bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ximelagatran Versus Warfarin: A Comparison of Bleeding Outcomes in Patients with Nonvalvular Atrial Fibrillation.
Authors: Douketis James D. , Arneklev Karin , Goldhaber Samuel , Spandorfer John , Halperin Frank , Horrow Jay 
Published: October 2019

Abstract
Background: The conventional anticoagulant management of patients with nonvalvular atrial fibrillation (AF) involves warfarin, administered to achieve a target international normalized ratio (INR) of 2.0–3.0. Ximelagatran is a novel oral direct thrombin inhibitor that, unlike warfarin, has a predictable anticoagulant effect and does not require dose adjustments based on the INR. In the SPORTIF III and V trials, ximelagatran was as effective as warfarin in preventing stroke and other thromboembolic complications in patients with nonvalvular AF. However, these studies were not designed to determine if ximelagatran was associated with a lower risk of major bleeding. Furthermore, these studies did not compare the case-fatality rate, time course, and anatomic sites of bleeding in ximelagatran- and warfarin-treated patients.
Methods: We undertook a pooled analysis of the SPORTIF III and V trials that involved 7329 patients with AF who received oral ximelagatran, 36 mg twice daily, or warfarin, administered to achieve a target INR of 2.0–3.0. Patients had nonvalvular AF and 1 or more risk factors for stroke: hypertension; age ≥75 yrs; previous stroke, transient ischemic attack or systemic embolism; left ventricular dysfunction; age ≥65 yrs and coronary artery disease; or age ≥65 yrs and diabetes. Major exclusion criteria were: mitral stenosis; previous heart valve surgery; transient AF; and increased risk for bleeding. Bleeding event rates were compared using Fisher’s exact test and the log-rank test and were expressed as the number of bleeds per year. The case-fatality rate of major bleeding was defined as the number of fatal bleeds divided by fatal plus nonfatal bleeds.
Results: The annual incidence of major bleeding was 2.0% in ximelagatran-treated patients and 2.7% in warfarin-treated patients (P = 0.029). The annual incidence of any (major or minor) bleeding was 31.7% in ximelagatran-treated patients and 38.8% in warfarin-treated patients (P < 0.0001). If episodes of intracranial hemorrhage were excluded, the annual incidence of major bleeding was 1.9% in ximelagatran-treated patients and 2.4% in warfarin-treated patients (P = 0.054). The case-fatality rate of major bleeding was 8.2% in ximelagatran-treated and 8.1% in warfarin-treated patients (P = 0.98). The time course and anatomic sites of major bleeding were not significantly different in ximelagatran-treated and warfarin-treated patients. Most bleeds involved the gastrointestinal tract, urinary tract or soft tissues.
Conclusion: In patients with nonvalvular AF who require long-term anticoagulation, treatment with oral ximelagatran, 36 mg twice daily, is associated with a lower risk of bleeding complications than warfarin.
Venous Thromboembolism Treatment with Low-Molecular-Weight Heparin during Pregnancy: A Systematic Review.
Authors: Greer Ian A. , Nelson-Piercy Catherine 
Published: October 2019

Abstract
Introduction Low-molecular-weight heparin (LMWH) has become the standard therapy for managing acute venous thromboembolism (VTE) during pregnancy. In the UK, Europe and Australasia, LMWH is widely used for the treatment of both deep-vein thrombosis and pulmonary embolism occurring during pregnancy, and this practice is endorsed by a peer-reviewed Royal College of Obstetricians and Gynaecologists (RCOG) guideline. However, there are currently no LMWHs licensed for use during pregnancy, and efficacy and safety data are derived mostly from small case series. Our aim was to evaluate the efficacy and safety of LMWH for VTE treatment during pregnancy by performing a systematic review of data from published literature.
Methods Data from published studies included in this systematic review were identified by searching MEDLINE and EMBASE up to the end of 2003. The reference lists from identified articles were also hand searched. Data on the LMWH treatment regime, VTE recurrence, and side effects of VTE treatment were extracted and entered into pre-piloted forms.
