bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating CD2 Negative T Cells in Pediatric Acute Leukemia
Authors: Li Weijie , Shao Lei , Ahmed Atif , Myers Doug , August Keith J 
Published: October 2019

Abstract
Introduction: Leukemia cells are able to escape from immunosurveillance using immune tolerance mechanisms as the majority of leukemia antigens are either shared or aberrantly expressed self-proteins. T cells reactive to these antigens are purged during thymic selection. CD2, a pan-T-cell antigen, is expressed early during T cell developments in thymus and is found on all subsets of mature T cells. Recent studies show that there are low levels of extrathymic CD2 negative (CD2-) T cells, which show immature T cell features and can be induced to differentiate into mature helper and cytotoxic T cells in vitro. Since circulating CD2- T cells could represent pre-selection immature T cells, they may play an important role in tumor immunity.
Methods: 81 pediatric B-cell acute lymphoblastic leukemia (B-ALL) patients, 22 pediatric acute myeloid leukemia (AML) patients and 22 normal controls were included in this study. B-ALL group included 45 NCI-standard risk (SR) patients and 36 NCI-high risk patients. All the leukemia patients were diagnosed at Children's Mercy Hospital in the past ten years with a diagnostic peripheral blood (PB) specimen. The PB specimens were studied by four-color multiparameter flow cytometry with antibodies for T cell markers (CD2, CD3, CD4, CD5, CD7 and CD8) and CD45, and analyzed by BD FACSDiva 8.0.1. CD2- and CD3+ T cells were recorded as % of total T cells. Student's t-test was used to compare results.
Results: The percentages of CD2- T cells in AML (mean ± STD: 1.31% ± 1.41%) and B-ALL (0.84% ± 0.67%) were significantly higher than that seen in control group (0.51% ± 0.52%, p<0.05). No significant difference was found between AML and B-ALL. There was no significant difference between HR B-ALL (0.96% ± 0.81%) and SR B-ALL (0.74% ± 0.52%). Interestingly, CD2- T cells in 4/5 B-ALLs with 11q23 (KMT2A) rearrangement were undetectable. All 3 therapy-related AML patients studied had KMT2A gene rearrangement, and had no detectable CD2- T cells with poor clinical outcome (overall survival less than 1 year). The 3 AMLs associated with Down syndrome, a prognostically favorable AML group, showed relative high levels (≥ 1.49%) of CD2- T cells.
Conclusions: Circulating CD2- T cells are increased in peripheral blood in pediatric AML and B-ALL patients. KMT2A gene rearrangement, an unfavorable cytogenetic abnormality, is associated with a decrease in CD2- T cells. The relationship of KMT2A gene rearrangement and decrease in circulating CD2- T-cells as well as the relationship of CD2- T cells to clinical outcome should be evaluated in future studies. The role of CD2- T cells in tumor specific immunomodulation should be explored, and may impact future studies of cell-based cancer immunotherapeutics.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Impact of Absolute Lymphocyte Count/Absolute Monocyte Count Ratio and Prognostic Score in Patients with Nasal Type, Extranodal Natural Killer/T Cell Lymphoma
Authors: Li Na , Zhang Li , Song Hao-lan , Zhang Jing , Weng Hua-wei , Zou Li-qun 
Published: October 2019

