RESUMO
Multiple myeloma (MM) is a clinically and genetically heterogenous cancer where tumour cells have dysregulated expression of a D-type cyclin, often in association with a recurrent IgH translocation. Patients whose tumour cells express cyclin D2, with the translocation t(4;14) or t(14;16), generally have more proliferative disease and inferior outcomes. The phosphatidylinositol-3-kinase (PI3K) pathway is a major regulator of D-type cyclin expression and cell cycle entry. We evaluated the effect of PI3K pathway blockade on cell cycle behaviour in MM cells, investigating differences between cyclin D2- and cyclin D1-expressing tumours. MM cell lines and primary bone marrow CD138(+) MM cells were exposed to the pan-PI3K/mTOR inhibitor, PI-103, and assessed for cell cycle profiles, [(3)H]-thymidine uptake and cell cycle proteins. We report, in both cell lines and primary MM cells, that PI-103 induced cell cycle arrest with downregulation of cyclin D2 and CDK4/6 in MM cells expressing cyclin D2 via t(4;14) or t(14;16) translocations. Cells expressing cyclin D1 via t(11;14) were insensitive to PI-103, despite exhibiting inhibition of downstream signalling targets. In primary MM cells, PI-103 enhanced the anti-proliferative effects of anti-MM agents. Treatment paradigms including blockade of the PI3K/mTOR pathway should be targeted at patients with IgH translocations associated with cyclin D2 overexpression.
RESUMO
OBJECTIVE: Prednisone (PRED) is recommended at discharge to reduce the relapse rate following emergency treatment for an asthmatic attack. However, PRED has systemic side effects. Inhaled anti-inflammatory medications, such as budesonide (BUD), are well tolerated. This study was designed to compare the effectiveness of PRED and BUD on relapse rate. DESIGN: A prospective, randomized, double-blind, double dummy, parallel group design. SETTING: Tertiary referral emergency departments. POPULATION STUDIED: One hundred and eighty-five patients with acute asthma who received standard treatment with bronchodilators and systemic glucocorticosteroids in the emergency department, had a forced expiration volume in 1 s (FEV1) greater than 50% predicted and who were deemed well enough to be discharged from the emergency department. INTERVENTION: Patients were randomized to receive either BUD Turbuhaler 600 microg qid or PRED 40 mg in the morning for seven to 10 days. At discharge and final visit, symptoms, medication use, FEV1, peak expiratory flow (PEF) and quality of life (QoL) were assessed. Relapse rate to the emergency department during the follow-up was determined by a yes and/or no questionnaire. MAIN RESULTS: The PRED (n=85) and BUD (n=90) treatment groups were comparable at baseline (emergency department discharge) for age (mean +/- SD; 27.6+/-8.5 years and 29. 2+/-8.7 years) and prebronchodilator FEV1 (1.77+/-0.79 L and 1. 75+/-0.78 L), respectively. BUD was at least as effective as PRED in preventing a relapse to the hospital; relapse rate was 10 (11.8%) during PRED treatment and nine (10.0%) for BUD treatment (95% CI PRED-BUD, -7.5% to 11.0%). Improvements in FEV1, asthma symptoms, PEF and QoL were not significantly different between treatments. CONCLUSIONS: In patients whose acute asthma has been stabilized in the emergency department, high dose BUD may be an alternate to PRED as a follow-up treatment.
