bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bleeding Incidence Among Patients With Venous Thromboembolism: A Large US Insurance Database Analysis
Authors: Liu Xianchen , Xie Lin , Phatak Hemant , Mardekian Jack , Tan Wilson , Baser Onur , Ramacciotti Eduardo 
Published: October 2019

Abstract

Introduction
It is crucial to assess clinical benefit and bleeding risk when selecting an anticoagulant for patients with venous thromboembolism (VTE). This study examined the incidence of major bleeding and non-major bleeding and clinical predictors of major bleeding among patients with VTE in the usual clinical practice setting.

Methods
VTE patients aged ≥18 years were identified from the Truven Health MarketScan commercial or Medicare supplemental insurance database. Index date was defined as the first VTE diagnosis between 07/01/2006 – 12/31/2011. Patients were required to have ≥2 VTE outpatient diagnoses within a 3-week window or have 1 VTE diagnosis in an inpatient setting, have a continuous health plan enrollment for 6 months prior to the index date (baseline), and have no VTE diagnosis in the baseline period. Major bleeding was defined as any bleeding that resulted in hospitalization or blood transfusion; all other bleeds were non-major bleeding. Patients were followed until major bleeding/non-major bleeding, death, disenrollment, or end of study. Multivariate Cox regression was used to examine factors associated with major bleeding.

Results
Of 267,655 eligible patients, 182,972 patients were with deep vein thrombosis (DVT) only (68.4%), 69,169 with pulmonary embolism (PE) only (25.8%); and 15,514 with both (5.8%). Mean age was 61.5 years, and 53.1% were female. Mean follow-up period was 17.3 months (median=12.1). The annual incidence of major bleeding and non-major bleeding were 3.9% and 20.1%, respectively. The median time to major bleeding from index VTE diagnosis was 2.2 months. Major risk factors at baseline for major bleeding (Risk increase>20%) were history of major bleeding (HR=10.78, 95%CI=10.30-11.28) and non-major bleeding (HR=1.61, 95%CI=1.54-1.68), chemotherapy (HR=1.27, 95%CI=1.20-1.35), age ≥65 vs.≤40 years (HR=1.27, 95%CI=1.18-1.37), alcohol abuse (HR=1.26, 95%CI=1.16-1.38), cancer (HR=1.25, 95%CI=1.19-1.31), and heart disease (HR=1.23, 95%CI=1.18-1.28) (Table). Baseline hormone therapy (HR=0.74, 95%CI=0.68-0.80) and pregnancy (HR=0.59, 95%CI=0.46-0.74) were associated with reduced risk for major bleeding.

Conclusions
Major and non-major bleeding were common in patients with VTE. Multiple factors, especially history of bleeding, age≥65 years, alcohol abuse, cancer and heart disease, were associated with increased risk for major bleeding. Further research needs to examine bleeding risk associated with anticoagulant therapy.

Disclosures:
Liu: Pfizer: Employment, Equity Ownership. Xie:StatInMed: Employment, Research Funding. Phatak:BMS: Employment, Equity Ownership. Mardekian:Pfizer: Employment, Equity Ownership. Tan:Pfizer: Employment, Equity Ownership. Baser:StatInMed: Employment, Research Funding. Ramacciotti:BMS: Employment, Equity Ownership.
Randomized Controlled Trial Of The Efficacy Of a Best Practice Exercise Program Post-Treatment On Physiological and Psychosocial Outcomes In Haematological Cancer Patients
Authors: Joske David J L , Furzer Bonnie , Ackland Tim , Wallman Karen , Petterson Anna , Wright Kemi , Gordon Sandy 
Published: October 2019

Abstract

Purpose
Following cancer treatment haematological patients exhibit significant physical deconditioning and psychological distress resulting from the treatment and the disease. Exercise has been shown as a safe and effective method of rehabilitation in cancer patients, with the potential to reverse the deleterious effects following diagnosis. Our aim was to investigate the efficacy of an immediate or delayed exercise program on various patient outcomes post treatment.

Patients and Methods
Between July 2010 and December 2011, haematological cancer patients from Western Australia, who had completed chemotherapy treatment, were randomly assigned to immediate exercise (IEG; n=18) or a 12-week delayed exercise program (DEG; n=19). The exercise intervention incorporated aerobic and resistance training performed three times per week for 12-weeks. Patient rated outcomes (PRO) included cancer related fatigue (CRF), quality of life (QoL), psychological distress, exercise habit and behaviour. Physiological outcomes included cardiovascular fitness, muscle strength, physical function and body composition.

