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Biomedical subjects

J Laver

Publications and source records attributed to J Laver.

At least 37 records · Page 2Linked to original sources
PubMed1994

Pulmonary insufficiency complicating therapy with high dose cytosine arabinoside in five pediatric patients with relapsed acute myelogenous leukemia.

BACKGROUND: The occurrence of fatal or nearly fatal pulmonary insufficiency in 5 of 22 pediatric patients with relapsed acute myelogenous leukemia (AML) treated with high dose cytosine arabinoside (Ara-C) at St. Jude Children's Research Hospital, Memphis, Tennessee, and institutions affiliated with the Pediatric Oncology Group (POG) is reported. METHODS: Cytosine arabinoside (1.0-1.5 g/m2/day) was given as a 5-day continuous infusion to all patients. Four patients with persistent leukemia received a second 3- or 5-day course. The POG protocol included the administration of granulocyte colony stimulating factor for the priming of myeloblasts. Diagnostic criteria for pulmonary insufficiency included noncardiogenic pulmonary edema with exclusion of underlying cardiorespiratory, infectious, or metabolic conditions. Autopsy material also was reviewed. RESULTS: Of the 22 patients 5 died (23%), including 2 who received a second course of Ara-C as a result of pulmonary insufficiency that developed at a median of 8 days (range, 3-38 days) after the first course. Three patients died despite intubation and pressor support. Two patients were managed successfully with colloids, diuresis, and oxygen by face mask; remission was achieved in both. The postmortem examination of one patient disclosed airless lungs, profound pulmonary edema, and subpleural nodules, but no evidence of leukemia. CONCLUSION: Pulmonary insufficiency from high dose Ara-C varies in severity and may be fatal. It may occur during or after treatment. Awareness of this potential complication, careful attention to fluid status, and aggressive supportive care may optimize outcome.

Acute Disease↗
PubMed1994

Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia.

Folylpolyglutamate synthetase (FPGS) is responsible for the metabolism of natural folates and a broad range of folate antagonists to polyglutamate derivatives. Recent studies indicated increased accumulation of methotrexate (MTX) polyglutamates (MTX-PG) in blast cells as a predictor of favorable treatment outcome in childhood acute lymphoblastic leukemia (ALL). We determined the expression of FPGS activity in blasts from children with ALL at diagnosis and after treatment with MTX as a single agent, before conventional remission induction therapy. The levels of enzyme activity in ALL blasts at diagnosis (median of 689 pmol/h/mg protein) were significantly higher (P = .003) than those found in acute nonlymphoblastic leukemia (ANLL) blasts (median of 181 pmol/h/mg protein). Comparable lineage differences in normal lymphoid versus nonlymphoid cells suggest a lineage-specific control of FPGS expression, FPGS activity increased in ALL blasts after in vivo exposure to MTX. The median increase in FPGS activity was significantly higher (P = .003) in B-lineage ALL (188%) than in T-lineage ALL (37%). Likewise, the percentage of intracellular long chain MTX-PG (Glu3-6) was significantly higher (P = .02) in B-lineage ALL (92%) than in T-lineage ALL (65%), consistent with higher FPGS activity in B-lineage blasts. This finding could explain, at least in part, the superior outcome in children with B-lineage ALL treated with antimetabolite therapy.

Burkitt Lymphoma↗
PubMed1994

Hyperfractionated total lymphoid irradiation and cyclophosphamide for preparation of previously transfused patients undergoing HLA-identical marrow transplantation for severe aplastic anemia.

PURPOSE: To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients. METHODS AND MATERIALS: From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32). RESULTS: One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series. CONCLUSION: Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.

Adolescent↗
PubMed1994

Pain in children and adolescents with sickle cell anemia: a prospective study utilizing self-reporting.

