bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low-Molecular-Weight Heparin Reduces the Cost of Venous Thromboembolism Treatment Compared with Unfractionated Heparin in US Hospitals.
Authors: Merli Geno J. , Ferrufino Cheryl P. , Lin Jay , Hussein Mohamed , Battleman David 
Published: October 2019

Abstract
Background: The current healthcare and economic burden of venous thromboembolism (VTE) in US hospitals is significant. In patients with confirmed VTE, evidence-based guidelines recommend treatment for a minimum of 5 days with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). However, the relative total hospital direct medical costs and VTE-related readmission rates of these regimens for VTE treatment in large real-world populations are, as yet, unresolved.
Methods: This retrospective cohort analysis of discharge and billing records from the Premier Perspective™ database included discharges of patients ≥18 years old and with a primary diagnosis of VTE from January 2003 through June 2005. Discharges with prior VTE during the 12-month period prior to the index hospitalization or a pre-existing contraindication to anticoagulant therapy were excluded from the analyses. Total hospital direct medical costs associated with VTE treatment (including drug costs, hospital costs, and professional costs) were collected and compared for UFH and LMWH. Furthermore, VTE-related readmission rates at days 30 and 90 post-discharge were compared for each of these agents. Total direct medical costs (US $) were compared using generalized linear models (SAS 9.1 PROC GENMOD), adjusting for patient and hospital characteristics. Logistic regression was used to compare the likelihood of readmission within 30 and 90 days.
Results: A total of 38,664 discharges surveyed met the inclusion criteria, 20,577 (53%) receiving LMWH and 18,087 (47%) receiving UFH. The two groups were broadly similar in clinical and demographic characteristics, although mean length of stay was 1.1 days longer in the UFH group (5.7 days [SD=2.9] vs. 4.6 days [SD=2.9] for LMWH, P<0.001). After adjustment for covariates, the mean total direct hospital costs were $3,618 for UFH and $3,068 for LMWH (difference $550, P<0.0001). LMWH was associated with reduced cost in most categories, although anticoagulation therapy costs were higher for LMWH ($242 versus $41 for UFH, P<0.0001). LMWH was associated with lower rates of VTE-related readmission at both 30 days (11.2% vs 12.1%; odds ratio [OR] 0.89, 95% confidence interval [CI] 0.84–0.96; P=0.001) and 90 days (13.1% vs 13.8%; OR 0.91, 95% CI 0.85–0.96; P<0.001).
Conclusion: In a large, real-world population of patients from across the United States, LMWH is associated with reduced total direct medical costs for the acute treatment of VTE when compared to UFH. This reduction occurs despite higher drug-related costs for LMWH. In addition, patients receiving LMWH are less likely to be readmitted to hospital within 90 days with recurrent VTE.
The N-Glycans Modulate the Binding of ADAMTS13 with von Willebrand Factor.