Results
Patient adherence to the exercise program was 85%, with patients completing, on average, 74 min per week of aerobic exercise and strength training intensity that ranged from 51-87% of maximum weight. A significant time by group interaction (p<0.05) was seen for PRO and physiological outcomes including CRF (p=0.01), QoL (p≤0.001), aerobic fitness (p≤0.001) and muscle strength (p≤0.001). Follow-up t-tests showed a significant difference in change between the IEG and DEG from weeks 0-12 (p≤0.001 to p=0.046), and significant differences between groups from weeks 12-24 (p≤0.001 to p=0.050), with no significant differences between groups at baseline or final assessment on any variables.

Conclusion
A 12-week exercise program, whether commenced immediately post treatment or delayed by 12-weeks, resulted in significant statistical (p≤0.05) and clinical improvements in PRO including QoL and CRF, and physiological outcomes, including aerobic fitness, in haematological cancer patients without any exacerbation of symptoms.

Disclosures:
No relevant conflicts of interest to declare.
Yin Yang 1 (YY1) Regulates The Transcription Of The Gene Krüppel-Like Factor 4 (KLF4) In Pediatric Burkitt Lymphoma: Clinical Implications
Authors: Vega Mario I , Valencia-Hipolito Alberto , Hernandez-Atenogenes Miriam , Vega Gabriel G , Mayani Hector , Huerta-Yepez Sara , Bonavida Benjamin , Martinez-Maza Otoniel 
Published: October 2019

Abstract
Krüppel-like factor 4 (KLF4) is a member of the KLF zinc-finger containing transcription factor family. Supporting evidence has established that KLF4 is either an oncogene or a tumor suppressor. Reported studies have indicated the involvement of KLF4 in the regulation of apoptosis, proliferation, and differentiation of B cells and B-cell malignancies. In contrast to adult lymphomas and solid tumors, recently, we have shown in a TMA the overexpression of KLF4 in pediatric NHL tumor tissues. The KLF4 overexpresion predicted unresponsiveness to CHOP treatment. In addition, we have also reported that the transcription factor Yin Yang 1 (YY1) is overexpressed in B-NHL and is a prognostic factor. We hypothesized that the coexpression of KLF4 and YY1 may result from the transcriptional regulation of KLF4 by YY1. This hypothesis was tested in various experimental designs both in cell lines and tumor tissues derived from patients. Analysis of the B-NHL cell line Ramos revealed that both KLF4 and YY1 are overexpressed compared to normal B cells. The transfection of Ramos with siRNA YY1 showed significant inhibition of KLF4. In silico analyses of the KLF4 promoter identified the presence of four putative binding sites for YY1. We confirmed that the -126 site as the binding site for YY1 by CHIP analysis. We also used a reporter system of the KLF4 promoter and mutated the putative binding site for YY1 (-126) and confirmed it as an important site for the regulation of KLF4. The co-expressions of KLF4 and YY1 were examined in TMA of pediatric lymphomas and showed by IHC that all of the tumor tissues exhibited a positive correlation of the expressions of KLF4 and YY1 and the correlation was markedly significant in the Burkitt subtype. These correlations were consistent with the bioinformatics analyses due by ONCOMINE in several data base. KLF4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. In addition, KLF4 suppresses the extrinsic apoptotic pathway by inhibiting the activation and cleavage of caspases (7, 9, and 3). Thus, the overexpression of KLF4 in lymphoma may be responsible, in part, in the pathogenesis, malignancy, and drug resistance. The putative function of KLF4 was examined by the use of chemical inhibitors for KLF4 (Kenpaullone) and inhibition of KLF4 resulted in the inhibition of cell proliferation and the spontaneous induction of apoptosis. The present findings suggest that both KLF4 and YY1 are prognostic biomarkers for pediatric lymphoma and are also potential therapeutic targets.

Disclosures:
No relevant conflicts of interest to declare.
Ofatumumab As Initial Therapy For Indolent B Cell Lymphomas: A Phase II Trial
Authors: Barnes Jeffrey A. , Feng Yang , Hochberg Ephraim P , Takvorian Tak , Weitzman James , Fisher David C. , Jacobsen Eric D. , Joyce Robin , Neuberg Donna S. , Abramson Jeremy S. 
Published: October 2019

Abstract

Background
Single agent monoclonal antibodies (mAb) such as rituximab are an attractive treatment option for patients with low grade B-cell lymphoma given proven efficacy and tolerability. Ofatumumab offers potential advantages over rituximab including increased affinity for the CD20 antigen, increased complement dependent cytotoxicity, and is fully humanized which may predict a lower incidence of infusion reactions. We therefore investigated ofatumumab\as initial therapy for indolent B-cell lymphomas.