PURPOSE: The purpose of this study was to characterize pain reporting among children with sickle cell anemia (SCA) experiencing painful vaso-occlusive crises. These patients were managed according to a protocol based on self-reports of pain. PATIENTS AND METHODS: Seventeen children (3-18 years) with SCA (Hb SS) who were admitted for painful crisis were asked to report their pain according to a rating scale of 0-5. These pain scores were analyzed according to the Mann-Whitney method to determine differences in pain reporting among young children (3-12 years) and adolescents (13-18 years). The Kruskal-Wallis method was utilized to determine relationships between the number of painful body sites, reported pain scores, and length of hospital stay. RESULTS: Children (3-12 years) reported significantly less severe pain than adolescents (13-18 years) (p < 0.01). The severity of pain reported was not related to the number of painful sites. However, the length of stay was significantly longer in patients with greater numbers of painful sites (p < 0.05). Patients who reported pain scores of > 2 at 24 h had significantly longer periods of hospitalization. CONCLUSION: A protocol based upon self-reports of pain was successfully utilized to provide analgesia during painful crises. There were characteristic differences between young children and adolescents in self-reporting of pain. Pain scores may be helpful in predicting length of hospitalization for painful crises.

Adolescent↗
PubMed1994

Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells.

Umbilical cord blood (CB) has been identified as a potential source of hematopoietic stem cells suitable for clinical transplantation. We used long-term cord blood cultures (LTCBC) to evaluate the hematopoietic potential of populations of umbilical CB cells phenotypically defined and isolated by flow cytometry. LTCBC initiated with CD34+HLA-DR+ and CD34+HLA-DR- CB cells were examined over a period of 8 weeks for the production of assayable burst-forming units-erythroid (BFU-E), colony-forming units-granulocyte/macrophage (CFU-GM), and colony-forming units-mixed (CFU-GEMM) in response to repeated additions of stem cell factor (SCF), interleukin-3 (IL-3), IL-6, and either erythropoietin (Epo) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The LTCBC-initiating cell (LTCBC-IC) appeared to be present among CD34+HLA-DR+ cells, in contrast to our previous findings in adult bone marrow (BM), where the long-term culture initiating cells were shown to be CD34+HLA-DR-. In addition, production of BFU-E, CFU-GM, and CFU-GEMM in CB CD34+HLA-DR+ cells displaying low uptake of the supravital dye rhodamine 123 (Rh123) exceeded those detected in the fraction of cells with high uptake of Rh123. Furthermore, on day 21 of LTCBC, the production of the high proliferative potential colony-forming units (HPP-CFC) by CB CD34+HLA-DR+Rh123dull cells was five-fold greater than that detected in cultures initiated with their Rh123bright counterparts. Collectively, these data show that, contrary to what has been documented in adult human BM, LTCBC-IC and presumably CB cells capable of in vivo engraftment reside in the CD34+HLA-DR+Rh123dull fraction of CB. Although the functional significance of these differences between the in vitro behavior of phenotypically defined populations of CB and BM remains to be determined, these findings constitute an objective parameter with which the suitability of CB for clinical transplantation may be assessed.

Antigens, CD↗
PubMed1994

Effects of recombinant human Steel factor (c-kit ligand) on early cord blood hematopoietic precursors.

The purpose of this study was to define the effects of recombinant human Steel factor (rhSF) (c-kit ligand) on early and late cord blood hematopoietic progenitors. In the presence of recombinant human erythropoietin (rhEpo), rhSF supported the development of granulocyte/macrophage, erythroid, and mixed colonies from CD34-positive cord blood cells. With increasing concentrations of rhSF, an increase in the number of mixed colonies was observed. This increase was paralleled by a decrease in the number of erythroid colonies, such that the total number of the two colony types was always constant. Similar results were observed when CD34+ cells were cultured in the presence of a combination of rhEpo, rhSF, and rhIL-3. These results indicate that the presence of rhSF enhanced the detectability of the nonerythroid components of mixed colonies. The effect of rhSF on early progenitors (pre-colony-forming units [pre-CFU]) was studied in a two-step assay. In this assay, cells positive for CD34 and resistant to treatment with 4-hydroperoxycyclophosphamide (CD34+/4-HCres) were cultured in suspension for 7 days with rhSF, rhIL-3, or rhSF plus rhIL-3 and then plated in clonogenic assays. Before suspension culture, CD34+/4-HCres cells had a low clonogenic potential (0.37%). After being cultured in suspension, however, these cells gave rise to a large number of colonies of all types when replated. Cells cultured in suspension with the combination of rhSF and rhIL-3 increased significantly in number and gave rise to more colonies, when compared to cells cultured with either factor alone (synergistic effect). In identical experiments, such as effect had not been observed with combinations of rhIL-3 and either rhIL-1 or rhIL-6. Thus, rhSF supports the expansion and differentiation of early progenitors in human cord blood.

