bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapy for Chronic ITP in Germany - A Patient Survey.
Authors: Matzdorff Axel C. , Arnold Gabriele , Salama Abdulgabar , Ostermann Helmut , Hummler Simone 
Published: October 2019

Abstract
Abstract 4471

Background
Guidelines recommend glucocorticoids and splenectomy as standard 1st and 2nd line treatments for chronic ITP. We sought to find out how German ITP-patients are treated in respect of these guidelines.

Methods
Members of a patient support association >18 y with self-reported history of chronic ITP (>6 mo) were surveyed. A questionnaire was developed from literature review with clinician and patient input, and administered on-line.

Results
123 questionnaires were evaluated. Age (median 51 years) and gender distribution (38% m, 62% f) are comparable to surveys from other countries. 70% of patients had chronic ITP for more than 5 years and 50% a “usual” platelet count of < 50.000/μl (20% < 30.000/μl). 69% had hematomas or petechiae within the last 12 months, 45% had oropharyngeal bleeds, and 11% had been admitted to a hospital within this year. 88% had received or receive glucocorticoids, 28% were splenectomized. IVIg was given to 55%, rituximab to 22%, anti-D to 11%, cyclosporine to 7%. Complementary and alternative medical treatments had been used by 36%. 38 women were under the age of 50 and 14 (36%) reported that they had been advised not to become pregnant. 23 became pregnant and 10 (44%) required ITP-treatment during their pregnancy.

Conclusion
Glucocorticoids are the most common therapy for chronic ITP but complementary and alternative treatments already come second and less than 1/3 of the patients are splenectomized. This and the frequent use of complementary medicines suggests dissatisfaction with conventional therapeutic approaches. Many patients receive off-label therapies (rituximab, anti-D, cyclosporine are not licensed for ITP in Germany). There is a major need for adequate counseling and care for pregnant ITP-patients.

Disclosures:
Matzdorff: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Honoraria. Off Label Use: Rituximab for chronic ITP Complementary medicines for ITP. Hummler:GlaxoSmithKline: Employment.
Short-Term Inhibition of p53 Combined with Keratinocyte Growth Factor Improves Thymic Epithelial Cell Recovery and Enhances T-Cell Reconstitution After Murine Bone Marrow Transplantation.
Authors: Kelly Ryan , Goren Emily , Taylor Patricia , Scott Hamish S , Komarova Elena , Gudkov Andrei , Hollander Georg A. , Blazar Bruce R. 
Published: October 2019

Abstract
Abstract 4485
Myeloablative conditioning prior to bone marrow transplantation (BMT) results in thymic epithelial cell (TEC) injury, T cell immune deficiency, and susceptibility to opportunistic infections. Conditioning regimen-induced TEC damage directly contributes to slow thymopoietic recovery following BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given prior to conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BMT recipients. Therefore, we investigated whether the addition of a pharmacological inhibitor, PFT-β to transiently inhibit p53 during radiotherapy could spare TEC from radiation-induced damage in congenic and allogeneic BMT. The combined pre-BMT administration of KGF plus PFT-β additively restored numbers of cortical and medullary TEC and improved thymic function post-BMT, resulting in higher numbers of donor-derived, naïve peripheral CD4+ and CD8+ T-cells. Improved T-cell reconstitution correlated with enhanced recovery of fibroblastic reticular cells in the lymph node stromal compartment, and a superior immune response against L. monocytogenes infection. Thus, transient p53-inhibition combined with KGF represents a novel and potentially translatable approach to promote rapid and durable thymic and peripheral T-cell recovery following BMT.

Disclosures:
No relevant conflicts of interest to declare.
Synthetic Retinoid Am80 Ameliorates Chronic Graft-Versus-Host Disease.
Authors: Nishimori Hisakazu , Sugiyama Haruko , Kobayashi Koichiro , Yamasuji Yoshiko , Kondo Eisei , Shinagawa Katsuji , Tanimoto Mitsune , Takeuchi Kengo , Maeda Yoshinobu 
Published: October 2019

