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J Cebon

Publications and source records attributed to J Cebon.

At least 37 records · Page 2Linked to original sources
PubMed1998

Spontaneous T cell responses to melanoma differentiation antigens from melanoma patients and healthy subjects.

The spontaneous cytotoxic T cell responses to melanoma differentiation antigens and influenza matrix peptide were compared in 20 HLA-A2+ melanoma patients and 17 healthy A2+ individuals. Cytotoxic T lymphocyte (CTL) responses were determined by mixed lymphocyte peptide culture (MLPC) involving two stimulations of unfractionated peripheral blood lymphocytes (PBLs) with peptide in vitro. CTL responses to Melan-A 9-mer (amino acids 27-35, AAGIGILTV) peptide were detected in 4 out of 16 normal individuals, but in none of the melanoma patients. CTL specific for influenza matrix peptide were frequently found in both normal individuals and melanoma patients, suggesting that generalized immuno-suppression was not responsible for this difference. No significant responses were observed in either normal individuals or melanoma patients to Melan-A 10-mer (26-35, EAAGIGILTV), two gp1OO epitopes (280-288, YLEPGPVTA; 457466, LLDGTATLRL) and two tyrosinase epitopes (1-9, MLLAVLYCL; 368-376, YMDGMSQV). Melan-A (27-35)-specific CTL cells generated by normal individuals and melanoma patients recognized both synthetic peptide-pulsed T2 cells and two HLA-A2+, Melan-A+ melanoma cell lines (ME272, LAR1) in an antigen-specific, MHC class I restricted manner. T cells generated against Melan-A 9-mer were also able to recognize Melan-A 10-mer-pulsed target cells. Spontaneous CTL responses to Melan-A 9-mer from three known responder normal individuals were further evaluated over a prolonged time course (6-11 months). All 3 subjects demonstrated specific Melan-A 9-mer responses throughout the study period, although lytic activity fluctuated over time for a given individual. We found the MLPC assay to be reliable and easy to perform for monitoring T cell responses, although it may still not be sufficiently sensitive to detect low numbers of precursor T cells.

Adjuvants, Immunologic↗
PubMed1998

Effect of filgrastim on the pharmacokinetics of MX2 hydrochloride in patients with advanced malignant disease.

PURPOSE: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. METHODS: A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50-80 mg/m2 (74-152 mg) with concomitant filgrastim (G-CSF, 5 microg/kg) given daily beginning at 24 h after the dose of MX2. RESULTS: The mean fast distribution half-life (1.5 +/- 1.0 min) and the mean plasma clearance (2.18 +/- 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8-107.5 mg) alone (3.3 +/- 2.2 min and 2.98 +/- 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 +/- 14.7 and 11.8 +/- 5.0 h for M1 and 14.8 +/- 4.1 and 12.3 +/- 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2-filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2. CONCLUSIONS: This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.

Antibiotics, Antineoplastic↗
PubMed1998

Dose escalation study of carboplatin and cyclophosphamide with filgrastim support: a phase I study.

This clinical trial was designed to explore dose escalation of carboplatin and cyclophosphamide when supported with filgrastim. Twenty-seven patients who had advanced solid tumors received up to six cycles of treatment; a total of 92 cycles of chemotherapy were delivered. Two control groups received standard-dose carboplatin (300 mg/m2) and cyclophosphamide (600 mg/m2), with and without filgrastim. Subsequently, the doses of both carboplatin and cyclophosphamide were increased simultaneously by 50% of the standard dose in sequential cohorts. Doses of up to 2.5 times the standard dose were explored. A final dose of carboplatin, 600 mg/m2, and cyclophosphamide, 1,500 mg/m2, was tested in 4 patients. The duration of neutropenia was brief, even at the highest dose levels. The mean duration of grade 3 or 4 neutropenia was 5.8 days at standard dose without filgrastim and 5.4 days at 2.5 times standard dose with filgrastim. More severe neutropenia was more prolonged at higher doses but remained brief in duration. The mean duration of neutropenia of less than 100 x 10(6)/l was 0.4 days at standard dose without filgrastim and 1.3 days at 2.5 times standard dose. There was no evidence of cumulative neutropenia over repeated cycles of treatment. In contrast, thrombocytopenia was both dose limiting and cumulative. The mean duration of grade 3 or 4 thrombocytopenia was 1.6 days at standard dose and 9.6 days at 2.5 times standard dose. An average of 2.3 platelet transfusions per cycle of treatment was required at the highest dose. Thrombocytopenia was worse with repetitive cycles of therapy. The mean duration of grade 3 or 4 thrombocytopenia was 2.2 days after the first cycle of chemotherapy and 7.8 days after cycle four. The maximum tolerated dose, as defined prospectively, was not reached but further dose escalation was not thought to be warranted because of the severity of thrombocytopenia. When supported with filgrastim, carboplatin and cyclophosphamide can be administered safely with substantially increased dose and acceptable toxicity.

