bluuebunny/crossref_metadata_2025_split huggingface dataset:
Venous Thromboembolism among 1,570 Patients Undergoing Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, Treatment and Outcomes.
Authors: Gerber David E. , Segal Jodi B. , Levy M. Yair , Kane Joyce M. , Jones Richard J. , Streiff Michael B. 
Published: April 2020

Abstract
Introduction: Venous thromboembolism (VTE) is increasingly diagnosed among individuals with hematologic malignancies. It is unclear whether patients undergoing hematopoietic stem cell transplantation (HSCT) are at risk for VTE. We aimed to describe the incidence of VTE and risk factors among patients undergoing HSCT.
Methods: Using ICD-9 procedure codes in a discharge database, we identified all patients undergoing inpatient HSCT at Johns Hopkins between July 1, 1993, and June 30, 2005. We reviewed electronic medical records for each patient to identify VTE and bleeding. The associations between VTE and clinical characteristics were tested using parametric and non-parametric statistical tests and survival analysis methods.
Results: 1,570 patients had 3,425 person-years of follow-up. Median age was 46 years and 51% of patients were male. All patients had indwelling central venous catheters; pharmacological VTE prophylaxis was not used for any patient but ambulation was encouraged. Between admission and 180 days after HSCT, 75 VTE occurred in 70 patients (4.5%; 95% CI, 3.5–5.6%). VTE included 55 (73%) catheter-associated and 11 (15%) non-catheter-associated deep venous thromboses (DVT), and 9 (12%) pulmonary emboli (PE). Median platelet count at time of VTE was 77 K/mm3 (interquartile range [IQR] 42–159 K/mm3), and platelet count was &lt; 50 K/mm3 at the time of VTE in 31% of cases. In multivariate analyses, VTE was associated with a history of prior VTE (OR 2.86; 95% CI, 1.25–6.55) and with graft-versus-host-disease (GVHD) (OR 2.36; 95% CI, 1.38–4.04). 86% of patients received anticoagulation for treatment. Clinically significant bleeding occurred in 238 patients after HSCT (15%), of whom 56 patients had fatal bleeding. Bleeding was associated with GVHD (OR 2.32; 95% CI, 1.71–3.16) and with initiation of anticoagulation for VTE diagnosed after HSCT (OR=3.00; 95% CI, 1.73–5.21). Bleeding was not associated with the continuation of anticoagulation initiated prior to admission (OR=1.13; 95% CI, 0.54–2.35).
Conclusions: VTE occurs relatively infrequently among patients undergoing HSCT and primarily in association with central venous catheter use. In contrast, clinically significant bleeding is a relatively common complication of HSCT, even in the absence of pharmacologic VTE prophylaxis. The unique hemostatic milieu associated with HSCT should be carefully considered when contemplating routine VTE prophylaxis in this patient population. The low risk of VTE associated with the high risk of bleeding makes pharmacologic VTE prophylaxis in this population both unnecessary and hazardous.
Clinical Trial of Therapeutic Blockade of CTLA4 with Ipilimumab in Patients with Relapse of Malignancy Following Allogeneic Hematopoietic Transplantation.
Authors: Bashey Asad , Medina Bridget , Corringham Sue , Pasek Mildred , Carrier Ewa , Vrooman Linda , Streicher Howard , Lowy Israel , Solomon Scott R. , Morris Lawrence E. , Holland Kent , Mason James R. , Soiffer Robert J. , Ball Edward D. 
