Platelet activating factor (PAF; 1-o-alkyl-2-0-acetyl-sn-glycero-3-phosphocholine-3-phosphocholine) a potential mediator of anaphylaxis, stimulates secretion of mucin by explants of trachea from four separate rodent species (guinea pig, rat, rabbit, ferret) in organ culture. Enhanced secretion is not a result of cell damage or release of histamine by cells within the explants (e.g., platelets). It is inhibited by equimolar concentrations of the potent PAF-receptor antagonist, Ro 19-3704. PAF provokes production of immunoreactive peptidyl leukotrienes (ir-LTC4, LTD4, LTE4) within the explants. The stimulatory effect of PAF on mucin secretion is blocked by equimolar concentrations of nordihydroguiaretic acid (NDGA) a "mixed" inhibitor of both cyclo- and lipoxygenase pathways of arachidonic acid metabolism. Leukotrienes are localized within tracheobronchial epithelium by immunohistochemical staining, and physical removal of epithelium from explants inhibits production of leukotrienes in vitro under nonstimulated conditions and after exposure to PAF. In addition, the stimulatory effect of PAF on mucin secretion is not altered by FPL-55712, a receptor antagonist of LTD4. These results are consistent with the hypothesis that PAF stimulates secretion of mucin by activating biosynthesis of lipoxygenase products (e.g., peptidyl leukotrienes) within epithelial cells of the respiratory mucosa.
We have analyzed the results of treatment of 117 patients with Ewing's sarcoma admitted to the National Cancer Institute since 1964. All patients received local irradiation to the primary site and a series of progressively more intensive systemic chemotherapy regimens using drugs known to be active as single agents in this disease. Four protocols were employed with varying numbers of patients in each treatment group. Initially, there appeared to be a difference among treatment groups with regard to disease-free survival (overall P = .06), with the later regimens having more favorable outcomes. We then undertook a statistical analysis of the influence of five pretreatment variables--age, sex, site of primary disease, serum lactic acid dehydrogenase (LDH), and metastatic status--on disease-free survival. Of these five factors, important indicators of favorable prognosis for the entire group (and for each of the treatment subgroups) were a distal site of primary disease, normal serum lactic acid dehydrogenase (LDH) level at presentation, and the absence of metastatic disease at the time of presentation. When we examined treatment results with respect to these prognostic factors, we found that the subgroups treated with the more agressive regimens contained higher proportions of patients with favorable prognostic factors. After adjustment for differences in composition of treatment groups with respect to prognostic factors, the apparent difference in disease-free survival vanished (P = .62). These results indicate that in the case of Ewing's sarcoma, prognostic factors must be carefully considered in the design of treatment protocols and the subsequent analysis of end results.
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