bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Consequences of Disseminating the Bortezomib Postmarketing Safety Alerts In Japan
Authors: Tanimoto Tetsuya , Murashige Naoko , Oshima Yasuo , Hori Akiko , Kodama Yuko , Matsumura Tomoko , Kami Masahiro 
Published: October 2019

Abstract
Abstract 2572

Backgroud:
In Japan, bortezomib (Velcade; Janssen Pharmaceutical Corporation, Tokyo, Japan) was approved on October 2006 for relapsed or refractory multiple myeloma, and sales began on the open market in December 2006. The approval process clarified potential risk for interstitial lung disease (ILD) among bortezomib-treated Japanese patients as we reported before (Blood 2006; 107:3492–4, Lancet Oncol 2008; 9:414–5). By 2007, various safety alerts were widely disseminated through the responsible pharmaceutical company, the media, the academic societies and the regulatory authority of Japan (Pharmaceuticals and Medical Devices Agency, PMDA) concerning the potential ILD risk of bortezomib (J Clin Oncol 2008; 26:5820–3). In this study, we investigated whether notification of patients and providers about these safety alerts influenced the clinical outcomes after bortezomib therapy in Japan.

Methods:
We reviewed all bortezomib-related adverse drug reaction (ADR) reports available from open source database of PMDA from December 2006 to December 2009. The indication of bortezomib remained unchanged in this period. We compared the number of reported cases and their outcomes between the early postmarketing period (from December 2006 to December 2007) and the late period after the dissemination of the safety alerts concerning ILD (from January 2008 to December 2009).

Results:
In the study period, 419 ADR cases were identified after bortezomib therapy. The proportion of ILD to any ADR was 25.0% (9 of the 36 cases) in December 2006, 8.3% (13 of the 156 cases) in 2007, 12.0% (17 of the 142 cases) in 2008 and 7.1% (6 of the 85 cases) in 2009 (Table 1). When we compared the early postmarketing period before the safety alerts and the late period after the safety alerts, the death proportion of the cases with any ADRs seemed similar. Forty of the 192 cases (20.8%) died in the early period and 47 of the 227 cases (20.7%) in the late period. On the other hand, the death proportion among ILD cases appeared to decrease remarkably (Table 2). Nine of the 22 ILD cases (40.9%) died in the early period and 1 of the 23 ILD cases (4.3%) died in the late period (p=0.004, Fisher's exact test).

Conclusions:
Notification of patients and providers about the safety alerts appeared to influence the clinical practice and to improve proportion of fatal outcomes for bortezomib-treated ILD patients. This study illusrates the importance of communicating drug safety information to the public.

Disclosure:
Oshima: Sanofi-Aventis: Employment.
Readiness for Transition From Pediatric Sickle Cell Care: Exploratory Analyses of Domains of Readiness and Total Scores
Authors: Smith Wally R. , Smith Virginia , Godder Kamar , Sisler India , Casper Robbie , Johnson Shirley , Brice Wanda , Bitsko Matthew , Engram April , Morgan Alma 
Published: October 2019

Abstract
Abstract 2576

Background:
In just one generation, the average survival of patients with sickle cell anemia has increased from 14 years to nearly 50 years, necessitating transition programs from pediatric to adult care. We developed a transition program to provide continuity of care from pediatric to adult settings. In order to provide education and skills via an individualized plan for transition of care, we assessed confidence/self-efficacy, knowledge, skills, and attitudes surrounding transition of 34 African-American individuals aged 15–21 (mean 17). We hypothesized that there would be correlation between each of these domains, and that such correlation would suggest that each domain predicts initial readiness/sophistication for transition.

Methods:
We administered a survey battery both of items we constructed and of previously used survey items assessing medical, Educational/Vocational, Health Benefits, Social, Independent Living, Feelings, Sickle Cell Stress, and Self-Efficacy domains. We assigned/mapped these content items, using clinical judgment and consensus, to four domains of “readiness for transition”: confidence/self-efficacy, knowledge, skills, and attitudes. Readiness scores for each domain were calculated such that a summary score of 100 would indicate perfect readiness in each domain. The complete question battery is available.
Results are shown in the table below.

