bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study
Authors: Blume KG , Kopecky KJ , Henslee-Downey JP , Forman SJ , Stiff PJ , LeMaistre CF , Appelbaum FR 
Published: October 2019

Abstract
Two novel preparatory regimens for conditioning of patients with leukemia for allogeneic bone marrow transplantation (BMT) from histocompatible sibling donors have been tested in a phase III trial under the auspices of the Southwest Oncology Group (SWOG 8612). These two regimens consisted either of fractionated total body irradiation and etoposide (FTBI/VP-16) or high-dose busulfan with cyclophosphamide (BU/CY). Only patients who had failed prior conventional management at least once were study eligible, ie, no patients with acute leukemia in first remission (CR) or in first chronic phase (CP) of chronic myelogenous leukemia (CML) participated. Patients were stratified according to the following risk criteria: “good-risk” patients were those who were in second CR of their acute leukemia or in accelerated phase (AP) of CML; “poor-risk” patients had further advanced stages of leukemia. During a 52-month period, 131 patients were registered of whom 122 (93%) were study eligible. Sixty-one eligible patients were randomized to the FTBI/VP-16 arm and 61 to the BU/CY regimen. Of these 122 patients, 114 (93%) proceeded to BMT according to protocol. Posttransplant immunosuppression to prevent graft-versus-host disease (GVHD) consisted of cyclosporine and prednisone (CSA/PSE). Neither overall survival nor disease-free survival (DFS) differed significantly between the two treatment groups (P = .89 and .69, respectively). Estimated DFS for “good-risk” patients who had been prepared with the FTBI/VP-16 regimen was 55% +/- 11%, as compared with patients treated with BU/CY whose DFS figure was 34% +/- 10% (P = .30). For “poor-risk” candidates, the DFS rates at 24 months were 17% +/- 6% (for FTBI/VP-16) and 24% +/- 8% (for BU/CY), respectively (P = .81). These figures do not differ significantly, especially in view of the fact that the “good- risk” patients prepared with the FTBI/VP-16 regimen were younger than those treated with BU/CY. Both regimens were well tolerated with no regimen-related deaths encountered during the 6-week period after BMT. This study also confirmed the efficacy of the CSA/PSE combination in the prevention of GVHD with 23 of 113 (20%) of BMT recipients developing moderate to severe acute GVHD. The leading cause for treatment failure was leukemic relapse (45 of the 114 BMT recipients suffered a recurrence of their leukemia), whereas 38 patients died without evidence of relapse. Thirty-one patients are alive and in continued CR after marrow transplantation; four are alive in relapse.(ABSTRACT TRUNCATED AT 400 WORDS)
Regulation of human B-cell precursor adhesion to bone marrow stromal cells by cytokines that exert opposing effects on the expression of vascular cell adhesion molecule-1 (VCAM-1)
Authors: Dittel BN , McCarthy JB , Wayner EA , LeBien TW 
Published: October 2019

Abstract
Self-renewal and differentiation of B-cell precursors is dependent on interactions with bone marrow (BM) stromal cells and associated extracellular matrix. We have recently developed an interleukin (IL)-7- dependent, BM-derived stromal cell culture that supports the growth of normal human B-cell precursors. In the current study, we have characterized the constitutive expression, cytokine-regulated expression, and function of adhesion molecules on BM stromal cells that are critical for adhesion of B-cell precursors. Flow cytometric analysis showed that cultured adult BM stromal cells expressed higher constitutive levels of vascular cell adhesion molecule (VCAM)-1 than intercellular adhesion molecule (ICAM)-1 (CD54). IL-1 beta upregulated VCAM-1 and CD54 in a dose-dependent manner, whereas IL-4 upregulated VCAM-1, but had no effect on CD54. In contrast, transforming growth factor (TGF)-beta decreased the level of BM stromal cell VCAM-1. Using an assay to measure the adhesion of 51Cr-labeled B-cell precursors to BM stromal cells, we observed a direct correlation between cytokine- regulated levels of VCAM-1 and the capacity of stromal cells to support the adhesion of B-cell precursors. Blocking studies using a panel of monoclonal antibodies (MoAb) showed that adhesion of B-cell precursors to untreated and cytokine-treated (IL-1 beta, IL-4) BM stromal cells was mediated by very late antigen (VLA)-4 (CD49d/CD29) and VCAM-1. Adhesion of B-cell precursors could also be enhanced by direct stimulation with MoAb to the CD29 subunit. Our collective results indicate that B-cell precursor/BM stromal cell adhesion is mediated by a VLA-4-VCAM-1 interaction, which in turn can be regulated at the level of the BM stromal cell by cytokines that specifically increase or decrease cell surface VCAM-1.
Rapid discrimination of early CD34+ myeloid progenitors using CD45-RA analysis
Authors: Fritsch G , Buchinger P , Printz D , Fink FM , Mann G , Peters C , Wagner T , Adler A , Gadner H 
Published: October 2019

