Systemic therapy with TAM after isolated locoregional recurrence of breast cancer significantly increased 5-year DFS rates from 36% to 59% compared with observation alone and prolonged median DFS by more than 4.5 years in patients with ER+ tumors or in the case of unknown ER status with a DFI of greater than 12 months and minimal tumor burden. Treatment with TAM currently has no significant impact on OS, but the median survival duration of the study population has not yet been reached.

AbstradThe 52 kD myeloid membrane glycoprotein CDI 4 represents the receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein (LBP); it is involved in LPS induced tumor necrosis factor-alpha production. Expression of CD14 increases in monocytes differentiating into macrophages, and it is reduced by rlFNg in monocytes in vitro. In the present study CD14 membrane antigen expression was investigated in cultures of human mononuclear leucocytes (PBL), in elutriated, purified monocytes, and in blood monocyte derived Teflon cultured macrophages. Cells were incubated for 15 or 45 h with rlL-I, rlL-2, rlL-3, rIL-4, rlL-5, rlL-6, rTNFa, rGM-CSF, rM-CSF, rTGFbl, rlFNa, lipopolysaccharide (LPS), and, as a control, rlFNg. The monoclonal antibodies Leu-M3 and MEM 18 were used for labelling of CD14 antigen by indirect immunofluorescence and FACS analysis of scatter gated monocytes or macrophages. lFNg concentrations were determined in PBL culture supernatants by ELISA. rlFNa and rlL-2 reduced CDI 4 in 15 and 45 h PBL cultures, an effect mediated by endogenous IFNg, since it was abolished by simultaneous addition of an anti-IFNg antibody. rlFNa and rlL-2 were ineffective in purified monocytes or macrophages. rlL-4 strongly reduced CDI 4 in PBL and purified monocytes after 45 h, whereas in macrophages the decrease was weak, although measurable after 15 h. The other cytokines investigated did not change CD14 antigen expression. Cycloheximide alone reduced CDI 4, but when added in combination with rlFNg the effect on CD14 downregulation was more pronounced. The effect of rlFNg on CD14 in PBL cultures was dose-dependently inhibited by rlL-4 and this inhibition is probably due to an IL-4 mediated blockade of lFNg secretion. LPS at a low dose increased CD14, at a high dose it produced a variable decrease of CD14 in PBL, which was probably due to LPS induced lFNg secretion. LPS strongly enhanced CDI 4 in 45 h cultures of purified monocytes. The results, showing that CD14 antigen expression is upregulated by LPS and downregulated by rlFNg and rlL-4, suggest that the LPS-LBP receptor is involved in the feedback response of IFNg and IL-4 to LPS stimulation.

Forty-eight samples of primary non-small-cell lung cancer (NSCLC) and normal tissue from the same patients were analyzed for allelic deletions on chromosome 11p. Five polymorphic loci were assessed to determine the incidence of 11p sequence deletions and to define hot-spots of deletions. Information was obtained from all patients in at least one locus. Our data show that the deletions observed were not randomly scattered over the short arm of chromosome 11. Rather, 2 hot-spots of deletions were observed: one in the area of the genes for catalase and beta-FSH corresponding to band 11p13, the other close to the IGF-II locus corresponding to band 11p15. A high incidence of loss of heterozygosity (LOH) was found with the probe for catalase (21/29), a locus flanking the centromeric region of the Wilms' tumor locus. Most of the samples exhibiting LOH of one or more of the alleles analyzed remained heterozygous for at least one other chromosome 11p allele. Furthermore, duplication of the intensity of the remaining allele was rarely observed. Our results indicate that LOH on the short arm of chromosome 11 is a common event in NSCLC and that the chromosomal region containing the Wilms' tumor locus is most commonly involved.

CD14 is a 53-kd glycoprotein that is mainly expressed in myeloid cells and exists in two forms. The membrane-bound form represents the receptor for complexes of lipopolysaccharide (LPS) with LPS binding protein. The function and regulation of the soluble form are unknown. In the present study we investigated the release of soluble CD14 (sCD14) in cultures of human mononuclear leukocytes, elutriated monocytes, and monocyte-derived macrophages. The release of sCD14 into the medium of the cells cultured for 15 and 45 h was investigated in the absence or presence of selected cytokines. sCD14 release occurred constitutively and correlated with cell number. In monocytes differentiating into macrophages, cumulative release of sCD14 was linear from day 1 to day 7. Spontaneous sCD14 release after 15 h of culture (2 x 10(6) cells/ml) was higher in the supernatant from monocytes (314 +/- 58 ng/ml) than that from mononuclear leukocytes (68 +/- 10 ng/ml) and similar to that from macrophages (469 +/- 79 ng/ml). Cycloheximide and actinomycin D inhibited sCD14 release. Recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-4 (rIL-4) directly decreased sCD14 release in mononuclear leukocyte, monocyte, and macrophage cultures. rIL-2 and rIFN-alpha reduced sCD14 release into the supernatants of mononuclear leukocytes only. Use of anti-IFN-gamma antibodies indicated that the down-regulation of sCD14 release by rIL-2 and rIFN-alpha was partially due to induction of endogenous IFN-gamma. The down-regulation of sCD14 release by all four cytokines was both time and dose dependent. rIFN-gamma and rIL-4 added simultaneously had a synergistic effect on sCD14 down-regulation. In conclusion, sCD14 release may have an immunomodulatory role in circulating monocytes, is apparently not related to the process of macrophage differentiation, and is selectively down-regulated during an immune response when levels of IFN-gamma and IL-4 are high.

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