasquale , Fianchi Luana , Aloe Spiriti Maria Antonietta , Buccisano Francesco , Pelliccia Sabrina , Fenu Susanna , Tendas Andrea , Latagliata Roberto , Alimena Giuliana 
Published: October 2019

Abstract
In the AZA001 trial, azacitidine prolonged OS in all cytogenetic IPSS risk subgroups and in particular reduced 67% risk of death for all patients with -7/del(7q). Aim of our study was to assess azacitidine efficacy according to cytogenetic risk at baseline in a large group of intermediate/high-risk MDS patients treated outside clinical trials. One hundred and sixty-six patients represented the whole cohort of patients with primary or secondary MDS (CMML were excluded) diagnosed and treated with azacitidine in 6 different hematologic units. Patients were recruited consecutively, without any criteria of exclusion. All patients received azacitidine with a schedule of 5+2+2 or of 7 consecutive days every 28 days until progression or unacceptable toxicity. Clinical parameters (age, sex, WHO classification, IPSS) and baseline cytogenetic evaluation were retrospectively collected. Of 166 patients recruited, 103 were males and 63 females; median age was 69.5 years (range 49-89). A median of 8 cycles was performed (range 1-60). According to IPSS stratification there were 29 patients with intermediate-1 risk, 118 patients with intermediate-2 and 15 high–risk (7 patients not determined). According to WHO classification, 37 patients were diagnosed as having RAEB-1, 101 patients as RAEB-2, 28 patients as RCMD. According to IPSS cytogenetic risk stratification, 88 patients were in the good risk, 22 patients were in intermediate risk and 39 in the poor risk. The most frequent cytogenetic aberration, apart from normal karyotype, was -7 or del(7q). According to cytogenetic stratification, after a median of 4 cycles for the first evaluation, we revealed the following responses according to IWG criteria: of 88 patients classified as good risk, 68 were evaluable and overall 30% achieved a complete (CR), partial remission (PR) or hematological improvement (HI), 59% maintained a stable disease, 4% progressed to acute leukemia and 7% failed to achieve any response. Of 22 patients classified as intermediate cytogenetic risk, 19 patients were evaluable after 4 cycles: overall, 52.6% achieved a CR/PR and 42% maintained a stable disease, none experienced a progression and 5% failed to achieve any response. Of 39 patients stratified as high cytogenetic risk, 30 were evaluable: 36.6% achieved a CR/PR/HI, 36% maintained a stable disease, 20% progressed to acute leukemia and 7% failed to achieve any response. Our results, based on a retrospective evaluation in a large series of patients treated outside clinical trials, shown that azacitidine was clinically effective independently from cytogenetic profile, as proved in the AZA001 trial.

Disclosures:
No relevant conflicts of interest to declare.
Effect Of Heterozygous JAK2 V617F On Thrombotic Risk In Patients With Polycythemia Vera: Measuring The Uncertain
Authors: Cacciola Emma , Cipolla Antonino , Di Francesco Ernesto , Seria Elisa , Torre Maria , Cacciola Rossella Rosari 
Published: October 2019

Abstract
The Janus Kinase (JAK)2 V617F mutation and its homozygous allele burden influences the thrombotic risk in Ph-negativemyeloid chronic disorders. Recent studies report that the vera polycythemia (PV) is a heterozygous JAK2V617F disease. The heterozygous PV is characterized by high hemoglobin (Hb), hematocrit (HCT) and red blood cell (RBC) and low thrombocytosis. Therefore, we evaluated allele burden, Hb, HCT, RBC and platelets and the occurrence of thrombotic events in patients with heterozygous PV disease. The study group included 50 patients (30 male, 20 female, mean age 68 years) affected by PV according WHO criteria. Their mean duration of disease was 11 years (range, 1-26 years). All patients were on aspirin. The percentage of granulocyte mutant alleles was evaluated using a quantitative real-time polymerase chain reaction-based allelic discrimination assay. Hb, HCT, RBC, platelets were measured by automated analyser. Of 50 patients, 28 had allele burden > 10% (34±5) and 22 had allele burden < 10% (6±1)). 10/28 had thrombosis (35%) including 6 transient ischemic attack (TIA), 2 myocardial infarction (MI) and 2 deep vein thrombosis (DVT), 18/22 (81%) had thrombosis including 8 transient ischemic attack (TIA), 4 myocardial infarct (MI) and 6 deep vein thrombosis (DVT). HB, HCT and RBC were elevated in all patients (19±1.8 g/dl, 56±4 %, 7±0.6 x106/L) and the platelets were higher in patients with allele burden > 10% than the patients with allele burden < 10% (500±127x109/L vs 381±128x109/L) (p = 0.030) whereas the thrombosis were more in patients with allele burden < 10% than the patients with allele burden > 10% (81% vs 35%). These data suggest that the heterozygous allele burden is a uncertain thrombotic risk factor.

