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Biomedical subjects

A R Turner

Publications and source records attributed to A R Turner.

At least 19 recordsLinked to original sources
PubMed2005

Alveolar soft-part sarcoma presenting with eosinophilia and shunt.

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumour found in young adults that usually arises in skeletal muscle and occurs most frequently in the lower limbs. Radiological and pathological findings of ASPS in a 34-year-old man who presented with increasing shortness of breath over a period of four to six weeks with peripheral blood eosinophilia, hypoxemia and a significant arteriovenous shunt are reported. The present article is the fourth report of eosinophilia in association with sarcoma, and the first involving ASPS.

Adult↗
PubMed2005

Prior red blood cell transfusions in cancer patients increase the risk of subsequent transfusions with or without recombinant human erythropoietin management.

Cancer patients often receive transfusions when their hemoglobin concentration falls to dangerously low levels due to chemotherapy or due to the disease itself. The availability of recombinant human erythropoietin (rHuEPO) has significantly reduced transfusion frequencies in cancer patients. However, the predictability of transfusions prior to the use of rHuEPO for future transfusions has not been evaluated. Data from five randomized, double-blind, placebo-controlled trials in cancer patients receiving chemotherapy and epoetin alfa were utilized to calculate the relative risk of subsequent transfusions in patients who were pretransfused. A meta-analysis with patient-level data was used to assess predictors of transfusion. Baseline data from an open-label study were used to compare quality-of-life (QOL) parameters between previously transfused and transfusion-naive patients. The mean relative risks (RR) of exposure to additional transfusion for pretransfused patients on placebo or epoetin alfa were 2.14 (95% confidence interval [CI]: 1.73, 2.65) and 2.51 (95% CI: 1.92, 3.27), respectively, compared with nontransfused patients. Data from the meta-analysis of patients on epoetin alfa showed that pretransfusion was the most significant predictor for subsequent transfusions (parameter estimate = -1.2628, p < 0.0001 from Logistic Regression Analysis). While epoetin alfa was similarly effective in reducing transfusion risks for patients with or without pretransfusions (compared with placebo), those who were pretransfused were more than twice as likely to be subsequently transfused, compared with those not pretransfused. QOL was significantly worse for pretransfused patients than for nontransfused patients, as measured by the Functional Assessment of Cancer Therapy -Anemia and the Linear Analogue Scale Assessment QOL instruments. The results suggest that transfusions prior to epoetin alfa therapy increase the risk of future transfusions, and early treatment with epoetin alfa might reduce the risk of subsequent transfusions.

Adolescent↗
PubMed2004

Target isotope effects for vibrationally-resolved electron capture in low-energy collisions of O3+ with molecular hydrogen.

Using a quantum-mechanical molecular-orbital coupled-channel (QMOCC) approach, we investigate single electron capture in collisions of O3+ with various molecular hydrogen isotopomers (H2, HD, T2) for collision energies of 1 and 100 eV u(-1). Potential energy surfaces and nonadiabatic couplings obtained with the spin-coupled valence-bond method are incorporated into QMOCC calculations of vibrationally-resolved cross sections of the product molecular ion. The infinite order sudden approximation is adopted and comparisons of the vibrational distributions are made with the centroid approximation, which incorporates ionization Franck-Condon factors. Intercomparison of the results is used to assess the reliability of the approximations and to give insight into the target isotope effects.

Journal Article↗
PubMed2003

Methylene blue for the treatment and prophylaxis of ifosfamide-induced encephalopathy.

Ifosfamide (IFOS) is used in cancer treatment. Ifosfamide-induced encephalopathy (IIE) can result in treatment delay or discontinuation as well as morbidity and mortality. Cases using methylene blue (MB) in acute and prophylactic treatments are discussed. For acute use, marked central nervous system (CNS) improvement occurred within 24h of MB administration. For prophylactic use, the severity of the symptoms decreased significantly compared with previous treatment cycles, and enabled patients to continue further IFOS therapy. MB has potential use in both the acute treatment and prophylaxis of IIE.

Adult↗
PubMed2002

Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis.

