bluuebunny/crossref_metadata_2025_split huggingface dataset:
Red Blood Cell (RBC) and Platelet (PLT) Transfusion after Allogeneic Transplant for Leukemia: Similar Utilization after Sibling (SIB) Peripheral Blood Stem Cell (PBSC) and Umbilical Cord Blood (UCB) Graft.
Authors: Brunstein Claudio G. , Larson Sarah , Rodgers Tyson , Eastlund Ted , Symons Katherine , Weisdorf Daniel 
Published: April 2020

Abstract
Transfusion independence is an important goal of hematopoietic stem cell transplantation (HSCT) for acute leukemia. We hypothesized that time to red blood cell (RBC) and platelet (PLT) transfusion independence would differ depending on the source of stem cells and the intensity of the preparative regimen. We retrospectively analyzed all transfusions administered to 146 acute leukemia patients who underwent a HSCT at our institution receiving a sibling (SIB) peripheral blood stem cell (PBSC) or an unrelated umbilical cord blood (UCB) graft, between 7/01 and 12/03. Median age was 35.6 yrs. (range 0.5–69.6) and 88 (60%) were male. Ninety-eight (67%) patients (pts) received an UCB and 48 (33%) a SIB graft. Thirty-four (71%) SIB and 56 (57%) UCB pts. received a myeloablative preparative regimen. Median time to RBC independence among all SIB PBSC recipients (n= 25) was 56 days [myeloablative conditioning (MA) (n= 18) 52.5 days; non-myeloablative conditioning (NMA) (n=7) 58 days], and the cumulative incidence of RBC independence at 6 months was 52% (95%CI: 39–69) [MA 53% (95%CI: 38–73); NMA 43% (95%CI: 28–89)]. For recipients of a UCB graft (n= 58) median time to RBC independence was 47 days [MA (n= 38) 56.5 days; NMA (n=20) 41.5 days], and the cumulative incidence of RBC independence at 6 months was 59% (95%CI: 50–70) [MA 68% (95%CI: 56–82); NMA 48% (95%CI: 34–66)]. Median time to platelet (PLT) independence among all SIB PBSC recipients (n= 27) was 25 days [MA (n= 19) 26 days; NMA (n=8) 12 days], and the cumulative incidence of PLT independence at 6 months was 56% (95%CI: 44–73) [MA 56% (95%CI: 41–76); NMA 57% (95%CI: 35–94)]. There was no statistically significant difference in the cumulative incidence of RBC independence between SIB PBSC vs. UCB (p=0.49), and MA vs. NMA (p=0.18). For recipients of an UCB graft (n= 68) median time to PLT independence was 43 days [MA (n= 44) 47.5 days; NMA (n=24) 39 days], and the cumulative incidence of PLT independence at 6 months was 69% (95%CI: 61–79) [MA 79% (95%CI: 68–90); NMA 57% (95%CI: 44–75)]. There was no statistically significant difference in the cumulative incidence of PLT independence between SIB PBSC vs. UCB (p=0.52), and MA vs. NMA (p=0.21). In multivariate analysis, the source of HSC and intensity of the preparative regimen were not predictors of RBC or PLT independence. This analysis shows similar RBC and PLT utilization in recipients of SIB PBSC and UCB following either MA or NMA conditioning. The substantial costs associated with transfusion support for allogeneic HSC transplant are similar in SIB PBSCT and UCB graft recipients.
A Randomized Trial of Heparin Plus Anti-Thrombin III (ATIII) vs. Heparin Alone To Prevent VOD after HSCT.
Authors: Jung Chul W. , Lee Jeeyun , Park Byeong Bae , Park Se H. , Kim Jung Han , Kwon Jung Mi , Oh Sung Yong , Kim Hyun Jung , Lee Hyorak , Kim Kihyun , Ahn Jin Seok , Kim Won Seog , Park Keunchil 
Published: April 2020

Abstract
Background: Hepatic veno-occlusive disease (VOD) is a devastating regimen-related toxicity after hematopoietic stem cell transplantation (HSCT). There is no safe and proven therapy for established VOD, and focus has been on its prevention. Previous studies have shown that ATIII level is markedly decreased in patients with VOD. We conducted a prospective, randomized trial to compare heparin plus ATIII versus heparin alone in HSCT recipients.