Antigens, CD↗
PubMed1994

Rapid exit from G0/G1 phases of cell cycle in response to stem cell factor confers on umbilical cord blood CD34+ cells an enhanced ex vivo expansion potential.

Currently, the most commonly used grafts of progenitor and stem cells for patients undergoing bone marrow transplantation (BMT) are derived from large collections of autologous or allogeneic adult human bone marrow (BM). The feasibility of using human umbilical cord blood (HUCB), normal peripheral blood (PB), and smaller collections of BM as sources of hematopoietic stem cell grafts for adult patients remains questionable. We investigated the ex vivo proliferative potential of HUCB CD34+ cells as a means of expanding HUCB grafts, thereby making them more acceptable for clinical transplantation. HUCB-derived CD34+HLA-DR+ cells, maintained for 5 days in suspension cultures supplemented with 10% HUCB plasma and a combination of stem cell factor (SCF) and interleukin-3 (IL-3), displayed a 10-fold increase in the total number of CD34+ cells. In contrast, only a four-fold increase was observed in identical cultures initiated with BM-derived CD34+HLA-DR+ cells. Whereas BM CD34+ cells failed to proliferate in response to SCF alone, HUCB CD34+ cells expanded 5.6-fold by day 5, thus demonstrating an enhanced response to SCF. When the effects of SCF on the exit of HUCB cells from G0/G1 phases of cell cycle were investigated, we found that although HUCB CD34+HLA-DR+ cells were more quiescent than BM CD34+HLA-DR+ and BM CD34+HLA-DR- cells (97.5% of HUCB CD34+HLA-DR+ in G0/G1 vs. 88.6% of BM CD34+HLA-DR+ and 92.0% of BM CD34+HLA-DR- [p < 0.005]), HUCB CD34+HLA-DR+ cells exited from dormancy more rapidly than BM cells, such that by 36 to 48 hours following exposure to SCF, only 55% remained in G0/G1. Furthermore, an 8.4-fold increase in the number of HUCB CD34+ cells still residing in G0/G1 was observed on day 5 in cultures supplemented with SCF and IL-3, suggesting the generation of large numbers of primitive hematopoietic progenitor cells (HPC) in vitro. When the contribution of HUCB plasma to the exist of HUCB CD34+HLA-DR+ cells from G0/G1 phases of cell cycle was investigated, it was found that in serum-free media supplemented with only SCF or IL-3, HUCB cells did not exist G0/G1 as rapidly as when HUCB plasma or SCF plus IL-3 was present. In contrast, when HUCB plasma was added to any cytokine combination, it did not enhance the exist of BM CD34+HLA-DR+ cells from G0/G1 phases of cell cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, CD↗
PubMed1994

Human umbilical cord blood hematopoietic progenitor cells: are they the same as their adult bone marrow counterparts?

In an attempt to expand the hematopoietic progenitor cell (HPC) content of a single collection of umbilical cord blood (CB), we investigated the ex vivo proliferative potential of CB CD34+ cells and the rate of exit of these cells from G0/G1 phases of cell cycle in response to different cytokine combinations. Initial experiments in which phenotypically defined populations of CB and adult bone marrow (BM) CD34+ cells were examined for their HPC content revealed that, contrary to BM, CB CD34+ human leukocyte A (HLA)-DR+ cells appeared to contain the majority of primitive HPC. In cultures of BM CD34+ HLA-DR+ cells incubated with stem cell factor (SCF)+interleukin-3 (IL-3), CD34+ cells increased five-fold over 5 days, while CD34+ cells from CB CD34+ HLA-DR+ cultures increased 11-fold under these same conditions, illustrating an enhanced proliferative potential of CB CD34+ HLA-DR+ cells vs. similar cells from adult BM. Furthermore, a 6.2-fold increase in the number of CB CD34+ still residing in G0/G1 was observed on day 5 in cultures supplemented with SCF and IL-3, suggesting the generation of large numbers of primitive HPC in vitro. The effect of SCF on the exit of CB and BM CD34+ HLA-DR+ cells from G0/G1 was then examined. Following 36- to 48-hour exposure to SCF, 45% of quiescent CB cells exited G0/G1 in contrast to only 13% of quiescent BM cells. In serum-free media supplemented with either SCF or IL-3 alone, CB CD34+ HLA-DR+ cells did not exit G0/G1 phases of cell cycle as rapidly as when CB plasma was present, unless SCF and IL-3 were added simultaneously. Collectively, these results suggest that CB CD34+ cells are more responsive to cytokine stimulation, especially SCF, and may represent more suitable candidates for ex vivo expansion of HPC than BM cells. Furthermore, these data illustrate potentially important biologic differences between the HPC content of subpopulations of BM and CB cells, and the response of these subpopulations to cytokine stimulation.