Adolescent↗
PubMed1998

Rapid hematopoietic recovery after multicycle high-dose chemotherapy: enhancement of filgrastim-induced progenitor-cell mobilization by recombinant human stem-cell factor.

PURPOSE: To assess the mobilization potential and safety of recombinant human stem-cell factor (SCF) when coadministered with filgrastim to untreated women with poor-prognosis breast cancer. PATIENTS AND METHODS: Eligible women had breast cancer with 10 or more positive axillary nodes, or estrogen receptor-negative tumor with 4 positive nodes, or stage III disease. Patients were randomized to receive SCF plus filgrastim or filgrastim alone. Filgrastim 12 microg/kg daily was administered for 6 days by continuous subcutaneous infusion. SCF was administered by daily subcutaneous injection at 5, 10, or 15 microg/kg concurrent with filgrastim for 7 days, or 10 microg/kg daily starting 3 days before filgrastim for a total of 10 days (SCF pretreatment). Apheresis was performed on days 5, 6, and 7 of filgrastim administration. Patients then had three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2 every 28 days, each supported by one third of the apheresis product. RESULTS: Sixty-two women were treated. Greater yields occurred in patients who received SCF 10 microg/kg daily plus filgastim than those who received filgrastim alone (P=.013 for CD34+ cells; P=.07 for granulocyte-macrophage colony-forming cells [GM-CFCs]). The difference was more marked with SCF-pretreatment than concurrent SCF. Fewer aphereses were required to reach the predetermined target of peripheral-blood progenitor/stem cells (PBPCs) in women who received SCF. SCF was generally well tolerated. Hematologic recovery was rapid after each of the three cycles of chemotherapy. There was no difference in recovery between the different treatment groups. CONCLUSION: Mobilization of PBPCs by filgrastim is significantly enhanced by coadministration of SCF, and commencing SCF before filgrastim can optimize this effect. SCF has the potential to reduce the number of aphereses required to collect a target number of PBPCs.

Adult↗
PubMed1998

Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS: Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION: KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

Adult↗
PubMed1998

A serum-free culture model for studying the differentiation of human dendritic cells from adult CD34+ progenitor cells.

The antigen-presenting capacity of dendritic cells (DCs) makes them attractive potential cellular adjuvants for vaccination strategies. Currently, most in vitro culture systems for the production of these DCs include serum. However, this is undesirable because serum contains growth factors that vary between individuals and could affect DC development. Unless the patient's own serum is used, foreign antigens and the risk of infection will detract from the usefulness of these cells in clinical strategies. In this study we investigated the production of DCs from CD34+ progenitor cells of cancer patients or normal donors under serum-free conditions. We have established a model system for the investigation of DC development and maturation. Dendritic cells that developed from myeloid precursors accumulated after 2 weeks in an intermediate CD1a , CD80-, CD83-, CD86- stage. Intermediate DCs adhered to plastic surfaces, expressed Birbeck granules, and were negative for CD2 and CD14. In the presence of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha, interleukin-4 promoted the development of these stages. Spontaneous maturation of intermediate DCs into fully activated DCs expressing CD83 and costimulatory molecules occurred asynchronously over the ensuing 2 to 3 weeks. This maturation involved increased expression of CD80, CD83, CD86, CMRF-44, HLA-A, -B, -C, and -DR as well as downregulation of CD1a and CD11b. Activated DCs are characterized by the lack of adherence to plastic surfaces and the absence of Birbeck granules. By day 28, these cells were nonphagocytic, potent antigen-presenting cells with an irreversible phenotype. This serum-free system offers advantages in that the process of differentiation and maturation of committed DCs is extended over a period of more than 28 days, allowing investigators to study the effects of individual cytokines or other supplements during distinct phases of DC development in a defined environment.