Conclusions:
Attitudinal readiness, knowledge readiness, confidence readiness, and skill readiness for transition were low initially in sickle cell adolescents enrolled in a transition program. Percentage of maximum possible scores was lowest for attitude, and highest for skill. Both attitude and knowledge scores showed very high correlation with total readiness score. However, several component scores were moderately correlated with each other. Transition programs for SCD should consider assessing and enhancing not only knowledge, but also attitudes, confidence, and skill.

Disclosure:
No relevant conflicts of interest to declare.
Coordinated Regulation of Embryonic and Adult Hematopoietic Stem Cell Activity by PTPN11/Shp2.
Authors: Zhu Helen He , Ji Kaihong , Alderson Nazilla , He Zhao , Li Shuangwei , Li Linheng , Feng Gen-Sheng 
Published: October 2019

Abstract
Abstract 2630
Shp2, a tyrosine phosphatase with two SH2 domains, is implicated in malignant blood diseases. Germline dominant active mutations in PTPN11 that codes for Shp2 are found in approximately 50% of Noonan syndrome (NS) patients who have high risk of juvenile myelomonocytic leukemia (JMML). Somatic gain-of-function mutations in PTPN11 have also been detected in nonsyndromic JMML, pediatric AML, B-cell precursor ALL and myelodysplastic syndromes. The majority of leukemia-associated PTPN11 mutations disrupt the auto-inhibitory interactions between its N-terminal SH2 and the phosphatase domain, resulting in elevated catalytic activity. However, the physiological function of Shp2 in normal hematopoiesis in adults remains to be elucidated, although a Shp2 function in embryonic hematopoiesis was documented previously. Mouse embryonic stem cells (mESCs) homozygous for targeted exon 3 deletion are defective in differentiation to all blood cell lineages, suggesting its role in commitment/specification of hematopoietic stem cells (HSCs) during embryogenesis. Indeed, our previous experiments suggested a developmental blockage from mESC to mesoderm and hemangioblast differentiation by the exon 3 deletion. Notably, distinct mechanisms are involved in embryonic and adult hematopoiesis. Despite an essential role for specification of HSC fate from embryonic mesoderm, SCL/tal-1 was found dispensable for HSC maintenance and differentiation in adults. Similar observation was made for transcription factor Runx. We show here that inducible ablation of PTPN11/Shp2 in the hematopoietic compartment leads to severe cytopenia in bone marrow, spleen and periphery. Shp2 removal suppressed the number and function of HSCs and myeloid progenitors. Shp2-deficient HSCs failed to reconstitute irradiated recipient mice, due to combined defects in homing, self-renewal and survival. Therefore, PTPN11/Shp2 indeed plays an essential role in maintenance of a functional HSC pool in adult mammals. This study reveals a critical signaling component conserved in embryonic and adult hematopoiesis. Given the essential role of Shp2 in normal HSCs, developing a chemical that distinguishes wild-type and mutant Shp2 enzymes may be a therapeutic approach for elimination of leukemic stem cells (LSCs) harboring mutant PTPN11/Shp2.

Disclosures:
No relevant conflicts of interest to declare.
A Meta-Analysis of Nodular Sclerosis Hodgkin Lymphoma Identifies Risk Loci at 6p21.32
Authors: Cozen Wendy , Li Dalin , Best Timothy , Berg David J. Van Den , Skol Andrew , Cortessis Victoria K. , Mack Thomas M , Glaser Sally L. , Schumacher Fred , Weiss Lawrence , Nathwani Bharat N. , Hwang Amie , Bhatia Smita , Strong Louise C , Robison Leslie L. , V Conti David , Onel Kenan 
Published: October 2019