Published: April 2020

Abstract
Relapse/progression of malignancy (RM) is an important cause of treatment failure and death following allogeneic hematopoietic stem cell transplantation (allo-HCT). CTLA-4 is an important negative regulator of effector T-cell activation. CTLA-4 inhibition has demonstrated potent anti-cancer effects in animal models, and in patients with some solid tumors. CTLA-4 blockade following allo-HCT may potentially augment graft-versus-malignancy but GVHD may also possibly be increased. We report the safety and preliminary efficacy of a dose-escalation study of a neutralizing human monoclonal antibody targeting CTLA-4 (ipilimumab) in patients with RM following allo-HCT. Eligibility criteria included allo-HCT ≥90 days previously, &gt; 50% donor T-cell chimerism, no prior grade 3/4 GVHD, no prophylaxis/therapy for GVHD for ≥ 6 weeks. Patients received a single dose of ipilimumab over 90 min. DLI at a dose of 5 × 10e6 CD3 cells/kg was allowed 8 weeks following ipilimumab if no GVHD occurred and RM was present. A total of 29 patients were treated at four centers (23M, 6F; median age 43 (21–65); Hodgkins disease [HD] =14 Myeloma [MM]=6, CML=2, CLL=2, AML=2, NHL=1, Renal Ca =1, Breast Ca=1; 19 related donors, 10 unrelated; 6 myeloablative, 23 RICT).(4 at dose-level 1 [DL1] 0.1 mg/kg, 3 at 0.33 mg/kg [DL2], 4 at 0.66 mg/kg [DL3], 3 at 1.0 mg/kg [DL4] and 15 at 3.0 mg/kg [DL5]). Eight patients had failed prior DLI. Median time between BMT and ipilimumab was 366 d (125–2368). Dose-limiting toxicity was not encountered. No patient developed clinically significant GVHD within 90 days following ipilimumab alone. Three possible immune adverse events were documented: grade 3 polyarthropathy 14 weeks following ipilimumab, and 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, DL1); grade 1 hyperthyroidism with thyroid-stimulating antibody 6 weeks post ipilimumab (CLL, DL3). Grade 2 pneumonitis responsive to corticosteroids (HD, DL5). Ten patients received DLI after ipilimumab. Three patients developed objective evidence of disease response after ipilimumab alone: PR in a patient with mantle cell NHL lasting 3m [DL4]; ongoing CR in a two patients with HD [DL5]. Two of these patients had failed prior DLI. Three additional patients demonstrated possible anti-cancer effects (MR in a HD patient, reduction of PB and BM blasts in AML, DL1; maintenance of molecular remission in a CML patient given ipilimumab alone for 3.5 yrs despite stopping imatinib, DL1). This study shows that doses of ipilimumab (up to 3.0 mg/kg) can safely be administered to patients with RM following allo-HCT without inducing/exacerbating GVHD while inducing regressions of malignancy including durable CR in some patients.
No Difference in Survival or Long-Term Disease Outcomes in Palifermin-Treated Patients with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Spielberger Ricardo , Territo Mary , Durrant Simon , Nimer Stephen , McCarty John , Hurd David , Berger Dietmar , Aycock Jeff , Chen Mon-Gy , Stiff Patrick 
Published: April 2020

Abstract
Background: Oral mucositis is an adverse effect of myeloablative therapy which has serious clinical and economic consequences as well as a negative impact upon quality of life. The duration and severity of oral mucositis can be reduced by administering palifermin to patients with hematological malignancies receiving myeloablative therapy and undergoing hematopoietic stem cell transplantation (HSCT). However, we still require additional data on the long-term disease outcomes of patients treated with palifermin. Therefore we present here the long-term, safety data for palifermin-treated HSCT patients followed up for approximately 60 months after the last palifermin dose.
Methods: The long-term safety data were collected during the follow-up phase of 4 parent trials where patients had received at least one dose of palifermin or placebo. Study assessments included overall survival (OS), progression-free survival (PFS), and secondary malignancies. Assessments were made at 6-month intervals during year 1 and annually thereafter until death or loss to follow-up. Kaplan-Meier curves for overall survival and PFS were calculated and the treatment groups were compared using stratified log-rank test.
Results: Altogether 662 patients were randomized to treatment and received either palifermin or placebo (421 palifermin, 241 placebo); 538 patients entered the follow-up study (342 palifermin, 196 placebo). The median follow-up time for patients alive at last visit was 49.8 months (palifermin N=290) and 49.5 months (placebo N=169). There were 131 (32%) and 72 (30%) deaths in the palifermin and placebo groups, respectively. The overall survival curves were similar for both groups (p=0.717). Disease progression occurred in 167 (41%) palifermin- and 87 (36%) placebo-treated patients; the difference in PFS between the two groups was non-significant (p=0.280). Secondary malignancies were observed in 8% of patients in both groups: the incidence of secondary hematologic malignancies was 4% (palifermin: 14/342) versus 5% (placebo: 10/196) while the incidence of solid tumors was 2% in both groups.
Conclusion: The results of this 60-month follow-up study indicate that long-term disease outcomes are not affected by administering palifermin to patients with hematological malignancies who are receiving myeloablative therapy and undergoing HS. There was no difference in OS and PFS between the palifermin and placebo groups. Furthermore there was no difference in the incidence of secondary malignancies between the two patient groups. The incidence of secondary hematologic malignancies and solid tumors was low, comparable between groups, and within the expected range for this patient population.
Experiment Therapy of Aplastic Anemia Using Cyclosporin A Combined with IDO Agonist.
