Cancer therapy: reimbursement of new therapeutic technologies.
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New drugs and technologies for cancer treatment are being developed at a rate that has created a reimbursement crisis. This article discusses third-party concerns about this problem and describes generic criteria that have proven to be useful in assessing any new technology. It is equally important to discontinue funding of ineffective and obsolete therapies as it is to devise a strategy for identifying and encouraging the development of new therapy that will be both clinically useful and cost-effective. Examples are provided to show that these are not necessarily mutually exclusive goals. Off-label application of standard therapy as well as the funding of new cancer therapy are considered. High-dose chemotherapy with autologous stem-cell support for treatment of a variety of neoplasms has become a major reimbursement challenge. Other technologies such as autolymphocyte therapy and use of colony-stimulating factors are considered in detail. Finally, a process for deciding how to fund new cancer therapy is described. (+info)
Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors.
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The Pim family of proto-oncogenes encodes a distinct class of serine/threonine kinases consisting of PIM1, PIM2, and PIM3. Although the Pim genes are evolutionarily highly conserved, the contribution of PIM proteins to mammalian development is unclear. PIM1-deficient mice were previously described but showed only minor phenotypic aberrations. To assess the role of PIM proteins in mammalian physiology, compound Pim knockout mice were generated. Mice lacking expression of Pim1, Pim2, and Pim3 are viable and fertile. However, PIM-deficient mice show a profound reduction in body size at birth and throughout postnatal life. In addition, the in vitro response of distinct hematopoietic cell populations to growth factors is severely impaired. In particular, PIM proteins are required for the efficient proliferation of peripheral T lymphocytes mediated by synergistic T-cell receptor and interleukin-2 signaling. These results indicate that members of the PIM family of proteins are important but dispensable factors for growth factor signaling. (+info)
Initial empirical antimicrobial therapy: duration and subsequent modifications.
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Neutropenic patients at low risk of complications can receive oral ciprofloxacin or levofloxacin as outpatients. These agents plus amoxicillin/clavulanate or other penicillins, cephalosporins, or penem compounds are indicated to treat infections with gram-positive organisms in patients with oral mucositis or skin lesions. Parenteral fourth-generation cephalosporins or carbapenems can be given. For high-risk patients, monotherapy with cefepime or the carbapenems can be used. Methicillin-resistant Staphylococcus aureus should be treated with vancomycin or teicoplanin. For combination therapy, a third- or fourth-generation cephalosporin or carbapenem plus an aminoglycoside is desirable. Defervescence in 3-5 days for at least 7 days is suggested for subsequent management. Initial antibiotic(s) can be continued for patients who remain in good condition. For persistent fever after 3-5 days, the patient should be thoroughly reassessed. An aminoglycoside should be added for those initially treated with monotherapy. The initial cephalosporin can be changed to another cephalosporin or a carbapenem, or the initial carbapenem can be changed to a broad-spectrum cephalosporin. For patients initially receiving dual therapy, the cephalosporin or carbapenem can be changed as with monotherapy, whereas the initial aminoglycoside should be changed to another aminoglycoside or intravenous ciprofloxacin. (+info)
Effects of anti-CD3 monoclonal antibody on engraftment of T-cell-depleted bone marrow allografts in mice: host T-cell suppression, growth factors, and space.
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To investigate the role of CD3-positive T cells in allogeneic marrow rejection in mice and to examine the effects of anti-CD3 monoclonal antibody (MoAb) on allogeneic marrow engraftment, a hamster MoAb, 145-2C11, with specificity for the CD3 epsilon portion of the murine T-cell receptor complex was administered to B6 (H-2b) mice that had been sublethally irradiated with 626 cGy and injected with 10 x 10(6) T-cell-depleted B6C3F1 (H-2b/k) bone marrow cells. Lymphoid chimerism status was assessed by flow cytometric analysis of peripheral blood lymphocytes using H-2k-specific MoAb 5 to 6 weeks after bone marrow transplantation. When hosts were treated with 400 micrograms of anti-CD3 MoAb at the time of marrow injection, the percentage of donor-type cells was 75.2% +/- 15.0%, while it was 1.9% +/- 1.2% in untreated mice. It was demonstrated that anti-CD3 MoAb not only suppressed T-cell function but also induced colony-stimulating factors in host mice, and that enhancement of marrow engraftment in anti-CD3 MoAb-treated mice was associated with factor release as well as suppression of host T-cell function. Results were consistent with engraftment being enhanced by a differential response of donor (rather than host) marrow to serum factors in association with host T-cell immunocompromise. (+info)
Suppression of growth factor-induced CYL1 cyclin gene expression by antiproliferative agents.
