bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic Stem Cell Transplantation in Angioimmunoblastic T-Cell Lymphoma (AITL): A Retrospective Survey from the Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT).
Authors: Kyriakou Charalampia , Canals C. , Taghipour G. , Finke J. , Kolb H. , Goldstone A. , Sureda A. , Schmitz N. 
Published: October 2019

Abstract
AITL is a rare peripheral T-cell lymphoma characterised by an aggressive behaviour, which primarily affects the elderly. Chemotherapy regimens fail to alter the high relapse rate and overall survival hardly exceeds 25% at 5 years. To date, there is no information on the potential role of allogeneic stem cell transplantation (allo-SCT) in the management of AITL. We report the outcome of 39 patients with a median age of 47 years (24–68), who underwent an allo-SCT between 1995 and 2004 for AITL, and were reported to the EBMT registry. The median time from diagnosis to transplant was 10 months (4–72). Thirty-four patients (87%) had previously received two or more treatment lines, and 16 patients (41%) a previous autologous SCT. Fifteen patients (38%) had a primary refractory disease, 13 (33%) were transplanted in partial remission and the remaining patients were in complete remission (CR) (mostly in 2nd and 3rd CR). Twenty-four patients were transplanted from an HLA-identical sibling and 15 from a matched unrelated donor. A myeloablative conditioning regimen (MAC) was used in 21 patients (cyclophosphamide + total body irradiation in 14), while 18 patients received fludarabine-based reduced intensity conditionings (RIC). Peripheral blood was the source of stem cells in 35 patients (90%). Three patients failed to engraft (one patient in the RIC group). Twenty-one patients (54%) developed acute graft versus host disease (grade I-II, n=16; grade III-IV, n=5). Twenty-eight patients (72%) achieved a CR after the allogeneic procedure. Nine patients died from transplant related mortality (TRM) and 5 patients from disease progression. The cumulative incidence of TRM at 12 months was 19% for the MAC and 26% for the RIC group. After a median follow-up for the surviving patients of 20 months (6–74), 25 patients are alive. Relapse rates at 1 and 3 years were estimated at 10% and 18% for the MAC and 16 and 20% for the RIC patients. Progression free survival rates at 3 years were 67% and 50% and the overall survival at the same time 71% and 56% for the MAC and RIC group of patients, respectively. Although follow up is rather short, these data suggest that allo-SCT results in good overall response and is associated with a low relapse rate in this group of poor risk heavily pre-treated and rather elderly group of AITL patients. Allo-SCT could be considered a therapeutic option for eligible high-risk AITL patients. Nevertheless, the impact of this approach should be further explored in prospective collaborative studies.
Once Daily YM150, an Oral Direct Factor Xa Inhibitor, for Prevention of Venous Thromboembolism in Patients Undergoing Elective Primary Hip Replacement.
Authors: Eriksson Bengt I. , Turpie Alexander G.G. , Lassen Michael R. , Prins Martin H. , Agnelli Giancarlo , Kälebo Peter , Wetherill Graham , Meems Lambertus 
Published: October 2019

Abstract
YM150 is an orally active direct FXa inhibitor in clinical development. Proof of concept of YM150 was previously obtained in a dose escalation study, demonstrating a statistically significant dose-related trend in VTE prevention in patients undergoing total hip replacement (ONYX; J Thromb Haemost2007;5:1660–5). The present study with YM150 is a double blind, parallel, multi-center dose finding study in patients undergoing elective primary hip replacement surgery, with open label enoxaparin as control. Patients were randomly treated with 5, 10, 30, 60 or 120 mg YM150 once daily orally or 40 mg enoxaparin once daily subcutaneously. Patients were treated in hospital for approximately 1–2 weeks followed by home treatment for another 4 weeks, for in total 33–38 treatment days (prolonged treatment for hip replacements according to guidelines of Am. College of Chest Physicians (Geerts et al. Chest2004:126;338–400)). The administration of YM150 started 6–10 h after surgery, while treatment with enoxaparin started 12 ± 2 h before surgery. Mandatory bilateral venography was performed after 7–10 days of treatment. Follow up visits were performed at 2 and 4 weeks during home treatment, and 2, 4, and 8 weeks after end of study treatment. The sample size was estimated to be 960 randomized patients in order to yield 110 patients per treatment group with an evaluable venogram. The primary efficacy endpoint was defined as deep vein thrombosis, and/or symptomatic VTE and/or death, and primary safety endpoint as the incidence of major bleeding during the first 7–10 days of study treatment. Secondary efficacy endpoints were proximal and distal DVT (during the first 7–10 days) and symptomatic VTE during home treatment, and follow up. Secondary safety endpoints were the incidences of major, clinically relevant non-major (CRNM) and minor bleeding during the three study periods. Independent Adjudication Committees reviewed all venograms, bleeding reports, symptomatic VTEs, and deaths unaware of treatment allocation. An independent DSMB monitored the data to ensure the safety of the patients. 1017 patients were randomized from 81 sites in 17 European countries. Preliminary data showed that DVT was detected in 149 out of 727 evaluable venograms, one patient had symptomatic VTE, and one patient died (myocardial infarction) during the hospital treatment period. This results in a total primary efficacy outcome rate of 20.7% (151/729) in the evaluable study population, with a corresponding rate of major bleeding of 0.6% (6/1017). The breakdown of the results according to treatment group will be presented.
