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W Leisenring

Publications and source records attributed to W Leisenring.

At least 19 recordsLinked to original sources
PubMed2001

Absence of major histocompatibility class II expression does not impair hematopoiesis in mice.

OBJECTIVE: Major histocompatibility class II (MHC II) molecules are among the earliest antigens to be expressed in hematopoietic progenitor cells; however, the functional role of these molecules in hematopoiesis remains controversial. We examined the role of MHC II antigens during hematopoiesis using a mouse model of MHC II deficiency related to the absence of the critical transcriptional activator, CIITA. METHODS: Sca-1(-), Sca-1(+)lin(+), and Sca-1(+)lin(-) populations of marrow cells from CIITA(-)(/-) and wild-type mice were analyzed by immunofluorescence for MHC II expression. Hematopoietic capacity was assessed in CIITA(-/-) and wild-type mice by CFU-S, CFU-GM, and radiation sensitivity assays. RESULTS: Flow cytometric characteristics of hematopoietic progenitors from CIITA(-/-) and wild-type mice were identical except for the absence of MHC II expression in CIITA null mice. There were no significant differences in capacity for hematopoietic reconstitution and clonogenicity as measured by radiation sensitivity, CFU-S, and CFU-GM assays among CIITA(-/-) and wild-type mice. CONCLUSIONS: These experiments show that downregulation of MHC II gene transcription does not effectively alter normal hematopoiesis, and provide strong evidence that MHC II expression on hematopoietic progenitors is not required for normal hematopoietic development.

Animals↗
PubMed2001

A proposed objective way to assess results of randomized prospective clinical trials with acute graft-versus-host disease as an outcome of interest.

The assessment of graft-versus-host disease (GVHD) as an end-point in clinical trials requires subjective judgement to distinguish morbidity caused by GVHD from morbidity caused by other complications. We developed a method based on ordinal regression for longitudinal assessment of morbidity involving the skin, liver and gut, regardless of cause as an objective end-point in randomized prospective phase III treatment or prevention trials for which GVHD is an outcome of interest. This method was validated for treatment studies by showing that morbidity was more severe among patients with grade II-IV GVHD than among those who did not have GVHD. We found no differences in morbidity involving the skin, liver and gut after the diagnosis of GVHD in a group of 30 patients who received peripheral blood stem cells and a group of 37 who received marrow in a randomized phase III clinical trial. These preliminary results suggest that objective end-points could be used in randomized clinical trials for treatment of GVHD. Further studies will be needed to determine if similar methods could be used in randomized clinical trials for prevention of GVHD.

Acute Disease↗
PubMed2001

Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers.

This report summarizes the experience with a conditioning regimen of cyclophosphamide and antithymocyte globulin in patients with severe aplastic anemia given HLA-matched related marrow grafts at 4 transplantation centers. Enrolled were 94 consecutive patients, of whom 87 had received multiple transfusions and 38 had failed immunosuppressive therapy. Their ages ranged from 2 to 59 years. After transplantation, 89 patients received a methotrexate/cyclosporine regimen for graft-versus-host disease (GVHD) prevention. Cyclosporine with or without prednisone was given in 4 patients, and no immunosuppression was given in 1 patient. Ninety-six percent of patients had sustained grafts, whereas 4% rejected grafts between 2 and 7 months after transplantation. Of the 4 rejecting patients, 3 are alive with successful second engraftments. Acute grade II GVHD was seen in 21% of patients, grade III in 7%, and grade IV in 1% of patients. Chronic GVHD was seen in 32% of patients, most of whom responded completely to immunosuppressive therapy. With a median follow-up of 6.0 years (range, 0.5-11.6 years), the survival rate was 88%. No unusual long-term side effects have been seen with the regimen. We conclude that the cyclophosphamide/antithymocyte globulin regimen combined with methotrexate/cyclosporine after transplantation is well tolerated and effective in heavily pretreated patients with aplastic anemia.

Adolescent↗
PubMed2001

Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia.