Abstract
Mononuclear cells (MNC) isolated by density centrifugation of cord blood and healthy bone marrow, and of peripheral blood (PB) from patients treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF after chemotherapy, were double-stained with anti CD34 monoclonal antibody (MoAb) (8G12) versus anti CD45, CD45-RB, CD45- RO, and CD45-RA, respectively, and analyzed by flow cytometry. In all specimens, CD34+ MNC co-expressed CD45 at a low level and the expression of CD45-RB was similar or slightly higher. Most CD34+ MNC were negative for CD45-RO, a weak coexpression was only seen in some bone marrow (BM) and blood samples. In contrast, CD45-RA could subdivide the CD34+ population into fractions negative, dim (+), and normal positive (++) for these subgroups, and typical staining patterns were observed for the different sources of hematopoietic cells: in BM, most CD34+ MNC were RA++. In PB, their majority was RA++ after G-CSF but RA+ or RA- after GM-CSF. In cord blood, the hematopoietic progenitors were mainly RA-/RO-. Semisolid culture of sorted CD34+ MNC showed that clusters and dispersed (late) colony-forming unit-GM (CFU- GM) originated from 34+/RA++ cells, while the 34+/RA- MNC formed compact and multicentric, both white and red colonies derived from early progenitors. Addition of 20 ng stem cell factor per milliliter of medium containing 34+/RA- cord blood MNC led to a change of many burst- forming unit-erythrocyte (BFU-E) to CFU-mix which was not, at least to this extent, seen in blood and BM. We conclude that early myeloid CD34+ cells are 45+/RA-. Because this population excludes 34+/19+ B cells and 33+ myeloid cells, both of which are RA++, two-color flow cytometric analysis using CD34 and CD45-RA facilitates the characterization and quantification of early myeloid progenitor cells.
Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding
Authors: Lee MH , Vosburgh E , Anderson K , McDonagh J 
Published: October 2019

Abstract
A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.
Expression of HERV-K proviruses in human leukocytes
Authors: Brodsky I , Foley B , Haines D , Johnston J , Cuddy K , Gillespie D 
Published: October 2019

Abstract
HERV-K is a 50-copy, human endogenous, class 1 retroviral element that contains some polycistrons with gag, pol, and env open reading frames. Although expression of HERV-K proviruses has been shown in cultured human cell lines, expression of these elements has not been shown in human blood leukocytes. Using both reverse transcriptase-polymerase chain reaction and ribonuclease protection techniques, we show HERV-K pol gene expression in human blood leukocytes. Expression in blood leukocytes from 7 normal individuals was from a variety of different HERV-K proviruses, while restricted expression was observed in blood cells of 5 leukemia patients and 3 polycythemia vera patients. Evidence is presented suggesting that the restricted expression in leukemia blood cells is a result of gene regulation, not gene amplification.
Role of leuCAM integrins and complement in platelet-monocyte rosette formation induced by immune complexes of human immunodeficiency virus- type 1-immune thrombocytopenic purpura patients
Authors: Hymes K , Nardi M , Leaf A , Karpatkin S 
Published: October 2019

