bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Use of Aprotinin to Reduce Transfusion Requirements in Children Undergoing Cardiac Surgery: A Meta-Analysis.
Authors: Arnold Donald M. , Fergusson Dean A. , Chan Anthony K. , Cook Richard J. , Fraser Graeme A. , Lim Wendy , Heddle Nancy M. , Blajchman Morris A. , Cook Deborah J. 
Published: October 2019

Abstract
Background. Aprotinin, an antifibrinolytic medication, reduces the requirement for allogeneic red blood cell (RBC) transfusion following elective cardiac surgery in adults. The effect of aprotinin for this indication in children is unclear.
Objective. To determine if intravenous aprotinin, administered perioperatively to patients <18 years of age undergoing cardiac surgery with cardiopulmonary bypass (CPB), reduces post-operative allogeneic blood transfusion requirements (RBCs or whole blood transfusions), compared to children who do not receive aprotinin.
Methods. Systematic review of all relevant randomized controlled trials. We searched MEDLINE, EMBASE, the Cochrane Library and published abstracts. In duplicate, 2 investigators independently selected studies based on explicit inclusion and exclusion criteria; disagreement was resolved by consensus. Using a validated scale, and blinded to outcomes, authors and journal, 2 investigators independently rated the methodological quality of each selected study. Study results were combined using the random effects model to obtain a pooled relative risk.
Results. Of 547 studies identified, 11 studies published from 1993 to 2003 were included. Four of the 11 studies were judged to be of good methodological quality. Overall, aprotinin was associated with a lower proportion of children requiring transfusion, but this was not significant (relative risk 0.73, 95% CI: 0.51–1.04). We found significant heterogeneity among studies (I2= 73.0%, p= 0.001), attributed largely to methodological quality. When we pooled the 4 studies of good methodological quality, aprotinin significantly reduced the proportion of children requiring transfusion (relative risk 0.60, 95% CI 0.38–0.95). Aprotinin had no effect on the total amount of blood transfused or on the volume of chest tube drainage.
Conclusions. Aprotinin reduced the proportion of children exposed to allogeneic blood transfusion following cardiac surgery by 40% in randomized trials of good methodological quality. Additional high quality studies are needed to confirm the potential benefit of aprotinin in this population.
Impact of HLA Mismatch on the Incidence of Acute GVHD and Rejection after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation (RICT).
Authors: Teshima Takanori , Matsuo K. , Matsue K. , Kawano F. , Taniguchi S. , Hatanaka K. , Nakao S. , Tanimoto M. , Hara M. , Eto T. , Wake A. , Abe Y. , Ohno Y. , Takemoto Y. , Harada M. , Takahashi S. , Ishida Y. , Kanda Y. , Imamura M. , Kasai M. , Takaue Y. 
Published: October 2019

Abstract
HLA incompatibility between the donor and recipient is the most critical factor governing the incidence of rejection and GVHD after conventional allogeneic stem cell transplantation. But the impact of HLA disparity on GVHD and graft rejection after RICT remains to be elucidated. We retrospectively analyzed the outcomes of 437 patients who underwent bone marrow (n=95) or peripheral blood stem cell RICT (n=342). The numbers of patients who received a graft from a HLA-matched (275 from siblings, 11 from family members, and 54 from unrelated donors), one-locus-mismatched, 2- or 3-loci-mismatched donor were 340, 65, and 32, respectively. The HLA-matched group included significantly higher population of patients who received cyclosporine alone for GVHD prophylaxis. The overall cumulative incidence of grade II-IV acute GVHD was 40% for all subjects. It was 38% (95% CI; 33%–43%) in recipients of HLA-matched donors, 43% (95% CI; 31%–54%) in those of one-locus-mismatched donors, and 54% (95% CI; 37%–68%) in those of 2–3-loci-mismatched donors. A Cox regression model adjusted for potential confounders including GVHD prophylaxis demonstrated that 2-3 loci-mismatch was identified as an independent risk factor of grade II-IV acute GVHD (Table). Use of antithymocyte globulin was identified as an independent better protective factor for GVHD (HR;0.66, p=.003). Cumulative incidence of rejection was significantly higher after one-locus mismatch RICT (Table) and the risk tended to increase in relation to an increase of HLA disparity. Malignant disease was identified as an independent prognostic factor for rejection. In patients with hematologic malignancies, overall survival (OS) of recipients of 2–3-loci-mismatched RICT at 1 year (38%, 95%CI; 21%–54%) was significantly worse than that after HLA-matched RICT (65%, 95%CI; 59%–70%). By contrast, there was no statistical difference in the incidence of grade II-IV acute GVHD and OS between HLA-matched RICT and one-locus-mismatched RICT. Multivariate analysis demonstrated 2–3-loci-mismatch (Table) and high-risk disease (HR; 2.3, p=.001) as independent risk factors for OS. Thus, HLA incompatibility between the donor and recipient is an important risk factor for rejection, acute GVHD and overall survival after RICT. Therefore RICT from a one-locus-mismatched donor may represent an effective alternative approach in patients lacking HLA-matched sibling donors.