Authors: Zhou Wenhua , Tsai Han-Mou 
Published: October 2019

Abstract
ADAMTS13, a circulating multidomain protease consisting a metalloprotease (MP), a disintegrin, a thrombospondin type 1 repeat [TSR], a cysteine rich region, a spacer, 7 additional TSR and 2 CUB domains, is critical for maintaining the homeostasis of von Willebrand factor (VWF). Severe deficiency of the enzyme can lead to VWF-platelet thrombosis in the microcirculation characteristic of thrombotic thrombocytopenic purpura (TTP). Sequence analysis predicts that ADAMTS13 contains 2 and 6 likely N-glycosylation sites respectively at or near the MP and spacer domains, and 2 possible sites in the CUB domains. To investigate the N-glycosylation status and the role of N-glycans in the function of ADAMTS13, we digested plasma derived ADAMTS13 and recombinant ADAMTS13 or its truncated variants with peptide-N-glycosidase F (PNGase F) or endoglycosidase H. SDS PAGE analysis showed that digestion with PNGase F, but not with endo H, decreased the molecular weights of plasma derived ADAMTS13 as well as recombinant ADAMTS13 proteins, including AD7 (residues 1-1427, full-length), AD5 (residues 1-745, MP-TSR#1), AD2 (residues 1-448, MP-TSR#1), AD8 (residues 556-748, spacer-TSR#2) and AD13 (residues 1016-1427, TSR#8-CUB#2), indicating that the MP, spacer and CUB domains were all N-glycosylated as predicted, and contained complex type carbohydrate chains. Enzyme linked immunoassay showed that removal of the N-glycans did not affect the binding of proteases to immobilized VWF multimers or VWF73 peptide. Removal of the N-glycans modestly affected the protease-TTP IgG binding, increasing the Kd by 190% for AD7 and by 50% for AD5. Expression experiments in Lec1 mutant Chinese hamster ovary (CHO) cells with defective GlcNAc-TI activity due to mutations in the Mgat1 gene showed that the resulting high-mannose type AD7 and AD5 variant proteases were secreted normally, showed no difference in VWF cleaving and TTP IgG binding activities, but exhibited increased binding to VWF multimers or VWF73 peptide. In summary, ADAMTS13 are N-glycosylated with complex type oligosaccharides at the MP, spacer and CUB domains. Intracellular conversion from high mannose to complex type glycans modulates the binding of the protease to VWF, suggesting that this process may help prevent depletion of the protease under conditions of high VWF levels in the circulation.
A Phase I/II Trial on Melphalan, Prednisone, Thalidomide and Defribotide Combination in Relapsed/Refractory Multiple Myeloma Patients.
Authors: Palumbo Antonio , Larocca Alessandra , Rus Cecilia , Gay Francesca , Rossi Davide , Pregno Patrizia , Falco Patrizia , Avonto Ilaria , Magarotto Valeria , Cavallo Federica , Iacobelli Massimo , Gaidano Gianluca , Mitsiades Constantine , Richardson Paul G. , Anderson Kenneth C. , Boccadoro Mario 
Published: October 2019

Abstract
Defibrotide (DF) showed antithrombotic properties and remarkable activity in Multiple Myeloma (MM), without significant anticoagulant effects and bleeding risk. DF may abrogate tumor cells interaction with marrow stromal cells and enhance sensitivity to chemotherapy, thus improving activities of Melphalan, Prednisone and Thalidomide, while protecting against thrombotic state. We designed a multicenter phase I/II trial to define efficacy and safety of Melphalan, Prednisone, Thalidomide and DF (MPTD) in relapsed/refractory MM. The MPTD treatment consisted of 6 35-days cycles of oral melphalan (0.25 mg/Kg day 1–4), prednisone (1.5 mg/kg day 1–4), thalidomide (50–100 mg/day continuously), DF at 3 dose levels (17 mg/Kg iv or 2.4 g po D 1–4, 1.6 g po D 5–35; 34 mg/Kg iv or 4.8 g po D 1–4, 3.2 g po D 5–35; 51 mg/Kg iv or 7.2 g po D 1–4, 4.8 g po D 5–35), every 35 days, without deep vein thrombosis (DVT) prophylaxis. Safety was assessed by defining dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). DLT was defined as the occurrence of febrile neutropenia, G4 neutropenia >1 week, any other G4 hematologic toxicity, or any >G3 non-hematologic toxicity. MTD was the dose level prior to that resulting in DLT. Efficacy was evaluated according to EBMT/IBMTR criteria. Twenty-four patients were enrolled between March and November 2006 and 19 patients completed at least 1 MPTD (median age 69, excluding primary refractory and/or patients receiving anticoagulation) and were evaluated for toxicity and response. Fourty-two percent of patients achieved at least partial response (PR) after a median of 3 cycles (including 16% very good PR), without significant differences among DF dose. The MTD was not reached. DLTs observed were not considered related to DF and included: G3 ileus (1st dose level) and acute myocardial infarction (AMI) in the 2nd. Toxicities ≥G3 consisted of neutropenia 47%, thrombocytopenia 10%, anemia 21%, whereas <5% of patients experienced non-hematological toxicities ≥G3. No DVTs or significant bleeding were detected. Treatment discontinuation occurred in 3 patients for adverse events: AMI (additional anticoagulation required), ileus (because of the diagnosis of amyloidosis AL and disease progression), and persistent G4 neutropenia (heavily pre-treated patients). In this phase I/II study we confirm the efficacy and feasibility of MPTD in the setting of advanced myeloma patients, interestingly a protective role of DF against thrombosis is also suggested. Pharmacokinetic studies and analysis of surrogates are ongoing. Updated data will be presented at the meeting.