Adult↗
PubMed1997

Enhanced levels and enhanced clonogenic capacity of blood progenitor cells following administration of stem cell factor plus granulocyte colony-stimulating factor to humans.

Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.

Administration, Cutaneous↗
PubMed1997

Increased tolerance to endotoxin by granulocyte-macrophage colony-stimulating factor-deficient mice.

The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-mediated septic shock has been assessed by treating GM-CSF-deficient mice with LPS. Hypothermia and loss in body weight were markedly attenuated in LPS-treated GM-CSF-deficient mice compared with similarly treated control mice; moreover, the levels of circulating IFN-gamma, IL-1alpha, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LPS-treated control mice. Intriguingly, the peak levels of TNF-alpha in response to LPS treatment were the same in the serum of GM-CSF-deficient mice and control mice, although in GM-CSF-deficient mice, TNF-alpha persisted longer. Activation of macrophages by LPS, resulting in expression of cytokines including TNF-alpha and IL-1, is thought to underlie endotoxin-mediated effects. Accordingly, the response of peritoneal macrophages from GM-CSF-deficient mice to LPS was studied in vitro. LPS-stimulated peritoneal macrophages from GM-CSF-deficient mice produced significantly less IL-1alpha and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-alpha production. Collectively, these observations indicate that GM-CSF contributes to cytokine production in LPS-mediated septic shock, and that the attenuated production of these secondary cytokines (IFN-gamma, IL-1alpha, and IL-6) may contribute to the endotoxin-resistant phenotype of GM-CSF-deficient mice.

Animals↗
PubMed1997

Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer.

Thrombocytopenia caused by chemotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocytopoiesis and prevents chemotherapy-induced thrombocytopenia in preclinical studies. We administered PEG-rHuMGDF with filgrastim after dose-intensive chemotherapy to 41 patients with advanced cancers to determine its safety and effects on hematologic recovery. Carboplatin 600 mg/m2 and cyclophosphamide 1,200 mg/m2 were administered to patients with advanced cancer. Patients were randomly assigned to receive blinded study drug, either PEG-rHuMGDF or placebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMGDF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 microg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days. All patients received concurrent filgrastim 5 microg per kilogram body weight per day until neutrophil recovery. Fifteen patients had received PEG-rHuMGDF alone in a previous phase I study. Platelet function and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuMGDF enhanced platelet recovery in a dose-related manner when compared with placebo. The platelet nadir occurred earlier in patients given PEG-rHuMGDF (P = .002) but there was no difference in the depth of the nadir. Recovery to baseline platelet count was achieved significantly earlier following PEG-rHuMGDF administration compared with placebo (median, 17 days for PEG-rHuMGDF 0.3 to 5.0 microg/kg versus 22 days for placebo, P = .014). In addition, platelet recovery was faster in patients who had previously received PEG-rHuMGDF, suggesting that pretreatment might be beneficial. Platelet function did not change during or after administration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemotherapy were significantly greater in patients administered PEG-rHuMGDF 0.3 to 5.0 microg/kg and filgrastim compared with those given placebo plus filgrastim. PEG-rHuMGDF was well tolerated at all doses. Two patients given PEG-rHuMGDF had a thrombotic episode. PEG-rHuMGDF accelerates platelet recovery after moderately dose-intensive carboplatin and cyclophosphamide, and is likely to be clinically useful in treatment of chemotherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient collection of stem cells for autologous or allogeneic transplantation.

Adult↗
PubMed1997

Pharmacokinetics and pharmacodynamics of MX2 hydrochloride in patients with advanced malignant disease.

The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10-50 mg/m2 (total dose 16.8-107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 +/- 1.68 l/min, the mean volume of distribution at steady state was 1460 +/- 749 l and mean elimination half-life was 10.8 +/- 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r2 = 0.43, P < 0.01 and r2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 +/- 5.0, 21.9 +/- 11.8, 19.0 +/- 11.3 and 12.3 +/- 6.3 h, respectively. The fractional Emax model produced a much better fit to the relative nadir neutrophil count versus dose data (r2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (Cmax) data (r2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 x 10(9)/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and Cmax than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or Cmax.

