bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recipient Epstein Barr Virus (EBV) Seropositivity with IgG Antibodies Against Early Antigens (EA) Could Be a Predictive Marker for the Early Onset of Post Transplant Lymphoproliferative Disorders (PTLDs) after Allogeneic Non T Depleted Stem Cell Transplantation.
Authors: Agbalika Felix , Larghero Jerome , Marais Dominique , Esperou Helene , Socie Gerard , Benbunan Marc , Gluckman Eliane , Marolleau Jean Pierre 
Published: October 2019

Abstract
After allogeneic bone marrow (BM) or peripheral blood stem (PBSC)cells transplantation, the occurrence of PTLDs most frequently associated with EBV represent a serious clinical management problem. Identification of risk factors to allow preventive strategies could be useful. In this single center retrospective study from1999 to 2003, we analyzed the EBV virus load in the graft and the EBV serological pretransplant status from 21 recipients with a PTLD and 28 control allografted patients without PTLDs. All patients received a non T cells depleted stem cells transplantation from geno and matched unrelated identical donors for various hematological disorders. The median time from graft to he onset of PTLD was two months (range 1–8 months). All the PTLDs patients received ATG in the conditioning regimen and had an EBV real time-PCR (RT-PCR) highly positive at time of diagnostic.
First, we assessed the EBV viral load in the infused cells by RT-PCR. In the PTLDs group, only 2 cases( one BM and one PBSC) contained infected EBV cells: 1,3x10e7 and 4,33x10e8 per 10e6 cells respectively. In the control group, we did not detect copies (the difference was not significant). The recipient pretransplant EBV infection status (median time: 15 days before transplant) was completed with serology anti-EA (IgA,IgG) and anti -VCA(IgA). Results are in the table 1. We found only a significant difference (p=0,00023) between the recipients with PTLDs and the control group for the early antigens positivity. Anti-EA are associated with a reactivation of EBV.
In conclusion, the EBV viral load in the infused cells is not associated with the onset of PTLD. However, our findings suggest that the detection of IgG antibodies to EA antigens in the recipient pretransplant serology could be a predictive marker of the early onset of a PTLD.
EBV recipient pre transplant status
anti-VCA IgG anti-VCA IgA anti-EBNA IgG anti-EA IgG anti-EA IgA # p=0,00023 PTLDs pts n=21 21/21 (100%) 0/21 (0%) 21/21 (100%) 12/21 (57%)# 0/21 (0%) Control pts n=28 28/28 (100%) 0/28 (0%) 28/28 (100%) 2/28 (7%)# 0/28 (0%)
A Genetic Basis for Adult Onset TTP?.
Authors: Camilleri Raymond S. , Mackie Ian J. , Scully Marie , Machin Samuel J. , Cohen Hannah 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP) presents in childhood or adult life and is caused by a deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity. Several mutations and polymorphisms have been reported in ADAMTS13 in congenital TTP. The study aim was to elucidate whether a mutation(s) may be linked to adult onset TTP, which may be precipitated by infection, pregnancy or oestrogen-containing preparations and is associated with antibodies to ADAMTS13. We investigated 58 adult onset TTP patients (median age 39 (range 16–74) years) with ADAMTS13 activity levels <5% of pooled normal plasma when tested pre-treatment during the acute phase of their TTP episode. Initial screening using WAVE® technology detected a novel sequence change in exon 24 of ADAMTS13 in 2/14 of these patients (both heterozygous). Gene sequencing identified this nucleotide change as C3178T which results in the significant amino acid substitution arginine to tryptophan (R1060W) in the terminal thrombospondin type 1 (TSP1-8) domain of ADAMTS13. We confirmed this C3178T nucleotide change using a specific PCR and restriction enzyme digest and studied the remaining 44 cases, identifying one homozygote (T3178T) and three additional heterozygous patients, giving a total of 6/58 (10.3%). Fifty-eight healthy normal subjects (median age 33 (range 22–57) years) were also screened for this C3178T nucleotide change and all had the wild-type (C3178C) genotype. There was a significant difference in prevalence of the C3178T missense mutation between the TTP patient and normal control groups (p=0.0072, χ2 test, odds ratio (OR) = 0.00, 95% confidence intervals (CI) = 0.00–0.67). The mutation was only detected in Caucasian patients (n = 6/41). It was not found in any of the Afro-Caribbeans (n = 8), Asians (n = 5) or patients in other ethnic groups (n = 4). The difference in prevalence remained significant amongst the Caucasian contingent (p=0.0024, χ2 test, OR = 0.00, 95% CI = 0.00–0.52). IgG antibodies to ADAMTS13 (found in 37/58 (63.8%) patients) were demonstrated in three of the five heterozygous C3178T TTP patients, but not in the homozygous patient. The C3178T mutation was also detected in the mother of one of these three heterozygous patients and the daughter of the homozygous patient, neither of whom have had TTP. In conclusion, the novel C3178T missense mutation appears to be associated with adult onset TTP and in some instances, antibodies to ADAMTS13. This raises the possibility that adult onset TTP may arise as a result of an interaction between genetic and acquired factors.