Methods: A clinical diagnosis of hepatic VOD was defined as satisfying two of the following criteria: bilirubin &gt; 2.0 mg/dl, unexplained weight gain of &gt; 2% from baseline, and hepatomegaly. The levels of PAI-1, TFG-β and TNF-α were measured at weekly basis for correlative analysis. Patients were randomized to receive or not receive prophylactic ATIII 1000U twice daily from day 1 until day +14 post-HSCT plus heparin 5U/kg/hr from day 1 until day +21 or discharge after HSCT.
Results: Thirty patients were enrolled for the study. Fourteen patients received heparin + ATIII and 16 patients received heparin alone for VOD prophylaxis during HSCT. There were 9 AML, 6 NHL, 4 ALL, 3 CML, 2 ABL, 2 MM, 1 MDS, 1 HD, 1 AA and 1 SLL patient. Of the 30 patients enrolled, 13 patients received sibling allogeneic HSCT, 13 autologous, 3 unrelated allogeneic and 1 cord blood HSCT. VOD occurred in 4 patients (25%) in the heparin alone group and none in the heparin + ATIII group (0%, P = 0.044). The incidence of bleeding complication was higher in the heparin alone group (4/16, 25%) than the heparin + ATIII group (1/14, 7%) without statistical significance (P = 0.190). The mean baseline level of PAI-1 was slightly higher in the heparin + ATIII group (30.9 ± 31.0 ng/ml) when compared to the heparin group (18.9 ± 13.0 ng/ml, P = 0.062). The PAI-1 level decreased markedly in the heparin + ATIII group (23.0 ±10.1 ng/ml) by the third week following VOD prophylaxis therapy (heparin group; PAI level 40.3 ± 40 ng/ml, P = 0.010). The mean baseline levels of TGF-β and TNF-α did not differ significantly between the two groups. There was no VOD-related death.
Conclusions: Although it was a preliminary analysis, the combination of ATIII and heparin for VOD prophylaxis in HSCT recipients seems to be more effective than heparin alone without increasing the hemorrhagic complication.
ZAP-70 Is Not Phosphorylated on the Activating Tyrosine Residue (Tyr319) in Chronic Lymphocytic Leukemia and B-Cell Lymphoma Cells.
Authors: Gobessi Stefania , Petlickovski Aleksandar , Laurenti Luca , Efremov Dimitar G. 
Published: April 2020

Abstract
The protein tyrosine kinase ZAP-70 is expressed at high levels in leukemic B-cells from chronic lymphocytic leukemia (CLL) patients with progressive disease and short survival. ZAP-70 is a key component of the proximal T-cell receptor signaling pathway and is highly homologous to Syk, an important B-cell receptor signaling (BCR) molecule. Recent studies indicate that ZAP-70 may participate in BCR signaling as well, but the mechanism of action is still not well understood. In T-cells, upon TCR stimulation ZAP-70 becomes phosphorylated on Tyr319 by the Src-like kinase Lck, which results in the release of the ZAP-70 kinase domain from an autoinhibited state to a fully active conformation. The Tyr319 site in ZAP-70 corresponds to the Tyr352 site in Syk, which is phosphorylated in B-cells following BCR stimulation. We therefore investigated the activation status of ZAP-70 and Syk in BCR stimulated CLL B-cells, using phosphorylation of Tyr319 and Tyr352 as markers of their activation. Analysis of 10 ZAP-70-positive CLL samples by immunoblotting with the phospho-ZAP70Tyr319/SykTyr352 antibody revealed that ZAP-70 is not phosphorylated at this site either before or after BCR stimulation, although in control experiments with Jurkat T-cells ZAP-70 became phosphorylated on Tyr319 upon TCR stimulation. Moreover, the Tyr352 site in Syk was phosphorylated following BCR stimulation in 6 of the 10 CLL B-cell samples. To further investigate the reasons for the unexpected lack of ZAP-70 activation in CLL B-cells, we produced stable transfectants of the BJAB lymphoma B-cell line that expressed ZAP-70 at levels similar to those found in CLL cases with progressive disease. In agreement with the CLL B-cell experiments, the Tyr319 site in ZAP-70 was not phosphorylated either before or after BCR stimulation. Since phosphorylation of Tyr319 is Lck-dependent in T-cells, and this kinase is expressed also in CLL B-cells, we ectopically expressed Lck in the ZAP-70-positive BJAB clones. Again, the Tyr319 site was not phosphorylated, indicating that ZAP-70 does not undergo activation of the kinase domain also in this cellular system. In contrast, BCR crosslinking in BJAB cells induced significant phosphorylation of Tyr352 in Syk, which was further enhanced in the clones that coexpressed ZAP-70. Furthermore, analysis of downstream signaling pathways following BCR stimulation showed stronger and prolonged activation of ERK and to a lesser extent Akt in the ZAP-70 positive clones, whereas no difference was observed in terms of activation of PLC-γ 2, JNK and degradation of the NF-kB inhibitor IkB. These data indicate that ZAP-70 does not undergo full activation in B-cells, but can still enhance activation of certain downstream BCR signaling pathways, possibly by affecting the activity of the related PTK Syk.
