ABC of breast diseases. Breast cancer.
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Breast↗
Biomedical subjects
D A Morgan
Publications and source records attributed to D A Morgan.
Can long-term survival be improved in patients with small-cell lung cancer (SCLC) and good performance status? Medical Research Council Lung Cancer Working Party.
Results from a long-term follow-up suggest that in patients with limited small-cell lung cancer (SCLC) and normal performance status intensive alternating chemotherapy and radiotherapy improve long-term survival rates. In a non-randomised study, 22 patients with SCLC of limited extent and good performance status were prescribed six cycles of etoposide, doxorubicin, cisplatin and cyclophosphamide at 4 week intervals with doses of thoracic radiotherapy following the second, third and fourth cycles. Although only six patients received all their prescribed treatment, nine (41%) were alive at 1 year, seven (32%) at 2 years, six (27%) at 3 years, and four are still alive at, respectively, 42, 47, 50, and 61 months, all four being in the subgroup of eight patients with WHO performance status grade 0 at the start of treatment. In a comparison with similar patients receiving conventionally scheduled chemotherapy and radiotherapy in a concurrent trial, no difference in survival was seen in the patients with performance status grade 1 or 2, but a large difference in favour of the alternating schedule in those with grade 0 status was seen. We encourage other investigators to report the results achieved with intensive treatment in patients with WHO grade 0 performance status at the start of treatment.
Antineoplastic Combined Chemotherapy Protocols↗
Intracerebroventricular insulin produces nonuniform regional increases in sympathetic nerve activity.
Insulin has been shown to increase sympathetic nerve activity (SNA). Although it has been proposed that insulin acts within the central nervous system (CNS) to increase sympathetic neural outflow, there is little evidence for direct central neural sympathoexcitatory effects of insulin. To determine whether intracerebroventricular insulin elicits increases in peripheral SNA, we infused insulin (0.1 microU/min, low; 10 microU/min, medium; and 100 microU/min, high doses) or artificial cerebrospinal fluid (aCSF) into the third cerebral ventricle of chloralose-anesthetized Wistar rats while recording lumbar SNA. In separate animals, 10 microU/min of insulin were infused while recording adrenal SNA and renal SNA. Blood glucose and plasma insulin levels did not significantly change during intracerebroventricular infusion of insulin. Lumbar SNA, expressed as percentage of baseline, did not change in rats infused with aCSF (+ 13% +/- 8%) but increased significantly in rats infused with low (+ 72 +/- 17%), medium (+ 119 +/- 30%), and high (+ 113 +/- 25%) doses of insulin (P < 0.05). Intracerebroventricular insulin failed to significantly increase adrenal SNA or renal SNA. Blood pressure and heart rate did not change during insulin infusion. The results indicate that administration of insulin into the third cerebral ventricle produces regionally nonuniform increases in sympathetic neural outflow in the absence of changes in blood glucose or plasma insulin.
Adrenal Glands↗
Sustained increases in aortic depressor nerve activity after acute elevation in arterial pressure.
OBJECTIVE: Despite the return of mean arterial pressure (MAP) to control levels, aortic depressor nerve activity remains elevated from control levels after sustained phenylephrine-induced increases in MAP in spontaneously hypertensive rats (SHR) (Kenney MJ, Morgan DA, Mark AL: Am J Physiol 1990, 258:H1476-H1481). This suggests that sustained increases in arterial pressure may produce prolonged pressure-induced changes in afferent baroreceptor nerve activity in SHR. However, because phenylephrine can exert an excitatory effect on the aortic arch baroreceptors, the increase in aortic depressor nerve activity might have resulted from a persistent direct effect of phenylephrine. The aim of the current study was to determine whether elevations in MAP induced by aortic occlusion produce increases in aortic depressor nerve activity which persist after the return of MAP to control levels. METHODS: MAP and aortic depressor nerve activity were recorded before, during and after sustained (15-30 min) periods of aortic occlusion in SHR with intact adrenal glands (n = 18) and in adrenalectomized SHR (n = 10). Control experiments were completed in which the same variables were recorded before, during and after sham aortic occlusion in intact (n = 8) and adrenalectomized (n = 8) SHR. RESULTS: Aortic occlusion increased MAP and aortic depressor nerve activity significantly from control levels. After aortic occlusion and the return of MAP to control levels, aortic depressor nerve activity remained significantly increased in 15 experiments, whereas in three experiments aortic depressor nerve activity was reduced. Aortic depressor nerve activity was increased significantly from control levels after aortic occlusion in adrenalectomized rats. Aortic depressor nerve activity remained unchanged from control levels after sham aortic occlusion in intact and adrenalectomized SHR. CONCLUSIONS: Sustained elevations in MAP induce increases in aortic depressor nerve activity in intact and adrenalectomized SHR, which persist after the return of MAP to control levels. These observations suggest that sustained increases in arterial pressure may produce prolonged pressure-induced changes in afferent baroreceptor nerve activity in SHR.