Methods
We conducted a phase II trial of ofatmumab monotherapy. Eligible patients were adults with previously untreated indolent B-cell lymphomas including follicular lymphoma grade 1-2, marginal zone lymphoma and small lymphocytic lymphoma. Subjects had to have measurable disease >2cm and not be candidates for potentially curative radiotherapy for localized disease. Ofatumumab was administered as 8 weekly infusions at a flat dose of 1000 mg. The primary end point was complete response rate (CRR) as defined by the International Workshop Response Criteria (1999). Restaging CT scans were performed 4 weeks after the final dose of study drug. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and toxicity. The study was designed with 90% power to show a 50% CRR, with a 30% CRR considered unworthy of further study.

Results
Between March 2011 and December 2012, 42 eligible subjects were enrolled (28 follicular lymphomas, 4 marginal zone lymphomas, and 10 small lymphocytic lymphomas). With 41 of 42 subjects completing all 8 infusions, the CRR was 9.5% with a PRR of 42.9% (ORR of 52%). The median PFS has not been reached at a median follow-up of 9 months. The 12 month PFS was 86% (95% CI [72%, 99%]). One patient died due to progressive disease. There were 22 (52%) grade 1-2 and 7 (17%) grade 3 infusion reactions despite standard pre-medications including acetaminophen, hydrocortisone, and diphenhydramine. There were no cases of grade 3-4 neutropenia.

Conclusion
Ofatumumab did not appear to improve the CRR compared to what would be expected from rituximab in patients with previously untreated indolent B-cell lymphomas. Incidence of infusion reactions was significant with this fully humanized mAb.

Disclosures:
Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of relapsed chronic lymphomcytic leukemia that is refractory to fludarabine and alemtuzumab.
The Expression Of CD200 As a Prognostic Factor In Newly Diagnosed Multiple Myeloma
Authors: Li Yi , Wu Wenjun , He Jingsong , Han Xiaoyan , Zheng Gaofeng , Zi Fuming , Yang Li , Wu Cai , He Donghua , Zhao Yi , Yang Yang , Wang Lijuan , Ye Xiujin , Huang He , Yi Qing , Cai Zhen 
Published: October 2019

Abstract

Introduction
multiple myeloma (MM) is currently an incurable hematological malignancy. Discovering molecular therapeutic targets is a new approach to improve the outcome in the treatment of the malignant disease. As CD200 is a type Ⅰmembrane glycoprotein expressed on myeloma cells, we asked if the expression of CD200 could serve as a prognostic marker for MM patients. Our data indicated that the expression level of CD200 is indeed correlated with the prognosis of the MM patients.

Methods
bone marrow samples from 96 newly diagnosed MM patients from April 2011 to July 2013 were evaluated by flow cytometry, using PE-conjugated anti-CD200 mAb, FITC-conjugated anti-CD138 mAb, and PE-Cy7-conjugated anti-CD45 mAb. PE-or FITC-conjugated normal mouse IgG was used as isotype-matched controls.

Results
96 MM patients were investigated in the present study, including 60 men and 36 women, with a median age of 63 years (range 34–86 years). 81/96(84%) MM patients were CD200 positive with a median Mean Fluorescence Intensity (MFI) of 127 as analyzed by flow cytometry, which was consistent with the previous studies. While in 15 of 96 patients, CD200 expression was undetectable. Among the CD200 positive ones 7.40% patients were classified as stage Ⅰ, 12.35% were stage Ⅱ, and 80.25% were stage Ⅲ according to Durie–Salmon staging criteria. 40.74% patients were stageⅠ, 22.22% were stage Ⅱ, and 37.04% were stage Ⅲ, according to the International Staging System (ISS). Analysis of the CD200 positive patients revealed the MFI<127 group had a better progression free survival (PFS) (p=0.046) (Fig 1A) and overall survival (OS) (p=0.069) compared to those with MFI≥127. In the patients with age ≥65 years old, PFS (p=0.023) (Fig 1B) and OS (p=0.044) (Fig 1C) were much shorter in the MFI≥127 group, compared to the MFI<127 ones.