Abstract
Nasal type, extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a heterogeneous disorder with poor prognosis, requiring risk stratification in this population. We designed to investigate the prognostic significance of absolute lymphocyte count (ALC), absolute monocyte count (AMC), ALC/AMC ratio and ALC/AMC prognostic score (low risk, normal ALC and AMC; intermediate risk, low ALC or high AMC; high risk, low ALC and high AMC) and to determine whether ALC/AMC ratio or prognostic score is a better predictor of prognosis in ENKTL. A total of 264 patients with newly diagnosed ENKTL were retrospectively analyzed in present study. Receiver Operating Curve analysis showed that optimal cut-off values of ALC, AMC and ALC/AMC ratio were 1.0×109/L, 0.5×109/L and 2.85, respectively. In multivariate analysis all tested factors including ALC, AMC, ALC/AMC ratio and prognostic score were independent risk factors. After a median follow-up of 30 months (range 1-87), an estimated 3-year overall survival (OS) in the 264 patients was 75.4%. Patients with ALC/AMC ratio≥2.85 had a better OS and progression-free survival (PFS) than those with ALC/AMC ratio<2.85 at diagnosis (3-year OS rate: 83.4% versus 61.9%, P < 0.001; 3-year PFS rate: 76.5% versus 53.0%, P< 0.001). Significant difference has been noticed in the patients according to ALC/AMC prognostic score in 3-year OS (low risk vs. intermediate risk, 88.3% vs. 66.5%, p = 0.001; low risk vs. high risk, 88.3% vs. 0%, p < 0.001; intermediate risk vs. high risk, 66.5% vs. 0%, p = 0.001) and in 3-year PFS(low risk vs. intermediate risk, 80.7% vs. 58.3%, p = 0.002; low risk vs. high risk, 80.7% vs. 0%, p < 0.001; intermediate risk vs. high risk, 58.3% vs. 0%, p = 0.003) . The International Prognostic Index (IPI) and Korean Prognostic Index (KPI) were used for predicting these patients' prognosis, the result showed that the discrimination was not power. When applying ALC/AMC ratio and prognostic score to the IPI and KPI model, the latter showed a better discrimination as compared to the former.

Disclosures
No relevant conflicts of interest to declare.
Development of a Novel Prognostic Scoring System of Time to First Treatment for Chinese Patients with Chronic Lymphocytic Leukemia
Authors: Li Heng , Xiong Wenjie , Li Zengjun , Li Shuhua , Lv Rui , Zou Dehui , Qiu Lugui 
Published: October 2019

Abstract
Background: The established clinical staging systems (Rai/Binet) of chromic lymphoma leukemia (CLL) had limitedly discriminated among prognostic groups, especially for the patients in early stages and without treatment indications. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated the prognostic improvement of the combination of more markers together. In order to predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional bio-markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index.
Patients and Methods: Taking advantage of a population of 402 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months (ms). Multivariable statistics were applied with software SPSS 17.0, and the end point was TTFT.
Results: Based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (Rai risk group), 17p deletion and unmutated IGHV. Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize four different risk groups [low risk (score 0), intermediate low (score 1), intermediate high (score 2) and high risk (score 3-6)] with significantly different TTFT (median TTFT of NR, 65.0 ms, 36.0 ms and 19.0 ms, respectively, p<0.001).
Conclusions: This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers (IGHVmutation status, 17p deletion) with traditional clinical stage (Rai staging system). This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.

Disclosures
No relevant conflicts of interest to declare.
Secondary Adrenal Insufficiency Is Associated with Poor Survival Outcomes in Multiple Myeloma
Authors: Ahn Seo-Yeon , Jung Sung-Hoon , Kim Hee Kyung , Kang Ho-Cheol , Yang Deok-Hwan , Lee Seung-Shin , Ahn Jae-Sook , Kim Yeo-Kyeoung , Kim Hyeoung-Joon , Lee Je-Jung 
Published: October 2019

