Photoradiation models for the clinical ex vivo treatment of autologous bone marrow grafts

To assess the potential of photoradiation therapy for the in vitro purging of residual tumor cells from autologous bone marrow (BM) transplants, we studied normal marrow and tumor cell clonogenicity in response to different light-activated compounds by using the fluorescent dyes dihematoporphyrin ether (DHE) and merocyanine-540 (MC- 540). After photoradiation of cells with white light, both DHE and MC- 540 showed high cytocidal activity toward lymphoid and myeloid neoplastic cells but had a significantly lesser effect on normal granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and mixed colony- forming (CFU-GEMM) progenitor cells. Acute promyelocytic leukemia (HL- 60), non-B, non-T, CALLA-positive acute lymphoblastic leukemia (Reh), and diffuse histocytic B cell lymphoma (SK-DHL-2) cell lines were exposed to different drug concentrations in combination with white light at a constant illumination rate of 50,000 lux. With DHE doses varying from 2.0 to 2.5 micrograms/mL and MC-540 concentrations of 15 to 20 micrograms/mL, clonogenic tumor cells could be reduced by more than 4 logs when treated alone or in mixtures with normal irradiated human marrow cells. However, preferential cytotoxicity towards neoplastic cells was highly dependent on the mode of light activation. MC-540 had no substantial effect on malignant lymphoid (SK-DHL-2) and myeloid (HL-60) cells and on normal marrow myeloid (CFU-GM) precursors when drug incubation was performed in the dark and followed by light exposure of washed cells. Equal doses of MC-540 (15 to 20 micrograms/mL) could preferentially eliminate tumor cells under conditions of simultaneous light and drug treatment (30 minutes at 37 degrees C). When using DHE (2.5 micrograms/mL), 29.3%, 46.8%, and 27.5% of normal marrow CFU-GM, BFU-E, and CFU-GEMM, respectively, were spared after sequential drug and light exposure of cells, whereas simultaneous treatment reduced both normal (CFU-GM) and neoplastic cells below the limits of detection. In summary, our results indicate the usefulness of various photoradiation models for the ex vivo treatment of leukemic and lymphomatous bone marrow autografts.     

Longitudinal changes in forced expiratory volume in one second in adults. Effects of smoking and smoking cessation

Longitudinal changes in FEV1 (delta FEV1) in relationship to smoking habits were examined in 1,705 adults enrolled in a prospective study of a general population sample. In both men and women, there were excessive rates of decline in FEV1 in smokers, at least in those smoking more than 10 cigarettes per day. The excess decline of smokers was age dependent, particularly in men, with much of the excess loss of function occurring between 50 and 70 yr of age. Effects of smoking on delta FEV1, observed minus expected delta FEV1 and observed minus expected percent delta FEV1, were greater in men than in women even when controlled for current cigarette dose. Ex-smokers show delta FEV1 values similar to those of nonsmokers. In subjects younger than 35 yr of age, quitting smoking during follow-up was associated with an actual increase in FEV1. In men 50 to 70 yr of age, smoking cessation early in the study appeared to lead to a relatively prompt return to normal rates of functional decline. Thus, the findings suggest relatively prompt beneficial effect of smoking cessation even in late middle age.