multivariate analysis n acute GVHD Rejection OS HR (95%CI) p HR (95%CI) p HR (95%CI) p match 340 1.0 1.0 1.0 1-mismatch 65 1.4 (0.9–2.2) 0.20 4.5 (1.1–17.9) 0.03 1.0 (0.6–1.6) 0.88 2–3-mismatch 32 2.2 (1.2–4.1) 0.02 7.0 (0.8–64.8) 0.08 3.3 (1.8–6.2) <0.001
Outcomes Analysis of Patients Surviving ≥2 Years after Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT).
Authors: Sobecks Ronald , Kalaycio Matt , Pohlman Brad , Andresen Steven , Rybicki Lisa , Kosar Jennifer , Serafin Mary , Sands Karen , Lalli Christy , Brown Stacey , Kuczkowski Elizabeth , Bolwell Brian 
Published: October 2019

Abstract
We have previously demonstrated the value of evaluating patients with NHL undergoing autologous HSCT at 2 years post-transplant; high grade lymphoma patients in CCR 2 years post-transplant are cured, whereas patients with intermediate and low grade histologies are at ongoing risk of relapse. We elected to perform a similar analysis of AHSCT patients. We retrospectively reviewed 161 consecutive AHSCT recipients who had a minimum of 2 years follow-up and who were alive 2 years post AHSCT. Patients received their transplants from 7/1988 to 7/2002. Median age was 36 years; 75% had myeloid malignancies and 25% lymphoid; AML was the most common diagnosis (39%) followed by CML (29%), ALL (14%), NHL (10%), MDS (6%), and myeloma (2%). 98% received bone marrow alone as the hematopoietic stem cell source; 98% received a busulfan/cyclophosphamide-based preparative regimen. 129 (80%) had a matched related donor. Of those patients alive 2 years post AHSCT, 31 patients (19%) have subsequently died, with a median follow up of 6 years. Relapse was the cause of death in 29%; GVHD in 35%; secondary malignancy in 7%; infections in 16%. Patients with myeloid malignancies faired better than those transplanted with lymphoid malignancies, as shown below; (p= 0.04)
Figure Figure
When we analyzed the pts who developed their first episode of any chronic GVHD or extensive chronic GVHD there were no significant differences between lymphoid and myeloid malignacy patients. Patients receiving a matched sibling donor transplant did not have a plateau in their survival curve, and it continued to inexorably decline. Patients receiving a matched unrelated donor transplant did have a plateau of their survival curve if patients survived at least 3 years (p=0.03). We conclude that the significant majority of patients alive after AHSCT do well with extended follow-up. The graft vs. tumor effect appears to be more robust in myeloid malignancies as compared to lymphoid malignancies. Although most of these patients do well with extended follow-up, the lack of a plateau in the survival curve for patients receiving a matched sibling donor allogeneic BMT warrants additional study.
A Role for Plasma Urokinase Plasminogen Activator Receptor (uPAR) in Thrombosis in Paroxysmal Nocturnal Hemoglobinuria (PNH).
Authors: Sloand Elaine M. , Mainwaring Lori , Wong Elaine , Tang Yong , Horne McDonald K. , Young Neal S. 
