No abstract

IntroductionThe efficacy of pegloticase, a polyethylene glycol (PEG)-conjugated mammalian recombinant uricase, approved for chronic refractory gout, can be limited by the development of antibodies (Ab). Analyses from 2 replicate, 6-month, randomized controlled trials were performed to characterize Ab responses to pegloticase.MethodsAnti-pegloticase, anti-PEG, and anti-uricase Ab were determined by validated enzyme-linked immunosorbent assays. Ab titers were analyzed for possible relationships with serum pegloticase concentrations, serum uric acid (sUA) lowering, and risk of infusion reactions (IRs).ResultsSixty-nine (41%) of 169 patients receiving pegloticase developed high titer anti-pegloticase Ab (> 1:2430) and 40% (67/169) developed anti-PEG Ab; 1 patient receiving placebo developed high titer anti-pegloticase Ab. Only 14% (24/169) of patients developed anti-uricase Ab, usually at low titer. In responders, patients showing sustained UA lowering, mean anti-pegloticase titers at week 25 (1:837 ± 1687 with biweekly and 1:2025 ± 4506 with monthly dosing) were markedly lower than in nonresponders (1:34,528 ± 42,228 and 1:89,658 ± 297,797, respectively). Nonresponder status was associated with reduced serum pegloticase concentrations. Baseline anti-pegloticase Ab, evident in 15% (31/212) of patients, did not predict subsequent loss of urate-lowering response. Loss of sUA response preceded IRs in 44 of 56 (79%) pegloticase-treated patients.ConclusionsLoss of responsiveness to pegloticase is associated with the development of high titer anti-pegloticase Ab that increase clearance of pegloticase and are associated with a loss of the sUA lowering effect and increased IR risk. Pre-infusion sUA can be used as a surrogate for the presence of deleterious anti-pegloticase Ab.Trial registrationNCT00325195. Registered 10 May 2006, NCT01356498. Registered 27 October 2008.

Pancreatic cancer occurs with increased frequency among persons with long-standing diabetes.

Objective: To compare the safety and efficacy of Varisolve® 1% polidocanol microfoam sclerosant with alternative treatments for patients with varicose veins and trunk vein incompetence. Methods: An open-label, multicentre, prospective trial of 710 patients randomized to receive either Varisolve® or alternative treatment (surgery or sclerotherapy). The endpoint was ultrasound-determined occlusion of trunk vein(s) and elimination of reflux, analysed against a non-inferiority hypothesis. Results: Overall, non-inferiority was demonstrated with 83.4% efficacy for Varisolve® compared with 88.1% for alternative treatment at three months, and the corresponding magnitudes were 78.9 and 80.4% at 12 months. Surgery was superior to Varisolve®, but the success rate of 68.2% for Varisolve® (surgery 87.2%) was poor compared with 93.8% success for Varisolve® achieved in those randomized to Varisolve® or sclerotherapy. Varisolve® was superior to sclerotherapy at 12 months ( P = 0.001). Deep vein thrombosis occurred in 11/437 (2.5%) after Varisolve®, in 1/125 (0.8%) after sclerotherapy and in none after surgery. No pulmonary emboli were detected. Conclusion: Overall, Varisolve® was non-inferior to alternative treatment. Surgery was more efficacious, but Varisolve® caused less pain and patients returned to normal more quickly. The Varisolve® technique is a useful additional treatment for varicose veins and trunk vein incompetence.

In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.