Authors: Huang Lifang , Dai Min , Liu Wenli , Zhou Jianfeng , Sun Hanying , Zhang Yicheng 
Published: April 2020

Abstract
Aplastic anemia(AA) is an unusual hematologic disease and the paradigm of the human bone marrow failure syndromes. Abnormal immunological responses have been found in most aplastic patients. Activated type 1 cytotoxic T cells may be the main contributing factor of pathogenesis. IDO is a rate-limiting enzyme in Tryptophan(Trp) metabolism. The proliferation of Th1 cells is specifically inhibited by the over-expression of IDO, which can degrade the Trp in local environment, hamper the conductioin of the activating signal in T cell and induce immune tolerance. 3,4-DAA is an IDO agonist and can activate IDO. In our experiment, Balb/c mice were irradiated (5.0Gy of 60Co), and then infused with 5×106 lymph node(LN) cells from DBA/2 mice in 4 hours. Blood count was monitored and marrow damage was assessed by histogical study. Concentrations of serum IFN-γ were measured by ELISA. The levels of Tryptophan and kynurenine were evaluated by high performance liquid chromatography (HPLC). CD4+CD25+ T cells in spleen were analyzed by flow cytometry. The level of Foxp3 in CD4+CD25+ T cell was measured by RT-PCR. Irradiation and infusion of LN cells led to rapid development of severe pancytopenia and bone marrow hypoplasia. Bone marrow of affected mice showed lymphocyte infiltration. Serum IFN-γ concentration increased 3.7 fold at d6 post infusion. The recipient mice were divided into 4 different treating groups as follow:
0.9% Sodium Chloride as control; Cyclosporin A (CsA) (50ug/g/d ×5d, peritoneal injection); 3,4-DAA(5mg/d, orally daily); the combination of CsA and 3,4-DAA.
The effects of CsA, IDO agonist and CsA combined IDO agonist were analyzed at day 6,10,14,21,24 and 28 after LN cells infusion. The white cell and the platelet recovered to near normal, respectively (4.2±0.32)×109, (937±190.47)×1012 at d21 in the combination group. Early stage treatment with CsA can improve periphery blood cells and BM nucleated cells, but long term effect was not remarkable. In contrast, the 3,4-DAA group exhibited slow and gradually enhanced role. Periphery blood cells and BM nucleated cells were improved remarkably in the combination group. The number and function of CD4+CD25+T cells also increased remarkably. In the treatment of AA, abnormal immune response in bone marrow was inhibited by CsA, meanwhile immune tolerance was induced through up-regulating the regulatory T cells(Treg) by 3,4-DAA. In this way, the balance of immune in bone marrow could be reestablished quickly. CsA combined IDO agonist could provide a new strategy for the management of AA.
Monosomy 7 Detected by FISH at Disease Presentation Is a Marker for Non-Response to Immunosuppression.
Authors: Sloand Elaine , Scheinberg Phillip , Fenlon Edward , Blancato Jan , Pfannes Loretta , Sloand Elaine M. , Young Neal S. 
Published: April 2020

Abstract
About fifteen percent of patients with severe aplastic anemia (sAA) who undergo immunosuppression therapy (IST) develop clonal disease in the decade following treatment. Of 122 patients treated with horse ATG/CsA at NIH, 13 developed cytogenetic abnormalities (monosomy 7 in 9 patients, 7p deletion in one, and trisomy 8 in 2) (Rosenfeld et al: JAMA289:1130; 2003). Monosomy 7 usually occurs in patients with sAA who are unresponsive to IST. Factors responsible for clonal progression in bone marrow failure are still unclear. We and others have reported that monosomy 7 may be detected by fluorescent in situ hybridization (FISH) months before conventional cytogenetics and that high levels of GCSF foster preferential expansion of the monosomy 7 clone in vitro (Sloand E et al; Proc. Natl. Acad. Sci2006;103:14483). We hypothesized that a clone of monsomy 7 cells might indicate an underlying stem cell disorder unlikely to respond to immunosuppression or reflect more severe disease marked by higher endogenous GCSF levels. FISH was undertaken on 40 bone marrow samples obtained from aplastic anemia patients at presentation and before immunosuppressive treatment. Bone marrow mononuclear cells were hybridized with centromeric probes specific for chromosome 7 and chromosome 8 (to control for hybridization efficiency); samples were assessed on duplicate slides by three investigators who were unaware of the diagnoses and outcomes. Twenty-five healthy controls were tested concurrently. The upper limit of normal was set at 6% based on control data. Of twenty-one patients with &gt; 6% monosomy 7 cells, response to IST was observed in 12 (57%), while 6 of 19 (84%) with normal FISH responded to IST (p=0.08). Thirteen patients had monosomy 7 frequencies of &gt;10%. Of these 5 (38%) responded to IST, compared with 23/27 (85%) with ≤10% monosomy 7. The proportion of monosomy 7 cells in the bone marrow correlated with age (R2 =0.6, p&lt;0.001). Two of the 23 non-responding patients later developed clonal progression with monosomy 7 or 7q-; both had &gt;10% monosomy 7 by FISH at presentation, but normal cytogenetics. The two responding patients tested with &gt;6% monosomy 7 prior to IST demonstrated &lt;2% following successful IST, suggesting that the high endogenous levels of G-CSF present before IST response may have facilitated expansion of the clone. Significant monosmy 7 clones may reflect a stem cell disorder in patients not responding to IST.