Abstract
Abstract 2686
Nodular sclerosis Hodgkin lymphoma (NSHL) is epidemiologically and pathologically distinct from other Hodgkin lymphoma subtypes. It is highly heritable and is the most common form of HL in young adults. In a combined analysis of results from two genome-wide association scans (one undertaken at the University of Southern California using the Illumina Human610-Quad beadchip and the other at the University of Chicago using the Affymetrix Genome-Wide Human SNP Array 6.0) of 395 European-origin NSHL patients and 3,245 controls, we identified two single nucleotide polymorphisms (SNPs) at chromosome 6p21.32 directly genotyped in both scans associated with disease risk at genome-wide levels of significance (rs9268542: p=8.2×10−10, odds ratio (OR)= 1.63, 95% Confidence Interval (CI) = 1.40–1.91; and rs204999: p=2.3×10-9, OR= 0.54, 95% CI: 0.44=0.66). These SNPs are located in distinct haplotype blocks and are in only weak linkage disequilibrium (LD) (r2=0.06). Joint analysis revealed that each SNP was independently associated with disease risk, with the global likelihood ratio test remaining statistically significant for each group (p-value for 2 df test USC = 7.46 × 10-9 and UC=.3.51 × 10-6). Neither SNP is in a known gene or microRNA. rs9268542 is in LD with SNPs in the HLA-DRA gene (r2=0.92-0.93) and is a cis-acting expression QTL (eQTL) for several HLA Class II genes (HLA-DRB1-HLA-DRB5; HLA-DQB1-HLA-DQB2; all p=1×10-5). Of note, rs6903608, an imputed SNP in the same region also surpassing genome-wide significance for association with NSHL, is an eQTL for these same HLA Class II genes at p=1×10-20. rs204999 is in LD with SNPs in the nearby PRRT1 (r2=0.82) and EGFL8 (r2=0.81) genes, for which function remains poorly defined. Thus, we identified one SNP on chromosome 6p21.32 associated with NSHL that, by eQTL analysis, may be implicated in the transcriptional regulation of HLA-class II genes, a known susceptibly region for NSHL, and one SNP in the genomic region that appears to be independently-associated with NSHL, but which does not appear to be linked to the HLA locus.

Disclosures:
No relevant conflicts of interest to declare.
High Incidence of Peripheral Blood Plasmacytosis In Patients with Dengue Virus Infection: a Prospective Study
Authors: Thai Khao T.D. , Wismeijer Josta A. , Zumpolle Catrien M. , de Jong Menno D. , Vde ries Peter J. , Kersten Marie Jose 
Published: October 2019

Abstract
Abstract 2772

Introduction:
One of the characteristic features of dengue virus (DENV) infection is the occurrence of leukopenia and thrombocytopenia, probably resulting from virus induced bone marrow suppression. Despite the general bone marrow suppression, polyclonal peripheral blood plasmacytosis has occasionally been described in DENV infected patients. The frequency of peripheral blood (PB) plasmacytosis in patients with dengue infection, the origin of these plasma cells (PCs) and the mechanisms by which they appear in the blood are not known. We initiated this prospective observational study to quantify and describe the kinetics and phenotype of PB plasmacells (PCs) in these patients.

Methods:
Morphological examination of the peripheral blood smear was performed in 35 sequential returned travelers suspected of DENV infection, with a history of less than 14 days of fever. Flow cytometric (FC) analysis for the characterization and immunophenotyping of lymphocyte subsets and PCs was performed in 31 patients. Follow-up samples were available for 8 patients.

Results:
Our results show that PB plasmacytosis is a very common hematological finding in DENV infection, with extreme values of up to 36% of total white blood cells in some patients. Depending on the number of days since the onset of fever at presentation, PB plasmacytosis was observed in 64% to 73% of 28 patients with confirmed DENV infection, and in none of 7 patients with other febrile illnesses. PB plasmacytosis was the most pronounced before 7 days after onset of illness and declined rapidly thereafter, to completely disappear after 14 days of illness. The median percentage of PCs at day 7 was 2.5% (range 0–36%; 25–75 interquartile range: 0–8%). The median percentage of PCs was significantly higher in patients with secondary DENV infection than in patients with primary infection (4.5% versus 1.0%; p=0.05). Viral RNA was detectable in 18 of 28 DENV infected patients with a highly variable viral load, but there was no correlation between viral load and percentage of PCs. We found an excellent correlation between percentage of PCs as assessed by morphology and by flow cytometry (r2= 0.85). The majority of CD138+ PCs (89%) had a shared immunophenotype (CD45+/CD19−/CD56−), which differed from normal plasmacells which are generally CD19+. In all cases the PCs were polyclonal.