A multicenter investigation of allogeneic bone marrow transplantation for children with sickle cell disease was conducted that included 27 European and North American transplant centers. Fifty-nine patients who ranged in age from 3.3 to 15.9 years (median, 10.1 years) received HLA-identical sibling marrow allografts between September 1991 and April 2000. Fifty-five patients survive, and 50 survive free from sickle cell disease, with a median follow-up of 42.2 months (range, 11.8 to 115 months) after transplantation. Of the 50 patients with successful allografts, 13 developed stable mixed donor-host hematopoietic chimerism. The level of donor chimerism, measured > or =6 months after transplantation in peripheral blood, varied between 90% and 99% in 8 patients. Five additional patients had a lower proportion of donor cells (range, 11% to 74%). Among these 5 patients, hemoglobin levels varied between 11.2 and 14.2 g/dL (median, 11.3 g/dL; mean, 12.0 g/dL). In patients who had donors with a normal hemoglobin genotype (Hb), the Hb S fractions were 0%, 0%, and 7%, corresponding to donor chimerism levels of 67%, 74%, and 11%, respectively. Among patients who had donors with sickle trait, the Hb S fractions were 36% and 37%, corresponding to donor chimerism levels of 25% and 60%, respectively. Thus, allograft recipients with stable mixed chimerism had Rb S levels similar to donor levels, and only 1 patient required a red blood cell transfusion beyond 90 days posttransplantation. None of the patients have experienced painful events or other clinical complications related to sickle cell disease after transplantation. These observations strongly suggest that patients with sickle cell disease who develop persistent mixed hematopoietic chimerism after transplantation experience a significant ameliorative effect.

Adolescent↗
PubMed2001

Comparison of multidimensional flow cytometry with standard morphology for evaluation of early marrow response in pediatric acute lymphoblastic leukemia.

PURPOSE: We compared multidimensional flow cytometry (MDF) with morphology in evaluating early marrow response to induction chemotherapy in pediatric ALL. METHODS: Chemotherapy response was determined by standard morphology or by MDF assessed by residual leukemic cell percentage remaining in the marrow on days 7, 14, and 28 of induction. Bone marrow response was classified as M3 (>25% leukemic blasts) or M1/M2 (< or = 25% leukemic blasts). Multidimensional flow cytometry evaluation was compared with that of standard morphology. Available day-7 and day-14 marrow slides were also reevaluated by a single pathologist without patients' clinical information. RESULTS: Of 46 day-7 specimens, eight (17%) had discordant MDF and morphologic results (P < 0.001), including six classified as M3 by morphology but were M1/M2 by MDF, and two were classified as M3 by MDF but were M1/M2 by morphology. Of 24 day-14 bone marrow specimens, five (20.5%) were discordant (P < 0.001), including two classified as M3 by morphology but were M1/M2 by MDF, and three were classified as M3 by MDF but were M1/M2 by morphology. Reevaluation of the blinded day-7 and day-14 marrow slides yielded discordance between repeated pathology readings of 11% (P < 0.001) and 6% (P = 0.04), respectively. CONCLUSION: Our data show significant discordance between the morphologic and MDF evaluation of early marrow response. Early response to therapy is a significant prognostic indicator in pediatric acute lymphoblastic leukemia and is used to alter subsequent treatment; thus, precise assessment of response is important. A larger comparison of MDF with morphology for the evaluation of early response, including correlation with clinical outcome, is warranted.

Adolescent↗
PubMed2000

Cytomegalovirus (CMV) DNA load in plasma for the diagnosis of CMV disease before engraftment in hematopoietic stem-cell transplant recipients.

Among hematopoietic stem-cell transplant (HSCT) recipients, cytomegalovirus (CMV) disease before engraftment is rare but often fatal, and cell-based diagnostic tests have low sensitivity in this clinical setting. We used the quantitative real-time polymerase chain reaction (PCR) assay to test for CMV DNA in plasma samples from 15 HSCT recipients who developed CMV disease before engraftment and from 33 matched control patients. CMV DNA was detected in plasma in 14 (93.3%) of the 15 patients who had CMV disease before engraftment, compared with 5 (15.2%) of 33 control patients (P<.001). CMV DNA was detected a median of 13 days before the onset of CMV disease (range, 0-35 days). The maximum CMV virus load in plasma was >1 log(10) higher among case patients than among control patients (median, 1700 [range, 50 to 5.5x107] vs. <50 [range, <50-350] CMV DNA copies/mL plasma, respectively; P<.001). Quantitative PCR for CMV DNA in plasma appears to be useful for the identification of HSCT recipients at risk for CMV disease before engraftment.

Adolescent↗
PubMed2000

Thalidomide for treatment of patients with chronic graft-versus-host disease.

In a randomized, placebo-controlled, double-blind trial, thalidomide or placebo together with glucocorticoids and either cyclosporine or tacrolimus was administered as initial therapy for clinical extensive chronic graft-versus-host disease (cGVHD). All patients had thrombocytopenia or cGVHD that evolved directly from acute GVHD as an indicator of a poor prognosis. The study drug (thalidomide or placebo) was administered initially at a dose of 200 mg orally per day, followed by a gradual increase to 800 mg/d if side effects were tolerable. Treatment with the study drug was discontinued before resolution of cGVHD in 23 (92%) of the 25 patients who received thalidomide and in 17 (65%) of the 26 patients who received placebo (P =.02). Neutropenia and neurologic symptoms were the most frequent reasons for early discontinuation of treatment with thalidomide. The duration of treatment with thalidomide was too short to assess its efficacy in controlling cGVHD. (Blood. 2000;96:3995-3996)

Actuarial Analysis↗
PubMed2000

Graft-versus-host disease and donor-directed hemagglutinin titers after ABO-mismatched related and unrelated marrow allografts: evidence for a graft-versus-plasma cell effect.