Fifty-seven patients receiving unrelated donor (UD) BMT were matched for disease and stage with 57 recipients of genotypically matched related donor (MRD) BMT. All UD recipients were matched serologically for A and B and by high resolution for DR and DQ antigens. All patients received CsA and 'short course' methotrexate with folinic acid. Unrelated donor BMT patients also received thymoglobulin 4.5 mg/kg (6 mg/kg if <30 kg) in divided doses over 3 days pretransplant. For UD and RD BMT, respectively, incidence of acute GVHD grade II-IV was 19 +/- 6% vs 36 +/- 8%, grade III-IV 10 +/- 6% vs 18 +/- 7%, chronic GVHD 44 +/- 8% vs 51 +/- 8%, non-relapse mortality 15 +/- 5% vs 8 +/- 4% at 100 days, 28 +/- 8% vs 36 +/- 7% at 3 years. At 3 years, relapse was 45 +/- 7% vs 42 +/- 7%, and disease-free survival 39 +/- 7% vs 37 +/- 7%. None of these differences are significant. Three-year overall survival was identical at 42 +/- 7%. For 29 patients with low/intermediate risk leukemia, disease-free survival was 68 +/- 10% after UD BMT vs 59 +/- 9% for RD BMT recipients (P = NS). Corresponding figures for high risk patients were 14 +/- 7% and 21 +/- 8%, respectively. We conclude that UD BMT recipients matched as above and given pretransplant ATG have similar outcomes to recipients of MRD BMT using conventional drug prophylaxis. Unrelated donor BMT should be considered in any circumstance where MRD BMT is routine.

Antilymphocyte Serum↗
PubMed2002

Bcr-abl-positive cells secrete angiogenic factors including matrix metalloproteinases and stimulate angiogenesis in vivo in Matrigel implants.

To further elucidate the role of angiogenesis in the pathogenesis of chronic myelogenous leukemia (CML) we evaluated the effects of the bcr-abl translocation on the secretion of the angiogenic factors VEGF, FGF-2, HGF, IL-8 and matrix metalloproteinases (MMPs) as well as on the angiogenic potential in vivo of bcr-abl+ cells. First, we examined murine FL5.12 cells transfected with the bcr-abl constructs p185, p210 and p230 and found that the transfected cells secreted as much as four-fold more VEGF (p185 > p210 >p230) than wild-type (wt) cells, as well as MMP-9 and MMP-2. When Matrigel fragments containing these bcr-abl+ cells were implanted subcutaneously in SCID or Balb-C mice they became significantly more vascularized and hemoglobinized than implants containing normal or wt cells (p185 > p210 > p230). Similarly, we found that myeloblasts expanded from bone marrow (BM) CD34+ cells derived from Philadelphia-positive CML patients secreted up to 10 times more VEGF, FGF-2, HGF and IL-8 compared to myeloblasts derived from normal donors' BM CD34+ cells and that BM mononuclear cells (MNC) isolated from CML patients induced vascularization of Matrigel implants in mice. Moreover, we found that peripheral blood MNC expressed MMP-2 and membrane-type (MT)1-MMP in about 50% of CML patients studied, and MMP-9 in all of them. Furthermore, VEGF stimulated the secretion of MMP-9 in these primary CML cells. We conclude that stimulation of angiogenesis by angiogenic factors, including MMPs, could play an important role in the pathogenesis of CML, suggesting that therapies targeting the newly formed endothelium could be developed for CML.

Adult↗
PubMed2001

Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment.