Conclusion:
PB plasmacytosis, characterized by a transient presence of polyclonal PCs in the circulation, is a common event in DENV infection and is probably the result of a vigorous humoral immune response to dengue. With an increasing number of travelers to areas where dengue virus is endemic, it is important also for hematologists to recognize this benign cause of sometimes extreme plasmacytosis, for which no invasive procedures such as bone marrow examinations are needed.

Disclosures:
No relevant conflicts of interest to declare.
Cross Laboratory Validation of An In Vitro Screen for Cytokine Release Syndrome
Authors: Bannish Gregory , Makropoulos Dorie , Perpetua Meredith , Thomas Gareth , Bate Simon , Walker Mindi , Bugelski Peter 
Published: October 2019

Abstract
Abstract 2778
Monoclonal antibodies (mAb) are widely used in anti-inflammatory and tumor therapy. They are highly effective in certain diseases, but can cause a range of adverse effects. Toxicity may result from the expected pharmacological effects of the antibody and from interactions with antigen expressed on tissues other than the intended target. The results range from mild infusion reactions to cytokine release syndrome (CRS). A number of mAbs are associated with CRS on the first dose in humans (including: anti-CD3, anti-CD52; anti-CD20, anti-CD25 and anti-CD28 superagonist) that were not predicted by preclinical studies in animals. To address this issue, we have developed an in vitro screen using cultured human whole blood that assess the potential for mAb to cause CRS. The purpose of these experiments was to determine if the assay can be transferred to different laboratory and conducted using a different analytical platform and different donors. mAbs are bound to Protein A coated polystyrene beads (Spherotech) and incubated with whole blood from 6 normal human volunteers diluted in media (1:10) in 96 well plates. PBS (no beads) and Autologous Plasma are negative controls, while LPS (1 ug/mL); LPS and superagonist anti-CD28 (ANC28.1/5D10, Ancell) serve the positive controls. After incubation for 48 hr, the supernatants are collected and cytokines (IFN-γ, TNFα, IL-1, IL-2, IL-6, IL-8, IL-10 and IL-12) assayed using SearchLight® (Aushon Biosystems) or MSD® (Meso Scale Discovery) platforms. The response to superagonist anti-CD28 was distinctly different from the response to LPS, anti-CD20 and anti-CD52. Although the absolute values for the cytokines differed across the analysis platforms, Spearman Rank Order analysis showed a statistically significant correlation for most cytokines. Moreover, when the average values were normalized to the response to LPS, hierarchical cluster analysis classified the responses measured by the two platforms in an identical manner. In conclusion, this study has shown that an in vitro whole blood based assay can classify mAb according to the potential to cause CRS in humans and suggest that the assay can be transferred successfully across laboratories and analysis platforms.

Disclosures:
No relevant conflicts of interest to declare.
Exploring the Biological Role of Kruppel-Like Factor 2 In Cytotoxic T Lymphocytes
Authors: Preston Gavin Charles , Cantrell Doreen A 
Published: October 2019

Abstract
Abstract 2783
Kruppel-like factor 2 (KLF2) is a transcription factor which has been shown to be a critical regulator of T lymphocyte quiescence and trafficking. KLF2 is highly expressed in naïve CD8 T cells but its expression is transcriptionally downregulated in effector cytotoxic T lymphocytes (CTL). To understand how KLF2 might co-ordinate biological processes in CTL, we have determined the impact of preventing KLF2 downregulation on the transcriptional program of antigen receptor triggered CD8 T cells. Our data show that CTL which fail to downregulate KLF2 have a strikingly different transcriptional program to normal CTL. Immune activated CD8 T cells that sustain KLF2 expression thus show increased expression of 672 genes and decreased expression of 205 genes compared to normal CTL that have lost KLF2. Previous studies have indicated that high levels of KLF2 correlate with long term T cell survival and the development of memory CD8 T cells. We therefore questioned whether the KLF2 regulated genes identified in our experiments gave any insight as to why increasing levels of KLF2 in immune activated T cells might control T cell memory. In this context, we noted that KLF2 downregulation is necessary for TCR triggering of the CTL mitotic pathway. The molecular basis for this effect includes that KLF2 drives expression of intracellular cell cycle inhibitors. It was equally striking, however, that KLF2 could induce expression of the inhibitory receptor Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (Ceacam1, CD66a), which can suppress the T cell proliferative response. The present report confirms that KLF2 controls the repertoire of chemokine receptors and adhesion molecules expressed by CTL. Previous studies have identified the adhesion molecule CD62L and the G protein coupled receptor S1P1 as direct gene targets for KLF2. The present data support that KLF2 positively regulates expression of these molecules but also describes a cell autonomous role for KLF2 to negatively regulate the expression of the inflammatory chemokine receptor CXCR3 in antigen primed CTL. The loss of KLF2 is thus essential to allow CTL to traffic to CXCR3 ligands. One other striking observation was that KLF2 expression in CTL upregulates expression of the IL-6 receptor and Serine Protease Inhibitor 6 (Spi6). The latter molecule has a key role in protecting CTL from self injury inflicted by granzymes and is critical for the generation of T cell memory. IL-6 receptor expression is similarly important for memory T cell survival. Collectively, these data identify new KLF2 regulated genes and biological functions in CD8 T cells and provide important insights as to how this transcription factor controls T cell immune responses and might determine the effector/memory fate of a CTL.

