Patients' preferred and perceived roles in making decisions about adjuvant chemotherapy for non-small-cell lung cancer.

BACKGROUND: People with cancer have varying preferences for involvement in decision-making between active, collaborative and passive roles. We sought the preferred and perceived involvement in decision-making among patients considering adjuvant chemotherapy (ACT) after resection of early non-small cell lung cancer (NSCLC). METHODS: Patients considering ACT for NSCLC were asked to complete a self-administered questionnaire at baseline and 6 months. Preferred and perceived decision-making roles were assessed by the Control Preferences Scale (CPS). We examined differences between preferred and perceived roles, differences in preferred roles over time, determinants of preferences, and differences in treatment preferences between patients preferring active and less active roles. RESULTS: 98 patients completed the baseline questionnaire; 75 completed the 6 month questionnaire. Most patients were male (55%) with a median age of 64 years (range, 43-79 years). Preferred role in decision-making at baseline (n=98) was active in 27%, collaborative in 47%, and passive in 27%. Perceived decision-making roles matched the preferred role in 79% of patients. Individuals' role preferences often varied between baseline and 6 months, but there was no consistent direction to the change (25% changed preference to more active involvement, 22% to less active). Preferring a more active role was associated with university education (OR 2.9, p=0.02), deciding not to have ACT (OR 5.0, p<0.01), and worse health-related quality of life (HRQL) during ACT: physical well-being (OR 4.4, p=0.05), overall well-being (OR 5.5, p=0.02), sleep (OR 8.4, p<0.01) and shortness of breath (OR 7.6, p=0.01). Patients who preferred an active decision-making role judged larger survival benefits necessary to make ACT worthwhile than those preferring a passive role. CONCLUSION: Most patients with resected NSCLC preferred and perceived a collaborative role in decision-making about ACT. Clinicians should elicit and consider patients' preferences for involvement in decision-making when discussing ACT for NSCLC.

Patients' and doctors' preferences for adjuvant chemotherapy in resected non-small-cell lung cancer: What makes it worthwhile?

BACKGROUND: Adjuvant chemotherapy (ACT) in non-small-cell lung cancer (NSCLC) improves overall survival, but the benefits must be weighed against its harms. We sought to determine the survival benefits that patients and their doctors judged sufficient to make ACT in NSCLC worthwhile. METHODS: 122 patients completed a self-administered questionnaire at baseline and 6 months (before & after ACT, if they had it); 82 doctors completed the questionnaire once only. The time trade-off method was used to determine the minimum survival benefits judged sufficient in four hypothetical scenarios. Baseline survival times were 3 years & 5 years and baseline survival rates (at 5 years) were 50% & 65%. RESULTS: At baseline, the median benefits judged sufficient by patients were an extra 9 months (Interquartile range (IQR) 1-12 months) beyond 3 years & 5 years and an extra 5% (IQR 0.1-10%) beyond 50% & 65%. At 6 months (n=91), patients' preferences had the same median benefit (9 months & 5%) but varied more (IQRs 0-18 months & 0-15%) than at baseline. Factors associated with judging smaller benefits sufficient were deciding to have ACT (P=0.01, 0.02) and better well-being (P=0.01, 0.006) during ACT. Doctors' preferences, compared with patients' preferences, had similar median benefits (9 months & 5%) but varied less (IQR 6-12 months versus 1-12 months, P<0.001; 5%-10% versus 0.1-10%, P<0.001). CONCLUSION: Most patients and doctors judged moderate survival benefits sufficient to make ACT in NSCLC worthwhile, but the preferences of doctors varied less than those of patients. Doctors should endeavour to elicit patients' preferences during discussions about ACT in NSCLC.

Marked differences in the structures and protein associations of lymphocyte and monocyte CD4: resolution of a novel CD4 isoform.

