GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and dif... more GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and differentiation of marrow cells and enhancing the functional activities of granulocytes and monocytes. These studies have indicated that GM-CSF may prove useful in the management of cancer patients by preventing or treating myelosuppression following cancer chemotherapy and in patients with myelodysplasia or aplastic anaemia. As well as determining the efficacy of GM-CSF as a therapeutic agent, these studies are also providing insights into the possible roles of GM-CSF in vivo. Pharmacokinetic studies of GM-CSF in patients with advanced cancer and myelodysplasia suggest that the ratio of efficacy to toxicity of GM-CSF can be modified by changing either the dose or the method of administration.
Chromosomal analysis of human hemopoietic malignancies has resulted in a better understanding of ... more Chromosomal analysis of human hemopoietic malignancies has resulted in a better understanding of their etiology, improved their classification, allowed a better prediction of prognosis, and proved useful for the detection of malignant cells present in low frequency in the bone marrow samples. An example of the usefulness of chromosomal analysis in the myeloid leukemias is the identification of the Philadelphia chromosome in Chronic Granulocytic Leukemia and of a new protein encoded by the abl bcr genes as a consequence of the translocation of the abl proto-oncogene to chromosome 22 adjacent to the bcr gene [1]. It is not difficult to extrapolate that these observations will lead to an understanding of the basis for the initiation and maintenance of the malignancy. Other examples in which specific nonran-dom chromosomal abnormalities have been identified include t(15;17) in acute promyelocytic leukemia and the inversion of chromosome 16 in the M4Eo subtype of ANLL [1].
The production of blood cells is known to be under the control of up to 20 different cytokines [1... more The production of blood cells is known to be under the control of up to 20 different cytokines [1]. In recent years many of the cytokines have been identified and cloned, and are now in clinical trials. Several of the cytokines, including interleukin-6 (IL-6), interleukin-3 (IL-3) and granulocyte—macrophage colony-stimulating factor (GM-CSF) act upon early progenitor cells, while others, such as granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF) and erythropoietin, act upon the more mature precursor cells and produce relatively pure populations of granulocytes, monocytes and red blood cells respectively. It is now clear that these cytokines, although acting on a limited number of specific lineages, have very different properties in vivo and in vitro.
Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-... more Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS)
Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purif... more Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purified using methods which typically required several sequential chromatographic steps and only yielded small amounts of hGM-CSF. We have purified and characterized hGM-CSF using monoclonal antibodies raised against bacterially synthesized hGM-CSF. Activated donor T-lymphocytes grown in interleukin-2 and then reactivated with phytohemagglutinin produce several forms of hGM-CSF which can be purified using immunoaffinity absorption followed by reversed phase high performance liquid chromatography. The purified hGM-CSF consisted of at least nine species ranging in molecular weight (Mr) from 14,500 to 32,000. The higher Mr forms contained one or two N-linked carbohydrate moieties and were more acidic by two-dimensional Western blot analysis, consistent with increasing sialation. N-terminal sequence analysis of high and low molecular weight hGM-CSF fractions corresponded to that predicted by the cDNA sequence. Using the AML 193 [3H]thymidine incorporation assay the specific activity of the heavily glycosylated hGM-CSF was 1 x 10(8) units/mg compared with 6 x 10(8) units/mg for the non-glycosylated hGM-CSF produced by Escherichia coli. The different hGM-CSF forms induced neutrophil superoxide anion production by a variable amount depending on the extent of N-linked glycosylation. Receptor binding studies demonstrated lower receptor affinity for the heavily glycosylated form (KD = 820 pM) compared to less heavily glycosylated (KD = 78 pM) and non-glycosylated hGM-CSF produced by E. coli (KD = 30 pM). These differences are due to differences in the kinetic association rate.