Abstract
Patients with human immunodeficiency virus-type 1-immune thrombocytopenic purpura (HIV-1-ITP) have elevated polyethylene glycol (PEG)-precipitable immune complexes (ICs) composed of IgG, IgM, and complement that are threefold to sevenfold higher than in healthy control subjects. These complexes contain anti-F (ab')2 as well as anti- idiotype antibodies versus anti-HIV-1gp120. Because anti-F (ab')2 and anti-idiotype antibodies correlate with thrombocytopenia (r = .83 [J Clin Invest 77:1756, 1986] and r = .90 [J Clin Invest 89:356, 1992], respectively) we studied the binding of ICs to platelets and monocytes as well as their role in platelet-monocyte rosette formation. ICs bind to platelets in a saturation-dependent manner (optimum at 10 micrograms/mL; 0.5% of serum conc). Binding to platelets could not be inhibited with platelet saturating concentrations of aggregated IgG or with monoclonal antibody (MoAb) IV.3 versus FcR gamma II. Platelet binding could be inhibited with Fab anti-C3, anti-Clq, or anti-C4 by 57%, 40%, and 46% respectively, not with control Fab (P < .001). Monocytes from HIV-1-ITP patients form rosettes with normal platelets 16.8 +/- 5.2 rosettes/100 monocytes compared with 4.8 +/- 0.8 control monocytes plus normal platelets (P = .009). Gel-washed HIV-1-ITP platelets formed 19 +/- 2.0 rosettes with U937 cells compared to 6.3 +/- 1.0 for normal platelets (P = 0.001). Arming of U937 cells with HIV-1- ITP ICs (5 micrograms/mL) formed 36.7 +/- 2.5 rosettes compared with 10.6 +/- 1.2 for control ICs (P < .01). Rosetting of armed U937 cells could be inhibited with MoAbs versus the alpha chains of CD11a (LFA-1), 11b (Mac-1), or 11c (p150,95) by 67%, 70%, and 61%, respectively (P < .007), whereas binding of ICs to U937 cells was unaffected. Isotype- matched control as well as MoAbs versus antigens on U937 cells (CD13, CD33) or the anti-FcR gamma II receptor had no effect. However, Fab fragments of polyclonal anti-C3 inhibited rosette formation by 78% (P < .01); control Fab had no effect. Thus, platelet-monocyte rosette formation is not Fc dependent. It is complement receptor dependent and requires the cooperation of all three leuCAM integrins.
Phenotypic diversity of natural killer (NK) populations in patients with NK-type lymphoproliferative disease of granular lymphocytes
Authors: Zambello R , Trentin L , Ciccone E , Bulian P , Agostini C , Moretta A , Moretta L , Semenzato G 
Published: October 2019

Abstract
Using monoclonal antibodies (MoAbs) termed GL183 and EB6, directed to a novel family of natural killer (NK) specific triggering molecules, four functional subsets of NK cells have been recently defined (GL183+EB6-; GL183+EB6+; GL183-EB6+; GL183-EB6-). In healthy individuals, all these subsets are represented in variable portion. The expression of EB6 and GL183 surface antigens has been analyzed in a series of 14 patients with lymphoproliferative disease of granular lymphocytes (LDGL) characterized by a chronic CD3-CD16+ lymphocytosis. Our data showed that in 11 of 14 cases, the proliferation was specifically sustained by one of the four possible subsets of granular lymphocytes (GLs) (seven cases: EB6-GL183-; three cases: EB6+GL183-; one case: EB6-GL183+). In the remaining three cases, a pattern was demonstrated that is consistent with that of healthy individuals (ie, the presence of all four subsets). When expressed on GL surfaces, in the majority of cases tested both EB6 and GL183 MoAbs behave as functional surface molecules as assessed in the redirected killing of P815 target cells. We also provided evidence that EB6+GL183+ proliferating cells show a definite (type 1) in vitro NK specificity as do their normal counterparts. The unique expansion of a defined subset of NK cells in most patients with LDGL suggests that the pathologic noxa leading to GL proliferation selectively acts on a specific subset of NK lymphocytes.
Kinetics of hemoglobin S polymerization and gelation under shear: I. Shape of the viscosity progress curve and dependence of delay time and reaction rate on shear rate and temperature
Authors: Briehl RW , Nikolopoulou P 
Published: October 2019

