One hundred and thirty-six patients autografted for relapsed or refractory non-Hodgkin's lymphoma (NHL) were evaluated to assess long-term event-free survival and to identify important prognostic factors. High-dose therapy consisted primarily of carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC) followed by unpurged autologous stem cell rescue. The 5-year Kaplan-Meier event-free survival (EFS) for the entire cohort was 34% (95% confidence interval: 24-44%) with a median follow-up of approximately 3 years (range 0-7.5 years). For patients entering with minimal disease (defined as all areas < or = 2 cm), the 5-year EFS was 40 vs 26% for those entering with bulky disease (P = 0.0004). In the multivariate analysis, minimal disease on entry and administration of involved-field XRT post-transplant were significantly associated with improved EFS; the latter association was observed mainly in the cohort of patients with bulky disease. The overall 100-day treatment-related mortality rate was 4.4% (3% for the last 71 patients). New strategies are needed to reduce the high rate of relapse (50-60%) following auto-transplantation for relapsed or refractory NHL.

Seventy consecutive patients with refractory or relapsed Hodgkin's disease who received high-dose chemotherapy followed by autologous stem cell rescue were analyzed to identify clinically relevant predictors of long-term event-free survival. High-dose therapy consisted primarily of carmustine (BCNU), etoposide, cytarabine and cyclophosphamide (BEAC). The 5-year Kaplan-Meier event-free survival (EFS) for the entire cohort was 32% (95% confidence interval; 18-45%) with a median follow-up of 3.6 years (range 7 months-7.6 years). The most significant predictor of improved survival was the presence of minimal disease (defined as all areas < or =2 cm) at the time of transplant: the 5 years EFS was 46 vs 10% for patients with bulky disease (P = 0.0002). Other independent predictors identified by step-wise regression analysis included the presence of non-refractory disease and the administration of post-transplant involved-field radiotherapy (XRT). Treatment-related mortality occurred in 13 of 70 patients: nine patients (13%) died within the first 100 days, mainly from cardiopulmonary toxicity. However, only one of 24 patients (4%) transplanted during the last 4.5 years died from early treatment-related complications. While high-dose therapy followed by autotransplantation led to long-term EFS of 50% for patients with favorable prognostic factors, a substantial proportion of patients relapsed, indicating that new therapeutic strategies are needed.

Interleukin-8 (IL-8), a recently described peptide cytokine, is a neutrophil chemoattractant and activator that exerts effects similar to fMLP, yet their receptors and their roles in pathophysiology differ. The effect of IL-8 on the neutrophil cytoskeleton has not been well studied; therefore, we compared and contrasted the effects of IL-8 and fMLP on neutrophil actin conformation and on the signal pathway regulation of actin responses. IL-8 caused a rapid, dose-dependent increase in neutrophil F-actin content within 30 seconds. The maximum increase was twofold. These changes were accompanied by the development of F-actin-rich pseudopods, as noted with fluorescence microscopy and scanning electron microscopy. Selected biochemical inhibitors were used to study the regulation of the IL-8-induced actin changes. Incubation of neutrophils with 2 micrograms/mL pertussis toxin resulted in a 67% inhibition of the IL-8-induced F-actin increase. The protein kinase C (PKC) inhibitors, staurosporine and H7, did not inhibit the increase in F-actin caused by IL-8. IL-8 caused a rapid increase in neutrophil intracellular calcium that could be completely inhibited by the chelating agent 1,2-bis(o-aminophenoxy)ethane-N,N-N′,N′-tetraacetic acid (BAPTA). However, BAPTA-treated neutrophils retained the ability to increase F-actin in response to IL-8. Similar results were seen with fMLP, indicating that, similar to fMLP, the IL-8-induced actin response is mediated through pertussis-toxin-sensitive G-proteins but is neither dependent on PKC nor increases in cytosolic calcium. Thus, although IL- 8 and fMLP exert their effects on neutrophils through different receptors, the signal transduction pathways used and the effects on actin conformation and pseudopod formation are similar.

The morphology of the amorphous, gelatinous, and crystalline varieties of monoclonal IgG cryoglobulins was analyzed by light and transmission and scanning electron microscopy. Each cryoglobulin had a characteristic fine structure that correlated with its gross morphology. Transmission electron microscopy showed that the amorphous precipitates were random and disorganized molecular clumps. In contrast, cryogels were thin-walled, well-organized, and hydrated strawlike clusters, whereas cryocrystals formed tightly compacted, highly structured molecular clusters. Crystals that formed in blood produced rouleaux, and analysis by scanning electron microscopy indicated that the crystals could form thick-walled, branching, macromolecular nets that could physically trap cells. The morphological properties provided visual impressions by which cryoglobulins could cause clinical disease secondary to vascular occlusion produced by self- associated IgG cryoglobulin molecules.

Summary:Unrelated donor marrow transplantation is associated with an increased incidence of graft-versus-host disease (GVHD) compared with sibling donor transplants. Forty-one patients undergoing unrelated donor transplants were treated with a GVHD prophylaxis regimen that consisted of continuous infusion cyclosporine from day −1 to 100 days post transplant along with nifedipine, glucocorticoids and short-course methotrexate. The regimen was well-tolerated in this cohort with mostly high risk disease. Fifty-one percent of patients developed acute GVHD, which was grade III-IV in 22% of patients. Six of 22 patients at risk for chronic GVHD developed extensive chronic GVHD, five of whom were adults. In patients Ͻ18 years of age, there was a Ͼ40% chance of 2 year disease-free survival. Use of continuous infusion cyclosporine with nifedipine as an immunosuppressant and protectant against cyclosporine-induced toxicities in unrelated donor transplants is well-tolerated, and results in acute GVHD incidence favorable to that reported with bolus cyclosporine.