Because human CD34+ and murine Sca-1+ hematopoietic stem-progenitor cells (HSPCs) express platelet-binding sialomucin P-selectin (CD162) and integrin Mac-1 (CD11b-CD18) antigen, it was inferred that these cells might interact with platelets. As a result of this interaction, microparticles derived from platelets (PMPs) may transfer many platelet antigens (CD41, CD61, CD62, CXCR4, PAR-1) to the surfaces of HSPCs. To determine the biologic significance of the presence of PMPs on human CD34+ and murine Sca-1+ cells, their expressions on mobilized peripheral blood (mPB) and on nonmobilized PB- and bone marrow (BM)-derived CD34+ cells were compared. In addition, the effects of PMPs on the proliferation of CD34+ and Sca-1+ cells and on adhesion of HSPCs to endothelium and immobilized SDF-1 were studied. Finally, the hematopoietic reconstitution of lethally irradiated mice receiving transplanted BM mononuclear cells covered or not covered with PMPs was examined. It was found that PMPs are more numerous on mPB than on BM CD34+ cells, do not affect the clonogenicity of human and murine HSPCs, and increase adhesion of these cells to endothelium and immobilized SDF-1. Moreover, murine BM cells covered with PMPs engrafted lethally irradiated mice significantly faster than those not covered, indicating that PMPs play an important role in the homing of HSPCs. This could explain why in a clinical setting human mPB HSPCs (densely covered with PMPs) engraft more rapidly than BM HSPCs (covered with fewer PMPs). These findings indicate a new role for PMPs in stem cell transplantation and may have clinical implications for the optimization of transplantations.

Animals↗
PubMed2001

Matrix metalloproteinase and tissue inhibitors of metalloproteinase secretion by haematopoietic and stromal precursors and their production in normal and leukaemic long-term marrow cultures.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate the turnover of the extracellular matrix and may modulate the biology of haematopoietic cells. We investigated whether MMPs and TIMPs are produced in long-term marrow cultures (LTMCs) established from normal donors and acute myelogenous leukaemia (AML) patients, and by fibroblast- (F), granulocyte macrophage- (GM) and megakaryocyte- (Meg) colony-forming unit (CFU) and erythroid burst-forming unit (BFU-E)-derived precursor cells. ProMMP-9 levels were highest (> 400 ng/ml) at week 1 of normal LTMC, whereas proMMP-2, TIMP-1, TIMP-2 and TIMP-3 levels peaked (up to 1000 ng/ml) after the establishment of the adherent layer. In LTMC from AML patients, these patterns of secretion were reversed. Moreover, we found that after a 24 h incubation in serum-free media, normal CFU-GM-, BFU-E- and CFU-Meg-derived cells secreted proMMP-9 and CFU-F-derived cells proMMP-2, in contrast to cells from LTMC adherent layer which secreted both active and latent forms of MMP-2 and MMP-9 under serum-free conditions. However, when these adherent cells were incubated in 12.5% fetal calf or horse serum or complete LTMC growth media, active forms of MMP-2 and MMP-9 were no longer detectable, and TIMP levels increased. Hence, we concluded that (i) MMPs/TIMPs are secreted by normal human bone marrow haematopoietic and stromal cells and may play an important role in intercellular cross-talk in haematopoiesis; and (ii) only latent forms of MMPs are present under LTMC conditions, indicating that the specific media used for weekly re-feeding of LTMC can block activation of MMP-2 and MMP-9, maintaining the integrity of the stromal layer and supporting haematopoiesis in vitro.

Bone Marrow Cells↗
PubMed1999

Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34(+) cells and their transmigration through reconstituted basement membrane.