Conclusions
Our study demonstrated that the expression and MFI of CD200 on primary multiple myeloma cells is correlated with the prognosis of the MM patients. The better PFS and OS were observed in the MFI<127 group compared to the patients with MFI≥127, especially in the patients with age≥65 years old. Improved PFS in CD200 positive ones is likely due to the immune suppression mediated by CD200. Our study suggests that targeting therapy against CD200 may become a new approach to the treatment of MM in clinical practice.

Disclosures:
No relevant conflicts of interest to declare.
Neutrophils Of Multiple Myeloma Are Dysfunctional and Immunosuppressive
Authors: Parrinello Nunziatina , Romano Alessandra , Conticello Concetta , Cavalli Maide , La Fauci Alessia , Rizzo Giuseppina , La Cava Piera , Chiarenza Annalisa , Tibullo Daniele , Giallongo Cesarina , Palumbo Giuseppe A , Di Raimondo Francesco 
Published: October 2019

Abstract

Introduction
Multiple Myeloma (MM) is a plasma cell malignancy with a well documented immune dysfunction. However the role and function of neutrophils in MM and monoclonal gammopathy of undetermined significance (MGUS) has been poorly investigated.

Methods
on neutrophils (N) of 65 MM at diagnosis, 74 MGUS and 30 healthy subjects we evaluated, by flow cytometer, phagocytic activity and surface expression of CD64, CD16, CD62L and CD11b, markers of neutrophil activation. We tested also the immunosuppressive properties of N isolated from MGUS or MM patients, through functional assays, based on in vitro co-culture of N isolated from patients and T-lymphocytes from healthy subjects and we evaluated the expression of the immunosuppressive molecule arginase-1 (Arg-1) by RT-PCR.

Results
Despite no differences in the absolute number of N between MM, MGUS and healthy subjects, we found a functional impairment in MM not evident in MGUS patients.
The phagocytic activity of MM-N was significantly reduced compared to healthy subjects-N (p<0.001) and MGUS-N (p<0.0001) and restored after induction chemotherapy (p=0.02).
Expression of CD64 was significantly elevated in MM-N compared to MGUS-N or healthy subjects-N (p=0.01 and p= 0.007 respectively) and was inversely correlated with phagocytic activity (p=0,01). No differences were observed among MM, MGUS and healthy subjects for the other surface markers evaluated.
MM-N exhibit an increased expression of ARG-1 compared to MGUS and healthy subjects (25.5 vs 6.2 vs 1 fold changes in gene expression, p=0.003), confirmed by functional assay of enzymatic activity of ARG-1, positively correlated with advanced disease. After PHA-P stimulation,T-lymphocytes isolated from healthy subjects missed the expression of activation markers such CD71, CD69, CD25, CD3ζ in the presence of MM-N for 72 hours, and in a less extensive way in the presence of MGUS-N.

Conclusion
Compared to controls, neutrophils obtained from MM patients have a reduced phagocytic activity, a greater expression of Arg-1 and exhibit an immunosuppressive function on T lymphocytes. Taken together, these findings indicated that neutrophils may contribute to impairment of immune function that characterizes MM patients.

Disclosures:
No relevant conflicts of interest to declare.
Both Host-Type and Donor-Type Mast Cells Protect Against Acute Graft-Versus-Host Disease
Authors: Araki Raita , Maeba Hideaki , Kuroda Rie , Mase Shintaro , Fujiki Toshihiro , Ikawa Yasuhiro , Koizumi Shoichi , Yachie Akihiro , Nishimura Ryosei 
Published: October 2019

