Citations

AbstractCertain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.

Background— The economic outcomes of clinical management strategies are important in assessing their value to patients. Methods and Results— Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized patients with type 2 diabetes mellitus and angiographically documented, stable coronary disease to strategies of (1) prompt revascularization versus medical therapy with delayed revascularization as needed to relieve symptoms and (2) insulin sensitization versus insulin provision. Before randomization, the physician declared whether coronary artery bypass grafting or percutaneous coronary intervention would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs and assessed the cost-effectiveness of these management strategies. Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization ( P <0.0001). In the coronary artery bypass grafting stratum, 4-year costs were $80 900 for revascularization versus $60 600 for medical therapy ( P <0.0001). In the percutaneous coronary intervention stratum, costs were $73 400 for revascularization versus $67 800 for medical therapy ( P <0.02). Costs also were higher for insulin sensitization ($71 300) versus insulin provision ($70 200). Other factors that significantly ( P <0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index ≥30, and albuminuria. Cost-effectiveness based on 4-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the percutaneous coronary intervention stratum ($600 per life-year added) with high confidence. Lifetime projections suggest that revascularization may be cost-effective in the coronary artery bypass grafting stratum ($47 000 per life-year added) but with lower confidence. Conclusions— Prompt coronary revascularization significantly increases costs among patients with type 2 diabetes mellitus and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for percutaneous coronary intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00006305.

We assessed adverse metabolic effects of atenolol and hydrochlorothiazide among hypertensive patients with and without abdominal obesity using data from a randomized, open-label study of hypertensive patients without evidence of cardiovascular disease or diabetes mellitus. Intervention included randomization to 25 mg of hydrochlorothiazide or 100 mg of atenolol monotherapy followed by their combination. Fasting glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and uric acid levels were measured at baseline and after monotherapy and combination therapy. Outcomes included new occurrence of and predictors for new cases of glucose ≥100 mg/dL (impaired fasting glucose), triglyceride ≥150 mg/dL, high-density lipoprotein ≤40 mg/dL for men or ≤50 mg/dL for women, or new-onset diabetes mellitus according to the presence or absence of abdominal obesity. Abdominal obesity was present in 167 (58%) of 395 patients. Regardless of strategy, in those with abdominal obesity, 20% had impaired fasting glucose at baseline compared with 40% at the end of study ( P <0.0001). Proportion with triglycerides ≥150 mg/dL increased from 33% at baseline to 46% at the end of study ( P <0.01). New-onset diabetes mellitus occurred in 13 patients (6%) with and in 4 patients (2%) without abdominal obesity. Baseline levels of glucose, triglyceride, and high-density lipoprotein predicted adverse outcomes, and predictors for new-onset diabetes mellitus after monotherapy in those with abdominal obesity included hydrochlorothiazide strategy (odds ratio: 46.91 [95% CI: 2.55 to 862.40]), female sex (odds ratio: 31.37 [95% CI: 2.10 to 468.99]), and uric acid (odds ratio: 3.19 [95% CI: 1.35 to 7.52]). Development of adverse metabolic effect, including new-onset diabetes mellitus associated with short-term exposure to hydrochlorothiazide and atenolol was more common in those with abdominal obesity.