Adult↗
PubMed1994

Predictive factors for the rate of engraftment of neuroblastoma patients autotransplanted with purged marrow.

Predictive values for patient engraftment in neuroblastoma have not been defined. By analyzing the parameters available to us at the time of harvest and post-harvest, we found that the MNC/kg after purging demonstrated significant correlation with patient engraftment as measured by the patient's time to reach a WBC count of 1,000/microL and an ANC count of 500/microL. Platelet and red cell independence was difficult to measure as some of these patients remain platelet- and red cell-dependent for extended periods of time. Platelet refractoriness, alloimmunization, infection and many other factors can delay platelet and red cell recovery following transplantation. A larger number of patients is needed to assess a correlation between the parameters analyzed and platelet and red cell recovery, as well as to validate our observation with myeloid recovery.

Antibodies, Monoclonal↗
PubMed1994

Bone marrow transplantation for sickle cell anemia.

PURPOSE: To investigate the role of bone marrow transplantation in patients with severe sickle cell anemia (SCA). PATIENTS AND METHODS: We have designed a protocol for selecting patients with severe SCA who may benefit from bone marrow transplantation (BMT). On the basis of this protocol, a girl 3 9/12 years of age who had severe recurrent pain crises and splenic dysfunction received a BMT from her brother, who is homozygous for hemoglobin A. RESULTS: Transplantation resulted in prompt engraftment, followed by durable hematologic and immunologic reconstitution with donor cells. One year after BMT, the patient continued to do well. She did not experience any graft versus host disease, her growth velocity increased, and recovery of splenic function was demonstrated. Since undergoing BMT, she has not experienced any painful crises. CONCLUSIONS: Bone marrow transplantation is an effective therapeutic modality that should be considered in patients with severe SCA.

Anemia, Sickle Cell↗
PubMed1992

Study of early hematopoietic precursors in human cord blood.

Human cord blood is a source of transplantable stem cells. These stem cells express the antigen CD34, are resistant to treatment with 4-hydroperoxycyclophosphamide (CD34+/4-HCres), and do not give rise to colonies when plated in clonogenic assays. We studied the number of CD34+ cells present in cord blood and developed a two-step assay for early precursors (pre-colony-forming units, pre-CFU) capable of giving rise to committed progenitors. In this assay CD34+/4-HCres cord blood cells were cultured in suspension with different growth factors. After 7 days in suspension the remaining cells were plated in clonogenic assays, for granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed lineage colony-forming units (CFU-MIX), in the presence of pure factors or a combination of recombinant human (rh) interleukin 3 (IL-3) and medium conditioned by the PU34 primate cell line. Pre-CFU for all precursors were identified. These pre-CFU developed into committed progenitors in response to rhIL-3. The combinations of rhIL-3 plus rh interleukin 1 (IL-1) or rhIL-3 plus rh interleukin 6 (IL-6) did not enhance recovery of progenitors. The developing CFU-GM were responsive to rh granulocyte-macrophage colony-stimulating factor (GM-CSF) and rh granulocyte colony-stimulating factor (G-CSF) but much less so to rhIL-3. BFU-E and CFU-MIX developed in suspension but could only be detected when cells were replated in the presence of a combination of rhIL-3 and PU34 but not rhIL-3 alone. This assay may be useful in evaluating the number of early hematopoietic precursors present in cord blood samples and in defining growth factor combinations that could enhance hematopoietic recovery after cord blood stem cell transplants.