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A recently identified novel mammalian cyclin (CYL1), induced by growth factors and apparently functional during the G1 phase of the cell cycle, is of potential significance, given that cell division is primarily controlled in G1. We have measured CYL1 gene expression in murine bone marrow-derived macrophages (BMM), a normal cell type dependent upon colony-stimulating factors (CSFs) for survival and proliferation. The induction of CYL1 mRNA levels correlated strongly with stimulation of DNA synthesis, since elevated CYL1 mRNA levels occurred in response to the mitogenic stimuli, CSF-1, and granulocyte/macrophage CSF, but not to nonmitogenic macrophage-activating agents. BMM are subject to cell cycle arrest by numerous agents, including tumor necrosis factor alpha, interferon gamma, bacterial lipopolysaccharide, and agents that increase cAMP. These antiproliferative agents suppressed CSF-1-stimulated CYL1 gene expression, even when added late in G1. This pattern of CYL1 gene expression was remarkably consistent with the ability of these agents to inhibit progression into S phase. The mechanisms of negative growth regulation are largely unknown, and given the likely importance of G1 cyclins in the control of cell division, we propose that antiproliferative agents may exert their effects by suppressing G1 cyclin gene expression. (+info)
Differential myelopoietic responsiveness of BALB/c (Itys) and C.D2 (Ityr) mice to lipopolysaccharide administration and Salmonella typhimurium infection.
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Inheritance of the Ityr or the Itys allele of the Ity murine gene confers resistance or increased susceptibility, respectively, to Salmonella typhimurium infection. Recent studies have documented that Ity gene expression may determine net intracellular replication of S. typhimurium by modulating macrophage function. The purpose of this study was to determine if Ity gene expression modulated macrophage stem cell proliferation as well. To detect possible Ity-associated alterations in macrophage stem cell proliferation during endotoxin challenge or S. typhimurium infection, the congenic strain pair BALB/c (Itys) and C.D2-Idh-1, Pep-3 N20F8 (Ityr) were injected intraperitoneally with 25 micrograms of bacterial lipopolysaccharide (LPS) or approximately 10(3) S. typhimurium, and myelopoiesis was evaluated. At 72 h after LPS injection, both BALB/c and C.D2 mice developed comparable degrees of bone marrow hypocellularity and splenomegaly, and cell sizing profiles indicated a normal response to a single injection of LPS in both strains of mice. Although an inhibitor to colony-stimulating factor activity was detected in the sera and plasma of C.D2 mice, the number of myeloid stem cells cultured from the bone marrow and spleen of each mouse strain were comparable. S. typhimurium infection resulted in earlier symptoms, a larger bacterial load, a higher mortality rate, and a greater bone marrow hypocellularity and splenomegaly in BALB/c mice compared with those in C.D2 mice. Despite a dramatic increase in bacterial load, a decrease in both bone marrow and splenic myeloid stem cell numbers was noted in BALB/c mice, while stem cell numbers remained constant in C.D2 mice between days 3 and 5 and increased dramatically at day 7 after infection. These data suggest that BALB/c and C.D2 mice may exhibit a divergent myelopoietic response to S. typhimurium infection. It appears that a paradoxical failure of myelopoiesis in Itys mice during S. typhimurium infection may contribute to the observed increase in mortality. (+info)
Expression of colony-stimulating factors and inflammatory cytokines in the uterus of CD1 mice during days 1 to 3 of pregnancy.
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Morphological and immunohistochemical analyses have documented the development of an acute inflammatory response, marked by the early appearance of granulocytes and later infiltration of mononuclear cells, in the uterus immediately after mating in mice. The response peaked on Day 1 and subsided by Day 3. In the present study, RNAs for macrophage colony-stimulating factor (CSF-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and for interleukin 1 alpha (IL-1 alpha), IL-1 beta, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were detected in uterine tissue on Day 1. With the exception of IL-6, which was higher on Day 3 than on Day 1, and IL-1 alpha, which was not reduced on Day 2, concentrations of cytokine mRNA decreased to Day 3. No bioactivity was detected for GM-CSF, granulocyte colony-stimulating factor or IL-3, but CSF-1, IL-1, IL-6 and TNF-alpha were detected on Day 1 using bioassays. Changes in concentrations approximately paralleled those for mRNA. The concentrations of mRNA for CSF-1, IL-1, IL-6 and TNF-alpha were higher on Day 1 of pregnancy than in the uteri of cycling mice 24 h earlier. The data are consistent with previous morphological observations demonstrating the expression of an acute inflammatory response in the mouse uterus after mating. Further, the data demonstrate the expression of genes for CSF-1, GM-CSF, IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha is induced in the uterus during mating. (+info)
E-ring 8-isoprostanes are agonists at EP2- and EP4-prostanoid receptors on human airway smooth muscle cells and regulate the release of colony-stimulating factors by activating cAMP-dependent protein kinase.
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8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E- and Falpha-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1beta (IL-1beta). The elaboration of GM-CSF and G-CSF by IL-1beta was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E(1) and 8-iso-PGE(2), but not by 8-iso-PGF(1alpha), 8-iso-PGF(2alpha), and 8-iso-PGF(3)alpha. AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP(1)-/EP(2)-/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE(1) and 8-iso-PGE(2) on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP(2)-subtype. In contrast, the facilitation by 8-iso-PGE(1) and 8-iso-PGE(2) of G-CSF release was unaffected by AH 6809 and the selective EP(4)-receptor antagonist L-161,982 [4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylme thyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]. However, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE and 8-iso-PGE concentration-response curves. The opposing (1)effect of E-ring (2)8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP- and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE(1) and 8-iso-PGE(2) act solely via EP(2) -receptors to inhibit GM-CSF release, whereas both EP(2)- and EP(4)-receptor subtypes positively regulate G-CSF output. (+info)