Disclosures:
No relevant conflicts of interest to declare.
The Combination of Azacitidine (AZA) and Recombinant Erythropoietin (rEPO) Can Induce Rapidly Hematological Response In Intermediate-2 and High-risk MDS (including RAEB-t)
Authors: Kartsios Haris , Loukidis Kostas , Papadopoulos Vassilios , Effraimidou Smaragda , Spyrou Anastasia , Kokoviadou Kyriaki , Papadakis Emmanouil , Kioumi Anna , Korantzis Ioannis 
Published: October 2019

Abstract
Abstract 2914

Background:
AZA, a DNA hypomethylating agent, provides 50–60% responses in higher-risk MDS after administration of 6 courses of treatment. Recent laboratory data suggests that demethylation with AZA upregulates EPO-receptor mRNA (Wallach, 2009). AZA might also affect several genes involved in cell cycle, metabolism and signal transduction which are down-regulated in bone marrow erythroid cells in MDS patients non-responsive to rEPO. There is currently insufficient data to combine AZA and rEPO in MDS patients.

Patients-Methods:
We explored the safety and the efficacy of the AZA-rEPO combination in a cohort of 10 (M/F: 5/5) patients (pts) with a median age of 75(67-83) years. Diagnosis (WHO classification) was: RAEB-2: 5, CMML: 2 and RAEB-t: 3; IPSS was: int-2 in 8/10 and high in 2/10 pts. Median time from diagnosis was 6(1-31) months. 9/10 pts were transfusion dependent, 8/10 were refractory to previous rEPO administration while 2/10 pts were not treated with rEPO but their diagnostic serum EPO levels were >200 U/L. Patients were given AZA at FDA/EMEA-approved schedule (75 mg/m2/d x7d/4-weekly) initially for 5 courses and continued if response was obtained. rEPO (40,000IU/week) was given until achievement of steady Hb level >10.5 g/dL or until AZA discontinuation.

Results:
Median follow-up was 6.5(1-14) months. Patients received a median of 5 cycles (range 2–13) of AZA; 9/10 pts were treated with ≥5 courses of AZA. The median time of rEPO administration was 82(76-142) days. Best response (IWG 2006 criteria) was CR in 1/10 pts (RAEB-2: 1), marrow CR in 1/10 pts (RAEB-t: 1), and stable disease with hematological improvement (HI) in 4/10 pts (RAEB-t: 1, RAEB-2: 2, CMML: 1) leading to an overall response rate of 60%. As soon as 2 courses of AZA-rEPO were given, 5/6 responders experienced HI-erythroid response, 3/6 obtained HI-platelet response and 2/6 achieved HI-neutrophil response. Adverse events included 2 episodes of febrile neutropenia, nausea (2/10 pts), reversible renal impairment (2/10 pts) and hemorrhagic complications (3/10 patients). Currently, 9/10 patients remain alive, 1 patient experienced progression to AML and the estimated probability of 1 year-Progression Free Survival is 75%.

Conclusions:
This study provides clinical evidence that the AZA-rEPO combination is safe and rapidly effective in higher risk MDS pts. Our results emphasize the necessity for randomized trials in order to further evaluate the AZA-rEPO combination in MDS.

Disclosures:
No relevant conflicts of interest to declare.