The structures, molecular interactions and functions of CD4 in a subset of T lymphocytes have been well characterized. The CD4 receptors of other cell types have, however, been poorly documented. We have previously shown that lymphocytes and monocytes/macrophages differ in their expression of CD4 monomers and dimers. In the present study, we have shown further significant differences. Variability in the blocking of CD4 mAb binding by sulfated polyanions indicated differences in exofacial CD4 structures. In contrast to the well-documented 55 kDa monomers in lymphocytic cells, monocytic cells were found to coexpress two monomer isoforms: the 55 kDa form and a novel 59 kDa species. Experimental uncoupling of CD4 disulfides indicated that the oxidized 55 kDa monomer could be converted to the 59 kDa form. This was achieved by chemical reduction of purified native or recombinant CD4, or in cell transfection experiments by mutation of cysteine to alanine in domain 1 (D1) (Cys16 or Cys84) and in domain 4 (D4) (Cys303 or Cys345). All of these modifications promote CD4 distension on SDS-PAGE analysis and indicate that, when CD4 inter-beta-sheet disulfides in the D1 and D4 Ig folds are disrupted, there is an unravelling of the oxidized form to an extended 59 kDa unfolded state. We hypothesize that this may be a transition-state, structural-intermediate in the formation of disulfide-linked homodimers. Also identified were CD4-tyrosine kinase dissimilarities in which lymphocyte CD4 associated with Lck, but monocyte CD4 associated with HcK. These findings show that there is complex heterogeneity in structures and interactions in the CD4 of T lymphocytes and monocytes.

Marked structural and functional heterogeneity in CXCR4: separation of HIV-1 and SDF-1alpha responses.

CXCR4, the chemotactic cell receptor for SDF-1alpha, is essential for immune trafficking and HIV infection. CXCR4 is remarkably heterogeneous and the purpose of this study was to better identify the isoforms expressed by cells and compare their structure and function. We found that cells express either a predominant isoform or multiple isoforms. These were best resolved on SDS-PAGE using sucrose-gradient-fractionated, triton-insoluble, membrane extracts. We hypothesized that glycosyl modification may underpin some of this heterogeneity and that cell isoform(s) differences may underscore CXCR4's multiple cell functions. A comparison of wild-type (WT) and dual N-linked glycosylation site, N11A/N176A, mutant CXCR4 expressed in 3T3 and HEK-293 cells served to implicate variabilities in glycosylation and oligomerization in almost half of the isoforms. Immunoprecipitation of CXCR4 revealed monomer and dimer non-glycosylated forms of 34 kDa and 68 kDa from the N11A/N176A mutant, compared with glycosylated 40 kDa and 47 kDa and 73 kDa and 80 kDa forms from WT. The functional specificity of isoform action was also implicated because, despite CEMT4 cells expressing high levels of CXCR4 and 11 different isoforms, a single 83 kDa form was found to bind gp120 for HIV-1 IIIB infection. Furthermore, comparative studies found that in contrast to SDF-1alpha-responsive Nalm-6 cells that expressed similar levels of a single isoform, CEMT4 cells did not show a Ca(++) flux or a chemotactic response to SDF-1alpha. Thus, CXCR4 can differ both structurally and functionally between cells, with HIV-1 infection and chemotaxis apparently mediated by different isoforms. This separation of structure and function has implications for understanding HIV-1 entry and SDF-1alpha responses and may indicate therapeutic possibilities.

Detergent-resistant membrane fractions contribute to the total 1H NMR-visible lipid signal in cells.

Leukocytes and other cells show an enhanced intensity of mobile lipid in their 1H NMR spectra under a variety of conditions. Such conditions include stimulation, which has recently been shown to involve detergent-resistant, plasma membrane domains (DRMs) often called lipid rafts. As there is much speculation surrounding the origin of cellular NMR-visible lipid, we analysed subcellular fractions, including DRMs, by NMR spectroscopy. We demonstrated that DRMs isolated by density gradient centrifugation from lymphoid (CEM-T4, stimulated Jurkat cells), and monocytoid (THP-1) cells produced NMR-visible, lipid signals. Large scale subfractionation of THP-1 cells determined that while cytoplasmic lipid droplets constituted much of the total NMR-visible lipid, the contribution of DRMs was significant. Qualitative and quantitative lipid analyses revealed that DRMs and lipid droplets differed in their lipid composition. DRMs were enriched in cholesterol and ganglioside GM1, and contained relatively unsaturated fatty acids compared with the lipid droplets. Both lipid droplets and DRMs contained neutral lipids (triacylgycerols, cholesterol ester, fatty acids in THP-1 cells) that could, in addition to phospholipids, contribute to the NMR-visible lipid. The lipid droplets also exhibited different protein profiles and contained 500-fold less protein than DRMs, confirming that DRMs and droplets were fractionated as separate entities. The NMR-visible lipid in DRMs is therefore unlikely to be a contaminant from lipid droplets. We propose a micropartitioning of the NMR-visible mobile lipid of whole cells between intracellular lipid droplets, where most of this lipid resides, and detergent-resistant plasma membrane domains.