The mechanism(s) underlying the release of stem/progenitor cells from bone marrow into the circulation is poorly understood. We hypothesized that matrix metalloproteinases (MMPs), especially gelatinases, which are believed to participate in the proteolysis of basement membranes and in the migration of leukocytes, may facilitate this process. First, we investigated whether CD34(+) stem/progenitor cells express gelatinases A (MMP-2) and/or B (MMP-9) and whether growth factors and cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], stem cell factor [SCF], macrophage colony-stimulating factor [M-CSF], interleukin-3 [IL-3], IL-6, IL-8, and tumor necrosis factor-alpha [TNF-alpha]) are able to modulate their expression. Next, we examined the transmigration of these stem/progenitor cells through reconstituted basement membrane (Matrigel) and its modulation by growth factors and cytokines. CD34(+) cells were obtained from steady-state bone marrow and peripheral blood (from leukapheresis products collected either in steady-state hematopoiesis or after mobilization with G-CSF plus chemotherapy or G-CSF alone). We found that peripheral blood CD34(+) cells, regardless of whether they were mobilized or not, strongly expressed both gelatinases (MMP-2 and MMP-9) in contrast to steady-state bone marrow CD34(+) cells, which did not. However, all the growth factors and cytokines tested could induce MMP-2 and MMP-9 secretion by the latter cells. Moreover, the stimulatory effects of G-CSF and SCF on both MMP-2 and MMP-9 secretion were found to be significantly higher in CD34(+) cells isolated from bone marrow than in those from peripheral blood. In addition TNF-alpha, GM-CSF, and IL-6 increased the secretion of a partially active form of MMP-2. Basal transmigration of bone marrow CD34(+) cells through Matrigel was lower than that of peripheral blood CD34(+) cells (P <.0001), but growth factors and cytokines increased it by 50% to 150%. Positive correlations were established between expression of gelatinases and CD34(+) cell migration (r >.9). The stimulatory effect of G-CSF was significantly greater on the migration of CD34(+) cells from bone marrow than on those from peripheral blood (P =.004). Moreover, CD34(+) cell migration was reduced to approximately 50% by antibodies to MMP-2 and MMP-9, tissue inhibitors of metalloproteinases (rhTIMP-1 and -2), and o-phenanthroline. TNF-alpha-induced gelatinase secretion and migration of CD34(+) cells and of clonogenic progenitors (colony-forming unit-granulocyte-macrophage [CFU-GM], burst-forming unit-erythroid [BFU-E], colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM], and colony-forming unit-megakaryocyte [CFU-MK]) were dose-dependent. Therefore, this study demonstrated that CD34(+) cells that are circulating in peripheral blood express both MMP-2 and MMP-9 and transmigrate through Matrigel. In contrast, CD34(+) cells from steady-state bone marrow acquire similar properties after exposure to growth factors and cytokines, which upregulate expression of gelatinases and transmigration of these cells when they enter the bloodstream. Hence, we suggest that growth factors and cytokines induce release of stem/progenitor cells from bone marrow into peripheral blood during mobilization, as well as during steady-state hematopoiesis, by signaling through gelatinase pathways.

Antigens, CD34↗
PubMed1999

Splenectomy during partial remission in thrombotic thrombocytopenic purpura with prolonged plasma exchange dependency.

Some patients with thrombotic thrombocytopenic purpura (TTP) remain plasma-exchange-dependent for prolonged periods of time. This exposes patients to risk, uses substantial resources, and requires prolonged hospitalization. We have splenectomized 7 such patients following 25-42 plasma exchanges while patients were in partial remission only and were clinically stable. In 6 patients, including 1 with TTP secondary to mitomycin C, thrombocytopenia promptly resolved. Relapse has not occurred during 18 or more months of observation. The seventh patient did not respond. We conclude that splenectomy should be considered as an alternative to continued plasma-exchange therapy in such patients.

Adrenal Cortex Hormones↗
PubMed1999

Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: influence of stem cell source on outcome.

We have compared the outcomes of 87 patients with acute myelogenous leukemia (AML) and myelodysplasia (MDS) receiving matched sibling transplants with stem cells from peripheral blood (blood cell transplant, BCT) or bone marrow (BMT). In good risk patients (AML in CR1) granulocytes recovered to 0.5 x 10(9)/l a median of 14 days after BCT compared with 19 days after BMT (P < 0.0001). For patients with poor risk disease (AML beyond CR1 and MDS) corresponding figures were 16 vs 26 days (P < 0.0001). Platelet recovery to 20 x 10(9)/l was also faster after BCT (good risk 12 vs 20 days, P < 0.0001; poor risk 17 vs 22 days, P = 0.04). Red cell transfusions were unaffected by cell source, but BCT recipients required less platelet transfusions (good risk 1 vs 5, P = 0.002; poor risk 5 vs 11, P = 0.004). Blood cell transplants resulted in more chronic GVHD (86% vs 48%, P = 0.005) and a significantly higher proportion of recipients with KPS of 80% or less (48% vs 5%, P = 0.004). Disease-free survival at 4 years was 23% for both groups of poor risk patients but outcome in good risk patients was better after BCT (93% vs 62%, P = 0.047) related mainly to less relapse. While disease-free survival may be better after BCT than BMT for AML in CR1, quality of life may be relatively impaired.