Disclosures:
No relevant conflicts of interest to declare.
Mechanistic Insights Into Ventricular Arrhythmias Associated With Sickle Cell Disease: Role Of Abnormal Repolarization
Authors: Greener I D , Rutledge C A , Abassi T , Yadav K , Desai A B , Oberoi M , Chunduru P , Parikh D P , Garcia J GN , Gordeuk Victor R. , Hillery Cheryl A. , Dudley S c , Machado Roberto F , Desai A A 
Published: October 2019

Abstract

Introduction
Sudden death, ventricular arrhythmias, prolonged QTc on ECG, and myocardial fibrosis have been documented independently in patients with sickle cell disease (SCD). We hypothesized that these electrical abnormalities are associated with myocardial fibrosis, ventricular arrhythmias, and death in SCD.

Methods & Results
A retrospective chart review of 195 SCD patients seen at the University of Illinois at Chicago was performed evaluating the association of ECG intervals with documented mortality and/or ventricular tachycardia (VT). Only ECGs demonstrating normal sinus rhythm and heart rates < 100 were included. Significant increases in PR (181 + 30 vs 162 + 26 ms, p=0.009), QRS (102 + 24 vs 89 + 11ms, p=0.0002), QTc (456 + 36 vs 441 + 25, p=0.02), and Tp-Te (duration between peak to end of T wave in lead V5, 114 + 46 vs 76 + 23, p=2.11X10-7) intervals were associated with a combined endpoint of all-cause mortality and VT (n=16 compared to n=179 SCD controls) with similar heart rates across both groups (78 + 14 vs. 77 + 11, p=0.72). To elucidate the mechanisms underlying this increased clinical risk in SCD patients, we investigated hearts from a mouse model of SCD. Cardiac electrical stimulation in vivo induced ventricular arrhythmias in 3/4 homozygous (-/-) SCD compared to only 1/5 wild-type (WT) hearts. Interestingly, Tp-Te– an established sudden cardiac death predictor- was significantly prolonged in -/- SCD vs. WT mice (5.6 + 0.29 vs. 4.1 + 0.37 msec ; p<0.05). Furthermore, left ventricular (LV) effective refractory periods (37+ 2.3 vs. 22 + 4.57 ms; p<0.05) and mid-anterior (LV) monophasic action potentials (MAPs) of -/- SCD mice, revealed increased duration compared to WT mice (53 + 2.3 vs. 33 + 6.9 ms; p<0.05).

Conclusion
In SCD patients, poor clinical outcomes are associated with abnormalities in depolarization and, prominently, repolarization. The SCD mouse exhibited arrhythmia vulnerability associated with repolarization abnormalities (Tp-Te, LV MAPs). The SCD mouse may represent a useful model for deciphering the mechanisms underlying the apparent increased arrhythmia burden in SCD patients.

Disclosures:
Hillery: Bayer: Consultancy; Biogen Idec: Consultancy.
Genetics and Epigenetics of Fetal Hemoglobin Control
Authors: Orkin Stuart H. 
Published: October 2019

Abstract
Expression of fetal hemoglobin (HbF, α2γ2) greatly ameliorates the severity of the major hemoglobin disorders, sickle cell disease (SCD), and the β-thalassemias. Efforts to reactivate HbF in adults with these disorders have relied on empirical observations or therapeutic modalities that are indirect. A major goal for the field is the development of targeted reactivation of HbF through relief of γ-globin gene silencing. The regulatory factors that participate in the switch from HbF to HbA in ontogeny and in γ-gene silencing in the adult have been elusive, therefore precluding mechanism-based reactivation of HbF. Recent findings, largely derived from genome-wide association studies (GWAS), have transformed the current understanding of globin switching. This presentation will review recent evidence supporting direct involvement of the zinc-finger repressor protein BCL11A in both developmental switching of globins and HbF silencing in the adult. These studies include the impact of naturally occurring genetic variation at the BCL11A locus on HbF levels, proof-of-principle experiments in genetically engineered mice suggesting that interference with BCL11A action alone may be sufficient to provide therapeutic elevation of HbF, and the nature of protein partners of BCL11A that may mediate some aspects of BCL11A function. Recent findings on the manner in which genetic variation within the BCL11A locus influences BCL11A expression provide special insight into quantitative aspects of HbF regulation and raise the possibility of new strategies to cripple BCL11A. The opportunities and challenges for the development of mechanism-based reactivation of HbF will be discussed in the context of ongoing efforts to exploit small molecule and genetic approaches. The tools are in hand to translate an improved understanding of globin gene regulation for the benefit of patients with the major hemoglobin disorders.