Published: October 2019

Abstract
Venous thrombotic events are responsible for serious morbidity and the most frequent cause of death in patients with paroxysmal nocturnal hemoglobinuia (PNH). Urokinase plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-linked protein which is expressed on neutrophils and endothelial cells and mediates endogenous thrombolysis through a urokinase plasminogen activator (uPA)-dependent mechanism. On the cell surface, pro-uPA binds to uPAR via its growth factor domain, promoting the conversion of pro-uPA to active uPA. Active uPA in turn cleaves the proenzyme plasminogen, yielding active plasmin. Previous work in PNH patients has shown that the membrane form of uPAR is decreased or absent on granulocytes, and soluble uPAR levels are increased in patient’s plasma. In the current study of 45 patients with PNH and 20 normal controls, we demonstrate that plasma suPAR concentrations correlated directly with the proportion of neutrophils lacking CD16, another GPI-anchored protein (R2=0.9), and that levels are 4-10-fold greater in PNH than in controls. Patients with a history of thrombosis had higher soluble uPAR levels (in stored samples pre-dating the thrombotic event) than did patients without a history of thrombosis (mean 2.2 ng/mL compared to 0.5 ng/mL; p=0.0001). suPAR levels returned to normal in all of five patients undergoing successful bone marrow transplantation. In normal persons soluble uPAR may be generated by alternative splicing or proteolytic cleavage. In vitro we demonstrated release of suPAR from PNH hematopoietic cells: supernatants obtained from PNH CD34 cells cultured in liquid media with standard growth factor in three experiments showed suPAR levels 20 fold greater than those obtained from normal CD34 cells. Platelets also appeared to be a substantial source of suPAR: uPAR was expressed on the surface of ADP-activated CD59-positive but not CD59-negative platelets from PNH patients. By an ELISA specific for suPAR and by immunoblot, we showed that substantial quantities of suPAR were released following collagen-activation of PNH but not normal platelets. Plasma from PNH patients contained much greater quantitites of suPAR than did peripheral blood cells from those patients. Theoretically, suPAR might bind to plasma uPA, preventing its interaction with the active membrane-anchored form. In vitro, we demonstrated dose-dependent decreases in the activity of single-chain urokinase following the addition of recombinant suPAR, with loss of 25% of the activity after the addition of 0.45nM suPAR. The absence of leukocyte and platelet plasma membrane associated uPAR and high levels of soluble uPAR in the circulation may be useful in predicting thrombosis and suggest mechanisms of anticoagulation in these unusual patients.
Decreased Incidence of Clonal Evolution to Myelodysplastic Syndrome with Monosomy 7 in Children with Aplastic Anemia Following Reduced Duration G-CSF Therapy and Early Indication for BMT from an Alternative Donor.
Authors: Yagasaki Hiroshi , Kazuko Kudo , Kato Koji , Matsumoto Kimikazu , Horibe Keizo , Kojima Seiji 
Published: October 2019

Abstract
A serious complication of aplastic anemia (AA) is an evolution to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In a previous nationwide retrospective study, development of MDS/AML with monosomy 7 was observed in a significant proportion (22%) of AA children who were treated with cyclosporine and G-CSF. In an examination of the risk factors for such malignant transformation, our previous prospective study suggested a close relationship between use of G-CSF and secondary MDS/AML in nonresponders to immunosuppressive therapy (IST). However, a recent nationwide survey showed a prominent decreased in incidence of secondly MDS/AML. Here, we attempt to address the question as to why the incidence of malignant transformation-monosomy 7 has recently decreased in Japan. Between 1988 and 2003, 60 patients (30 male, 30 female; median age, 9 years; range, 0–17 years) at two hospitals received IST consisting of antithymocyte globulin (ATG) and cyclosporine with or without G-CSF and survived more than 1 year after diagnosis of AA. Because 13 IST nonresponders received alternative donor BMT as salvage therapy, we evaluated the incidence of malignant transformation in the 47 patients who did not received BMT. Because all patients were enrolled in the prospective multicenter study since 1993, which was the year that the Japan Marrow Donor Program was established, we compared the incidence of MDS/AML among children who were diagnosed between 1988 and 1992 (group A: n=27, with all but one receiving G-CSF), and those who were diagnosed between 1993 and 2003 (group B: n=20, with 12 receiving G-CSF). MDS with monosomy 7 was observed in 7 of the 27 patients (26%) in group A, and all of these received G-CSF, with the evolution occurring between 17 and 102 months after diagnosis, while no of the 20 patients in group B developed MDS/AML during the follow up of 1 to 11 years (median of 6 years; p=0.014). The response rate to IST did not differ significantly between group A and group B (50% vs 60%, p=). Three of 14 (21%) IST nonresponderss in group A and 10 of 12 (83%) non responders in group B received BMT from an alternative donor (p<0.01). The duration of G-CSF therapy was significantly longer in group A than in group B (186 days vs 56 days, p<0.01).