Bortezomib in Combination with Bendamustine and Prednisone in the Treatment of Patients with Refractory/Relapsed Multiple Myeloma.
Authors: Poenisch Wolfram , Bourgeois Malvina , Wang Song-Yau , Heyn Simone , Jaekel Nadja , Braunert Leanthe , Rohrberg Robert , Hurtz Hans Juergen , Hoffmann Franz Albert , Schwarzer Andreas , Becker Cornelia , Al Ali Haifa , Niederwieser Dietger W. 
Published: October 2019

Abstract
Introduction: Bortezomib is a novel proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in relapsed/refractory multiple myeloma (MM). The combinated treatment of bortezomib with bendamustine and prednisone (BPV) was assessed to determine the efficacy and toxicity of this regiment in patients with advanced MM.
Methods: Between January 2005 and July 2007, 46 patients (median age 63; range 31–77 years) with relapsed or refractory MM (29 patients stage III a, 17 patients III b) were treated with bendamustine 60 (−80) mg/qm on day 1 and 2, bortezomib 1,3 mg/qm on day 1, 4, 8 and 11, and prednisone 100 mg on day 1, 2, 4, 8 and 11. Cycles were repeated every 21 days until maximum response or progressive disease. The time from first diagnosis ranged from 1 to 183 (median 36) months. The duration of the last remission before beginning the BPV-therapy was 6 (range 0–36) months. Previous therapy lines (median 2, range 1–6) included 18 × thalidomide, 10 × autologous PBSCT, and 9 × autologous/allogeneic PBSCT. 16 patients were refractory to the last treatment. 22 patients had preexistent severe thrombocytopenia, leukocytopenia or anemia (WHO grade 3 or 4). Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR).
Results: 36 patients (78%) responded after at least one cycle of chemotherapy with 2 CR, 5 nCR, 6 VGPR, 15 PR and 8 MR. 4 patients had stable disease and 6 patients had a progress. With a median follow up of 13 months, EFS, and OS at twelve months for patients without severe haematological toxicities due to previous treatments (n=24) were 46% and 79%, respectively. Outcome for these patients was significantly better compared to patients with severe haematological toxicities (grade 3 or 4, n=22) where EFS, and OS were 10% and 22%, respectively (p<0,01). The median number of the BPV-treatment was 2 (1–7) cycles. 20 of 36 responding patients showed a rapid decrease of the myeloma protein and reached the best response after the first cycle and 12 after the second cycle. The regimen was well-tolerated with few significant side effects reported. New cytopenias occured infrequently (four patients had a thrombocytopenia grade 3, and two patients had a grade 4 thrombocytopenia). 1 patient had a moderate new polyneuropathy (grade 2).
Summary: These results indicate that the combination of bortezomib, bendamustine and prednisone is effective and well tolerated in a heavily pretreated population of patients with relapsed or refractory MM.
Coagulation-Related Effect of Bortezomib Treatment in Patients with Relapsed or Refractory Multiple Myeloma.