Adolescent↗
PubMed1999

Expression of matrix metalloproteinases (MMP-2 and -9) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in acute myelogenous leukaemia blasts: comparison with normal bone marrow cells.

We compared the expression of matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in bone marrow acute myelogenous leukaemia (AML) blasts and leukaemic cell lines (HEL, HL-60, K-562 and KG-1) with their expression in normal bone marrow cells. All AML samples and leukaemic cell lines tested expressed MMP-9 and/or MMP-2 mRNA and, accordingly, these gelatinases were secreted into media. Moreover, TIMP-1 and TIMP-2 mRNA and secreted proteins were demonstrated in all the AML samples. Although all the leukaemic cell lines expressed TIMP-1, the HL-60 cells also expressed TIMP-2. In contrast, normal steady-state bone marrow immature progenitor cells (CD34+ cells) did not express or secrete either MMP-2 or MMP-9, but more mature mononuclear cells from normal bone marrow expressed and secreted MMP-9. Also, normal bone marrow CD34+ cells and mononuclear cells expressed TIMP-1 and TIMP-2 mRNA, but these proteins were not detectable by reverse zymography. Furthermore, whereas bone marrow fibroblasts and endothelial cells secreted only latent MMP-2, the activated form of this enzyme was found in media conditioned by cells obtained from long-term cultures of normal and AML bone marrow adherent layers. Our finding of up-regulated production of gelatinases, TIMP-1 and TIMP-2 by leukaemic cells suggests that these proteins may be implicated in the invasive phenotype of AML.

Adolescent↗
PubMed1998

The management and clinical course of testicular seminoma: 15 years' experience at a single institution.

Testicular seminoma is one of the most curable solid neoplasms, with 5-year survival rates in excess of 90%. However, controversy persists around its optimum management, particularly for Stage I disease. The outcome of 314 patients with testicular seminoma who were treated at a single institution is reported. A comparison of adjuvant radiotherapy and surveillance for Stage I is presented, and the possible prognostic influence of an elevated serum beta-human chorionic gonadotrophin (beta hCG) is assessed. The 5-year disease-free survival for all stages of presentation was 95.5%. There were more relapses in Stage I patients undergoing surveillance (14/94, 15%) than postorchidectomy radiotherapy (6/144, 4%; P = < 0.05). However, survival was identical irrespective of treatment policy, with no disease-related deaths in either group of Stage I patients. There were eight tumour-related deaths from advanced disease and 14 deaths from non-tumour causes. Three were due to cardiorespiratory disease, four to an unrelated second malignancy, two from infection and one from suicide; in four patients, the cause was unknown. Preoperative beta hCG was elevated in 29 (18%) of Stage I patients and in 24 (62%) of those presenting with Stage II disease. Patients were more likely to have advanced disease (> or = Stage II) if beta hCG was elevated (P < 0.001). Neither disease-free nor overall survival were influenced by the preoperative level of beta hCG. Surveillance appears to be a safe alternative to postorchidectomy radiotherapy for Stage I disease, provided the patient is prepared for intensive long term follow-up. An increased risk of relapse, but not of tumour death, can be expected and unnecessary treatments avoided.

Adolescent↗
PubMed1998

Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC).

Nucleoside analogs are important components of treatment regimens for acute leukemia in adults. Plasma membrane permeation of the nucleoside analog molecules, the initial event in the cellular conversion of nucleosides to active agents, is mediated by nucleoside-specific membrane transporters. The widely-expressed es nucleoside transporter accepts as substrates diverse nucleoside analogs, including cytarabine (araC), 2-chlorodeoxyadenosine, and fludarabine. The cellular content of es transporter sites has been measured in blasts from patients with acute lymphoblastic leukemia and acute myelogenous leukemia, by a sensitive, quantitative flow cytometry assay that employs the tightly-bound es ligand, SAENTA fluorescein. Values for es transporter expression varied ten-fold among samples from patients with acute myelogenous leukemia. In this article, we review current findings that document, in confocal fluorescence microscopy images and in flow cytometry assays of SAENTA fluorescein-stained cells, the patient-to-patient variance of es transporter expression in leukemic blasts from patients. Our data show a correlation between the expression of es transporters and the in vitro sensitivity to nucleoside drugs of blasts from acute leukemia patients. These findings show that the flow cytometry assay of es expression provides a facile means of predicting resistance of leukemia cells to the cytotoxicity of araC and other nucleosides.