A G&gt;A Transition in the Non-Coding Exon 1 of the Factor XI Gene as the Cause of Factor XI Deficiency in Three Afro-Caribbean Patients.
Authors: Mitchell Michael J. , Dai Letian , Alhaq Anwar , Savidge Geoffrey F. 
Published: April 2020

Abstract
Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of 9%, associated with two common founder mutations E117X (Type II) and F283L (Type III). However, factor XI deficiency is found in all ethnic groups, with causative mutations being highly heterogeneous - mutations having been described in all exons with the exception of the non-coding exon 1.
In a study of &gt;120 ethnically diverse factor XI deficient patients, three patients of Afro-Caribbean origin were found to be heterozygous for a G&gt;A transition at nucleotide −53 within exon 1 of the factor XI gene. All three patients showed a low FXI:C on at least 3 different occasions (SM[female] 44.3–57.1, AB[female] 42.3–51.2 and GA[male] 70.3–72.9, Range 76–136u/dl). The 2 female patients were both reported to have a lupus anticoagulant which may explain the lower levels seen, although a lupus screen was negative. No variation within the coding sequence of the factor XI gene was detected. Two of the patients were heterozygous for the −403 G&gt;T promoter polymorphism, whilst the remaining patient was homozygous for the −403 T allele and heterozygous for the −273 C&gt;G polymorphism. Analysis of &gt;50 factor XI alleles in patients of Afro-Caribbean origin failed to detect this base change in individuals with normal factor XI levels.
Purine-rich sequences, such as that in exon 1 affected by the −53 G&gt;A substitution, are known to form extremely stable minihairpin loops. These sequences /structures have been shown to be important as splicing enhancers and in mRNA stability, particularly in making them more resistant to nucleases. Within the 5′ untranslated region (5′-UTR) of genes they have been demonstrated to be important in modulating translation efficiency. The -53 G&gt;A substitution is located just 10 bases prior to the start of the factor XI mRNA and any of these mechanism could potentially explain the causative nature of this change. The -53 G&gt;A substitution is predicted to cause ‘slippage’ within the postulated minihairpin loop, potentially making it unstable. Further work is on-going to try and prove and explain the causality of this mutation.
We speculate that the -53 G&gt;A base change affects the normal processing of factor XI mRNA and, possibly in combination with the promoter polymorphisms, results in a mildly reduced plasma factor XI level.
Severe Aortic and Mitral Valve Regurgitation Are Associated with von Willebrand Factor Defect.
Authors: Susen Sophie , Vincentelli Andre , Le Tourneau Thierry , Caron Claudine , Zawadzki Christophe , Prat Alain , Goudemand Jenny , Jude Brigitte 
Published: April 2020

Abstract
Severe aortic stenosis can be associated with mucosal and gastrointestinal bleeding probably related to loss of high molecular weight (HMW) multimers of VWF. Possible mechanisms of this loss are enhanced proteolysis by shear-dependant metalloprotease (ADAMTS 13) of HMW multimers of VWF or increased platelet-VWF interactions leading to clearance or degradation of HMW multimers of VWF. The aim of our study was to investigate wether this high shear-stress induced loss of HMW multimers of VWF is observed in other cardiac defects associated with high pressure blood flow such as severe aortic or mitral valve regurgitation.