Summary.During a study of recombinant human granulocyte colony stimulating factor (rhG‐CSF) admin... more Summary.During a study of recombinant human granulocyte colony stimulating factor (rhG‐CSF) administration, 15 patients received twice daily i.v. infusions and nine patients received daily s.c. infusions of rhG‐CSF for 5 d prior to cytotoxic therapy, and then a second course subsequent to melphalan administration. There was a striking dose‐related neutrophilia and the appearance in the blood of early myeloid cells that express the intercellular adhesion molecule CD54. In addition, giant neutrophils or macropolycytes were observed in the peripheral blood of all patients. These cells were evident on the display of the Technicon H*1 as a population of large peroxidase positive cells, and using Feulgen staining these cells were shown to be tetraploid. Bone marrow kinetics studies performed on Day 4 or 5 indicated an increase in the proportion of bone marrow cells in S phase, G2 and mitosis, reflecting a proliferative response of the marrow. Large myeloid precursors and occasional binucl...
To define the clinical and hematologic effects of subcutaneously administered bacterially synthes... more To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Single arm nonrandomized dose escalation study. Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy. Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently. All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient. Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.
We have undertaken a phase 1 — phase 2 study of the effectiveness of photoirradiation therapy or ... more We have undertaken a phase 1 — phase 2 study of the effectiveness of photoirradiation therapy or photodynamic therapy (PDT) in the treatment of advanced esophageal cancer.
To investigate the degree and type of delays in performing diagnostic biopsies in medical patient... more To investigate the degree and type of delays in performing diagnostic biopsies in medical patients with suspected malignancy. Retrospective survey of clinical histories of patients referred between January 1985 and March 1989. Inner city teaching hospital internal medicine (non-oncologic) services. Patients with gastrointestinal and lung cancers, adenocarcinoma of unknown primary site, and lymphomas were referred as inpatients by internists. Two hundred fifty-five patients were eligible, and 177 were evaluable. The number, type, and results of tests done before and after biopsy were analyzed. In 67% of patients the biopsied lesion was detected by the second day of evaluation; however, there was an 8- to 10-day delay before a biopsy was done. This delay was consistent across the four malignancy groups studied. Although logistic and other unavoidable delays occurred in 40% of the cases, in 60% delays could only be attributed to continued, frequently low yield, noninvasive tests. An average of 3.3 tests were made per patient, with only 24% leading to a definitive biopsy. Because of the performance of many other tests, a substantial delay exists in proceeding to biopsy during the diagnosis of cancer by internists.
A monoclonal antibody, Leo Mel 3, raised against a melanoma cell line (LiBr), binds to a carbohyd... more A monoclonal antibody, Leo Mel 3, raised against a melanoma cell line (LiBr), binds to a carbohydrate determinant of cell surface gangliosides, the simplest of which is GD3. This monoclonal antibody was screened for by its capacity to block the recognition and lysis of the melanoma cells by cytotoxic T-lymphocytes with anomalous killer cell function, illustrating a novel approach for identifying monoclonal antibody to biologically relevant tumor-associated antigens. Leo Mel 3 reacted selectively with melanoma cells by indirect immunofluorescent and immunoperoxidase staining; it reacted with tissue from all primary and metastatic melanoma tested, and it bound to cells from all but one of six cultured melanoma cell lines. Leo Mel 3 did not react with a variety of carcinomas, lymphomas, leukemias, and other neuroectodermal tumors, nor with adult or fetal tissues, except fetal liver. Very weak staining of cutaneous basal melanocytes was noted in a minority of skin sections, and 50 to 80...
Australian and New Zealand journal of medicine, 1981
Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single ... more Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single high doses of busulphan. The action of busulphan on the in vivo kinetics of circulating progenitor cells (colony forming cells) was measured using an agar culture system which involved scoring of total colonies and clusters at 7 days and of granulocyte, monocyte and eosinophil colonies at 14 days. High dose busulphan was found to be effective in suppressing circulating granulocyte, monocyte and eosinophil progenitor cells. The effect of busulphan on progenitor cells was rapid and their levels fell by at least 85% within five days. By contrast, the white blood cells fell by only 9% and the platelets fell by 10% over this time. Subsequently, the white cell count and platelet count fell to near normal levels. The progenitor cell levels began to rise again at a mean of 35 days following busulphan treatment and the white blood cells at a mean of 39 days in four patients. One patient remained ...
European journal of cancer & clinical oncology, 1989
Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mo... more Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granu...
GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and dif... more GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and differentiation of marrow cells and enhancing the functional activities of granulocytes and monocytes. These studies have indicated that GM-CSF may prove useful in the management of cancer patients by preventing or treating myelosuppression following cancer chemotherapy and in patients with myelodysplasia or aplastic anaemia. As well as determining the efficacy of GM-CSF as a therapeutic agent, these studies are also providing insights into the possible roles of GM-CSF in vivo. Pharmacokinetic studies of GM-CSF in patients with advanced cancer and myelodysplasia suggest that the ratio of efficacy to toxicity of GM-CSF can be modified by changing either the dose or the method of administration.
Chromosomal analysis of human hemopoietic malignancies has resulted in a better understanding of ... more Chromosomal analysis of human hemopoietic malignancies has resulted in a better understanding of their etiology, improved their classification, allowed a better prediction of prognosis, and proved useful for the detection of malignant cells present in low frequency in the bone marrow samples. An example of the usefulness of chromosomal analysis in the myeloid leukemias is the identification of the Philadelphia chromosome in Chronic Granulocytic Leukemia and of a new protein encoded by the abl bcr genes as a consequence of the translocation of the abl proto-oncogene to chromosome 22 adjacent to the bcr gene [1]. It is not difficult to extrapolate that these observations will lead to an understanding of the basis for the initiation and maintenance of the malignancy. Other examples in which specific nonran-dom chromosomal abnormalities have been identified include t(15;17) in acute promyelocytic leukemia and the inversion of chromosome 16 in the M4Eo subtype of ANLL [1].
The production of blood cells is known to be under the control of up to 20 different cytokines [1... more The production of blood cells is known to be under the control of up to 20 different cytokines [1]. In recent years many of the cytokines have been identified and cloned, and are now in clinical trials. Several of the cytokines, including interleukin-6 (IL-6), interleukin-3 (IL-3) and granulocyte—macrophage colony-stimulating factor (GM-CSF) act upon early progenitor cells, while others, such as granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF) and erythropoietin, act upon the more mature precursor cells and produce relatively pure populations of granulocytes, monocytes and red blood cells respectively. It is now clear that these cytokines, although acting on a limited number of specific lineages, have very different properties in vivo and in vitro.
Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-... more Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS)
Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purif... more Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purified using methods which typically required several sequential chromatographic steps and only yielded small amounts of hGM-CSF. We have purified and characterized hGM-CSF using monoclonal antibodies raised against bacterially synthesized hGM-CSF. Activated donor T-lymphocytes grown in interleukin-2 and then reactivated with phytohemagglutinin produce several forms of hGM-CSF which can be purified using immunoaffinity absorption followed by reversed phase high performance liquid chromatography. The purified hGM-CSF consisted of at least nine species ranging in molecular weight (Mr) from 14,500 to 32,000. The higher Mr forms contained one or two N-linked carbohydrate moieties and were more acidic by two-dimensional Western blot analysis, consistent with increasing sialation. N-terminal sequence analysis of high and low molecular weight hGM-CSF fractions corresponded to that predicted by the cDNA sequence. Using the AML 193 [3H]thymidine incorporation assay the specific activity of the heavily glycosylated hGM-CSF was 1 x 10(8) units/mg compared with 6 x 10(8) units/mg for the non-glycosylated hGM-CSF produced by Escherichia coli. The different hGM-CSF forms induced neutrophil superoxide anion production by a variable amount depending on the extent of N-linked glycosylation. Receptor binding studies demonstrated lower receptor affinity for the heavily glycosylated form (KD = 820 pM) compared to less heavily glycosylated (KD = 78 pM) and non-glycosylated hGM-CSF produced by E. coli (KD = 30 pM). These differences are due to differences in the kinetic association rate.