Durable Molecular Remission in Two Acute Promyelocytic Leukemia (APL) Patients Treated with Arsenic Trioxide at First Molecular Relapse.
Authors: Douer Dan , Ramezani Laleh , Watkins Kristy , Louie Robert , Tallman Martin S. 
Published: October 2019

Abstract
Background: The recurrent detection of the PML- RARα transcripts in APL patients in complete remission (CR) is predictive of clinical relapse. Intervention at the time of molecular relapse rather than at the time of overt clinical relapse may minimize the risks associated with the disease as well as treatment-related complications. Previous studies have shown that patients treated at molecular relapse had improved overall survival compared to patients treated at clinical relapse; however, the optimal approach to the treatment of molecular relapse has not yet been established. Arsenic trioxide is active as a single agent in APL patients who developed overt clinical relapse after treatment with ATRA and anthracycline chemotherapy. We evaluated the use of single agent arsenic trioxide in APL patients who are still in first hematological CR but have become RT-PCR positive.
Methods: So far, 2 patients were studied, both females with the long form of RAR RARα (bcr1), aged 29 and 39 years. These patients had normal bone marrow morphology but were found to be RT-PCR positive twice in an interval of at least 2 months, while in first CR at 12 and 36 months, respectively. Arsenic trioxide, 0.15 mg/kg/dose, was administered intravenously for 5 days per week for 5 weeks (total of 25 doses) with a 3 to 6 week rest period between cycles up to a maximum of 4 cycles.
Results: Both patients became PCR negative after the first cycle of arsenic trioxide. One patient completed four cycles of therapy. The second patient had a history of diabetes mellitus, received only 20 doses of the first cycle and was removed from the study because of grade III sensory neurotoxicity. The only other side effects were grade II headache in both patients and self-limited grade III liver toxicity in one patient. Both patients remain RT-PCR negative at 30 and 28 months after enrollment, respectively, without further therapy.
Conclusions: Without treatment, these patients could be expected to have developed a clinical relapse within 4–10 months. Arsenic trioxide induced a durable second molecular relapse, extending disease-free survival and obviating the need for more intensive treatment, such as chemotherapy and stem cell transplantation.
All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.
Authors: Schlenk Richard F. , Doehner Konstanze , Kerz Martina , Hartmann Frank , del Valle Francesco , Glasmacher Axel , Pralle Hans , Goetze Katharina , Koller Elisabeth , Gastl Guenther , Mergenthaler Hans G. , Salwender Hans , Kirchen Heinz , Haase Detlef , Kremers Stephan , Nerl Christoph , Theobald Matthias , Matzdorff Axel C. , Ganser Arnold , Doehner Hartmut ,   for the German-Austrian, AML Study Group (AMLSG)
Published: October 2019

Abstract
Introduction: Response to first induction therapy is one of the most important prognostic factors in patients with adult myeloid leukemia (AML). Induction of CR or PR is the primary aim in these patients.
Methods: Between 1993 and 2005 225 consecutive patients (median age: 48.4 yrs, range 16–60 yrs) treated within the AMLHD93 (n=45), AMLHD98A (n=157) and AMLSG 05-04 (n=23, still active) trials were evaluated. All patients had primary refractory AML after one cycle of ICE. The different salvage therapies were as follows: AMLHD93 sequential-HAM (S-HAM) for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11], HAM for patients >=55 years of age [cytarabine 3g/m2 bid., days 1–3, mitoxantrone 12mg/m2 days 2,3]; AMLHD98A: A-HAM [HAM with ATRA 45mg/m2 days 3–5, 15mg/m2 days 6–28]; AMLSG 05-04: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m2 day 1].
Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=117, GO-A-HAM n=23, other n=31 no further therapy n=11. Response according to salvage therapy was as follows:
response GO-A-HAM A-HAM S-HAM HAM CR 11 (48%) 40 (34%) 5 (23%) 3 (14%) PR 4 (17%) 33 (28%) 5 (23%) 4 (19%) RD 6 (26%) 36 (31%) 12 (54%) 12 (57%) death 2 (9%) 8 (7%) 0 2 (10%)
No CTC-grade 3-5 liver toxicity was seen in patients receiving GO-A-HAM. Multivariable analyses revealed that regimens containing ATRA (odds ratio 2.5, p=0.01) and cytogenetic subgroup [t(11q23) odds ratio 4.2 p=0.04 (n=13), non-complex high risk aberrations odds ratio 4.2 p=0.007 (n=34)] were associated with a significantly better response rate (subsuming CR and PR). 119 of 225 patients have received stem cell transplantation. No case of veno occlusive disease was in 10 so far transplanted pts who have had GO-A-HAM. Median survival was 10.7 months.
Conclusions: Although retrospective in nature our study suggests that ATRA as adjunct to salvage chemotherapy in primary refractory AML patients improves the response rate. The addition of GO in a dosage of 3mg/m2 results in promising response rates without increasing toxicity.
A Phase I Pharmacokinetic Trial of Decitabine Administered as a 3-Hour Infusion to Patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS).
Authors: Cashen Amanda , Shah Ajit , Helget Angela , Todt Laura , Fisher Nicholas , DiPersio John 
Published: October 2019

Abstract
Background: Decitabine (DacogenTM) is a cytosine analogue that promotes hypomethylation of DNA. Although decitabine has been extensively studied in Phase II and III trials in patients with MDS, relatively limited pharmacokinetic (PK) data is available in this patient population. Recently, a Phase III trial of decitabine in advanced MDS demonstrated that decitabine administered as a 3-hour infusion of 15 mg/m2 every 8 hours for 3 days (cycles repeated every 6 weeks) results in a significantly higher response rate and improves time to AML or death compared to best supportive care (J Clin Oncol. 2005;23(suppl 16S):570s).
Methods: The PK of this dosing regimen was evaluated in twelve patients (8M/4F, age 50–87 yr) with MDS (n=6, IPSS ≥ 1.5) or relapsed/refractory AML (n=6). Patients were treated with the same dose and schedule as the Phase III trial, with a second cycle repeated six weeks after the first. Plasma samples were obtained pre-dose and during the first 8-hour dosing interval on each dosing day during cycle 1, and at pre-dose and just prior to the end of infusion during cycle 2. PK samples were assayed for decitabine by a sensitive and specific LC/MS/MS method.
Results: Day 1 cycle 1 PK results (mean±SD) from ten patients are shown in the table below (data from two patients excluded due to dosing error).
In plasma, decitabine did not accumulate during three days of dosing, and CLp remained unchanged. For the 5 patients who have received decitabine for two cycles, Cmax values for cycle 1 (49.0±22.2 ng/mL) and cycle 2 (62.7±45.2) were comparable, indicating unchanged PK during both cycles. This regimen of decitabine was generally well-tolerated. Serious adverse events included neutropenia and fever (2 patients) and infection (one patient with gram positive bacteremia and pneumonia). In addition, one patient died of sepsis, and two died of progressive AML. Of four patients who have been assessed for response after 2 cycles of decitabine, one patient with MDS had a complete response, one patient with MDS had hematologic improvement, and two patients (one MDS, one AML) had no response.
Conclusions: We conclude that repeated administration of decitabine does not result in systemic accumulation of the drug, and PK remains unchanged from cycle to cycle. It will be of interest in future studies to correlate pharmacokinetics of decitabine with pharmacodynamic changes in CpG island methylation and clinical responses.
Cmax (ng/ml) Tmax (hr) AUC(0-∞) (ng•hr/ml) T1/2 (hr) CLp (L/hr/m2) Vdss (L/m2) AUC Ratio (Day3/Day1) *Geometric mean 79±54.1 2.67±0.55 170±105 0.65±0.30 122±73.0 75.8±70.1 0.92±0.15 65.1* 144*
Dual Inhibition of Blood Coagulation Factors Xa and Iia Synergize To Reduce Thrombus Weight and Thrombin Generation in a Rabbit Arteriovenous Shunt Model of Thrombosis.
Authors: McClanahan Thomas B. , Baxi Sangita M. , Chi Liguo , Dahring Tawny , Gould Weston R. , Johnson Ted , Hicks Gary , Welch Kathy , Leadley Robert J. 