Authors: Zangari Maurizio , Guerrero Jose , Cavallo Federica , Burns Michael J. , Prasad Keshava , Adcock Dot , Marlar Richard , Tricot Guido , Fink Louis 
Published: October 2019

Abstract
Proteasomes inhibitors have been recently identified as potential agents, which can influence processes leading to thrombosis. We have previously reported a reduced incidence of deep vein thrombosis (DVT) in 69 patients enrolled in Total Therapy III and treated with (B), dexamethasone, thalidomide, cisplatin and doxorubicin with prophylactic anticoagulation. Patients with relapse MM, not previously exposed to B with normal baseline coagulation parameters (PT, PTT fibrinogen and platelet count) were eligible for the study. Except for the two PCR-based genotyping assays Factor V Leiden and Prothrombin Gene, which were assessed only at enrollment, in table one are listed coagulation factors serially assessed at baseline and within 1 hour after the first dose of B on day 1 and 4 of the first treatment cycle. Platelet Aggregation, with epinephrine, collagen, arachidonic acid, ADP and P- selectin by flow cytometry, were obtained at same time points.
Results: Median values of coagulation factors pre and post B infusion are shown in table 1. Platelet count on platelet rich plasma (PRP) decreased after each B treatment (204.1±69.2 × 103 platelets/μL versus 160.8±50.3 × 103 platelets/μL). Platelet aggregation in PRP induced by 10 μM ADP was reduced by 20% and 29% in post-B on day one and four with p-values of 0.033 and 0.009 rispectively. Ristocetin induced platelet agglutination and epinephrine-induced aggregation were both negatively affected by B administration, p=0.0077 and p=0.034. Platelet aggregations elicited by collagen and arachidonic were not affected by B P-selectin expression on platelet surface was overall decrease with each agonist after B administration however no statistical differences were observed. In conclusion this pilot study has shown that even a short in vivo B exposure can significantly impaired platelet number and function and could explain clinical observations.
Table 1 Test Day 1 Pre-dose Median Day 1 Post-dose Median Day 4 Pre-dose Median Day 4 Post-dose Median PT (sec) 13.4 13.85 13.55 14.4 PTT (sec) 17.35 26.2 26.95 25.5 Fibrinogen (mg/dL) 385 360 386 341.5 Protein C (70%–160%) 114 102 120 115 Protein S (65–140%) 89 85 92 92.5 Antithrombin II (190–127%) 98 97.5 100.5 102 APC Ration 2.345 2.33 2.3 2.22 T.T. (<20s) 18.2 17.9 17.7 19.45 D-Dimer (ug/mL) 0.56 0.5 0.5 0.59 Homocysteine (umol/L) 8.77 8.99 8.69 8.13
Ex Vivo Expansion of Cord Blood NK Cell Have In Vivo Efficacy Against Leukemia.
Authors: Xing Dongxia , Fang Wendy , Decker William K. , Li Sufang , Robinson Simon N. , Yang Hong , Steiner David , Thomas Michael , Champlin Richard E. , McMannis John D. , Shpall Elizabeth J. , Zweidler-Mckay Patrick A. 
Published: October 2019

Abstract
Introduction Allogeneic stem cell transplantation has demonstrated the ability to prevent leukemic relapse via an immune-mediated graft-vs.-leukemia effect. Natural killer (NK) cells have been shown to comprise a significant component of this anti-leukemia effect and have been reported to enhance engraftment and reduce graft-vs.-host disease. Ex-vivo expansion of peripheral blood-derived NK cells has been demonstrated. Cord blood (CB) is a promising alternate source of NK cells with enhanced cytokine/antigen-responsiveness, proliferation and increasing availability. We studied expansion conditions for the generation of CB NK cells for clinical use, and evaluated them in vivo in NOD-SCID/IL2Rgnull mice engrafted with human leukemia.
Methods Two expansion protocols were compared:
CD56+ NK cells were isolated and cultured with irradiated CD56− feeder cells in RPMI-1640 supplemented with 100ng/mL IL-2 for 21 days. CB mononuclear cells were depleted of CD3+ cells prior to culture.