Twenty four consecutive patients were operated on for aortic valve regurgitation (n=11) or mitral valve regurgitation (n=13). Before surgery recent mucosal bleeding was reported in 25% patients (n=5).VWF Closure Time of PFA 100® (CTADP) were prolonged in 87% of patients (n=20). The ratio of ristocetin cofactor activity to antigen and the ratio of collagen-binding activity to antigen were decreased in 28%(n=5) and 45%(n=10) of patients respectively. HMW multimers of VWF were decreased in 82 % (n=18) of patients. Six months after surgery, CTADP were normal in 71% (n=17) of patients, ratios were normal in all patients evaluable for this parameter (n=14) and HMW multimers of VWF increased in all patients as compared with preoperative value (8±2,5%vs10±2,3; p=0.04) but remain under value of control plasma in 63% (n=14) of patients.
In this study we demonstrated that VWF defect can be associated with severe aortic or mitral valve regurgitation and that platelet function-analyzer closure time, abnormalities of von Willebrand factor, or both could be frequent in those valve disease and might cause mucosal bleeding.
Relationship of Harvest CD34+ and CD3+ Counts To Chronic Graft-Versus-Host Disease (cGVHD), Relapse and Survival Following Sibling Allogeneic Stem Cell Transplant.
Authors: Kew Andrea K. , Couban Stephen , Thompson Kara , Djulbegovic Benjamin 
Published: April 2020

Abstract
G-CSF mobilized peripheral blood stem cells are increasingly used as a source of cells for sibling allogeneic transplantation. In comparison with bone marrow transplants (BMT), peripheral blood stem cell transplants (PBSCT) have been associated with increased chronic graft-versus-host disease (cGVHD). In order to examine the relationship between CD34+ and CD3+ counts and the development of cGVHD, we analyzed the outcome of patients from an international database of nine randomized trials comparing PBSCT and BMT. There were a total of 1111 patients: 305 patients developed extensive cGVHD, 261 limited cGVHD, 368 had no cGVHD and 177 did not have adequate information concerning cGVHD for analysis. We excluded patients with limited cGVHD because this can be a difficult diagnosis to make with certainty. We also excluded those without adequate data and thus the analysis is based on 673 patients (305 with extensive cGVHD and 368 with no cGVHD). There was no common baseline hazard for the development of extensive cGVHD among studies and thus the analysis was stratified by study. The primary outcomes were time to development of extensive cGVHD and time to the composite endpoint of death or relapse. Harvest CD34+ and CD3+ counts were analyzed as dichotomous variables based on the median cell counts. In the PBSCT group, the median CD34+ and CD3+ counts were 6.05 and 288.01×106/kg and in the BMT group, the median CD34+ and CD3+ counts were 2.89 and 32.79×106/kg respectively. As previously reported, there was an increased risk of developing extensive cGVHD with PBSCT compared to BMT (hazard ratio 1.77, 95% CI 1.39–2.23). The time to develop extensive cGVHD was not affected by the CD34+ or CD3+ count within either the PBSCT or BMT group. In addition, the composite endpoint of death or relapse was also not affected by either the CD34+ or CD3+ count in the PBSCT group. However, in the BMT group, a higher median CD3+ count was associated with an increased risk of death or relapse (p=0.04). Furthermore, a higher median CD34+ count was associated with a trend to a decreased risk of death or relapse (p=0.09). In summary, we confirm the higher risk of developing extensive cGVHD with PBSCT compared to BMT. In this analysis, we did not find a relationship between CD34+ and CD3+ counts and the risk of extensive cGVHD within either the PBSCT or BMT groups. However, our analysis suggests an association between higher median CD3+ counts and an increased risk of death or relapse in the BMT group. If this observation is confirmed, further studies are required to determine whether the higher CD3+ cell content of the marrow graft exerts a direct effect on the risk of relapse or death, or whether it is a surrogate for a less effective marrow harvest.
Pulmonary Complications after T-Cell Depleted Allogeneic Stem Cell Transplantation: Low Incidence and Strong Association with Acute GVHD.
Authors: Huisman Cynthia , van der Straaten Hanneke M. , Canninga-van Dijk Marijke R. , Fijnheer Rob , Verdonck Leo F. 
Published: April 2020

Abstract
Lung injury limits the success of hematopoietic stem cell transplantation (HSCT). The overall incidence varies from 30–50% and noninfectious causes occur in one third to one half of these. We reviewed pulmonary complications in 369 patients who received either allo-BMT or allo-PBSCT at our institution between 1993 and 2003. Control subjects were selected from the same database and matched on sex, underlying diagnosis, age, type of transplantation and cytomegalovirus-serostatus. For all patients the conditioning myeloablative regimen consisted of cyclophosphamide (60 mg/kg/day for 2 days) followed by total body irradiation (total lung dose 850 cGy). The graft was partially T-cell depleted (1–2 x 105 T cells/kg).