Published: October 2019

Abstract
Several compounds currently in development for the treatment of thrombotic disorders demonstrate high levels of specificity for single targets of the blood coagulation cascade such as factor Xa and thrombin. However, development of a single molecule dual inhibitor against factor Xa and thrombin may expand the efficacy to safety ratio of treatment options for arterial and venous thrombosis. The objective of this study was to determine if simultaneous administration of PD 0313052, a selective Xa inhibitor and argatroban, a direct thrombin inhibitor, would lead to a synergistic antithrombotic effect in a rabbit AV shunt model of thrombosis. Intravenous administration of PD 0313052 alone at doses of 0.1, 0.3, and 1.0 mg/kg/min resulted in thrombus weight (TW) reductions of 11±3, 25±10 and 67±7 % compared to the vehicle group. Argatroban at 1, 3 and 10 mg/kg/min reduced TW 16±13, 47±10 and 75±6 %. When PD 0313052 was administered at 0.1 mg/kg/min in combination with argatroban at 1, 3 or 10 mg/kg/min TW was reduced 50±7, 60±7 and 82±9 %. Likewise, argatroban at 1 mg/kg/min combined with 0.1, 0.3 or 1mg/kg/min of PD 0313052 resulted in TW reductions of 56±9, 60±9 and 84±5 %, respectively. At the lowest combined doses of PD 0313052 and argatroban there was no change in bleeding time relative to the additive fold-increases from each drug alone. The EC50 of intravenously administered PD 0313052 and argatroban was 67±23 and 178±58 ng/ml, respectively. When the drugs were combined the EC50 was reduced to 12±6 ng/ml with the PD 0313052/argatroban combination and to 83±29 ng/ml with the argatroban/PD 0313052 combination. A synergistic effect was also observed in an ex vivo assay of thrombin generation (TG). Predicted additive inhibition of TG based on the individual effects of each compound was −9±7, 9±2 and 29±7 % compared to 10±5, 32±5 and 55±3 % with the 313052/argatroban combination. The predicted effects of the argatroban/PD 0313052 combination was −9±7, 1±7 and 16±9 % compared to the actual inhibition of 5±3, 14±5 and 31±7 %. These results demonstrate a significant synergistic antithrombotic effect by combining low doses of a factor Xa and a thrombin inhibitor and support the hypothesis that development of a single molecule inhibitor against different hemostatic targets may offer greater efficacy in the prevention and treatment of venous and arterial thrombosis.
Anti-Thrombotic Action of DZ-697b, a Novel Anti-Platelet Agent, on Photochemically Induced Thrombosis with Lower Bleeding Risk in Guinea Pigs.
Authors: Shibutani Tomoko , Iijima Takako , Kaneda Yuki , Muramatsu Sumie , Ogihara Yoshiyasu , Shibano Toshiro 
Published: October 2019

Abstract
Introduction: DZ-697b, a novel anti-platelet compound, selectively inhibits ristocetin- and collagen-induced platelet aggregation, whose pharmacological profile is different from any current medicines. In order to clarify the benefit and risk balance as an anti-thrombotic agent, effects of DZ-697b and aspirin were compared on thrombus formation and gastric bleeding model in guinea pigs.
Materials and Methods: Fasted male Hartly guinea pigs under anesthesia were used. DZ-697b (3 - 200 mg/kg) or aspirin (100–300 mg/kg) was orally administered 60 min prior to evaluation.
PIT model: Left carotid artery was exposed. Photochemically induced thrombosis (PIT) was initiated by intravenous injection of rose-bengal (10 mg/kg) and exposure of green light (540 nm) to the carotid artery. The time to occlusion by thrombus formation was measured by pulse Doppler blood flow meter.
Gastric bleeding model: The stomach was exposed, and esophagus and pylorus were ligated. A cannula was inserted into stomach and gastric hemorrhagic erosion was induced by intraluminal application of 0.7N HCl in a volume of 5mL. Gastric contents were collected every 10 min and measured hemoglobin (Hb) leakage as indices of bleeding.
Results: DZ-697b at 3 mg/kg to 100 mg/kg dose-dependently prolonged the time to occlusion in the PIT model, and significant anti-thrombotic effects were observed from 10 mg/kg. However, gastric bleeding induced by 0.7N HCl in gastric lavage was not affected by DZ-697b up to 100 mg/kg. Statistically significant increase in gastric bleeding was observed when DZ-697b was administered at 200 mg/kg. Aspirin at doses of 100–300 mg/kg tended to lengthen the time to thrombotic occlusion in a dose-dependent manner, but there was no statistically significant difference. In contrast, aspirin dose-dependently increased gastric bleeding in the lavage and significant enhancement was found at doses of 200 and 300 mg/kg. Both DZ-697b and aspirin did not give any influences on the area of hemorrhagic erosion induced by gastric application of 0.7N HCl. Thus, the balance between anti-thrombotic effect and bleeding risk of DZ-697b seemed more favorable than that of aspirin.