Abstract
Abstract 4487
Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including those for contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis. We hypothesized that the administration of ATRA or Am80 could modulate cGVHD. BALB/c (H-2d) mice were subjected to sublethal irradiation and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells from major histocompatibility complex-matched, multiple minor histocompatibility antigen-mismatched B10.D2 (H-2d) mice. Then, the mice were given oral ATRA (200 μg/body), Am80 (1.0 mg/kg body weight), or vehicle daily, beginning from day 0. ATRA slightly decreased the clinical cGVHD score, whereas Am80 significantly reduced the score (Table). When administered daily, Am80 decreased the clinical score beginning from day 21, as in a treatment setting (data not shown). Histopathological examination of the skin showed significantly reduced GVHD pathology in recipients of Am80 (Table). Flow cytometry analysis of the peripheral draining lymph nodes on day 16 showed significant reductions in IFN-γ+, IL-17+, and Foxp3+ cells in Am80-treated recipients compared to controls (Table), whereas no reduction in IL-13+ cells was observed. Cytometric bead arrays and enzyme-linked immunosorbent assays (ELISA) revealed decreased levels of the cytokines IFN-γ, IL-17, TNF-α, and IL-6 in the supernatant of peripheral lymph nodes from Am80-administered recipients (data not shown). Real-time RT-PCR of ears from these recipients on day 21 showed that the administration of Am80 reduced the expression of Foxp3 and TGF-β (Table and data not shown). Therefore, the administration of retinoids ameliorates cGVHD by reducing Th1 and Th17 inflammatory cytokines and the fibrosis factor TGF-β. Thus, treatment with retinoids may be effective for prophylaxis and treatment of cGVHD.

Disclosures:
No relevant conflicts of interest to declare.
Vav3 and Rac2 Activation Are Required for B Progenitor Transformation Induced by p190-BCR-ABL.
Authors: Chang Kyung-Hee , Sanchez-Aguilera Abel , Sengupta Amitava , Arnett Jorden , Dunn Susan , Williams David A , Cancelas Jose 
Published: October 2019

Abstract
Abstract 449
The Philadelphia chromosome-positive (Ph+) hematologic malignancies are characterized by the reciprocal translocation between the BCR serine/threonine kinase and the ABL tyrosine kinase genes. Fifty percent of adult B-cell Ph+ acute lymphoblastic leukemia (B-ALL) and most cases of pediatric Ph+ B-ALL express the p190 BCR-ABL isoform, which causes abnormal expansion of lymphoid progenitors and a poor prognosis despite the administration of tyrosine kinase inhibitors. A major signaling pathway activated by BCR-ABL is the Rac/Rho GTPase signaling pathway. We had previously demonstrated that p210-BCR-ABL activates Rac GTPases and the deficiency of Rac2, or even more, the deficiency of both Rac1 and Rac2, impairs myeloid leukemogenesis induced by p210 BCR-ABL in vitro and in vivo (Thomas EK et al., Cancer Cell 2007). The p190-BCR-ABL isoform also activates Rac GTPases and the deficiency of Rac2 induces resistance to develop proB-ALL (Sanchez-Aguilera et al., ASH 2008). Since p190-BCR-ABL is devoid of guanine nucleotide exchange factor (GEF) activity through the absence of the BCR Dbl-homology (DH) domain, it probably requires the recruitment of intermediate GEFs to activate Rac GTPases. The Vav family of GEF has been shown to bind the SH3/SH2 domains of ABL and become activated. Three isoforms of Vav (Vav1, Vav2 and Vav3) are expressed in hematopoietic cells. Several studies have indicated that Vav3 has a role distinct from Vav1 or Vav2. Here, we hypothesized that the hematopoietic specific Rho GTPase, Rac2, may mediate key signals in the transformation of B-cell progenitors upon Vav-mediated activation. We have found that both Vav1 and Vav3 are overexpressed and hyperphosphorylated in p190 BCR-ABL expressing human B-ALL cells as well as in BCR-ABL transduced murine proB cells. While the combined deficiency of Vav1 and Vav2 does not impair leukemogenesis in vivo, Vav3 deficiency reverses p190-BCR-ABL induced transformation phenotypes. Specifically, Vav3 deficiency in p190-BCR-ABL expressing proB-ALL cells associated with a significant reduction of Rho and Rac activation (75% and 56%), apoptosis induction (4-fold) and impaired ex-vivo expansion (33% reduction). In addition, p190-BCR-ABL-induced adhesion-to-fibronectin defect and hypermigratory response to CXCL12 were corrected by deletion of Vav3 (2.1-fold increase and 60% decrease, respectively), suggesting that Vav3 deficiency reverses the transformation-associated phenotype associated to BCR-ABL expression. Collectively, our work identifies a critical role of Rac2 and its activator Vav3 for p190 BCR-ABL induced B-cell progenitor leukemic transformation and may define a novel therapeutic target for this poor prognosis disease.