In vivo NK cytolytic activity was measured via chromium release assays on leukemia cell lines (K562, Nalm6) and fresh patient leukemia blasts. Functionality was confirmed in vivo as well by injecting 106 K562 cells or 2.5 ×104 Nalm6 cells into NOD-SCID/IL2Rgnull mice. 2 ×106 CB-expanded NK cells were administered on day +1, and an additional 5×106 CB NK cells were administered on day +7. NK killing of leukemic targets was then confirmed by flow cytometry.
Results Feeder cells mediated >30-fold expansion of CB NK cells, generating a nearly pure population that contained 97% CD3−CD56+ cells. Expanded CB NK could lyse >90% of K562 targets at an E:T ratio of 10:1, as well as >40% of patient leukemia blast. In CD3− depleted cultures, similar expansions were observed, however only 55% of these cells were CD3−CD56+ with the remainder being 10% CD3+CD56+ NK/T and 35% CD3+ T lymphocytes. In the NOD-SCID~/IL2Rgnull model, ex vivo expanded CB NK cells demonstrated the ability to reduce the leukemia burden of both AML (K562) and ALL (Nalm6) cells >50%.
Conclusions We have demonstrated the feasibility of expanding CB NK ex vivo to clinically-relevant doses with minimal manipulation. These expanded CB NK cells demonstrated cytotoxic activity in vitro and in vivo against a variety of human leukemic cell lines and patient leukemia blasts. These results provide rationale for immunotherapy of leukemia with CB-derived NK cells.
A Cross-Sectional MRI T2* Study of Pancreatic and Pituitary Hemosiderosis in 180 Thalassemia Major Patients in Hong Kong.
Authors: Au Wing Y. , Lam Wynnie , Chu Winnie , Yuen Hui-leung , Ling S.C. , Li S.H. , Chan M.H. , Lee K.K. , Law M.F. , Liu Herman , Liang Raymond , Ha Shau-yin 
Published: October 2019

Abstract
Background: The use of magnetic resonance imaging (MRI) for organ specific iron assessment has allowed better tailoring of chelation therapy. Since endocrine failure is common in thalassemia major (TM) patients, we explored the utility of rapid T2* MRI assessment of hemosiderosis in the pancreas and pituitary. The results were correlated with standard T2* heart and liver MRI assessments and clinical data.
Material and methods: A total of 180 TM patients (M:F = 91:89, median age, range 12–48) were scanned on a 1.5 T scanner. (Sonata, Siemens Medical, Erlanger, Germany). T2* myocardium was assessed by a cardiac gated single breath hold 8-echo sequence (CMRtools; London, UK). The T2* liver, pancreas and pituitary were performed by a breath hold 20-echo sequence. Subcutaneous deferoxamine was used for chelation, except for addition of deferiprone in 24 cases for 1 year.
Results: There was a high incidence of hemosiderosis of heart (severe T2*<12ms: 34%, mild-moderate <20ms, 15%) and liver (severe T2*<1.4ms, 14% mild-moderate <6.3ms, 63%). Iron overload above normal control was commonly found in the pancreas (T2*<23ms, 84%) and pituitary (T2*<5.9ms, 24%). Pancreatic T2* correlated with pituitary T2* (p=0.007, r=0.2), cardiac T2*(p<0.001, r=0.33), liver T2* (p<0.001, r=0.35), ferritin (p=0.004, r=−0.19) and age (p=0.033, r=0.16). Similarly pituitary T2* related to cardiac T2* (p<0.001, r=0.36) and liver T2* (p=0.026, r=0.17). On multivariate analysis, however, pancreatic T2* related to both heart T2* (p<0.001) and liver T2* (p=0.001), while pituitary T2* only related to heart T2* (p<0.001). Documented complications amongst the cases included heart failure (ejection fraction EF<55%, n=28, 16%), hypogonadism (n=84,47%), diabetes mellitus (n=44, 25%), hypoparathyroidism (n=16, 9%) and hypothyroidism (n=36, 20%), with hepatitis B and C carrier state in 2% and 25% respectively. On univariate and multivariate analysis, all 4 endocrine failures correlated with only cardiac T2* results (all p<0.001) and age (all p<0.001), but not with pituitary or pancreatic T2* results. The EF correlated with T2* of pituitary, pancreas and heart, but only MRI heart T2* correlation remained significant on multivariate analysis.