A Novel Splicing Factor RBM25 in Erythroid Differentiation.
Authors: Zhou Anyu , Cho Aeri , Huang Shu-Ching , Benz Edward J. 
Published: April 2020

Abstract
Many protein factors that guide pre-mRNA modification pathways are composed of RNA recognition motif (RRM) domains. In an effort to identify splicing regulators in erythroid cells, we cloned a RRM-containing protein RBM25 and characterized its role in alternative splicing. RBM25 consists of a proline-rich region and a RRM domain at the amino-terminal end, an ER rich domain at the central region, and a PWI domain at the carboxyl terminal end. RBM25 partially co-localized with splicing factor SC35 in nuclear speckles. While both the RRM and PWI domains are diffusely distributed in the nucleoplasm, the ER domain is highly concentrated in nuclear speckles. We examined cellular mRNA targets of RBM25 in HeLa cells and demonstrated that it binds Bcl-x mRNA and affects its alternative splicing. Depletion of RBM25 by RNA interference caused accumulation of anti-apoptotic Bcl-x(L), whereas its up-regulation increased the levels of pro-apoptotic Bcl-x(s). The expression level of RBM25 also correlated with the degree of cell death, further suggesting that it functions in regulating apoptotic factor(s) expression. Apoptosis plays an important role in red cell development; earlier erythroid progenitors are more sensitive to apoptosis while mature erythroblasts are resistant to apoptosis. A significant decrease in RBM25 expression occurs during erythroid differentiation and correlates with resistance to apoptosis. Our results suggest that erythroblasts may acquire resistance to apoptosis during maturation through differential expression of crucial splicing regulators of the apoptotic machinery.
Localization of Factor VIII Interactive Site within Plasmin/Plasminogen Which Is Responsible for Plasmin-Catalyzed Activation/Inactivation of Factor VIII.
Authors: Nishiya Katsumi , Nogami Keiji , Okada Kiyotaka , Matsuo Osamu , Takeyama Masahiro , Ogiwara Kenichi , Tanaka Ichiro , Yoshioka Akira , Shima Midori 
Published: April 2020

Abstract
Plasmin (Plm), an active form of plasminogen (Plg), not only functions as a key enzyme in the fibrinolytic system, but also directly inactivates several coagulation factors. Especially, factor VIII is inactivated by Plm immediately after the activation by limited proteolytic cleavage at Lys36, Arg336, Arg372, and Arg740 in the heavy chain, and at Arg1689 and Arg1721 in the light chain (Nogami et al. J. Biol. Chem. 2007, 282, 5287). We recently have identified the plasmin-interactive sites on the A2 domain responsible for cleavages at Arg336 and Arg372, and on the light chain responsible for cleavage at Lys36 (Abst #1991/1709, BLOOD 102/108, 2005/2006). In the present study, we attempted to localize a factor VIII-interactive site on Plm (and Plg). Competitive binding assay using 6-aminohexanoic acid (6-AHA), a competitor of lysine-binding site (LBS) of Plm/Plg, showed that 6-AHA markedly inhibited (by &gt;90%) the light chain binding to active-site modified Plm (anhydro-Plm), whilst inhibited weakly the A2 binding (by ∼30%). These results suggested that the light chain interaction with Plm was mainly dependent upon LBS, but the A2 interaction was independent. The addition of monoclonal antibody (mAb) against Plg kringle 5-catalytic domain (K5-CD) significantly inhibited Plm-catalyzed activation/inactivation of factor VIII or VIIIa with an ∼4-fold lower rate constant. On the other hand, anti-K1-3 and anti-K4 mAbs any little affected. SDS-PAGE analysis revealed that only anti-K5-CD mAb blocked Plm-catalyzed cleavages at Arg336 and Arg372 by ∼90% in dose-dependent manners (IC50: ∼20 nM). Surface plasmon resonance-based assays showed that the isolated K5-CD bound to factor VIII with an ∼50-fold higher affinity (Kd: 3 nM) compared to the K1-3 and K4, similar to the affinity obtained with anhydro-Plm (Kd: 4 nM). In particular, the K5-CD bound to the A2 domain with an ∼5-fold higher affinity (Kd: 42 nM) than those obtained with the K1-3 and K4. In contrast, both the K1-3 and K4 bound to the light chain predominantly (Kd: 43 and 87 nM, respectively), whilst the K5-CD failed to bind. Furthermore, the addition of a goat antibody against the CD (C-14; Santa Cruz Biotechnology) completely blocked the A2 and K5-CD interaction (by ∼95%). These findings suggest that the CD of Plm (and Plg) interacts with the factor VIII A2 domain through the LBS-independent mechanisms, whilst the K1-3 (and/or K4) interacts with the light chain through the LBS-dependent mechanisms. Furthermore, the CD and A2 interaction would regulate the activation/inactivation of factor VIII by proteolytic cleavages of Arg336 and Arg372.
