Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.

PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis.

We conducted a placebo-controlled, double-blind, randomized study to evaluate the microbiological efficacy and safety of inhaled tobramycin for treatment of patients with bronchiectasis and Pseudomonas aeruginosa. Patients were randomly assigned to receive either tobramycin solution for inhalation (TSI) (n = 37) or placebo (n = 37), which was self-administered twice daily for 4 wk and followed by 2-wk off-drug. At Week 4, the TSI group had a mean decrease in P. aeruginosa density of 4.54 log(10) colony-forming units (cfu)/g sputum compared with no change in the placebo group (p < 0.01). At Week 6, P. aeruginosa was eradicated in 35% of TSI patients but was detected in all placebo patients. Investigators indicated that 62% of TSI patients showed an improved medical condition compared with 38% of placebo patients (odds ratio = 2.7, 95% confidence interval [CI] 1.1 to 6.9). Tobramycin-resistant P. aeruginosa strains developed in 11% of TSI patients and 3% of placebo patients (p = 0.36). The mean percent change in FEV(1) percent predicted from Week 0 to Week 4 was similar for the TSI and placebo groups (p = 0.41). More TSI-treated patients than placebo patients reported increased cough, dyspnea, wheezing, and noncardiac chest pain, but the symptoms did not limit therapy. Additional study is warranted to further evaluate TSI in bronchiectasis patients.

Health risk above the reference dose for multiple chemicals.

Recent work indicates that the regression of toxicity data viewed as categories of pathological staging is useful for exploring the likely health risk at doses above a Reference Dose (RfD), which is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Toxic effects, which may include both quantal and continuous data, are classified into ordered categories of total toxic severity (e.g., none, mild, adverse, severe). These severity categories are regressed on explanatory variables, such as dose or exposure duration, to estimate the probability of observing an adverse or severe effect. In this paper, categorical regression has been expanded to compare the likely risks across multiple chemicals when exposures are above their RfDs. Existing health risk data for diazinon, disulfoton, S-ethyl dipropylthiocarbamate, fenamiphos, and lindane were analyzed. As expected, the estimated risks of adverse effects above the RfD varied among the chemicals. For example, at 10-fold above the RfD these risks were modeled to be 0.002, 0.0001, 0.0007, 0.002, and 0.02, respectively. The results and impacts of this analysis indicate that categorical regression is a useful screening tool to analyze risks above the RfD for specific chemicals and suggest its application in evaluating comparative risks where multiple chemical exposures exist.

Multicenter phase III trial to evaluate CD34(+) selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma.

High-dose chemotherapy followed by autologous transplantation has been shown to improve response rates and survival in multiple myeloma and other malignancies. However, autografts frequently contain detectable tumor cells. Enrichment for stem cells using anti-CD34 antibodies has been shown to reduce autograft tumor contamination in phase I/II studies. To more definitively assess the safety and efficacy of CD34 selection, a phase III study was completed in 131 multiple myeloma patients randomized to receive an autologous transplant with either CD34-selected or unselected peripheral blood progenitor cells after myeloablative therapy. Tumor contamination in the autografts was assessed by a quantitative polymerase chain reaction detection assay using patient-specific, complementarity-determining region (CDR) Ig gene primers before and after CD34 selection. A median 3.1 log reduction in contaminating tumor cells was achieved in the CD34 selected product using the CEPRATE SC System (CellPro, Inc, Bothell, WA). Successful neutrophil engraftment was achieved in all patients by day 15 and no significant between-arm difference for time to platelet engraftment occurred in patients who received an infused dose of at least 2.0 x 10(6) CD34(+) cells/kg. In conclusion, this phase III trial demonstrates that CD34-selection of peripheral blood progenitor cells significantly reduces tumor cell contamination yet provides safe and rapid hematologic recovery for patients receiving myeloablative therapy.

Experimental lesions in rats corresponding to advanced human asbestosis.

Rats inhaling chrysotile asbestos developed a progressive interstitial fibrosis similar in most respects to human asbestosis. The earliest lesions were focal deposits of fibrous tissue in the walls of respiratory bronchioles and alveolar ducts. Later alveolar septa between adjacent bronchioles became progressively thickened to produce lesions with similarities to human honeycombing. The thickened septa between alveoli or "micro-honeycomb" spaces were mainly surfaced with cuboidal epithelial cells although some spaces lined by ciliated columnar epithelium were also found. Transmission electron microscopy of these advanced lesions showed that the cuboidal epithelial cells retained most of the characteristics of type 2 pneumocytes but that they frequently exhibited apical cytoplasmic blebs normally associated with the apocrine secretion of Clara cells. Columnar cells exhibited all stages from fully cilitated to cells with only an occasional cilium among the normal cell surface microvilli. Alveolar or micro-honeycomb spaces frequently contained clusters of pulmonary macrophages with their surface processes interdigitated but with no signs of fusion to giant cells. At more than 18 months after the end of dust inhalation these macrophages contained no chrysotile asbestos. The basement membranes beneath the epithelial layers of thickened septa were irregular and often convoluted as well as being much thicker than normal. Microscopic deposits of calcification were frequently found within the basement membrane material. Some thickened septa were relatively acellular, consisting mainly of masses of collagen fibrils but others were cellular and contained many macrophages, fibroblasts, plasma cells and mast cells. In these advanced lesions extremely little chrysotile asbestos was found and this was present in two sites only. Some chrysotile, always as individual fibrils and usually of short length, was present among collagen fibrils in areas of fibrosis and some was present within the thickened basement membranes.