Abstract
Background: Glucocorticoids has been a backbone of various treatment regimens for multiple myeloma (MM). The repeated and chronic use of high doses of glucocorticoids is associated with development of secondary adrenal insufficiency (AI), and AI could be a major problem in critically-ill patients. However, there has been no specialized data about incidence and clinical significance of secondary AI in hospitalized patients with MM.
Purpose: The objective of this retrospective study is to evaluate incidence, predictive factors, and clinical significance of secondary AI in hospitalized patients with MM.
Methods: We retrospectively evaluated medical records of MM patients who were hospitalized in Chonnam National University Hwasun Hospital, South Korea from December 2014 to December 2015. The definite AI was diagnosed when the peak cortisol concentration was less than < 500 nmol/L (18 mcg/dL) after ACTH administration.
Results: Between December 2014 and December 2015, 77 patients were hospitalized, and 58 underwent rapid ACTH stimulation test. The most frequent cause of hospitalization was infection (70.7%), followed by weakness (24.1%), and the others (5.3%). The definite AI was confirmed in 19 patients (32.7%). To evaluate the predictive factors of AI, all variables including clinical characteristics, laboratory results, cumulative steroid dose, and treatment duration at hospitalization were analyzed, but there were no significant predictors for AI. In addition, the patients with AI had a significantly poor survival outcomes compared to those without AI (the median overall survival of 42.3 months vs. 82.7 months; P = 0.037) (Figure 1).
Conclusions: This study showed that the secondary AI is not a rare condition among hospitalized patients with MM, and there was no specific predictable symptoms or signs. In addition, development of AI in the treatment period is associated with a poor prognosis. This study suggests that evaluation of AI is routinely needed in hospitalized patients with MM.

Disclosures
No relevant conflicts of interest to declare.
Simple Prognostic Score for Evaluation of Elderly Multiple Myeloma Patients
Authors: Radocha Jakub , Zak Pavel , Machalkova Katerina , Beranova Katerina , Hanousek Jiri , Maisnar Vladimír 
Published: October 2019

Abstract
Introduction: Treatment of elderly multiple myeloma patients remains a clinical challenge. The frailty and comorbidities represent major obstacles in successful treatment. We therefore conducted a single center analysis of elderly myeloma patients in order to identify possible prognostic factors which affect their prognosis. We focused on simple clinical parameters that can be used as a clinical tool in daily practice.
Methods: All patients treated at our department for myeloma from years 2007-2014 who were older than 65 years were included in the analysis. Demographic, baseline disease and treatment characteristics were collected. Adverse clinical characteristics were selected based on univariate analysis. These include renal insufficiency at the time of diagnosis (creatinine >2.0 mg/dL), male sex a performance status ECOG>2 on diagnosis. The simple model assigning one point for each of these factors was given to each specific patient. Overall survival was calculated based on subgroups with 0-3 points as a sole endpoint in elderly patients.
Results: We identified 184 patients (83 males and 101 females, median age 73 years) with multiple myeloma. 76 patients (41.3%) were older than 75 years, 47 (25.5%) patients had renal insufficiency, 59 (32.1%) patients were ECOG>2. Only 20 patients (10.9%) were offered autologous transplantation. 165 patients (89.7%) were treated with novel agents frontline (bortezomib, thalidomide or lenalidomide). The median overall survival was 58.2, 44.4, 31.6 and 3.9 months in groups assigned 0, 1, 2 and 3 points respectively. The differences were statistically significant (p=0.0001, log-rank test).
Conclusion: This simple model might easily identify patients at high risk of early mortality based on three simple clinical characteristics available in all patients at the time of disease onset. Model like this needs a validation using a larger cohort of patients.
Supported by PRVOUK P37.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Inferior Vena Cava Filter - Appropriate Use and Retrieval
Authors: Shah Rena , Turk Anita , Rahim Bilal , Arafat Waddah , Nazeef Moniba , Mattison Ryan J. 
Published: October 2019