Results Sixteen studies (including six case reports) reporting 177 patients were included. One hundred and eight (61%) women were treated with enoxaparin, 49 (28%) with dalteparin and 20 (11%) with nadroparin. In 31 (18%) cases, VTE was initially treated with unfractionated heparin for two days to two weeks after diagnosis. LMWH was administered twice daily in 154 (87%) cases. Recurrent VTE was reported in three (1.7%) women: one receiving dalteparin 10,000 IU od, one receiving enoxaparin 40 mg bd, and one receiving enoxaparin 1mg/kg bd. There were no maternal deaths. Severe maternal bleeding occurred in three (1.7%) women. In two cases, the LMWH could have contributed to the extent of bleeding originating primarily from obstetric causes, and in the other from epistaxis. Minor allergic reactions occurred in two (1.1%) women, thrombocytopenia (unrelated to LMWH) in one (0.6%) woman, and osteoporosis in none.
Conclusion Our findings are consistent with LMWH being both effective and safe in the treatment of acute VTE during pregnancy.
CHIR258: A Multitargeted Growth Factor Receptor Tyrosine Kinase (RTK) Inhibitor Induces Significant Apoptosis of Human FLT3 ITD Acute Myelogenous Leukemia Cells In Vitro and in Vivo.
Authors: Menezes Daniel L. , Wiesmann Marion , Lee Sang Hoon , Lee Isabelle , Peng Jing , Tang Yan , Ye Helen , Oei Yoko , Goldbeck Cheryl , Garrett Evelyn N. , Heise Carla 
Published: October 2019

Abstract
Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. CHIR258, a novel, orally active, small molecule exhibits potent activity against FLT3 kinase and other RTKs involved in myeloid leukemias as well as endothelial and solid tumor cell proliferation (biochemical IC50 for FLT3 = 1 nM; cKIT = 2 nM; VEGFR1/2/3 ~ 8 nM, FGFR1/3 ~ 10nM, PDGFRβ = 27 nM, CSF-R1 = 36 nM). CHIR258 was tested in two human leukemic cell lines with differing FLT3 mutational status (MV4;11, FLT3 ITD vs. RS4;11, FLT3 WT). Cell cycle analysis of leukemic cells incubated with CHIR258 (0.1 μM, 48 h) showed a significant increase in the sub-Go/G1 cell population in MV4;11cells compared to the RS4;11 cells. The pro-apoptotic activity of CHIR258 against MV4;11 cells in culture was confirmed by AnnexinV staining, and appearance of cleaved poly ADP-ribose polymerase (PARP) after 24 h. Interestingly, cleaved PARP fragments were detected with either pulsed (1 h) or continuous incubations of MV4;11 cells with CHIR258. In addition, cell cycle arrest and apoptosis was consistent with degradation of survivin and loss of phosphorylation of Retinoblastoma (Rb) protein observed at CHIR258 concentrations ≥ 0.1 μM. The mechanism of action of CHIR258 was examined in a subcutaneous (s.c.) xenograft model of leukemia in SCID-NOD mice. In s.c. xenografts, daily oral doses of CHIR258 resulted in dose-dependent increased efficacy against FLT3-ITD MV4;11 tumors compared to RS4;11 WT tumors. Modulation of FLT3 downstream signaling molecules (p-FLT3, p-ERK) was achieved in MV4;11 tumors at biologically active doses in vivo, confirming molecular mechanism of action. Target modulation (p-FLT3) was maintained for up to 24 h post-dose. MV4;11 tumor responses to CHIR258 were evidenced within 1–2 days of initiating drug treatment. Immunohistochemical analyses of MV4;11 tumors revealed that early responses to CHIR258 correlated well with decreased tumor cellularity, and proliferation. Tumors stained positive for active caspase-3 and cleaved PARP suggesting cell death was mainly mediated via apoptosis. Efficacy was also demonstrated in an intravenous MV4;11 bone marrow (BM) engraftment model, wherein daily CHIR258 treatments substantially increased the life span of mice, with 33% long term survivors or “cures”. Strikingly, CHIR258-treated mice were devoid of MV4;11 tumor cells in BM as confirmed by flow cytometry and immunohistochemical analyses. In conclusion, our data indicates that CHIR258 might become a highly effective therapy in AML associated with FLT3 expression and warrants clinical trials with AML patients.
Variant Forms of Human Interleukin-3 (IL-3) Linked to Truncated Diphtheria Toxin (DT388), Have Enhanced Cytotoxicity Against Acute Myeloid Leukemia (AML) Progenitors.