Sixty-one patients (16.5%) developed pulmonary complications, which were diagnosed at a median of 22 weeks after transplantation (range 2–263). Twenty-one patients (5.7%) developed infectious pneumonia. Non-infectious complications were further subclassified as BO (3.5%), BOOP (0.5%), DAH (0.8%), IPS (5.4%) or mixed etiology (0.5%). Acute GVHD ≥ grade II was significantly more common in patients with pulmonary complications than in the controls (36/61 versus 24/61 patients, P=0.02). There was no significant difference in the incidence of chronic GVHD (in 26/48 pulmonary patients versus 20/55 controls, P=0.1). Median survival was 41 weeks (range 4–583) for the pulmonary patients and 173 weeks (range 8–582) for the control subjects. These data illustrate that the incidence of pulmonary complications is low after T-cell depleted HSCT and demonstrate a clear association with acute GVHD. Improvement of the poor outcome of pulmonary complications is of utmost importance. Current studies at our institution are focused at the detection of early markers so that possible pre-emptive-like therapy can be initiated before symptomatic lung damage arises.
Effective Asparagine Depletion with Pegylated Asparaginase Results in Improved Outcomes in Adult Acute Lymphoblastic Leukemia (ALL) — Cancer and Leukemia Group B Study 9511.
Authors: Wetzler Meir , Sanford Ben L. , Owzar Kouros , Kurtzberg Joanne , DeOliveira D. , Frankel Stanley R. , Powell Bayard L. , Kolitz Jonathan E. , Bloomfield Clara D. , Larson Richard A. 
Published: April 2020

Abstract
CALGB study 9511 used pegylated asparaginase (PEG-ASP) in lieu of the native enzyme on days 5 and 22 of the 5-drug induction course and days 15 and 43 of the first intensification of the CALGB 8811 regimen (Blood1995; 85:2025). The aim of the study was to explore differences in the overall-survival (OS) and disease-free survival (DFS) profiles of those patients who did versus those who did not achieve asparagine depletion defined as enzyme levels &gt; 0.03 units/ml for 14 consecutive days after at least one of four possible administrations of PEG-ASP (2000 U/m2, subcutaneously, capped at 3750 U). One hundred and four patients were enrolled between 7/95 and 12/97; 43F and 61M. Median age was 40 years (range, 17–71). Performance status (PS) was 0–1 in 81%. Thirty-one patients had an unfavorable [t(9;22), t(4;11), −7, +8] karyotype. Median WBC count was 86.5 x 109/L; 76/104 patients had &gt; 30 x 109/L. PEG-ASP was tolerable (although grade 3 or 4 bilirubin occurred in 54%, hyperglycemia in 40%, and low fibrinogen in 30%). Treatment mortality was 9%. Antibodies to PEG-ASP were detected in 13/85 patients (15%). The complete remission (CR) rate was 76%. Median survival was 22 months [95% CI=13–29]. After a median follow-up of 90 months, 22 patients are alive without disease; three are alive after relapse. Samples were available from 85 eligible patients. Asparagine depletion was not significantly associated with achievement of CR (87.3% vs. 72.7%; P=0.55). Univariate analyses suggest that patients who achieved asparagine depletion (63 patients) had superior OS (two-sided P&lt;0.0016; hazard ratio 2.4 [95%CI=1.4–4.2]) and DFS (P&lt;0.011; hazard ratio 2.3 [95%CI=1.2–4.2]) profiles versus those who did not (22 patients). After adjusting, in the framework of an additive log-linear Cox model, for CR status (OS only), age, gender, PS, unfavorable karyotype, WBC count, detection of antibody to PEG-ASP, and transplantation, the difference between the OS profiles remained statistically significant (P&lt;0.019; hazard ratio 2.1 [95%CI=1.1–3.9]) while the DFS profiles were borderline significant (P&lt;0.052; hazard ratio 2.0 [95%CI=1.0–4.1]). We conclude that effective asparagine depletion with PEG-ASP as part of an intensive multi-agent therapeutic regimen in adult ALL is feasible and associated with improved outcomes.
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