Autologous Stem Cell Transplantation (ASCT) for Elderly Patients (≥ 60 Years) with Non-Hodgkin’s Lymphoma (NHL): An Analysis Based on EBMT Registry.
Authors: Jantunen Esa , Canals Carmen , Blaise Didier , Rambaldi Alessandro , Tilly Herve , Conde Eulogio , Gisselbrecht Christian , Dreger Peter , Ossenkoppele G.J. , Allione Bernardino , Pfreudschuh M. , Craddock Charles , Sureda Anna 
Published: April 2020

Abstract
Limited data is available on feasibility and efficacy of ASCT in elderly patients with NHL.
Patients: In 2000–2005 15869 NHL patients with ASCT were reported to EBMT database, 3133 (20%) were ≥ 60 years. Only patients with MED-B dataset and those with either diffuse large B-cell lymphoma (DLBCL), mantle cell (MCL) or follicular lymphoma (FL) were subjected to more detailed analysis. This group included 906 elderly NHL patients (median age 63 years, range 60–75) (DLBCL, n = 463; MCL, n = 208; FL, n = 235) who were compared with 3661 patients &lt; 60 years (DLBCL, n = 2149; MCL, n = 435; FL, n = 1077) regarding outcome. Bulky disease was more common in younger patients (26% vs. 15%, p &lt; 0.001) as well as B-symptoms at diagnosis (42% vs. 36%, p = 0.02). Elderly patients had received more often at least two treatment lines before ASCT (70% vs. 59%, p&lt;0.001). The median follow-up for the surviving patients was 14 months.
Results: Non-relapse mortality (NRM) was higher in patients ≥ 60 years of age: 3.8% vs.2.3% at 100 days, 6.9% vs. 3.9% at 1 year and 9.4% vs. 5.8% at 3 years (p&lt;0.001). No differences in NRM were observed between patients aged 60–64 years (n = 633) and those aged 65–69 (n = 240). A higher NRM was observed in DLBCL and MCL patients compared to FL patients (p=0.001and p=0.002, respectively). Other variables associated with a higher NRM were an elevated LDH at diagnosis (p=0.04), ≥ 2 treatment lines before ASCT (p&lt;0.001); a poor performance status at ASCT (p&lt;0.001); not being in CR1 at ASCT (chemosensitive disease vs. CR1, p=0.02; chemorefractory disease vs. CR1, p&lt;0.001) and BM as stem cell source (p=0.02). In multivariate analysis, elderly patients showed a higher NRM [RR = 1.6 (CI 1.2–2.1), p=0.001]. In patients with DLBCL, age ≥ 60 years at ASCT was associated with a trend to a higher risk of relapse or progression (p =0.07) and a worse PFS (p=0.008). PFS at 2 years was 69% vs. 79% for patients in CR1 and 52% vs. 60% for patients with sensitive disease at ASCT, respectively. In MCL, elderly patients had worse PFS (p=0.008). PFS at 2 years was 78 vs. 81% for MCL patients in CR1 and 52% vs. 67%, respectively for those patients autografted with sensitive disease. Older age was not a significant prognostic factor either for relapse rate or for PFS in patients with FL. PFS at 2 years was 69% and 81% for FL patients in CR1, and 69% and 69% for FL patients with sensitive disease, respectively.
Conclusions: ASCT is feasible in selected NHL patients aged 60–69 years. The outcome is promising taking into account the generally poorer prognosis of lymphomas in elderly population.