Disclosures:
Cancelas: CERUS CO: Research Funding; CARIDIAN BCT: Research Funding; HEMERUS INC: Research Funding.
Improving Tumor Immunotherapy by Using Distinct Subpopulations of the γδT Cell Repertoire with High Anti-Tumor Reactivity.
Authors: van Dorp Suzanne , Hol Samantha , Marcu-Malina Victoria , Thuss Nicole , Lokhorst Henk , Kuball Juergen 
Published: October 2019

Abstract
Abstract 4504

Introduction
Currently innate immune cells such as γ9δ2T cells are explored in tumor immunotherapy e.g. by adoptive transfer of in vitro expanded bulk γ9δ2T cells.

Objective
We speculated that γ9δ2T cells are highly variable in function and specificity due to differences in γ9δ2TCR, NKG2D and KIR expression and that efficacy of adoptively transferred γ9δ2T cells can be increased by transfer of defined subpopulations or clones rather than bulk γ9δ2T cells.

Methods
A variety of γ9δ2T cell clones, derived from a healthy donor, were tested for expression levels of γ9δ2TCR, NKG2D and KIRs by flow cytometry analysis. The sequence of the γ9δ2TCR of different clones was further analyzed. Reactivity of γ9δ2T cell clones to a panel of tumor and normal cell lines was tested and these functional analyses were correlated to receptor expression levels and compared with bulk γ9δ2T cells of the same donor.

Results
Functional analyses revealed a high interclonal variability in recognizing leukemia or solid tumor cell lines. Consequently, γ9δ2T cell clones with high anti-tumor reactivity were superior in killing tumor cells when compared to bulk γ9δ2T cells. Different variable regions of γ9δ2-chains and different expression levels of NKG2D and KIRs were detected in multiple clones. No correlations could be found between TCR, NKG2D, and KIR expression on γ9δ2T cell clones and their response to different tumor cell lines when clones expressed different γ9δ2TCRs. However, analysis of γ9δ2T-cell clones with identical γ9δ2TCRs revealed that a clone with higher reactivity against cancer cells expresses higher amounts of NKG2D and lower inhibitory KIRs when compared to a clone with lower reactivity.

Conclusion
γ9δ2TCR, NKG2D and KIR expression in γ9δ2T cells is highly variable and cannot be directly correlated to an effective anti-tumor response. Only, when T-cells express one defined γ9δ2TCR, a modulating activity of NKG2D and KIRs can be observed. Thus, we conclude that anti-tumor reactivity is fine tuned by all three receptors and thereby we speculate that the γ9δ2TCR defines tumor-specificity and activity is further modulated by NKG2D and KIRs. These results support the application of distinct subpopulations or of genetically engineered γδT cells with defined receptors rather than bulk γ9δ2T cells in the context of anti-tumor immunotherapies.

Disclosures:
No relevant conflicts of interest to declare.
Microvesicle Mediated Genetic Phenotype Modulation.
Authors: Aliotta Jason M , Pereira Mandy , Dooner Mark , Dooner Gerri , Ramratnam Bharat , Lee David , Johnson Kevin , Hixson Douglas , DePaz Nicole , Berz David , Josic Djuro , Brilliant Kate , Quesenberry Peter J. 
Published: October 2019

Abstract
Abstract 4509

Objective
We have previously reported that lung-derived microvesicles (MVs) can enter target marrow cells, resulting in increased levels of lung-specific mRNAs (Stem Cells 25:2245, 2007). Marrow cells which have been exposed to MVs also show increased production of pulmonary epithelial cells after transplantation into irradiated mice. The present studies have addressed the universality of the mRNA modulation and the underlying mechanisms.