Adult↗
PubMed1997

Immunotherapy of melanoma: targeting defined antigens.

The clinical experience that spontaneous anti-melanoma immune reactivity can occur has stimulated the search for methods to induce this in patients diagnosed with melanoma. Non-specific approaches using a variety of immune stimulants such as BCG or cytokines have met with limited success, as have vaccines derived from tumour cells. More recently, melanoma antigens have been identified that can act as specific targets for immune recognition. Cell surface glycolipids such as the gangliosides GM2 and GD3, can be targeted by antibodies. This has provided the basis for clinical trials with ganglioside vaccines and monoclonal antibody infusions. Antigens recognized by cytotoxic lymphocytes have also been described in the last 5 years. These are peptide antigens derived from intracellular proteins which are present on the cell surface in association with HLA molecules. These antigens include MAGE 1 and 3, tyrosinase, MelanA/MART-1 and gp100. Clinical trials with these have commenced and novel treatment strategies are being developed. Since tumours can be typed for specific antigens and specific immune responses can be measured, the reasons for treatment success or failure can be analysed more effectively than in the past. For example, the emergence of antigen-negative tumour variants can be assessed. This should enable a more systematic approach for developing new immunotherapies for melanoma.

Antigens, Neoplasm↗
PubMed1997

Viability and quantification of progenitor cells in venesected blood from patients receiving escalated-dose epirubicin and cyclophosphamide with G-CSF for lymphoma: potential role in further increasing dose-intensity.

We assessed the concentration of haemopoietic progenitors in peripheral blood in six patients with de novo intermediate grade non-Hodgkin's lymphoma receiving multiple cycles of escalated dose epirubicin and cyclophosphamide on day 1 followed by 5 microg/kg of G-CSF (filgrastim) on days 2-14. Specimens were taken at days 12, 15 and 18 in cycles 1 and 2 and on day 15 for cycles 3-6. Progenitor numbers were maximal on day 15 in cycles 1 and 2. The median number of granulocyte-macrophage colony forming cells (GM-CFC) and CD34+ cells on day 15 of cycles 1 and 2 was 3.8 x 10(4)/ml and 11 x 10(4)/ml, respectively. A 600 ml venesection at this time would contain a median of 36 x 10(4) GM-CFC/kg (range 25-47) and 1.04 x 10(6) CD34+ cells/kg (range 0.73-1.4), based on individual patient weights. Day 15 progenitor numbers were maintained for the first 3 cycles but tended to fall thereafter. The viability of the progenitors collected in whole blood and stored at 4 degrees C for various time intervals was also assessed. The median percent of GM-CFC and erythroid blast forming units (BFU-e) surviving after storage for 48 hrs was 79% and 69% respectively and after 72 hrs was 48% and 63% respectively. Serum collected 2 hrs after the completion of chemotherapy had minimal inhibitory effect on progenitors collected prior to treatment. Our data demonstrate that two weeks after anthracycline-based chemotherapy and G-CSF in previously untreated patients the peripheral blood contains large numbers of progenitors. A 600 ml venesection at this time stored at 4 degrees C, and then reinfused after the next cycle of chemotherapy would contain sufficient viable progenitors to potentially hasten haematological recovery.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer.

BACKGROUND: Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocyte colony formation and platelet production. It is likely to be useful in the management of severe thrombocytopenia. To determine its clinical activity and safety, we gave it to patients with advanced cancer before chemotherapy. METHODS: Patients were randomly assigned to receive either PEG-rHuMGDF or placebo in a three to one ratio. PEG-rHuMGDF was given at a dose of 0.03, 0.1, 0.3, or 1.0 microgram/kg body weight. The study drug or placebo were administered daily by subcutaneous injection for up to 10 days or until a target platelet count was reached. FINDINGS: 17 patients, median age 59 years, received either PEG-rHuMGDF (13 patients) or placebo (four patients). PEG-rHuMGDF produced a dose-dependent increase in platelet counts. Patients given placebo. 0.03, and 0.1 microgram/kg of PEG-rHuMGDF had median increases in platelet counts of 16%, 12%, and 39%. Those receiving 0.3 and 1.0 microgram/kg of PEG-rHuMGDF had an increase in blood platelets of between 51% and 584%. Platelets rose from day 6 of PEG-rHuMGDF administration and continued to rise after stopping the drug. The platelet count peaked between days 12 and 18 and remained above 450 x 10(9)/L for up to 21 days. There were no alterations in white-blood-cell count or haematocrit, and low toxicity. Platelets taken from patients during PEG-rHuMGDF administration and at the time of peak platelet count were morphologically and functionally normal. INTERPRETATION: The potency with which PEG-rHuMGDF stimulates platelet production and its low toxicity indicate that this is likely to be a useful agent for the management of thrombocytopenia.