The gradual disappearance of host antidonor isohemagglutinins after major ABO-mismatched hematopoietic stem cell (HSC) allografts has been attributed to the gradual destruction of host plasma cells by graft-versus-host effects. To corroborate this hypothesis, we retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998. All patients were conditioned by high-dose pretransplant therapy and given methotrexate/cyclosporine for graft-versus-host disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched related and 228 had unrelated grafts. We asked whether unrelated recipients experienced a more rapid disappearance of isohemagglutinins than related recipients, and whether, within the groups of related and unrelated recipients, the titer disappeared faster in patients with GvHD than in those without GvHD. The median time to reach undetectable antidonor IgG and IgM titers was significantly shorter in unrelated recipients (46 versus 61 days; P =.016). In addition, related recipients with GvHD had a 2. 2-fold increased likelihood (1.12-4.39,95% CI; P =.02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of antidonor isohemagglutinins led to significantly increased red blood cell (RBC) transfusion requirements in the ABO-mismatched related patients compared with ABO-matched counterparts. However, time to neutrophil and platelet engraftment, incidence of GvHD, and survival were not influenced by ABO incompatibility. In conclusion, our results corroborate the hypothesis that the rate of disappearance of antidonor isohemagglutinins after ABO-mismatched allogeneic HSC grafts is influenced by the degree of genetic disparity between donor and recipient, suggesting a graft-versus-plasma cell effect.

Adolescent↗
PubMed2000

Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease.

Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)

Adolescent↗
PubMed2000

Granulocyte colony-stimulating factor given to donors before apheresis does not prevent aplasia in patients treated with donor leukocyte infusion for recurrent chronic myeloid leukemia after bone marrow transplantation.

We conducted 2 sequential studies of donor leukocyte infusion (DLI) in 26 patients with chronic myeloid leukemia in hematologic relapse after unmodified allogeneic bone marrow transplantation. In the first study, cells for DLI were collected from 13 donors who were not treated with granulocyte colony-stimulating factor (G-CSF) (group 1). In the second study, cells were collected from 13 donors who received G-CSF before apheresis (group 2) in an attempt to avoid aplasia after DLI. Patients in group 2 received 550-fold more CD34+ cells than those in group 1. We found no significant difference in the incidence (31% versus 22%), onset time (41 vs. 48 days), or duration (15 vs. 14 days) of cytopenia after DLI in the 2 groups. G-CSF given to donors before collection of cells did not prevent aplasia. These findings support the hypothesis that the pathogenesis of aplasia after DLI is not restricted to the destruction of recipient hematopoietic cells but also involves failure of donor hematopoiesis by undefined mechanisms.

Adolescent↗
PubMed2000

Enumeration of HPC in mobilized peripheral blood with the Sysmex SE9500 predicts final CD34+ cell yield in the apheresis collection.

Enumeration of CD34+ cells in the peripheral blood before apheresis predicts the quantity of those cells collected, although the cytometric techniques used are complex and expensive. We found that a subpopulation of lysis-resistant cells in the peripheral blood, identified by the Sysmex SE9500 and designated as HPC, can serve as a surrogate marker predictive of the yield of CD34+ cells. Spearman's rank statistics were used to examine the correlation between WBC, MNC, HPC and CD34+ cells in the peripheral blood and final CD34+ cell yield for 112 samples of peripheral blood and matching apheresis collections from 66 patients and donors. The results indicate that WBC and MNC in the peripheral blood were poor predictors of CD34 content, while HPC gave a correlation coefficient of 0.62. The positive predictive values of different cutoff levels of HPC in the peripheral blood ranging from 5 to 50 x 106/l increased from 0.80 to 0.93 when the target collection was 1 x 106cells/kg. However, for patients with HPC levels below various cutoff levels, the proportion of the collections not reaching that target goal ranged between 0.36 and 0.43, indicating that most collections will still exceed the target goal of CD34+ cells. When the target collection was 2.5 x 106 CD34+ cells/kg, the positive predictive value was lower and negative predictive value was higher.

Adolescent↗
PubMed2000

Maternal birth weight and cesarean delivery in four race-ethnic groups.