Methods/Results
Co-culture of heart, brain, liver, and lung tissue across from murine marrow, but separated by a 0.4 micron cell-impermeable membrane, show tissue specific elevations of mRNA. MVs were found to contain lung-specific mRNA and 200 microRNAs. Proteomic studies of MVs showed up to 75 individual proteins, some of which are known to be associated with MV biogenesis and trafficking. Studies using rat/mouse hybrid cultures demonstrated that the target cell induced lung-specific mRNA elevations were mediated by transcriptional mechanisms. In these experiments, rat lung was co-cultured across from murine marrow cells and RT-PCR was performed using rat or mouse-specific primers for surfactant B. High levels of rat-specific surfactant B were seen in the co-cultured marrow cells indicating that transcription had been induced in the target cells. These conclusions were supported by additional studies employing the transcription factor inhibitors actinomycin-D and alpha-amantin. RNase treatment of conditioned media prior to marrow cell co-culture suggested that transfer of RNA may be involved in these mRNA elevations. However, our transcriptional studies indicate that we are not observing a simple transfer of MV lung-specific mRNA. One possible mechanism may be transfer of microRNA with epigenetic changes resulting in lung-specific mRNA production.

Conclusion
In summary, these observations suggest the existence of unique pathways for information transfer and cell phenotype determination. MV transfer could represent an underlying mechanism for much of the previous reported stem cell plasticity in different tissues.

Disclosures:
No relevant conflicts of interest to declare.
Human Granulocytic Anaplasmosis: a Case Report and Review of Literature.
Authors: Ouyang Jian , Zhang Qiguo , Xu Jingyan , Chen Bing , Zhou Rong-Fu 
Published: October 2019

Abstract
Abstract 4518

Purpose
To discuss the clinical and laboratory features, diagnosis and treatment of human granulocytic anaplasmosis.

Methods
We present the clinical and laboratory features, diagnosis and treatment of a patient with human granulocytic anaplasmosis.

Case presentation
The patient with human granulocytic anaplasmosis presented with fever,cough?Adiarrhea?Amyalgia?Afacies typhosa?Arelative infrequent pulse and swelling of lymph nodes. Laboratory examination showed the patient had leukopenia?Athrombocytopenia?Aproteinuria?Aliver injury?Ablood clotting abnormal?AEBV-DNA positive. We also found the patient's ferritin?Acreatase?Aamylase and lipase increased. In the patient's bone marrow, plasma cells were increased, hemophagocyte and intragranulocytic inclusions were found. The patient did not respond to the treatment of imipenem, cefepime hydrochloride and teicoplanin. But he was treated successfully with moxifloxacin.

Conclusion
Patient with human granulocytic anaplasmosis can present leukopenia, thrombocytopenia, blood clotting abnormal and plasma cells increased in bone marrow. It's quite necessary to make differential diagnosis with some blood diseases. The patient can be accompanied with EBV infection and hemophagocytic syndrome. The patient can be cured by antibiotics-quinolones.

Disclosures:
No relevant conflicts of interest to declare.
Two-Dimensional Speckle Strain for Evaluation of Left Ventricular Systolic Deformation in Children with Thalassemia Major.
Authors: Abd Rab-Rassol Tolba Osama , El-Shanshory Mohamed Ramadan , Hagag Adel Abd El-Halum 
Published: October 2019

Abstract
Abstract 4520

Objective
In β-thalassemia major, Identifying early myocardial insult is important since significant cardiac involvement may predate a decrease in left ventricular systolic functions. The aim of this study is to clarify the value of 2 D-strain (2DS) in early detection of segmental and global left ventricular systolic dysfunction in thalassemic children.

Subjects and Methods
This study included two age-matched groups:Group 1 (n=30) thalassemic children and Group 2 (n=10) healthy control children. They undergo conventional echo-Doppler measures of left ventricular (LV) systolic and diastolic functions. The pulsed tissue Doppler of lateral mitral annulus was recorded. Longitudinal 2D strain in 18 left ventricular segments using 2 dimensional (2DS) speckle-tracking imaging from apical 4, 2, and 3-chamber views, using a Vivid 7 ultrasound system. The images were analyzed using Echopac soft ware.

Results
There was no significant difference among thalassemic patients and controls in LV fraction shortening, peak systolic and diastolic tissue velocities of lateral mitral annulus. But by the 2 D strain study there were a significant multi-segmental affection of the LV mainly the posterior, anterior walls with predilection mainly to the apical segments, also there was a significant affection of the peak global LV systolic strain with a median value (-17.7 versus -20.75; P = 0.008.). There was no significant correlation between all segmental or global LV systolic strain and the serum ferretin.