Adrenal Glands↗
Stem cell factor influences the proliferation and erythroid differentiation of the MB-02 human erythroleukemia cell line by binding to a high-affinity c-kit receptor.
Stem cell factor (SCF) acts in synergy with other growth factors such as erythropoietin (Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interleukin-3 (IL-3), to stimulate the growth of primitive hematopoietic cells. Because of the prominent role of CSF in the maintenance of normal erythropoiesis in vivo, we examined the effects of SCF on the Epo-inducible human erythroleukemia cell line MB-02, and characterized the c-kit receptor in these cells. MB-02 cells cultured in serum-containing media do not survive in the absence of exogenous growth factors, but the addition of SCF, Epo, or IL-3 as a single factor enhanced MB-02 survival. Furthermore, in the presence of Epo, SCF (5 to 25 ng/mL) enhanced MB-02 proliferation in a dose-dependent manner, and increased the relative and absolute number of benzidine-positive cells generated. SCF also enhanced cell proliferation in the presence of either IL-3 or low concentrations of GM-CSF. A neutralizing anti-c-kit receptor monoclonal antibody (SR-1) blocked binding of 125I-SCF to MB-02 cells by 98%, and the effect of SCF on MB-02 growth, c-kit receptor-binding parameters were quantitated by equilibrium-binding experiments with 125I-SCF. MB-02 cells display a single class of high-affinity (50 pmol/L) c-kit receptors, with approximately 8,000 receptors per cell. The molecular weight of the c-kit receptor was determined by affinity cross-linking 125I-SCF to MB-02 cells. 125I-SCF-c-kit receptor complexes of approximately 155,000 and approximately 310,000 daltons were found, likely representing the monomeric and dimeric forms of the c-kit receptor. The binding affinity and molecular weight of the c-kit receptor on MB-02 cells are similar to those of normal human marrow cells. These results suggest that SCF synergizes with Epo to influence not only the proliferation but the erythroid differentiation of MB-02 cells. Thus, the MB-02 cell line may be a useful model in which to investigate the molecular mechanisms of SCF action.
Antibodies, Monoclonal↗
Radiotherapy plus chemotherapy for head and neck cancer.
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Combined Modality Therapy↗
Sciatic nerve stimulation induces hypotension but not renal or lumbar sympathoinhibition in hypertensive Dahl rats.
Sustained reductions in arterial pressure and sympathetic nerve activity occur after prolonged sciatic nerve stimulation in spontaneously hypertensive and pre-hypertensive Dahl salt-sensitive rats whereas these responses are not observed in renal hypertensive or Dahl resistant rats. These observations suggest that the development of post-stimulation hypotension and sympathoinhibition may be related to the genetic predisposition for hypertension rather than to the increased level of arterial pressure. However, it is not known whether the magnitude of the post-stimulation blood pressure and sympathetic nerve responses are influenced by the increased level of arterial pressure in addition to the genetic predisposition to hypertension. In the present study, we sought to determine if sustained sciatic nerve stimulation induces post-stimulation hypotension in hypertensive Dahl sensitive (DS) rats. For this purpose, mean arterial pressure (MAP), heart rate (HR), renal (RSNA) and lumbar (LSNA) sympathetic nerve activity were recorded during and after sciatic nerve stimulation in hypertensive DS rats (n = 17) fed an 8.0% NaCl diet for 7-8 weeks. Sciatic nerve stimulation increased HR (control, 443 +/- 10 b.p.m.; stimulation, 487 +/- 8 b.p.m.; p < 0.05) and tended to increase MAP, RSNA and LSNA. Two hours after stimulation, MAP was reduced (control 145 +/- 5 mmHg; recovery, 124 +/- 8 mmHg; p < 0.01) from control values. In contrast, RSNA and HR remained unchanged whereas LSNA was increased (69 +/- 20%; p < 0.05) from control values 120 min after stimulation. MAP, HR and RSNA were unchanged from control values during and for 2 h after sham stimulation in eight DS rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Afferent Pathways↗
Multiple fractions daily for head and neck cancer: spinal cord effects and other late results.