Subcutaneous Alemtuzumab (MabCampath) in Fludarabine-Refractory CLL (CLL2H Trial of the GCLLSG).
Authors: Stilgenbauer Stephan , Winkler Dirk , Bühler Andreas , Zenz Thorsten , Groner Silja , Busch Raymonde , Hensel Manfred , Dührsen Ulrich , Finke Jürgen , Dreger Peter , Jäger Ulrich , Lengfelder Eva , Trümper Lorenz , Söling Ulrike , Schlag Rudolf , Hallek Michael , Döhner Hartmut 
Published: October 2019

Abstract
Fludarabine-refractory CLL has a poor prognosis with a median overall survival time of less than 12 months despite salvage chemotherapy and intravenous alemtuzumab (Campath-1H) is the approved treatment based on a remission rate of 33% and a median survival time of 16 months (Keating et al., Blood 2002). The CLL2H trial of the GCLLSG was initiated to evaluate the subcutaneous application of 3 × 30 mg alemtuzumab weekly in fludarabine refractory CLL. The current analysis is based on 109 consecutive patients enrolled until completion of the trial in April 2006. Median age was 63 (36–81) years, 71% were male. A median number of 3 (1–9) prior lines of therapy had been given. Subcutaneous treatment was performed on an outpatient basis in all cases and had to be temporarily interrupted in 68 patients due to neutropenia (43%), anemia (6%), thrombocytopenia (3%), infections (40%, CMV reactivations 30%), and was stopped early in 63 cases due to insufficient response (44%), hematotoxicity (16%), infection (17%), and CMV reactivation (13%). The median alemtuzumab dose given was 722 (3–2203) mg. Toxicity was mostly grade I/II apart from hematotoxicity (grade III/IV anemia: 42%, thrombocytopenia: 52%, neutropenia: 54%) and grade III/IV infections (25%). After a median follow up time of 21.4 months, 56 deaths have occurred (due to progression 52%, infections 39%, not CLL related 9%). The overall response rate was 33% (CR 4%, PR 27%), the median progression free survival time was 7.7 months, and median overall survival time was 19.1 months. Genetic high-risk factors were present in the vast majority of cases (unmutated VH 66%, 17p–29%, 11q–19%, TP53 mutation 39%). Responses (CR or PR) were observed in 22% of VH unmutated, 24% of 11q-, 39% of 17p-, and 33% of TP53 mutated cases. Progression free survival and overall survival were not significantly different when comparing the genetic subgroups, particularly TP53 mutated, 11q-, and 17p- (see figure). In conclusion, subcutaneous alemtuzumab is feasible in an outpatient setting in a high-risk population of fludarabine-refractory CLL and appears to be of similar efficacy as by intravenous administration. Most importantly, genetic high risk subgroups with unmutated VH, 11q- or 17p- appear to respond to alemtuzumab.
Figure Figure
Cytotoxicity of the Type 4 Phosphodiesterase Inhibitor CD160130 for Freshly Isolated Human CLL Cells In Vitro.