Authors: Wong Siaw Hui , Frankel Arthur E. , Hogge Donna E. 
Published: October 2019

Abstract
To develop a cytotoxic drug which targets the IL-3 receptor (IL-3R) on human AML cells we previously developed a fusion protein containing a truncated form of diphtheria toxin which lacks the native binding site (DT388) fused to human IL-3. This molecule kills leukemic progenitors from many AML patients while showing little toxicity to normal hematopoietic progenitors. However, some AML samples showed little or no cell kill after exposure to this molecule. To attempt to improve the cytotoxicity of DT388IL-3 two variants of the toxin were constructed which contain alterations in the IL-3 residues that are designed to enhance binding affinity to the IL-3R. The two variants, DT388IL3[K116W] and DT388IL3[D125-133], have substitution of a hydrophobic tryptophan group at the 116 position and an eight amino acid deletion from the C-terminus of the IL-3 molecule, respectively, while the catalytic and translocation domains of DT388 remain unchanged. These variant DT388IL3 molecules and the unmodified ‘native’ fusion toxin were compared for their ability to kill AML colony forming cells (AML-CFC) from the peripheral blood of 13 newly-diagnosed AML patients and myeloid CFC from 3 normal bone marrows (NBM). AML and NBM cells were cultured for 24h with or without fusion toxin at concentrations varying between 1 and 250 ng/ml prior to plating in CFC assays. Little or no AML-CFC kill was observed for 3/13 samples. The mean % AML-CFC kill for the remaining 10 AML samples ranged from 21 – 61% for the lowest and highest concentration of native DT388IL3 tested and was significantly higher (P<0.05, paired T test) for both variants at all concentrations tested (mean 36 – 72% kill and 44 – 91% kill for the D125-133 and K116W variants, respectively, at 1-250 ng/ml). There was no significant increased kill of NBM CFC with either variant (mean % kill ranging from 4 – 44%, 17 – 58% and 19 – 54% for the native toxin, D125-133 and K116W variants, respectively, at 1-250 ng/ml). The K116W variant achieved the greatest AML-CFC kill for 7 of the 10 responding AML samples, with >90% kill achieved for 6 of these at concentrations as low as 1 ng/ml. The concentration of DT388IL3[Kll6W] required to achieve ≥50% kill of AML-CFC was on average ≥5-fold lower than the concentration of native toxin required to achieve the same effect. Thus, the variant DT388IL3 molecules tested show enhanced cytotoxic activity against AML progenitors with little change in the toxicity profile against normal hematopoietic precursors. In particular, the DT388IL3[K116W] variant warrants further testing against more primitive normal and leukemic progenitors as a potentially promising new therapeutic agent for AML. Such studies are underway.
Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).
Authors: Faderl Stefan , Ferrajolil Alessandra , Wierda William , Verstovsek Srdan , Ravandi-Kashani Farhad , Garcia-Manero Guillermo , Estey Elihu , Thomas Deborah A. , Kornblau Steve , Kwari Monica , Gandhi Varsha , Kantarjian Hagop M. 
Published: October 2019

Abstract
Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.
Interleukin-12 Gene Expression into Acute Myeloid Leukemia-Derived Dendritic Cells Overcomes T-Cell Functional Impairment Induced by Leukemic Microenvironment.
Authors: Curti Antonio , Pandolfi Simona , Aluigi Michela , Isidori Alessandro , Alessandrini Isabella , Chiodoni Claudia , Testoni Nicoletta , Colombo Mario P. , Baccarani Michele , Lemoli Roberto M. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) cells are poorly immunogenic and release soluble factors inhibiting T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen presentation capacity than leukemic blasts but share with AML cells some immunosuppressive features. In this study, we show that AML-DCs generated from CD14− AML samples (which represent 80% of total AML patients) are defective in IL-12 production. We, then, transfected CD14−-derived AML-DCs with IL-12 gene through the novel non-viral method nucleofection. IL-12 gene-nucleofected AML-DCs produce significant amount of IL-12 while maintain leukemia-specific karyotype, DC-like phenotype and function. In presence of the supernatant from the human leukemic cell line K562, allogeneic T-cell proliferation and interferon (IFN)-γ production induced by mock-transduced AML-DCs are significantly reduced. This effect is mainly directed on T cells, since AML-DC phenotype and cytokine production are not affected by leukemic supernatant. However, when stimulated by IL-12-producing AML-DCs, T cells produce higher concentrations of IFN-γ, thus maintaining a Th1 cytokine profile. In conclusion, IL-12 gene can be expressed into AML-DCs defective in endogenous IL-12 production by using a novel non-viral method which does not modify their phenotypical, cytogenetic and functional features. IL-12 gene expression into AML-DC counteracts the inhibitory effect of leukemic microenvironment on T lymphocytes
Reduced Intensity Compared to High Dose Conditioning for Allotransplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Comparative Clinical Analysis.