Conclusions: MRI pituitary and pancreatic evaluation is viable in a cohort of poorly chelated Chinese thalassemia major patients on subcutaneous deferoxamine treatment. However, an abnormal cardiac T2* result is a good surrogate for endocrine iron overload and appeared more relevant in predicting endocrine complications.
Toxicities of Intravenous (IV) Pegasparaginase (ONCASPAR®) in Adults with Acute Lymphoblastic Leukemia (ALL).
Authors: Advani Anjali , Earl Marc , Douer Dan , Rytting Michael , Bleyer Archie 
Published: October 2019

Abstract
Background: With the multiple reports of asparaginase-containing regimens used in pediatric ALL therapy achieving a greater survival rate that non-asparaginase treatment regimens used in adult patients, asparaginase therapy is now being increasingly applied in chemotherapy regimens for adults with ALL. One reason for this resurgence is the availability of a long-acting form of the enzyme, pegylated asparaginase, and more recently, flexibility in administration of pegasparaginase via either intramuscular or intravenous routes (Oncaspar®). Given an initial impression in the 1970s that adults were more vulnerable to the toxicities of asparaginase than were children, we assessed the initial experience of intravenous asparaginase in adults with ALL.
Methods: The intial experience with pegylated asparaginase at the University of Southern California (USC), Cleveland Clinic, and University of Texas M.D. Anderson Cancer Center were compiled and compared between institutions and with published results in pediatric patients.
Results (Table): In 76 adult patients administered 192 doses of pegasparaginase in combination with other chemotherapy agents for ALL, hepatotoxicity was most common, with grade 3–4 elevation of serum liver enzymes and grade 3–4 hyperbilirubinemia in 36% and 14% of the patients, respectively. Hyperglycemia and chemical pancreatitis were next most common, having occurred at grade 3–4 levels in 25% and 5% of patients, respectively. Grade 3–4 toxicities in the 5–10% range were thrombosis, hypofibrinogenemia, nausea/vomiting, and fatigue. Grade 3–4 allergy/hypersensitivity, neuropathy, and CNS ischemia were reported in 1–5% of patients.
Conclusions: Intravenous pegasparaginase is hepatotoxic in ∼1/3 of adult patients and has a variety of other, non-hepatic toxicities in <10% of patients, of which the most common are pancreatitis, thrombosis, nausea/vomiting and fatigue. Intravenous pegasparaginase has a toxicity profile, in combination with other chemotherapy agents used in ALL therapy, in adult patients that similar to that in pediatric patients, and warrants increased use in adult patients with ALL.
Grade 3–4 Toxicities of IV Pegasparaginase in Adults USC Cleveland Clinic MD Anderson Total Median Age (Years) 28 37 20 33 Age Range (Years) 17–57 20–68 14–28 17–68 No. Doses / Patients 81 / 45 41 / 18 70 / 13 192 / 76 % Patients with Grade 3–4 Toxicity Elevated liver enzymes 31% 28% 62% 36% Hyperbilirubinemia 13% 22% 15% 14% Hyperglycemia 27% 17% 31% 25% Elevated serum amylase 0% 0%R 0% 5% Fatigue 7% 0% 0% 7% Thrombosis 4% 6% 6% 0% Hypofibrinogenemia 0% 28% 28% 0% Elevated PT/INR 0% 0% 0% 7% Bleeding 0% 0% 0% 8% Nausea/vomiting 2% 17% 17% 1% Allergy/hypersensitivity 0% 0% 0% 1% Neuropathy 2% 0% 0% 4% CNS ischemia 0% 0% 15% 3%