Authors: Weinberg J. Brice , Jiang Ning , Volkheimer Alicia D. , Chen Youwei , Bond Karen M. , Moore Joseph O. , Gockerman Jon P. , Diehl Louis F. , de Castro Carlos M. , Rizzieri David A. , Levesque Marc C. , Mugridge Kenneth , DeAngelo Joe 
Published: October 2019

Abstract
B cell chronic lymphocytic leukemia (CLL), the most common subtype of leukemia in the United States of America and in Europe, is treatable but incurable. New drugs are needed for its management. Phosphodiesterase inhibitors (PDEi) block catabolism of cyclic nucleotides resulting in accumulation of cellular cAMP and cGMP. These PDEi also decrease production of inflammatory cytokines such as tumor necrosis factor. Furthermore, they inhibit expression of inducible nitric oxide synthase (NOS2) mRNA and NO production. Researchers have previously noted that nonspecific PDE inhibitors such as theophylline as well as a relatively specific PDE4 inhibitor (rolipram) cause CLL cell death in vitro, while relatively sparing normal peripheral blood mononuclear cells (PBMC). The purpose of this study was to evaluate the effectiveness of CD160130 in the killing of freshly isolated CLL cells in vitro. CD160130 is a novel, orally available heterocyclic pyrimido-indole derivative that is relatively PDE4-specific. Patients were from the V.A. and Duke University Medical Centers, and normal controls were from the community. Control normal PBMC were isolated by ficoll-Hypaque centrifugation, and CLL cells were purified using negative selection with antibodies. We determined cytotoxicity using the MTS colorimetric assay. Samples from 10 CLL patients (6 male and 4 female) and 10 normal controls were examined. Nine of 10 patients were stage 0 at presentation, and 1 was stage 2. They had been followed 6.1 yr (median; range 0.7–19.1 yr). One of 10 was CD38 positive, and 6 of 10 were Zap-70 positive. Of nine analyzed, one had unmutated IgVH gene, and 9 were mutated. Six patients had not been treated, and 4 had been treated with chlorambucil, fludarabine, and/or rituximab. Four had normal cytogenetics by FISH analysis; one had trisomy 12; three had 13q14 del; and one had 17p del. Of seven determined, two had elevated CLL cell lipoprotein lipase mRNA elevated. CD160130 induced cell death in a dose-dependent fashion in all patients’ samples, with a mean cytotoxicity of 96% at 12.5 uM. The mean ED50 for killing was 233 nM in media with FBS and 314 nM in serum-free medium, while that for PBMC was higher at 7500 nM with FBS and 5210 nM with serum-free medium. The agent was 32.2 fold more potent for killing of CLL cells compared to PBMC in medium with FBS and 16.6 fold more potent for CLL cells in serum-free medium. In summary, the PDE4 inhibitor CD160130 potently kills freshly isolated CLL cells in vitro in the presence or absence of serum. The killing is relatively selective for CLL cells compared to normal PBMC. In vivo trials of CD160130 in patients with CLL should help determine the toxicity and efficacy in patients.
Neutralization of Tumor-Derived Soluble Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand Present in Cancer Patient Sera Increases Anti-Tumor Reactivity of NK Cells.
Authors: Baltz Katrin M. , Krusch Matthias , Baessler Tina , Bringmann Anita , Kanz Lothar , Brossart Peter , Salih Helmut R. 