Acute Disease↗
PubMed1997

Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein.

Cytarabine (araC) is converted to araC 5'-triphosphate after entering leukemia cells as a substrate for nucleoside transport processes. This study tested the relationship between araC cytotoxicity, measured in an in vitro tetrazolium dye reduction assay of cell viability, and the cellular abundance of es nucleoside transport elements, assayed by a flow cytometric method that used the es-specific stain, 5-(SAENTA-x8)-fluorescein (5-(Sx8)-F), in cultured leukemia cells and in myeloblasts and lymphoblasts (blasts) from leukemia patients. Cellular es site abundance (B(max) value for 5-(Sx8)-F binding) varied sixfold among nine leukemic myeloblast samples from patients. In cultured OCI/AML-2 myeloblasts and CCRF-CEM T-lymphoblasts, and in fresh leukemic blasts, es sites were fractionally blocked by treatment with graded concentrations of nitrobenzylthioinosine (NBMPR), an inhibitory es site ligand, to simulate the variation in es expression found in leukemic blasts from patients with acute myeloid leukemia. When the cytotoxicity of a single concentration of araC was determined in NBMPR-treated leukemia cells, cell kill correlated closely with the intensity of 5-(Sx8)-F fluorescence (r = .92 to .99), a measure of the cell surface abundance of functional es nucleoside transporter sites. Concentrations of NBMPR that achieved half-maximal reduction (4.3 to 12 nmol/L) of cellular 5-(Sx8)-F fluorescence (measured by flow cytometry) approximated IC50 values (1 to 10 nmol/L) previously found for inhibition by NBMPR of es-mediated nucleoside fluxes in several cell types, supporting the view that 5-(Sx8)-F interacted with the estransporter. The correlation of araC cytotoxicity and the B(max) for 5-(Sx8)-F binding to es sites in cultured leukemia cells and in leukemic blasts from acute leukemia patients (r = .95) suggests that the flow cytometry assay of es capacity may be useful in predicting clinical response to araC.

Acute Disease↗
PubMed1997

Partially mismatched blood cell transplants for high-risk hematologic malignancy.

Eleven patients with high-risk hematologic malignancy received cryopreserved but otherwise unmanipulated blood cell transplants (BCT) from partially mismatched family members in whom progenitor cells had been mobilized by G-CSF. Donors were mismatched by up to one antigen in the GVH direction and up to three antigens in the rejection direction. Outcomes were compared with those of 22 patients receiving BCT from fully matched donors. Two mismatched patients died without engraftment on day 21 and 32. One had rejected bone marrow from the same donor, the other was mismatched by two antigens in the rejection direction and received the lowest dose of CD34+ cells. Median time to granulocyte engraftment was 21.5 (range 16-33) days for the mismatched group compared with 16 (11-28) days for the matched group (P = 0.01). No correlation was found between CD34+ cell dose and time to granulocyte or platelet recovery. In the mismatched and matched BCT groups respectively, the risk of grade II-IV acute graft-versus-host disease (GVHD) was 73% vs 28% (P = 0.001) and of chronic GVHD 100% vs 78% at 18 months (P = 0.01). The relationship of T cell dose to acute GVHD could only be evaluated in the matched group and no correlation was found. One of 11 mismatched patients and eight of 22 matched patients had relapse or persistent disease. Disease-free survival at 1 year was similar at 55% for mismatched and 50% for matched BCT. These results indicate that allogeneic BCT from partially mismatched family members is accompanied by a high incidence of GVHD but may result in comparable survival to BCT from fully matched donors.

Adolescent↗