Abstract
Originally mast cells have been known as effector cells in the IgE-mediated allergic responses. In addition, recent studies demonstrated that mast cells exerted pro-inflammatory or anti-inflammatory effects in complicated immune response depending on the situation. In allogeneic hematopoietic stem cell transplantation (HSCT), exact role of mast cells in graft-versus-host disease (GVHD) remains unclear. First we investigated whether host mast cells protect acute GVHD or not in a murine HSCT model using mast cell deficient mice. When lethally irradiated wild type (WT) B6 or mast cell deficient mice were transplanted with bone marrow cells and spleen cells from WT Balb/c mice, mast cell deficient B6 host mice showed significantly lower survival rate than WT B6 mice (p<0.01) due to acute GVHD. Moreover when irradiated mast cell deficient host mice (B6 derived) were given BM cells and splenocytes from mast cell deficient Balb/c mice, these mice died much faster compared to the mice receiving WT BM plus splenocytes (p<0.01) as shown below. Next, we demonstrated that bone marrow derived cultured mast cells (BMCMCs) inhibited mixed lymphocyte reaction (MLR) in a dose-dependent manner, when added to the coculture (Stimulator: dendritic cells (DCs) from B6, Responder: spleen cells of Balb/c, BMCMCs from B6). In addition when mast cells generated from the same strain of responder cells (Stimulator: DCs from B6, Responder: spleen cells from Balb/c, BMCMCs from Balb/c) were added to the MLR mixture, MLR was also suppressed even in this condition. Taken together, we have clearly demonstrated that both host-type and donor-type mast cells suppressed alloreaction in vivo and in vitro. However when we used anti-CD3 and anti-CD28 monoclonal antibodies to stimulate T-cells instead of DCs, BMCMCs could not suppress the lymphoproliferation any more. It suggested that mast cells could suppress MLR via the regulation of DCs directly, not T-cells. Next we have shown that BMCMCs dominantly regulated the alloreaction in a cell contact-dependent manner by using transwell system, though mast cells contain many kinds of substances to regulate immune reactions such as IL-10. DCs highly expressed costimulatory molecules such as CD80, CD86, CD40, I-A, however expression level of these molecules was not changed during coculture of BMCMCs and DCs. Finally, we compared the MLR suppression rate between naïve and activated BMCMCs using IgE and specific antigens, however no difference was observed between them. In conclusion, both host and donor-type mast cells have a protective role against acute GVHD.

Disclosures:
No relevant conflicts of interest to declare.
New Interleukin-15 Superagonist (IL-15 SA) Significantly Enhances Graft-Versus-Tumor Activity After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Bailey Cavan P , Sauter Christopher , Panis Michelle M , Budak-Alpdogan Tulin , Wong Hing , Flomenberg Neal , Alpdogan Onder 
Published: October 2019

Abstract
Interleukin-15 (IL-15) is a pleiotropic cytokine, which plays various roles in the innate and adaptive immune system, including the development, activation, homing and survival of immune effector cells. IL-15 has been previously shown to increase CD8+ T and NK cells number and function in normal mice and recipients of stem cell transplantation. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To overcome this, a new IL-15 mutant (IL-15N72D, J. Immunol, 2009; 183:3598) has been developed, with increased biological activity. Co-expressing IL-15N72D, in conjunction with IL-15RαSu/Fc produced a biologically active and highly potent IL-15 superagonist complex (IL-15SA, also known as ALT-803, Cytokine, 2011; 56:804). We evaluated the effects of IL-15-SA on immune reconstitution and graft-versus-tumor (GVT) activity in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Lethally irradiated BALB/c recipients were transplanted with T-cell depleted (TCD) bone marrow (BM) cells from B6 mice. IL-15 SA was administered via IP injection in two doses on days +17 and +24 after transplant. Animals were sacrificed at day 28. Administration of IL-15 significantly increased the numbers of CD8+ T cells and NK cells. IL-15 SA also augmented interferon-γ secretion from CD8+ T cells. We observed similar activity in B6CBA→CB6F1 transplant model. Interestingly IL-15 SA upregulates NKG2D and CD107a expression on CD8+ T cells. IL-15 SA administration also specifically increased slow-proliferative CD8+ T-cell proliferation in conjunction with robust IFN-γ and TNF-α secretion in CD8+ T cells in recipients of CFSE (carboxyfluorescein succinimidyl ester) labeled-T-cell infusion, whereas there was no effect on CD4+ T-cell proliferation. We then tested the anti-tumor activity of IL-15 SA in three different tumor models; murine mastocytoma (P815), murine B cell lymphoma (A20) and murine renal cell carcinoma (Renca). We found that IL-15 SA administration enhanced GVT activity against P815 and A20 in recipients of allogeneic HSCT though this activity required a low-dose T cell infusion with HSCT. Interestingly, augmented GVT activity against to Renca after IL-15 SA administration in recipients of allogeneic HSCT did not require T cell infusion.
We conclude that IL-15 SA is a very potent cytokine complex for enhancing CD8+ and NK cell reconstitution and function after HSCT, which would be a candidate for post-transplant immunotherapy.

Disclosures:
Wong: Altor Bioscience: Employment.