Published: October 2019

Abstract
Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while tumor cells express GITRL, and GITR-GITRL interaction downregulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Many TNF family members are released as soluble forms, which affects cell-cell interactions by reduction of ligand density and distally modulates effector cells bearing the respective receptor. Here we report that human tumor cells spontaneously release a soluble form of GITRL (sGITRL), which can be detected in tumor cell culture supernatants by ELISA (detection limit 0.01ng/ml). We demonstrated that NK cell cytotoxicity and IFN-γ production in cocultures with the tumor cell lines SK-Mel (Melanoma), PC-3 (prostate), HCT116 (colon), and LX-1 (lung) were significantly (both p<0.01, Mann-Whitney U-test) and concentration dependently reduced (up to 50%) by tumor-derived sGITRL, and NK cell effector functions could be restored by neutralization of sGITRL using a GITR-Fc fusion protein. While tumor-derived GITRL did not induce apoptosis in NK cells, it diminished nuclear localized RelB indicating that sGITRL negatively modulates NK cell NF-κB activity. Furthermore, we demonstrate that significantly elevated sGITRL levels (mean 0.4ng/ml, range from 0.01 to 3.5ng/ml) were contained in 40 out of 50 sera of patients with various cancers (colon, lung and germ line), while sera of healthy volunteers (n=8) contained no detectable levels of sGITRL. Addition of sGITRL containing patient sera to cocultures of NK cells and GITRL-negative tumor cells significantly reduced NK cell cytotoxicity and IFN-γ production about 30% and 45%, respectively (both p<0.05, Mann-Whitney U-test). Again the inhibitory effects of sGITRL on NK cell effector functions could be completely restored by neutralization of sGITRL with GITR-Fc. The strong correlation of tumor incidence and elevated sGITRL levels clearly suggests that sGITRL is released at significant amounts from malignant cells in vivo and may reduce immune surveillance of human tumors. Our data indicate that determination of sGITRL levels may be implemented as an immunological diagnostic marker in tumor patients, and GITRL-neutralization may be employed in therapeutic strategies like adoptive NK cell transfer.
Recombinant Thrombin Has a Superior Immunogenicity Profile Compared with Bovine Thrombin in a Well-Controlled, Randomized, Double-Blind, Phase 3 Study of Topically Applied Thrombins in Four Surgical Settings.
Authors: Zuckerman Linda A. , Pederson Susan , Boster Dan R. , Appesland Lisa , Jackson Dana M. , Giste Erika , Newman Jonathan D. , Alexander Allan 
Published: October 2019

Abstract
Topical hemostatic agents have been used for more than 50 years. Currently, bovine thrombin is isolated from bovine plasma and has an inherent risk of transmitting blood-borne pathogens. Approximately 20% or more patients who receive various bovine thrombin preparations have been reported to develop antibodies to bovine thrombin product and impurities. In rare cases, these antibodies can cross-react with human endogenous coagulation proteins and may lead to alterations in coagulation laboratory parameters, hypersensitivity reactions, or severe bleeding or thrombosis. ZymoGenetics, Inc. has developed recombinant Thrombin (rThrombin) as an alternative to bovine and human plasma-derived thrombin preparations. The potential immunogenicity of rThrombin (n=198) and bThrombin (n=200) were compared in a well-controlled, randomized, double-blind Phase 3 study. Two enzyme-linked immunosorbent assays (ELISAs) were developed and validated under the principles of FDA Guidance Documents (FDA Guidance for Industry: BioAnalytical Method Validation, May 2001) to detect antibodies binding to either rThrombin or bThrombin product. A time-to-clot based assay was developed and validated to characterize whether antibodies to rThrombin had neutralizing activity for plasma-derived thrombin. Study results demonstrated rThrombin’s superior immunogenicity profile compared with bThrombin (1.5% versus 22%, respectively, p < 0.0001; antibodies developed to the products, as defined by seroconversion or significant change in titer units). Characterization of the binding antibodies demonstrated none of the anti-rThrombin antibodies neutralized human plasma thrombin. No subjects in either group had evidence of antibody-mediated coagulopathy. These results demonstrate that rThrombin has a superior immunogenicity profile when compared with bThrombin.
A Point Mutation in the Juxtamembrane Wedge of CD45 Impacts Myeloid Development and Generates a Novel Model for Hemophagocytic Disorders in the Context of a MHC I-Restricted Transgene.