Reports of late spinal cord damage after multiple fractions daily radiotherapy regimens for head and neck cancer are infrequent, but increasing. We have reviewed our experience of head and neck cancers treated thrice daily to examine this problem. Between 1982 and 1990, 65 patients with advanced head and neck cancer were treated by primary radiotherapy using three small fractions delivered on 5 days per week, with an inter-fraction interval of 3-4 hours during normal working hours. In 25 patients, the cervical spinal cord received > 39 Gy. In 13 patients, 39.6 Gy was given in 1.1 Gy fractions, and five received 41.8 Gy in 1.1 Gy fractions, two received 45.1 Gy in 1.1 Gy fractions and five received 45 Gy in 1.5 Gy fractions. Eleven of these patients have survived over 2 years, and can be assessed for late spinal cord damage. Ten of these received 1.1 Gy fractions with no cord damage. The only 2-year survivor whose cord received 45 Gy in 1.5 Gy fractions has developed mild, non-progressive long tract signs. Other late side effects were equivalent to those after conventionally fractionated radiotherapy. Tumour control was good, especially for the larynx. We feel that, for radiotherapy given with three small fractions daily and an inter-fraction interval of 3-4 hours, the spinal dose should not exceed 40 Gy.
Carcinoma, Squamous Cell↗
Immunoscintigraphy of small-cell lung cancer: a study using technetium and indium labelled anti-carcinoembryonic antigen monoclonal antibody preparations.
Immunoscintigraphy with radiolabelled anti-carcinoembryonic antigen monoclonal antibody was performed on 21 patients with active small-cell lung cancer. Patients received either In-111-labelled Mab F6 F(ab')2 fragments or Tc-99m-labelled BW 431/26 intact antibody. Tumour was imaged in 13 patients (62%). Of 38 known sites of disease, 18 sites were positively detected. Serum CEA levels were known in 19 patients and were abnormally elevated in three (tumour being detected in all three patients). Eight of 15 patients with normal serum CEA had positive imaging. Using the In-111-labelled antibody seven out of ten patients (nine out of 18 sites) gave positive scans; with the Tc-99m-labelled antibody these were obtained in nine out of 18 patients (nine out of 20 sites).
Carcinoembryonic Antigen↗
Malignant melanoma of the nasal cavity and paranasal sinuses.
Malignant melanoma affecting the nasal cavity and paranasal sinuses is a rare condition with a poor prognosis. The Head and Neck Oncology Clinic at the University Hospital Nottingham has treated 16 patients in an 8-year-period. Twelve patients were treated with primary radical surgery and salvage radiotherapy was used for 7 patients with local recurrence. This resulted in tumour shrinkage in 4 patients. Eight patients treated surgically, have died of systemic spread. Four are currently alive, although 2 have local disease.
Adult↗
Successful replication of parvovirus B19 in the human megakaryocytic leukemia cell line MB-02.
The pathogenic human parvovirus B19 has been shown to undergo productive replication in the erythroid lineage in primary normal human hematopoietic progenitor cells. However, none of the established erythroleukemia cell lines has allowed B19 virus replication in vitro. The remarkable erythroid tissue tropism of B19 virus was evaluated with a human megakaryocytic leukemia cell line, MB-02, which is dependent on the growth factor granulocyte-macrophage colony-stimulating factor but can be induced to undergo erythroid differentiation following treatment with erythropoietin (Epo). Whereas these cells did not support B19 virus DNA replication in the presence of granulocyte-macrophage colony-stimulating factor alone, active viral DNA replication was observed if the cells were exposed to Epo for 5 to 10 days prior to B19 virus infection, as detected by the presence of the characteristic B19 virus DNA replicative intermediates on Southern blots. No replication occurred if the cells were treated with Epo for 3 days or less. In addition, complete expression of the B19 virus genome also occurred in Epo-treated MB-02 cells, as detected by Northern blot analysis. B19 progeny virions were released into culture supernatants that were biologically active in secondary infection of normal human bone marrow cells. The availability of the only homogeneous permanent cell line in which induction of erythroid differentiation leads to a permissive state for B19 virus replication in vitro promises to yield new and useful information on the molecular basis of the erythroid tissue tropism as well as parvovirus B19-induced pathogenesis.
Cell Differentiation↗
Nonuniform regional sympathetic nerve responses to hyperinsulinemia in rats.