Authors: Flynn Catherine , Barker Juliet N. , Miller Jeff S. , Wagner John E. , DeFor Todd , Blazar Bruce R. , Burns Linda J. , MacMillan Margaret L. , Arora Mukta , Weisdorf Daniel 
Published: October 2019

We evaluated the comparative safety and efficacy of stem cell transplantation using reduced intensity (RI) vs myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Thirty two patients [18 males, median age 54 (range 19–69)] underwent a RI HSCT from January 2000- September 2003, and these were compared to 187 patients [93 males, median age 39 (range 18.4–60.3)] who received MA transplants between January 1990 – September 2003. Disease status in the 2 groups was similar, (AML in CR1: RI 38% vs MA 38%; CR2: 22% vs 15%; AML relapse: 13% vs 20% and MDS 28% vs 27%). Patients were eligible for RI if age >55 with HLA matched sibling donor (Sib) or >45 with unrelated bone marrow (BM) or umbilical cord blood (UCB) donor; extensive previous therapy including previous transplant or major co-morbidity.
RI donors were Sib (n=17, 53%), unrelated UCB (n=14, 44%), or unrelated BM (n=1). MA donors were Sib (n=176, 94%) and UCB (n=11, 6 %), p<0.01. RI conditioning included an alkylator (busulfan (Bu) or cyclophosphamide (Cy), a nucleoside analogue (fludarabine or cladribine) and 200 cGy total body irradiation (TBI), while MA conditioning was Cy/TBI (1320 cGy) (n=177) or Bu/Cy (n=10). Median follow up is 1.7 years in RI recipients and 4.2 years in MA. Neutrophil engraftment was more rapid in the RI group (median =11.5 days vs 21 days) with 3% and 6% graft failure respectively in the RI and MA groups. The cumulative incidence of Grade III–IV acute graft versus host disease (GVHD) was 22%±14% in RI vs 12±4% after MA HSCT. The cumulative incidence of relapse or disease progression at 1 year was 31% after RI vs 22% after MA HSCT (p=0.06). Disease free survival (DFS) at 1 year was 31± 16% in RI and 37%± 7% in the MA group (p=0.14). Multivariate regression analysis showed that neither conditioning intensity (NST RR=1.4, p=0.14) nor donor choice (UCB RR 0.9, p=0.63) significantly altered DFS. More failures (relapse or death) followed transplant for AML in relapse (RR=1.5, p=0.05), recipient seropositive for CMV (RR1.4, p=0.03) and development of Grade III/IV GVHD (RR 1.9, p<0.01), with MDS having an outcome similar to AML in remission (RR 1.2,p=0.28). These data suggest that allografts for AML or MDS using RI conditioning, even for older patients or using unrelated UCB can yield satisfactory outcomes and extended DFS. Advances in GVHD management and new approaches for patients in relapse are needed to improve these outcomes.
Total Body Irradiation (TBI), Fludarabine (F), Melphalan (M) and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Pediatric Hematologic Malignancies.