Authors: Hermiston Michelle L. , de Graaf Fleur R. , Weiss Art 
Published: October 2019

Abstract
The receptor like-protein tyrosine phosphatase CD45 is highly expressed on all nucleated hematopoietic cells and functions by modulating the activity of Src family kinases. We previously generated mice containing a point mutation in the juxtamembrane wedge of CD45 that leads to constitutive phosphatase activity. Demonstrating the critical negative regulatory function of the wedge, the CD45E613R mutation led to a lymphoproliferative disorder, lupus-like autoimmune syndrome, and premature death at 9–12 months of age. To address the intrinsic effects of the wedge mutation on the CD8 T cell lineage, we introduced a CD8 restricted T-cell receptor (TCR) transgene, OT1, specific for the antigen ovalbumin, into CD45E613R mice. Surprisingly, 100% of the CD45E613R/OT1+ mice succumb by 6 weeks of age to a rapidly progressive disease characterized by severe cachexia, hemophagocytosis, and markedly elevated interferon gamma levels. This phenotype shares similarity to the human hemophagocytic syndromes hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). The aims of this study are to identify the mechanistic basis and the cell type(s) responsible for this phenotype. Using a genetic approach, we demonstrate that the phenotype is maintained in CD45E613R/OT1+mice on a Rag1−/− background, thus implicating myeloid and/or CD8 T cells in disease pathogenesis. Analysis of myeloid cell development, phagocytic function, and signaling indicate that the wedge mutation operates in this lineage. Despite the intrinsic hyperresponsiveness of CD45E613R macrophages, adoptive transfer experiments demonstrate they are not essential for disease. However, adoptive transfer of purified CD45E613R/OT1+ CD8 T cells into either CD45 mutant or CD45 wildtype (wt) is sufficient to initiate disease. Interestingly, CD45E613R CD8 OT+ T cells are not dominant over CD45wt CD8+ cells. In addition we show that transfer of CD45wt CD8+ T cells into ill mice can delay disease progression. We hypothesize that, in the setting of the wedge mutation, the restricted repertoire of the CD8 T cells in CD45E613R/OT1+ mice might not be able to limit macrophage activation. We believe these mice may represent a useful model for understanding the molecular pathogenesis of hemophagocytic disorders, devastating and often fatal diseases in humans.
Gene Expression Analysis of B-Cell Post Transplant Lymphoproliferative Disorders Provides Insights into Disease Biology.
Authors: Vakiani Efsevia , Basso Katia , Klein Ulf , Dalla-Favera Riccardo , Pasqualucci Laura , Bhagat Govind 
Published: October 2019

Abstract
Background: B-cell post transplant lymphoproliferative disorders (PTLDs) encompass a diverse group of entities, the majority representing EBV-driven lymphoproliferations, which arise in the setting of iatrogenic immunosuppression. Their pathogenesis, especially the genetic relationship of PTLD with other types of B-cell non-Hodgkin lymphomas (B-NHLs), is not well understood and the association of polymorphic PTLD (P-PTLD) with monomorphic PTLD (M-PTLD) is presently unclear. Thus, in order to address these issues we analyzed gene expression profiles of PTLD and compared them with those derived from other types of B-NHL, normal B-cell subsets, and B-cell derived cell lines.
Material and methods: Paraffin embedded and H&E stained sections were used for morphologic analysis and PTLD were classified according to the WHO classification. Phenotypic characterization was performed using a comprehensive panel of antibodies and in situ hybridization for EBER. Frozen tissue from PTLD, different B-NHL, purified normal B-cell subsets, EBV-transformed lymphoblastoid cell lines (LCLs) and multiple myeloma cell lines, was used to generate complementary RNA (cRNA) that was hybridized to HGU95 arrays (Affymetrix). Gene expression data were analyzed using unsupervised and supervised clustering algorithms and classifiers were generated to determine the relationship between PTLD and cells corresponding to different stages of mature B-cell development.
Results: The 12 PTLD analyzed represented an infectious mononucleosis-like (IM-like) lesion, 5 P-PTLD, and 6 M-PTLD. All P-PTLD and 5 M-PTLD had late-germinal center (GC)/post-GC phenotypes and 8 PTLD, including the IM-like lesion, were EBV+, while 4 PTLD were EBV−. The expression profiles of late GC/post GC PTLD appeared homogeneous and distinct from other B-NHL, however no segregation of P-PTLD and M-PTLD or EBV+ and EBV− PTLD was noted. Surprisingly, on supervised analysis, only 4 genes were expressed at higher levels in PTLD compared to B-NHL and normal B-cell subsets (BLIMP-1, XBP-1, IFITM3, PCMT1) and only 2 genes were differentially upregulated in EBV+ PTLD (CD27 ligand, MTDH). The expression profiles of PTLD appeared most similar to LCLs.
Conclusions: B-cell PTLDs of late-GC/post-GC phenotype represent a distinct type of B-NHL, which are possibly derived from activated B-cells. Despite morphologic distinctions, P-PTLD and M-PTLD have overlapping genetic profiles suggesting disease heterogeneity within different categories.