Disclosures:
No relevant conflicts of interest to declare.
Genome Regulation by Long Non-Coding RNAs
Authors: Chang Howard Y. 
Published: October 2019

Abstract
The discovery of extensive transcription of long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation. Discussions will cover genome-scale strategies to discover and characterize lncRNAs. An emerging theme from multiple model systems is that lncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators, and both control and target these enzymatic activities to appropriate locations in the genome. Consistent with this notion, long non-coding RNAs can function as modular scaffolds to specify higher order organization in RNP complexes and in chromatin states. More recently, lncRNAs have been found to control post-transcriptional processes and signal transduction as well. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs in developmental patterning and cancer.

Disclosures:
Chang: RaNA Therapeutics: Membership on an entity’s Board of Directors or advisory committees.
Monocyte Trafficking, Inflammation, and Atherosclerosis
Authors: Randolph Gwendalyn J. 
Published: October 2019

Abstract
Macrophages are central to the progression of atherosclerosis. An increased number of macrophages in plaque are associated with larger, more stenotic lesions. Furthermore, activated plaque macrophages promote rupture, the most significant clinical event affecting mortality. Plaque macrophages derive from monocytes that are recruited from blood. We have thus focused our efforts on understanding the mechanisms that regulate plaque macrophages, with emphasis on how macrophage-burden might be reduced to lower disease risk. We have developed techniques to discern whether macrophage contraction in plaques is due to emigration out of the plaque environment. Although this idea was our leading hypothesis, data obtained in a model of regression carried out in apoE-/- mice indicates that emigration of macrophages does not occur during regression. The idea was based on previous literature that monocyte-derived cells might be removed from sites of acute inflammation by emigrating to local lymph nodes. After finding that emigration of macrophages from resolving plaque in apoE-/- mice was poor, we revisited models of acute inflammation; in particular, thioglycollate-induced peritonitis, where emigration had been claimed to account for macrophage removal. New methodology to improve the quantification of macrophage loss from the peritoneum indicated that, like atherosclerosis, emigration of macrophages was a minor contributor to the contraction of macrophages associated with resolution. Instead, in both settings, macrophage loss was associated with a strong suppression of monocyte recruitment, coupled with ongoing macrophage apoptosis. These data strongly suggest that methods to block monocyte recruitment may provide a viable approach to reversing atherosclerosis. Current efforts focus on integrating the role of monocyte recruitment with local proliferation of macrophages in plaques, investigating macrophage motility in plaques during different disease states, and evaluating contraction of macrophages from plaques using other models of disease regression.

Disclosures:
No relevant conflicts of interest to declare.
The Potential to Enhance Hemostasis by Inhibiting Tissue Factor Pathway Inhibitor
Authors: Mast Alan E. , Maroney Susan A. 
Published: October 2019

Abstract
Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits tissue factors (TF) X and VIIa. As such, it is a major regulator of the extrinsic clotting pathway. Compounds that block TFPI activity, or “inhibit the inhibitor,” effectively restore hemostasis in animal models of hemophilia. These compounds are thought to act by allowing unfettered TF-mediated thrombin generation through the extrinsic pathway in a manner that bypasses the need for the intrinsic pathway proteins, factor VIII and factor IX. Improved understanding of TFPI tissue expression and function is needed to better recognize how pharmaceutical agents targeting TFPI alter biochemical and physiological mechanisms of blood coagulation. Several advances have been made recently. TFPI is an alternatively spliced protein with two primary isoforms, TFPIα and TFPIβ, which have distinct cellular expression patterns and anticoagulant functions. TFPIα is produced by endothelial cells, and appears to localize within an intracellular granule with release following stimulation with thrombin or heparin. TFPIα is also produced by megakaryocytes and is released from activated platelets. Platelet TFPIα limits clot growth following vascular injury and alters bleeding in a murine hemophilia model. Interestingly, the anticoagulant activity produced by platelet TFPIα appears to be isoform specific and not mediated through inhibition of TF. TFPIβ is made by endothelial cells, localizes to endothelium, and is not present in platelets. TFPIβ is an effective inhibitor of TF-mediated cellular migration and dampens the effects of TF-induced intravascular coagulation in mice. This new knowledge of TFPI isoform expression patterns and anticoagulant activities has important implications for the development of TFPI-blocking pharmaceuticals to treat hemophilia. The recent findings also provide new insights into the biochemical mechanisms that activate blood coagulation pathways and regulate TF-mediated thrombotic and inflammatory disease.

Disclosures:
Mast: Novo Nordisk: Honoraria, Research Funding.