Conclusion
2DS is a sensitive and accurate tool for early detection of segmental and global cardiac insult in thalassemic children.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Usefulness and Safety of Peripherally-Inserted Central Catethers (PICC) in Hematological Patients.
Authors: Morano Giacomo Salvatore , Mercanti Caterina , Federico Vincenzo , Matturro Angela , Micozzi Alessandra , Latagliata Roberto , Breccia Massimo , Girmenia Corrado , Brunetti Gregorio Antonio , Berneschi Paola , Giampaoletti Massimo , Foà Robin , Alimena Giuliana 
Published: October 2019

Abstract
Abstract 4545
The use of Peripherally-Inserted Central Catheters (PICC) as an alternative to Central Venous Catethers (CVC) is becoming very frequent in different setting of patients. To highlight the role of PICC also in patients with haematological malignancies, we revised our single Institute experience from 11/2008 to 7/2009. On the whole, 33 PICCs (BARD Groshong 4 Fr) were inserted in 32 patients [M/F 11/21, median age 59.9 years, Interquartile Range (IR) 47.1 – 74.7] for a total number of 1979 days. Twelve patients had Acute Myelogenous Leukemia (AML), 3 Acute Lymphoblastic Leukemia (ALL), 6 Non-Hodgkin Lymphoma (NHL), 5 Hodgkin Lymphoma (HD), 6 Myelodysplastic/Myeloproliferative Disorders (MDS/MPD); as to disease phase, 6 patients were at onset, 10 in complete response (3 before consolidation therapy and 7 before autologous peripheral stem-cell transplantation), 5 at disease relapse, 7 in chronic phase with transfusional requirement and 4 in advanced phase. PICC was successfully inserted in all cases with US-guide (in 21 cases via basilica vein, in 11 via brachial vein and in 1 via cephalic vein). At insertion, platelets count was < 50 × 109/l in 17/33 cases (51.5%) while WBC count was < 1.0 × 109/l in 6/33 cases (18.1%). An accidental PICC extraction occurred after 13 days; in addition, there were 2/33 (6.0%) (0,03/1000 gg) thrombophlebitic complications after 15 and 21 days respectively and 6/33 (18.1%)(0.10/1000 gg) infective complications [4 sepsis catheter-related from Staphylococci (3) or Acromobacter (1) and 2 local flogistic infiltration]. On the whole, 17/33 PICCs (51.5%) were removed after a median period of 39 days (IR 17 – 64); the reasons for removal were completion of treatment in 4 patients, death unrelated to the PICC in 6 and catheter-related complications in 7 (5 for infection, 1 for thrombosis and 1 for accidental extraction). The remaining 16/33 PICCs (48.5%) are still in use after a median period of 73 days (IR 30 – 93). In conclusion, PICC seems to be a useful, safe and promising alternative to conventional CVC for many haematological malignancies in a wide spectrum of clinical settings, ranging from intensive chemotherapy (including autotransplant procedure) to chronic management and very advanced phases requiring palliative approach.

Disclosures:
No relevant conflicts of interest to declare.
Cost-Effectiveness of Targeted Cancer Therapies for Hematological Malignancies.
Authors: Topaloglu Ozlem , Stevens Chuck , Aggarwal Saurabh 
Published: October 2019

Abstract
Abstract 4547
Targeted cancer therapies for hematological malignancies have rapidly gained uptake in different types of indications, and some have become gold standard of treatment. However, the high cost of these therapies poses challenges for payers, patients and physicians.

Methods
To understand the cost-effectiveness of these new classes of drugs we reviewed the published cost-effectiveness studies and analyzed their cost/QALY, time horizon, comparators, indications and model approaches.

Results
Targeted therapies for hematological cancers have much lower and less variable cost/QALY than branded drugs indicated for solid tumors. For example, incremental cost effectiveness ratio (ICER) for imatinib ranges from $40,000 to $45,000/QALY, while ICER for bevacizumab ranges from $125,000 to $325,000/QALY. Secondly, the choice of comparator in some occasions may depend on the country of use, therefore models are required to be customized to local regimens. In one of the cost-effectiveness analysis for bortezomib for refractory multiple myeloma patients, NICE questioned the use of high dose dexamethasone (HDD) as comparator. Third, there is also some variability in methods used by different manufacturers, some used cost/QALY whereas others used cost/LYG. Conclusion: This analysis shows the range, variability and methods used for calculation of ICER values for these targeted cancer therapies and provides lessons for executives and policy makers.

Disclosures:
No relevant conflicts of interest to declare.