Abstract
Inferior vena cava (IVC) filters, first introduced in 1998, have been utilized to reduce risk of pulmonary embolism (PE) in the setting of an inability to anticoagulate patients. The use of IVC filters has increased and continues to rise, especially with the introduction of retrievable IVC filters. Since their initial introduction, guidelines have been developed on the appropriate use of IVC filters. According to the American College of Chest Physicians (ACCP), the use of an IVC filter is limited to patients with an absolute contraindication to therapeutic anticoagulation or failure or complication of anticoagulation in the setting an acute proximal venous thrombus. Relative indications for IVC filter placement include high clot burden in setting of low cardiopulmonary reserve, high risk patients, or severe trauma without documented thrombosis. In 2010, the FDA announced a safety communication recommending removal of retrievable IVC filters due to reports of several adverse clinical outcomes associated with retained filters including thrombus formation, recurrent PE, filter migration, erosion or perforation through the IVC wall, and filter fracture with fragment embolization. In 2014, the FDA recommended removal of the IVC filter within 2 months after filter placement if the patient's risk of thrombosis had passed.
In this retrospective analysis of IVC filter management, we reviewed indications for placement according to current guidelines as set by the ACCP, initiation of appropriate anticoagulation, complication rates, and retrieval rates. In addition, we compared the data prior to the FDA recommendations in late 2014 and data after the recommendations to determine if there was a change in practice.
After reviewing 179 patients, 89 patients in 2014 and 90 patients in 2015, who underwent IVC filter placement, only 81% (N=145) of patients had appropriate indications for IVC filter placement and 30% (N=54) of patients had inappropriate anticoagulation after IVC filter placement, given as prophylactic dosing of low molecular weight heparin. A comparison of retrieval rates prior to and after the FDA warning, showed a 19% (60% in 2014 vs 79% in 2015) improvement in IVC filter removals. There was an 11% complication rate, mainly related to IVC filter related acute DVT or IVC occlusion.
A root cause analysis specifically for inappropriate IVC filter placement and appropriate anticoagulation and determined that familiarity of the guidelines and non-evidence based recommendations from consultants were major factors. Based on the analysis, we next plan to utilize the electronic health record system to help clinicians understand indications and when to initiate appropriate anticoagulation, with the opportunity for hematology consultants to be involved in situations that do not clearly fit within published guidelines.

Disclosures
No relevant conflicts of interest to declare.
JAK2V617F Promotes Atherosclerosis
Authors: Wang Wei , Wang Ying , Woods Brittany , Abramowicz Sandra , Welch Carrie , Levine Ross L. , Tall Alan , Wang Nan 
Published: October 2019

Abstract
Myeloproliferative disorder (MPD) patients are at high risk of atherothrombotic events including myocardial infarction and stroke. The somatic mutation (JAK2V617F) is commonly found in MPD patients and is associated with increased vascular risk. Moreover, the prevalence of JAK2V617F mutation is also significantly increased in non-MPD coronary artery disease (CAD) and peripheral artery disease (PAD) patients compared to the general population. Our goal was to investigate potential mechanisms of accelerated atherothrombosis using a JAK2V617F mouse model.
Subletahlly irradiated Ldlr-/- mice were transplanted with bone marrow cells from wild type (WT) or Mx1-Cre/Jak2V617F (Jak2VF) mice and fed a high fat high cholesterol Western type diet (WTD). After 7 weeks of WTD Jak2VFmice had sustained neutrophilia, monocytosis and erythrocytosis; despite lower plasma cholesterol levels they showed ~1.6 fold larger atherosclerotic lesions in the aortic root (p=0.003) and accelerated carotid artery thrombosis (FeCl3 injury). After 12 weeks of WTD feeding, lesion area was only increased 1.3-fold compared to controls but showed features of plaque instability (increased necrotic core area). Early lesions (7 weeks) displayed significantly increased neutrophils (p=0.05, n=7) but not Mac 3+ macrophages. The increased neutrophil infiltration in Jak2VF mice correlated with atherosclerotic lesion size (p=0.001, r=0.78), suggesting a critical role of neutrophils in early atherogenesis. Advanced lesions (12 weeks) also showed significantly increased neutrophil (p=0.001) and macrophage (p=0.05) infiltration. No difference in CD3+ T cells or CD41+ platelet infiltration was observed at either time-point. In addition, five out of nine Jak2VF mice had prominent iron deposition (Prussian blue) and RBC marker Ter-119 staining in advanced atherosclerotic lesions (p<0.05). RBC marker Ter-119 co-localized with Mac-3(+) macrophages surrounding necrotic cores, indicating erythrophagocytosis and plaque instability.
In summary, the Jak2V617F mutation promotes early atherosclerotic lesion development and plaque instability in advanced lesions. Neutrophil infiltration appears to be an important contributor to both early lesion development and necrotic core formation. These studies also suggest a novel role for RBC infiltration, iron deposition and erythrophagocytosis in advanced lesional necrotic core formation in JAK2V617F mice.