Summary.During a study of recombinant human granulocyte colony stimulating factor (rhG‐CSF) admin... more Summary.During a study of recombinant human granulocyte colony stimulating factor (rhG‐CSF) administration, 15 patients received twice daily i.v. infusions and nine patients received daily s.c. infusions of rhG‐CSF for 5 d prior to cytotoxic therapy, and then a second course subsequent to melphalan administration. There was a striking dose‐related neutrophilia and the appearance in the blood of early myeloid cells that express the intercellular adhesion molecule CD54. In addition, giant neutrophils or macropolycytes were observed in the peripheral blood of all patients. These cells were evident on the display of the Technicon H*1 as a population of large peroxidase positive cells, and using Feulgen staining these cells were shown to be tetraploid. Bone marrow kinetics studies performed on Day 4 or 5 indicated an increase in the proportion of bone marrow cells in S phase, G2 and mitosis, reflecting a proliferative response of the marrow. Large myeloid precursors and occasional binucl...
To define the clinical and hematologic effects of subcutaneously administered bacterially synthes... more To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Single arm nonrandomized dose escalation study. Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy. Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently. All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient. Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.
We have undertaken a phase 1 — phase 2 study of the effectiveness of photoirradiation therapy or ... more We have undertaken a phase 1 — phase 2 study of the effectiveness of photoirradiation therapy or photodynamic therapy (PDT) in the treatment of advanced esophageal cancer.
To investigate the degree and type of delays in performing diagnostic biopsies in medical patient... more To investigate the degree and type of delays in performing diagnostic biopsies in medical patients with suspected malignancy. Retrospective survey of clinical histories of patients referred between January 1985 and March 1989. Inner city teaching hospital internal medicine (non-oncologic) services. Patients with gastrointestinal and lung cancers, adenocarcinoma of unknown primary site, and lymphomas were referred as inpatients by internists. Two hundred fifty-five patients were eligible, and 177 were evaluable. The number, type, and results of tests done before and after biopsy were analyzed. In 67% of patients the biopsied lesion was detected by the second day of evaluation; however, there was an 8- to 10-day delay before a biopsy was done. This delay was consistent across the four malignancy groups studied. Although logistic and other unavoidable delays occurred in 40% of the cases, in 60% delays could only be attributed to continued, frequently low yield, noninvasive tests. An average of 3.3 tests were made per patient, with only 24% leading to a definitive biopsy. Because of the performance of many other tests, a substantial delay exists in proceeding to biopsy during the diagnosis of cancer by internists.
A monoclonal antibody, Leo Mel 3, raised against a melanoma cell line (LiBr), binds to a carbohyd... more A monoclonal antibody, Leo Mel 3, raised against a melanoma cell line (LiBr), binds to a carbohydrate determinant of cell surface gangliosides, the simplest of which is GD3. This monoclonal antibody was screened for by its capacity to block the recognition and lysis of the melanoma cells by cytotoxic T-lymphocytes with anomalous killer cell function, illustrating a novel approach for identifying monoclonal antibody to biologically relevant tumor-associated antigens. Leo Mel 3 reacted selectively with melanoma cells by indirect immunofluorescent and immunoperoxidase staining; it reacted with tissue from all primary and metastatic melanoma tested, and it bound to cells from all but one of six cultured melanoma cell lines. Leo Mel 3 did not react with a variety of carcinomas, lymphomas, leukemias, and other neuroectodermal tumors, nor with adult or fetal tissues, except fetal liver. Very weak staining of cutaneous basal melanocytes was noted in a minority of skin sections, and 50 to 80...
Australian and New Zealand journal of medicine, 1981
Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single ... more Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single high doses of busulphan. The action of busulphan on the in vivo kinetics of circulating progenitor cells (colony forming cells) was measured using an agar culture system which involved scoring of total colonies and clusters at 7 days and of granulocyte, monocyte and eosinophil colonies at 14 days. High dose busulphan was found to be effective in suppressing circulating granulocyte, monocyte and eosinophil progenitor cells. The effect of busulphan on progenitor cells was rapid and their levels fell by at least 85% within five days. By contrast, the white blood cells fell by only 9% and the platelets fell by 10% over this time. Subsequently, the white cell count and platelet count fell to near normal levels. The progenitor cell levels began to rise again at a mean of 35 days following busulphan treatment and the white blood cells at a mean of 39 days in four patients. One patient remained ...
European journal of cancer & clinical oncology, 1989
Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mo... more Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granu...
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Papers by George Morstyn