The optimum treatment conditions of interferon (IFN) a therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CMLstudy I and it had been planned in advance to add the HU patients of study I (n ¼ 194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n ¼ 21), major in 14% (n ¼ 24), and at least minimal in 35% (n ¼ 59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (Po0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P ¼ 0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

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Serum lidocaine concentrations were measured in a series of ten patients during and after topical lidocaine spray anesthesia used for diagnostic fiberoptic bronchoscopy. Mean total dose of lidocaine ranged from 480-720 mg. Peak serum lidocaine concentrations averaged 3.6 micrograms/ml (range: 1.9 to 7.4 micrograms/ml), and were attained shortly after the start of the procedure. Repeated topical administration of lidocaine spray therefore may lead to large cumulative doses and serum concentrations which are in the therapeutic or potentially toxic range.

Serum lidocaine concentrations were measured in a series of patients during and after topical administration of lidocaine used to anesthetize the nasal mucosa, pharynx, and larynx for diagnostic fiberoptic bronchoscopy. In one group of patients (N = 9) the trachea and bronchi were sprayed with a 2% lidocaine solution administered in 2 mL volumes. Another group (N = 14) received a 2% lidocaine solution which was administered by inhalation of lidocaine dispensed by a high-frequency nebulizer. Multiple serum samples drawn over a 1-hour period were analyzed by gas chromatography with nitrogen-phosphorous detection. In the spray group versus the inhalation group, there were no differences in mean age (54 vs 55 years), total lidocaine dose (572 vs 525 mg), or time of peak serum lidocaine concentration (43 vs 41 minutes after dose). However, the peak serum lidocaine concentrations were significantly lower in the inhalation group vs the spray group (1.40 vs 3.63 micrograms/mL). Thus, administration of lidocaine via inhalation by ultrasonic nebulization results in lower peak serum concentrations, and a reduction in the likelihood of toxicity, than when administered by conventional topical spray.

The plasma clot culture system containing erythropoietin (Ep) permits erythroid precursors from bone marrow or spleen to form in vitro small colonies of hemoglobin-synthesizing erythroblasts (1). Early erythroid precursors (committed erythroid stem cells) most likely comprise a multistage compartment that is interposed between the pluripotential stem cells (CFU) and the morphologically recognizable proerythroblasts (2, 3). The position of the colony-forming erythroid precursors (CFU-E) within this compartment and the factors regulating or influencing their population size are not exactly known. Erythropoietin injection into hypertransfused mice has been shown by Gregory et al. (4) to increase the number of femoral or splenic CFU-E, but increasing the concentration of Ep in the medium above a plateau level failed to increase colony formation. The injection of endotoxin into mice is known to increase their splenic erythropoiesis as measured by 59Fe incorporation ( 5 , 6), and the present study was undertaken to examine the effect of endotoxin on the number of splenic CFU-E in the presence or absence of Ep. It will be shown that endotoxin injection indeed induced splenic CFU-E in normal mice and in mice whose endogenous erythropoietin production was suppressed by posthypoxic polycythemia. Differences in increases in CFU-E between those induced by Ep and those induced by endotoxin will be discussed.Methods. Female CF, mice of from 23 to 27 g body weight were used in groups of eight. Mice were made polycythemic by 3 weeks of exposure (18 hr/day) to an atmospheric pressure of from 380 to 340 mm Hg. Endotoxin (lipopolysaccharide B, S . typhosa, Difco) was diluted in normal saline and injected ip. Human erythropoietin (56 This study was supported by USPHS Grant AM 07239.