Enhanced DNA Repair Via Fanconi Anemia/BRCA Pathway Is Involved in Melphalan-Resistant Myeloma Cells.
Authors: Chen Qing , Van der Sluis Pieter C. , Hazlehurst Lori , Dalton William S. 
Published: October 2019

Abstract
Melphalan, a DNA crosslinker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). Interstrand cross-links (ICL) are amongst the most toxic types of DNA damage; therefore, DNA cross-linking agents are important drugs in cancer treatment. Unfortunately, although most patients respond to standard and high dose melphalan therapy, eventually patients acquire drug resistance. Acquired melphalan resistance has been associated with reduced DNA crosslinks, elevated levels of glutathione and increased radiation survival. However, mechanisms associated with resistance are not well understood.
Evidence has accumulated to suggest that ICL repair contributes to the melphalan resistance. In this study, we compared the gene expression profile (GEP) of the melphalan-resistant myeloma cell line, 8226/LR5 to the 8226/S drug sensitive cell line, and found genes involved in FANC/BRCA DNA cross-link repair pathway had increased expression in drug resistant cells. The aim of our study was to determine whether FANC-BRCA pathway affects the DNA cross link repair capacity and accounts for acquired melphalan-resistance.
Using real time RT-PCR and Western Blotting, we examined the expression levels of FANC/BRCA pathway genes in two different drug sensitive and resistant cell lines: 8226/S 8226/LR5, and U266/S and U266/LR6. The results showed that increased expression of FANC/BRCA pathway genes correlated with the melphalan resistance. The formation of ICL at 5 hours after a 2 hour melphalan exposure was reduced in the LR5 compared to the drug sensitive cell 8226 using single cell comet assay. Using siRNA to knock down FANCL or FANCF in melphalan-resistant cell line LR5 reversed the drug resistance. Conversely, overexpression of FANCL or FANCF in the 8226/S drug sensitive cell line enhanced cell survival. These data show that enhanced DNA repair via Fanconi anemia/BRCA pathway is involved in melphalan-resistant myeloma cells.
A Comparison of Apheresis Cell Content Collected from the Same Donors Mobilized with Granulocyte Colony Stimulating Factor (G-CSF) Vs. a Single Injection of AMD3100.
Authors: Chakrabarti Sakti , Takahashi Y. , Read E.J. , Khuu H. , Goodwin R. , Leitman S. , Bolan C. D. , Srinivasan R. , Barrett A.J. , Calandra G. , Childs R. 
Published: October 2019

Abstract
AMD3100 (AMD) is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 to its cognate receptor CXCR4 present on CD34+ hematopoetic progenitor cells. Recently, investigators have shown that substantial numbers of CD34+ cells are released into circulation following a single injection of AMD, making this a potentially attractive mobilization agent for both autologous and allogeneic hematopoietic cell transplantation. Mononuclear cells transplanted in G-CSF (G) mobilized allografts mediate both desirable and undesirable post-transplant events (i.e. Graft-vs-tumor and GVHD); therefore, to determine the suitability of AMD mobilized products for allografting, we assessed the cellular content of apheresis collections obtained from the same donors mobilized with AMD vs G. Between 11/03–07/04, 6 healthy donors (male=3, female=3), median age 43 years (range 18–57), underwent a 15–25 liter apheresis following G mobilization (10mcg/kg/d x 5 days); 66–143 (median 82) days later, the same donors underwent repeat apheresis 6 hours following a single subcutaneous injection of AMD (240mcg/kg); the apheresis blood volume processed after AMD mobilization was matched to the volume processed after G mobilization in 5/6 donors. Data on peripheral blood (PB) and apheresis cellular content with both mobilization agents are shown in Table-1. AMD was well tolerated (no > grade I toxicities) and effectively mobilized CD34+ cells in the majority of donors who had a previous successful G mobilization. Both drugs significantly increased PB CD34+ counts and the total WBC count, and absolute neutrophil counts (ANC), monocyte counts (AMC) and lymphocyte counts (ALC) above pre-mobilization baselines. In the PB, the increase in WBC count, ANC, and the CD34+ counts were significantly higher after G mobilization compared to AMD. In contrast, there was a trend towards a higher blood ALC increase following AMD administration compared to G. Apheresis collections mobilized with AMD contained similar numbers of mononuclear cells and CD3+ T-cells, higher numbers of CD19+ B-cells and lower numbers of monocytes and CD34+ cells compared to G mobilized collections; whether prior G mobilization negatively impacted the CD34+ cell content in AMD mobilized grafts can not be determined from this study. One patient failed mobilization with both G (CD34+ pre-count 6 /uL) and AMD (CD34+ pre-count 6 /uL); a trial investigating the efficacy of combining AMD with G in patients who fail to mobilize with G alone is currently being pursued. A detailed phenotypic analysis of lymphocyte subsets mobilized with G vs AMD3100 will be presented in a separate analysis.