The insulin hypothesis of hypertension proposes that hyperinsulinemia increases sympathetic nerve activity (SNA) and raises arterial pressure. The goals of this study were 1) to determine if hyperinsulinemia produces regionally uniform or nonuniform increases in SNA and 2) to test the hypothesis that spontaneously hypertensive rats (SHR) have exaggerated sympathoadrenal responses to hyperinsulinemia. We measured plasma insulin, blood glucose, mean arterial pressure, and adrenal, renal, and lumbar SNA in alpha-chloralose-anesthetized SHR and normotensive Wistar-Kyoto (WKY) rats before and during infusion of two doses of insulin for 60 min each while maintaining euglycemia. In WKY rats, graded increases in plasma insulin from 27 +/- 5 (SE) to 200 +/- 29 microU/ml increased lumbar SNA from 100% to 285 +/- 26% but failed to significantly increase adrenal or renal SNA. In SHR rats, similar increases in plasma insulin from 27 +/- 4 to 213 +/- 33 microU/ml caused significant increases in adrenal (100% to 174 +/- 16%) and lumbar (100% to 307 +/- 26%) SNA but not in renal SNA. Despite increases in SNA, mean arterial pressure did not increase significantly in either group of rats. We conclude that 1) hyperinsulinemic euglycemic clamp produces regionally nonuniform increases in sympathetic nerve activity, and 2) there is a potentiated increase in adrenal SNA in SHR compared with WKY rats during hyperinsulinemia, whereas lumbar SNA responses were similar in the two strains, and renal SNA did not increase in either strain.
Animals↗
Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines.
We have previously reported that certain genes of the HOX2 cluster of homeobox genes on human chromosome 17 are specifically expressed in human leukemic cell lines with erythroid potential, suggesting that these genes are involved in hematopoietic differentiation. We now show that the expression of the HOX 2.2 gene decreases during erythropoietin-induced differentiation of the erythroid cell line MB02. In order to study the role of the HOX 2.2 homeobox gene in hematopoiesis, vectors producing sense or antisense transcripts were introduced into K562 and HEL cells, pluripotent lines with erythroid and myeloid features. Overexpression of HOX 2.2 is associated with loss of erythroid features in both lines and an increase in certain myelomonocytic markers in K562 cells. Expression of antisense HOX 2.2 is associated with an increase in erythroid features in HEL cells and a mild decrease in myeloid characteristics in K562 cells. Overexpression of the adjacent HOX 2.1 gene in K562 cells does not produce similar phenotype changes. These data demonstrate that modulation of a specific HOX 2 homeobox gene can change the phenotype of somatic cells and suggest that certain HOX 2 genes play a role in blood cell differentiation.
Blotting, Northern↗
Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction.
The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Malignant paraganglioma of the mediastinum: a further diagnostic and therapeutic use of radiolabelled mIBG.
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3-Iodobenzylguanidine↗
Infection control. Wound management.
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Anti-Infective Agents, Local↗
Infection control. Eusol--(E) useful or (e) useless?
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Borates↗
Granulocyte-macrophage colony-stimulating factor-dependent growth and erythropoietin-induced differentiation of a human cell line MB-02.
Peripheral blood blasts from a patient with acute megakaryoblastic leukemia were placed into liquid cultures with recombinant growth factors. Growth, but not differentiation, was supported by interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF) for the first 30 days of culture. Sustained growth occurred only with GM-CSF and gave rise to the cell line MB-02, which has been in continuous culture for over 1 year. The cell line retained the surface phenotype of the leukemic megakaryoblasts except for the loss of glycoproteins Ib and IIb/IIIa, which were induced after exposure to phorbol esters. The induction of erythropoiesis occurred when GM-CSF-deprived cells were cultured with erythropoietin (Epo). Well-defined morphologic stages of differentiation ranging from primitive erythroblasts to nuclei-extruding normoblasts were seen. Transforming growth factor-beta inhibited GM-CSF- and Epo-dependent growth, but not erythroid maturation. Indirect immunofluorescence using globin chain-specific monoclonal antibodies detected fetal, but not adult hemoglobin in the uninduced cells. beta-globin was induced and gamma-globin was increased after Epo exposure. Both globin species accumulated in the developing erythrocytes until terminal differentiation. Quantitative S1 analysis of beta-like globin transcripts showed very low levels of epsilon- and beta-globin expression and high levels of gamma-globin expression in cells maintained in GM-CSF. Five days after induction with Epo, epsilon message decreased to barely detectable levels while gamma and beta transcripts increased threefold and 20-fold, respectively. This novel cell line not only retains many characteristics of the leukemic megakaryoblasts from which it was derived, but also can be induced to recapitulate apparent normal erythropoiesis.
Antigens, CD↗