Authors: Petropoulos Demetrios , Worth Laura L. , Mullen Craig A. , Mahajan Anita , Choroszy Mary S. , Chan Ka Wah 
Published: October 2019

Abstract
The FM reduced-intensity preparative regimen has been used successfully in adults for allogeneic HSCT. Its role in pediatric hematologic malignancies is unclear. We studied the engraftment efficacy and the antineoplastic effect of adding TBI to the FM combination. Between July 1998 and January 2004 a total of 29 pediatric (19 males) patients were treated. Twenty-two had acute lymphoblastic leukemia (ALL), 6 had acute myeloid leukemia (AML), and 1 anaplastic large cell lymphoma. Disease status at the time of SCT was: CR2 (19 patients), CR3 (5), CR1 (2, with Ph+ leukemia), and induction failure/relapse (3). Six patients received this regimen for a second HSCT. The donor was unrelated in 21 cases: 1–2 antigen mismatched cord blood (CB) in 20, and peripheral blood stem cells (PBSC) in one. Of the 8 related-donor HSCT, 2 were not genotypically identical. The conditioning regimen was TBI 9Gy (3 fractions on day -7, -6, and -5), F 30 mg/m2 IV daily (days -4 to -1) and M 140 mg/m2 IV on day -1. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. No anti-thymocyte globulin was used. The regimen was well-tolerated, with grade II-III oral mucositis and diarrhea the most common side effects seen. Twenty-seven patients achieved ANC engraftment after a median time of 16 days (range 11–35), and 23 also had platelet engraftment at a median of 42 days (range 14–200). There was one case of primary graft failure and one early death. Six of 27 evaluable patients developed grade III-IV acute GVHD and three chronic GVHD. There were seven deaths in the first 100 days (3 from interstitial pneumonitis, 1 GVHD, 1 renal failure, 1 VOD, 1 graft failure), all in patients with ALL. Nine patients (7 with ALL) relapsed at a median of 8 months post-transplant (range 2–54). With a median follow-up of 54 months (range 7–79), 7 of 22 ALL, 5 of 6 AML, 1 of 1 lymphoma patients are alive and in remission (12 are over two years post HSCT). In conclusion, the addition of TBI to FM leads to successful engraftment of allogeneic HSC (including 1–2 antigen mismatched unrelated cord blood units) in heavily pretreated pediatric patients with hematologic malignancies, without the inclusion of ATG. The regimen was well tolerated and its activity in AML deserves further evaluation.
Association of the 1580 (C/T) Polymorphism in the Surfactant Protein B Gene with the Severity of Respiratory Failure after Allogeneic Transplantation.
Authors: Illmer Thomas , Theuser Catrin , Thiede Christian , Schaich Markus , Trautmann Simone , Hoeffken Gert , Ehninger Gerhard , Bornhaeuser Martin 
Published: October 2019

Abstract
Respiratory failure is a serious early complication confounding the clinical effect of allogeneic stem cell transplantation and early detection may be crucial for efficient treatment. We introduced a system of intensive oxigenation monitoring in patients transplanted in our center between November 2001 and December 2003. All allogeneic transplanted patients were followed by a twice daily measurement of oxi-index (paO2/FiO2) during the transplantation period (untill day + 25). Patients that fulfilled criteria of acute lung injury (oxi-index <300) were treated by O2 application vs. non-invasive ventilation (NIV). Failure to increase oxi-index above the threshold of 300 led to referral of the patient to ICU were intensified NIV was applied and/or mechanical ventilation (MV) was initiated based on a defined scoring system. 165 patients were followed for the development of ALI. 48 (29.1%) developed oxiindices <300 (ALI). Development of ALI predicted for a significantly higher rate of ICU admissions (37.5% vs. 6.8% in non-ALI patients; p<0.001) and MV (20.8 % vs. 1.7 in non-ALI patients; p<0.001). ALI was most commonly diagnosed during the engraftment period but was at diagnosis not associated with other criteria like respiration rate, CRP and tachycardia. Since members of the pulmonary innate immune system may be associated with the development of ALI and ARDS we screened the 165 patients for the presence of alternative alleles in the Surfactant Protein B (SP-B) gene. A polymorphism at position +1580 (T/C variation) of SP-B has been previously found to be associated with the development of ARDS. Polymorphism of SP-B were not associated with the development of ALI and did not predict for the need of intensified ICU treatment. However, the rate of MV varied considerably. Nine patients with the T/T genotype (9 out of 42, 21.4%) required intubation and mechanical ventilation whereas none of the patients with C/C had to receive MV (0 out of 30; p=0.01).The data indicate that measurement of the oxiindex is an early sensitive parameter of respiratory failure in allogeneic transplantation and that severity of respiratory damage may be predicted by the T allele at the SP-B +1580 site