Defibrotide (DF) Targets Tumor-Microenvironmental Interactions and Sensitizes Multiple Myeloma and Solid Tumor Cells to Cytotoxic Chemotherapeutics.
Authors: Mitsiades Constantine S. , Rouleau Cecile , Menon Krishna , Teicher Beverly , Iacobelli Massimo , Anderson Kenneth C. , Richardson Paul G. 
Published: October 2019

Abstract
Introduction: Defibrotide (DF) is a polydisperse oligonucleotide with anti-thrombotic, thrombolytic, anti-ischemic, and anti-adhesive properties, which selectively targets the microvasculature and has minimal hemorrhagic risk. DF is an effective treatment for veno-occlusive disease (VOD), an important regimen-related toxicity in stem cell transplantation characterized by endothelial cell injury. DF also augments stem cell mobilization by modulating adhesion in vivo. Because of its cytoprotective effect on the endothelium, we specifically investigated whether DF protects tumor cells from cytotoxic anti-tumor agents. Further, because of its broad anti-adhesive properties, we evaluated whether DF modulates the interaction of MM cells with bone marrow stromal cells (BMSCs), which confers growth, survival and drug resistance in the BM milieu.
Methods: In vitro studies in isogenic dexamethasone (Dex)-sensitive and resistant MM cell lines (MM-1S and MM1R, respectively) showed that DF does not attenuate the sensitivity of MM cells to Dex, the proteasome inhibitor bortezomib (PS-341), melphalan (MEL), vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel) or platinum (cisplatin), but does decrease their sensitivity to doxorubicin. These selective effects in vitro of DF in protecting tumor cells against doxorubicin and modestly sensitizing MM cells to platinum was also confirmed in solid tumor breast (MCF-7) and colon (HT-29) carcinoma cell lines. Although DF had minimal in vitro inhibitory effect on MM or solid tumor cell growth in vitro, it showed in vivo activity as a single agent and enhanced the responsiveness of MM tumors to cytotoxic chemotherapeutics, such as MEL or cyclophosphamide, in human MM xenografts in SCID/NOD mice. The in vivo single-agent activity and chemosensitizing properties of DF, coupled with its lack of major in vitro activity, suggested that DF may not directly target tumor cells, but rather modulate tumor cell interaction with BMSCs. In an ex vivo model of co-culture of primary MM tumor cells with BMSCs (which protects MM cells against conventional chemotherapy), DF alone had a only modest effect on tumor cell viability, but it significantly enhanced MM cell sensitivity to cytotoxic chemotherapy (e.g. MEL), suggesting that a major component of the biological effects of DF may be attributable not to direct targeting of tumor cells, but to modulation of the interactions that tumor cells develop with the local stromal milieu.
Conclusion: Our studies show that DF mediates in vivo anti-MM activity by abrogating interactions of MM cells with their BM milieu, thereby enhancing sensitivity and overcoming resistance to conventional chemotherapy. These data support future clinical trials of DF, in combination with both conventional and novel therapies, to improve patient outcome in MM.