Abstract
Polymerization and gelation of deoxyhemoglobin S makes red blood cells (RBCs) rigid and is the immediate basis of pathogenesis in sickle cell disease. Hence, characterization of hemoglobin S viscosity and its time- dependent development as RBCs pass through the microvasculature is important in understanding pathogenesis. Because RBCs and the intraerythrocytic milieu in vivo are subject to shear, the shear dependence of polymerization kinetics is also important. In steady- state cone-plate viscometry we find: (1) gelation under shear progresses exponentially with time; (2) shear markedly increases exponential rate and (3) shortens delay time independent of when in the delay time it is applied; (4) shear greatly decreases the temperature dependence of the exponential rate and delay time; (5) simultaneous with its acceleratory effect on polymerization, shear breaks down gel structure. We conclude that shear acts to accelerate gelation by breaking fibers and creating new growing ends, a process that occurs in addition to the homogeneous and heterogeneous nucleation of new fibers that occurs in the absence of shear. Fibers that break are part of a gel network rather than in free solution. The shear dependence of gelation rates means that the critical clinical issue, whether the delay time is long enough and gelation slow enough to permit deoxygenated cells to pass through the microvasculature before they rigidify, depends on in vivo shear rates as well as on degree of unsaturation and hemoglobin concentration.
Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support
Authors: Rabinowitz J , Petros WP , Stuart AR , Peters WP 
Published: October 2019

Abstract
Endogenous cytokines are thought to mediate numerous biologic processes and may account for some adverse effects experienced following the administration of recombinant proteins. This study describes the pattern of endogenous cytokine exposure following high-dose chemotherapy. Blood concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF), and erythropoietin (EPO) were measured by enzyme-linked immunosorbent assay (ELISA) methods in 68 patients receiving the same ablative chemotherapy regimen (cyclophosphamide, cisplatin, carmustine). Patients were grouped according to cellular support (autologous bone marrow [BM] CSF-primed peripheral blood progenitor cells [PBPCs]) and prescribed growth factor (recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor [rHuG- CSF or rHuGM-CSF]). Leukocyte reconstitution was most accelerated in the groups treated with PBPCs and rHuG-CSF. IL-6, M-CSF, and TNF-alpha concentrations were higher in the groups treated with rHuGM-CSF and without PBPCs. Maximal endogenous cytokine concentrations occurred approximately 12 days after BM reinfusion. High concentrations of EPO occurred in patients experiencing significant hypotension despite routine transfusions for hematocrit < 42%. High M-CSF and IL-6 levels were associated with increased platelet transfusion requirements. Concentrations of all four cytokines were significantly higher in patients experiencing renal or hepatic toxicity, with elevations occurring in a predictable sequence and M-CSF elevations occurring first. This report shows that endogenous cytokine concentrations may be influenced by either cellular or CSF support and are associated with differences in platelet reconstitution and organ toxicity.
A gene for a myosin peptide is disrupted by the inv(16)(p13q22) in acute nonlymphocytic leukemia M4Eo
Authors: van der Reijden BA , Dauwerse JG , Wessels JW , Beverstock GC , Hagemeijer A , van Ommen GJ , Breuning MH 
Published: October 2019

Abstract
Chromosome 16 aberrations are well known in acute nonlymphocytic leukemia (ANLL). The most frequent chromosome 16 aberration in ANLL subtype M4Eo is the inv(16)(p13q22). Recently, we showed that in 5 inv(16) patients with ANLL M4Eo the short arm breakpoints are clustered within a 14-kb genomic EcoRI fragment. We report here the identification of a gene situated in the 14-kb fragment. The gene, which codes for a myosin peptide, is disrupted by the inversion of chromosome 16 in the 5 patients. To the best of our knowledge, this is the first report of a myosin gene disrupted in leukemia.
Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases
Authors: Mullen CA , Anderson KD , Blaese RM 
Published: October 2019