Antigens, CD↗
PubMed1991

Marrow transplantation from human leukocyte antigen-identical or haploidentical donors for correction of Wiskott-Aldrich syndrome.

Since 1979, a total of 17 patients with Wiskott-Aldrich syndrome have undergone allogeneic bone marrow transplantation at Memorial Sloan-Kettering Cancer Center. Eleven patients received marrow from either human leukocyte antigen (HLA) genotypically identical siblings (nine patients) or an HLA phenotypically identical parent (two patients). Six patients received marrow grafts from HLA-disparate parents. Cytoreduction was accomplished with busulfan and cyclophosphamide for the HLA-identical recipients and total-body irradiation followed by high-dose cytarabine therapy in the mismatched recipients. All 11 recipients of HLA-identical marrow had successful grafts, and 10 of 11 are alive and well 28 to 145 months after transplantation. One patient died 10 months after transplantation of chronic graft-versus-host disease and interstitial pneumonitis caused by cytomegalovirus. Only one of the six mismatched graft recipients survives, 52+ months after transplantation; the other patients have died of extensive chronic graft-versus-host disease (one patient), lymphoma (three patients), or progressive pancytopenia accompanying Candida sepsis (one patient). Thus bone marrow transplantation represents the treatment of choice in patients with Wiskott-Aldrich syndrome who have an HLA-identical donor. However, our approach for patients lacking a histocompatible family donor requires modifications to overcome allogeneic resistance and decrease the posttransplantation immunoincompetence in these patients.

Adult↗
PubMed1990

Cytokine networks involved in the regulation of haemopoietic stem cell proliferation and differentiation.

Additive and synergistic interactions between haemopoietic growth factors and cytokines can be demonstrated in vitro in clonogenic and suspension cultures of murine and human bone marrow. Purification of early stem cells by combinations of purging with cytotoxic agents (5-fluorouracil, 4-hydroperoxy-cyclophosphamide) and selection with monoclonal antibodies for CD34+, CD33- cells permits analysis of factor interactions at the level of the primitive pluripotential stem cell. Interactions between interleukins, tumour necrosis factor and the colony-stimulating factors can be monitored. In vivo, IL-1 alone, or in combination with G-CSF produces accelerated reconstitution of haemopoiesis after chemotherapy, irradiation and bone marrow transplantation in murine and primate systems. IL-1 elicits cytokine cascades that may have positive or negative actions on lymphohaemopoiesis. Induction of products of the cyclooxygenase and lipooxygenase pathways, as well as tumour necrosis factor and TGF-beta, modulate haemopoiesis.

Animals↗
PubMed1990

High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates.

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.

Adult↗
PubMed1990

Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates.

Interleukin-3 (IL-3) is a hematopoietic growth factor that supports the growth of early hematopoietic progenitors in vitro. In vivo administration of recombinant human interleukin-3 (rhIL-3) to normal primates results in a modest and delayed leukocytosis secondary to increases in neutrophils, basophils, and eosinophils. We postulated that the effects of rhIL-3 might be more pronounced in hematologically stressed primates, and therefore administered rhIL-3 to primates after intensive myelosuppressive therapy. Primates received either cyclophosphamide (CPM) at 60 mg/kg or 5-fluorouracil (5-FU) at 75 mg/kg i.v. on two consecutive days. Subsequently, rhIL-3 was administered intravenously or subcutaneously at 20 micrograms/kg per d for 14 d. Compared to controls, all rhIL-3 treated primates experienced higher absolute neutrophil count (ANC) nadirs and dramatic decreases in the period of severe neutropenia (ANC less than 500) after myelosuppressive therapy. RhIL-3 administration resulted in a significant basophilia and eosinophilia, which resolved after discontinuation of the drug. RhIL-3 did not enhance erythroid recovery. Platelet recovery was earlier in rhIL-3-treated animals. However, variations in the platelet recovery observed in control animals, precluded accurate estimation of this effect or its significance. Our results indicate that the administration of rhIL-3 following intensive myelosuppressive therapy dramatically enhances myeloid recovery and ablates the predicted period of prolonged severe neutropenia.

Animals↗