OBJECTIVE: We hypothesized that maternal birth weight was associated with the risk of cesarean delivery for nulliparous women. STUDY DESIGN: In a population-based cohort study, maternal birth data were linked to a Washington State database, including the birth certificates of 18,905 first-born singleton infants (1987-1995). RESULTS: Among non-Hispanic white subjects, maternal birth weight of 2500 to 3999 g was associated with a 20.9% risk of cesarean delivery, which was the lowest risk, compared with 24.5% for a maternal birth weight <2500 g (P <.05) and 24.0% for a maternal birth weight > or =4000 g (P <.05). Similar patterns of risk were noted among Hispanic and Native American subjects, although the associations did not reach statistical significance. Risk of cesarean delivery was not associated with maternal birth weight among African American subjects. Among non-Hispanic white subjects, the risk of cesarean delivery was 3.23 times greater with a maternal birth weight <2500 g and an infant birth weight > or =4000 g compared with pregnancies with both maternal and infant birth weights between 2500 and 3999 g (P <. 001). Adjustment for socioeconomic factors did not alter these results. CONCLUSION: Low and high maternal birth weights exert an intergenerational risk of cesarean delivery in nulliparous non-Hispanic white women.

Adult↗
PubMed2000

Comparisons of predictive values of binary medical diagnostic tests for paired designs.

Positive and negative predictive values of a diagnostic test are key clinically relevant measures of test accuracy. Surprisingly, statistical methods for comparing tests with regard to these parameters have not been available for the most common study design in which each test is applied to each study individual. In this paper, we propose a statistic for comparing the predictive values of two diagnostic tests using this paired study design. The proposed statistic is a score statistic derived from a marginal regression model and bears some relation to McNemar's statistic. As McNemar's statistic can be used to compare sensitivities and specificities of diagnostic tests, parameters that condition on disease status, our statistic can be considered as an analog of McNemar's test for the problem of comparing predictive values, parameters that condition on test outcome. We report on the results of a simulation study designed to examine the properties of this test under a variety of conditions. The method is illustrated with data from a study of methods for diagnosis of coronary artery disease.

Biometry↗
PubMed1999

Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation.

High-dose therapy with autologous peripheral blood stem cell (PBSC) rescue is widely used for the treatment of malignant disease. CD34 selection of PBSC has been applied as a means of reducing contamination of the graft. Although CD34 selection results in a 2 to 3 log reduction in contaminating tumor cells without significantly delaying engraftment, many other types of cells are depleted from the CD34-enriched grafts and immune reconstitution may be impaired. In the present study, 31 cytomegalovirus (CMV)-seropositive patients who received myeloablative therapy followed by the infusion of CD34-selected autologous PBSC were assessed for the development of CMV disease in the first 100 days posttransplant. Seven patients (22.6%) developed CMV disease and 4 patients (12.9%) died from complications of their infection. In a contemporaneous group of 237 CMV-seropositive patients receiving unselected, autologous PBSC, only 10 patients (4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate logistic regression analysis, the use of CD34-selected autologous PBSC after high-dose therapy was associated with a marked increase in the incidence of CMV disease and CMV-associated deaths.

Adolescent↗
PubMed1999

Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.

A topic that has received attention in both the statistical and medical literature is the estimation of the probability of failure for endpoints that are subject to competing risks. Despite this, it is not uncommon to see the complement of the Kaplan-Meier estimate used in this setting and interpreted as the probability of failure. If one desires an estimate that can be interpreted in this way, however, the cumulative incidence estimate is the appropriate tool to use in such situations. We believe the more commonly seen representations of the Kaplan-Meier estimate and the cumulative incidence estimate do not lend themselves to easy explanation and understanding of this interpretation. We present, therefore, a representation of each estimate in a manner not ordinarily seen, each representation utilizing the concept of censored observations being 'redistributed to the right.' We feel these allow a more intuitive understanding of each estimate and therefore an appreciation of why the Kaplan-Meier method is inappropriate for estimation purposes in the presence of competing risks, while the cumulative incidence estimate is appropriate.

Confounding Factors, Epidemiologic↗
PubMed1999

The Washington State Intergenerational Study of Birth Outcomes: methodology and some comparisons of maternal birthweight and infant birthweight and gestation in four ethnic groups.

A statewide database of vital records and hospital discharge summaries of obstetric and neonatal admissions for Washington State in 1987-95 was linked to the birth certificates of mothers born in the state. A total of 46,000 births to mothers of four racial/ethnic groups were studied: Whites, African-Americans, Native Americans and Hispanics. For all four groups inverse associations were found between maternal birthweight and infant low birthweight and preterm birth. The birthweight distribution of African-American mothers was displaced markedly downwards compared with the Whites; this difference in maternal birthweight is offered as a partial explanation of the greater prevalence of suboptimal pregnancy outcomes in the former. In contrast, the maternal birthweight distributions of Whites, Native Americans and Hispanics are similar; differences in pregnancy outcomes are probably more related to maternal preconceptional and postnatal factors in these groups as well as differences in pregnancy-related factors. Mothers' birthweight may have clinical value in identifying high-risk pregnancies.

Adult↗