Dose-Response Relationship, Drug↗
PubMed1996

Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation.

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.

Cohort Studies↗
PubMed1995

Transient hypoxaemia during neutrophil recovery in febrile patients.

In previous anecdotal reports, treatment with granulocyte colony-stimulating factor has been associated with pulmonary toxicity. In 35 consecutive admissions for chemotherapy-induced febrile neutropenia, transient hypoxia occurred in 12. 10 of the 12 followed treatment with filgrastim to induce neutrophil recovery. There was no consistent association with cytotoxic regimen.

Adolescent↗
PubMed1995

Long-term treatment of canine cyclic hematopoiesis with recombinant canine stem cell factor.

Grey collie dogs have cyclic fluctuations in their blood cell counts caused by a regulatory defect of hematopoietic stem cells. To examine the role of stem cell factor (SCF) or its receptor in this disorder, we investigated the stimulatory effects of recombinant canine SCF (rc-SCF) on in vitro marrow cultures, cloned and sequenced the grey collie SCF gene, and treated three grey collies with rc-SCF, either alone or in combination with recombinant canine granulocyte colony-stimulating factor (rcG-CSF). Colony-forming unit granulocyte-macrophage formation from grey collie or normal dog marrow showed similar dose-response curves for rc-SCF. Cloning and sequencing the SCF gene for two grey collies showed no evidence of mutations in the coding region of the SCF gene. Treatment with rc-SCF (10 to 100 micrograms/kg/d) did not induce neutrophilia except at the highest dose (100 micrograms/kg/d), but daily rc-SCF abrogated the neutropenic periods in doses of 20 micrograms/kg/d or greater. Combination of rc-G-CSF (0.5 to 1.0 microgram/kg/d) with rc-SCF treatment (20 to 50 micrograms/kg/d) suggested a synergistic effect, ie, the neutrophil levels on combined therapy were higher than the sum of the levels when these two cytokines were given separately. Long-term treatment of these dogs with rc-SCF in doses of 10 to 30 micrograms/kg/d was generally well tolerated, suggesting that SCF may be useful as a therapy for some chronic hypoproliferative disorders of hematopoiesis.

Animals↗
PubMed1995

Differential alterations in plasma colony-stimulating factor concentrations in meningococcaemia.

To determine whether circulating levels of any of the colony-stimulating factors (CSF) might contribute to the host response in severe sepsis, plasma concentrations of granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), and macrophage CSF (M-CSF) were measured by immunoassays in 20 subjects with meningococcaemia, a bloodstream infection caused by Neisseria meningitidis, that has proven to be a valuable model to study the responses of other inflammatory mediators during sepsis and septic shock in humans. Plasma G-CSF concentrations were transiently elevated in most subjects during the early phase of meningococcaemia, and were higher in subjects with septic shock (mean +/- s.d. = 165 +/- 142 ng/ml, n = 9) compared with those who remained normotensive (mean +/- s.d. = 7 +/- 2 ng/ml, n = 10) (P < 0.05). Peak plasma G-CSF concentrations > 10 ng/ml were associated with the development of septic shock (P < 0.01), disseminated intravascular coagulation (P < 0.01), fulminant infection (P < 0.05), and a fatal outcome (P < 0.01). Plasma GM-CSF concentrations > 1 ng/ml were briefly present in subjects with life-threatening septic shock (1-15 ng/ml, n = 5), and were strongly associated with fulminant meningococcaemia (P < 0.01). Plasma M-CSF concentrations were marginally elevated in all subjects, but were not associated with complications related to or arising from sepsis-induced organ injury. This study demonstrates that plasma levels of G-CSF, GM-CSF and M-CSF show very different responses during meningococcaemia, changes which presumably reflect the different roles played by these mediators in sepsis and, potentially, in septic shock.

Adolescent↗