Abstract
This study describes the effects of two major treatment options, splenectomy and/or bone marrow transplantation, on the natural history of the Wiskott-Aldrich (WAS) syndrome. The records of 62 patients with the WAS evaluated at the National Institutes of Health Clinical Center from 1966 to 1992 were reviewed. Nineteen patients were treated with bone marrow transplantation (BMT) and the results were largely dependent on the source of the graft. Twelve of 12 patients receiving HLA-matched sibling marrow achieved satisfactory immunologic and hematologic reconstitution. By contrast, only 2 of 7 patients receiving haploidentical, parental, or matched unrelated marrow survived more than 1 year after BMT. Thirty-nine patients who lacked suitable bone marrow donors early in their course underwent splenectomy for management of their thrombocytopenia; most received prophylactic antibiotics to minimize the risk of sepsis. Nearly all these patients achieved normal platelet counts and the rate of serious bleeding was reduced nearly sevenfold. Median survival in the untransplanted splenectomy group was 25 years, compared with less than 5 years in unsplenectomized patients. We conclude that HLA-matched sibling donor BMT is the treatment of choice for patients with WAS and that splenectomy and daily prophylactic antibiotics provide a significant survival advantage to those boys without a matched sibling donor. Splenectomy should probably be used in preference to unmatched BMT until results with alternative donor BMT significantly improve or gene therapy becomes available.
Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583 [see comments]
Authors: Ozer H , George SL , Schiffer CA , Rao K , Rao PN , Wurster-Hill DH , Arthur DD , Powell B , Gottlieb A , Peterson BA 
Published: October 2019

Abstract
We investigated whether recombinant alpha 2b interferon (r alpha 2bIFN) would reduce the proportion of bone marrow Philadelphia chromosome (Ph) cells in chronic-phase chronic myelogenous leukemia (CML) by treating 107 previously untreated patients daily with r alpha 2bIFN at 5 x 10(6)IU/m2 subcutaneously. Patients with complete remission, partial remission, or partial hematologic remission received treatment until progression; those with progressive disease were taken off study and observed for survival. Sixty-three (59%) of the patients achieved at least a partial hematologic remission (24 complete remissions and 39 partial remissions). The median time to response for the 63 responders was 3.4 months, with a median duration of remission of 52 months and with 81% of responders continuing in remission beyond 12 months. The median survival for the 107 patients was 66 months. Of 78 patients with cytogenetic follow-up data, 31 (40%) achieved a partial cytogenetic response (n = 17) or a complete cytogenetic response (n = 14). The percentage of cytogenetic responders among all patients was 29% (31 of 107 patients). The median time to first cytogenetic response was 9 months. A major dose reduction of r alpha 2bIFN (> or = 50%) was required at some time during treatment in 38% of patients, 26% required 10% to 49% dose reductions, and 36% had minor dose reductions of < or = 10%. No association was observed between dose received and the attainment of a cytogenetic response. None of the usual prognostic factors (sex, race, performance status, weight loss, time from diagnosis to treatment, hepatosplenomegaly, age, symptoms, hemoglobin, or platelet, blast, basophil, or white blood cell count) were significantly related to survival. These data provide confirmation that major cytogenetic responses to prolonged administration of subcutaneous r alpha 2bIFN occur in 20% to 38% (95% confidence interval) of chronic- phase Ph-positive patients. Although it is hypothesized that patients achieving major cytogenetic responses to r alpha 2bIFN should have prolonged remission duration and survival compared with nonresponders, analyses of the effect of cytogenetic responders by both “landmark” and time-dependent covariate techniques fail to provide statistically significant evidence for an effect of cytogenetic response on remission duration or survival. This may be due in part to an effect size insufficiently large to be detected with the number of patients treated in this study. Thus, confirmation of remission duration or survival benefit, if any, of r alpha 2bIFN therapy in Ph-positive chronic-phase CML must await the outcome of randomized trials comparing IFN with conventional agents.