Disclosures
Levine: Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Tall:Amgen: Consultancy; CSL Behring: Consultancy.
Large Scale Discoveries of Genes and Polymorphisms Associated with Variation in Hematologic Traits
Authors: Soranzo Nicole 
Published: October 2019

Abstract
Hematopoiesis generates mature blood cells from hematopoietic stem cells (HSC) in distinct lineages to release of trillions of mature cells each day into the peripheral blood stream to perform essential functions such as oxygen transport, hemostasis and host defense. The formation and turnover of blood cells are tightly controlled and so the properties of blood cells, including their volume and count, have large heritabilities and are easily influenced by genetic variation. Here we describe the most statistically powerful genome wide association study (GWAS) of blood cell indices to date. We tested associations of 29.5 million polymorphic DNA sequence variants derived using the the Affymetrix axiom array with interpolation of 20 million variants using the UK 10000 genome data with 36 different hematological indices of red cells, white cells and platelets, some of which, such as the reticulocyte count, have been explored for the first time. We discovered significant associations at thousands of associated genetic variants, including hundreds of associations for low frequency genetic variants, thus identifying associations with larger effects on indices than those reported for common variants by previous discovery studies. We have described detailed follow-up studies of the novel associations. Using cell type-specific epigenome and gene expression data generated by the BLUEPRINT project and results from chromatin conformation capture in major blood cell types, we can identify the likely causal variants and their functional impact at a large number of the novel loci. Finally, we have evaluated the contribution of genetic variants to common and complex diseases. In conclusion, we have interrogated phenotypes across the whole hematopoietic tree and increased the number of traits associated with blood cell phenotypes by an order of magnitude. Overall, our results demonstrate widespread and powerful genetic influences on the formation and regulation of the major human blood cell types, identifying many novel genes involved and show the value of genome-wide functional annotation from relevant primary cell populations for interpreting genetic association results.

Disclosures
No relevant conflicts of interest to declare.
Shwachman-Diamond Syndrome and the Quality Control of Ribosome Assembly
Authors: Warren Alan J. 
Published: October 2019

Abstract
The synthesis of new ribosomes is a fundamental conserved process in all cells. Ribosomes are pre-assembled in the nucleus and subsequently exported to the cytoplasm where they acquire functionality through a series of final maturation steps that include formation of the catalytic center, recruitment of the last remaining ribosomal proteins and the removal of inhibitory assembly factors. Surprisingly, a number of key factors (SBDS, DNAJC21, RPL10 (uL16)) involved in late cytoplasmic maturation of the large (60S) ribosomal subunit are mutated in both inherited and sporadic forms of leukemia. In particular, biallelic mutations in the SBDS gene cause Shwachman-Diamond syndrome (SDS), a recessive bone marrow failure disorder with significant predisposition to acute myeloid leukemia. By using the latest advances in single-particle cryo-electron microscopy to elucidate the function of the SBDS protein, we have uncovered an elegant mechanism that couples final maturation of the 60S subunit to a quality control assessment of the structural integrity of the active sites of the ribosome. Further molecular dissection of this pathway may inform novel therapeutic strategies for SDS and leukemia more generally.
References:
1. Weis F, Giudice E, Churcher M,et al. Mechanism of eIF6 release from the nascent 60S ribosomal subunit. Nat Struct Mol Biol, (2015) Nov;22(11):914-9.
2. Wong CC, Traynor D, Basse N, et al. Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper, Blood. 2011 Oct 20;118(16):4305-12.
3. Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev (2011) 25: 917-929.
4. Menne TM, Goyenechea B, Sánchez-Puig N, et al. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95.

Disclosures
No relevant conflicts of interest to declare.