Conclusion: DZ-697b showed anti-thrombotic effects at doses much lower than those inducing gastric bleeding in comparison with aspirin. These results suggest that inhibitors of vWF and collagen related signaling pathway are promising target in the development of new anti-platelet drugs with lower bleeding risk.
Coupling Tissue Type Plasminogen Activator to Carrier Erythrocyte Protects Against Plasma Inhibitors.
Authors: Ganguly Kumkum , Cines Douglas B. , Muzykantov Vladimir R. 
Published: October 2019

Abstract
Conjugating tissue plasminogen activator (tPA) to carrier red blood cells (RBC) restricts its permeation into tissues and pre-existing hemostatic clots, minimizing side effects, and prolongs its circulation, which permits it to be incorporated within nascent clot which it lyses from inside. We now report that RBC/tPA dissolves clots formed from mouse blood more effectively than free tPA, while they were equipotent against clots formed in vitro from PAI-1 KO mouse blood. To test whether tPA acquires resistance to plasma inhibitors when conjugated to RBC, we compared the activity of RBC/tPA vs free tPA in the presence of purified PAI-1, α2 macroglobulin (α2M) and α1anti-trypsin (α1AT). At equimolar concentrations, PAI-1 completely inhibited the activity of soluble tPA in vitro, whereas RBC/tPA retained 100% and 75% of its amidolytic and fibrinolytic activity, respectively. RBC/tPA, but not free tPA, was also resistant to equimolar concentrations of α2M and α1AT. However, tPA coupled to RBC pre-incubated with a mixture of hyaluronidase, heparinase and neuraminidase was as susceptible to inactivation by PAI-1, α2M and α1AT as free tPA. Further, tPA coupled to glycocalyx-stripped RBC bound two-fold more 125I-labeled PAI-1 than tPA coupled to naïve RBC. We conclude that the RBC glycocalyx protects tPA from inactivation by PA inhibitors, likely by steric hindrance. This unexpected benefit may enhance the utility of RBC/tPA in thromboprophylaxis and suggests a previous under-appreciated role for the glycocalyx in modulating PA activity on the vasculature and other cell surfaces.
Incidence of HCV and HIV NAT Positive in Cord Blood Donors.
Authors: Rhamy Jennifer , Beltz Mark , John Karla , Feria David , Waxman Dan , Dracker Robert 
Published: October 2019

Abstract
Introduction:
Donors of cord blood (CBD) are screened similarly to whole blood donors (WBD). It has been reported that CBD have a higher incidence of both true positive and false positive disease markers tested by EIA[1]. This abstract compares the rate of positive results for viral RNA (NAT) in CBD vs. WBD in a large cohort of donors.
Methods:
NAT was performed using the Chiron Procleix MPX or discriminatory assays. EIA testing was performed using Abbott bead methodology following manufacturer’s instructions. Confirmatory results for EIA were performed with Chiron RIBA. Results from 12/17/04 to 6/30/05 were collated.
Results
EIA HIV EIA HCV NAT HIV/HCV HIV EIA POS(%) HCV EIA POS (%) HIV NAT POS HCV NAT POS WBD 74299 74299 74299 75(0.10) 107(0.14) 1 (0) 31(0.04) CBD 11996 12001 12007 50(0.42) 46(0.38) 0 13 (0.11)
A higher percentage of CBD were positive for HIV and HCV EIA as previously reported1. HIV NAT positive donors were 0.00% for both populations. The ratio of HCV EIA positive to HCV NAT positive donors was 28.97% for WBD and 28.26% in CBD. The ratio of CBD HCV EIA positives to WBD HCV EIA positives is 2.71 and the ratio of WBD HCV NAT positives to WBD HCV NAT positives is 2.75. The ratio of HIV CBD EIA positives to HIV WBD EIA positives is 4.10, which is significantly higher (p=<0.01).
Conclusions
Both CBD and WBD have a low rate (0%) of HIV NAT positive donors, but CBD have a 4x higher rate of HIV EIA. This suggests a 4x higher donor loss to false positive antibody results. The CBD donors have a 2.7x higher rate for both EIA and NAT positive results, showing a higher rate of viremic donors in CBD. The similar ratios for EIA positive to NAT positive donors in the two populations suggest that the false positive rate is not elevated in CBD versus WBD.
The higher incidence of HCV infection in CBD could be geographic or ethnic in origin. More study is needed to determine the reasons and further predict donor loss. The HIV EIA results are not predictive of actual infection in this population. A more aggressive logarithm for reentry than used for WBD may be merited.