Sun, Junfeng

SUMMARY Aim To evaluate the risks of restrictive red blood cell transfusion strategies (haemoglobin 7–8 g dL −1 ) in patients with and without known cardiovascular disease (CVD). Background Recent guidelines recommend restrictive strategies for CVD patients hospitalised for non‐CVD indications, patients without known CVD and patients hospitalised for CVD corrective procedures. Methods/Materials Database searches were conducted through December 2017 for randomised clinical trials that enrolled patients with and without known CVD, hospitalised either for CVD‐corrective procedures or non‐cardiac indications, comparing effects of liberal with restrictive strategies on major adverse coronary events (MACE) and death. Results In CVD patients not undergoing cardiac interventions, a liberal strategy decreased ( P = 0·01) the relative risk (95% CI) (RR) of MACE [0·50 (0·29–0·86)] ( I 2 = 0%). Among patients without known CVD, the incidence of MACE was lower (1·7 vs 3·9%), and the effect of a liberal strategy on MACE [0·79, (0·39–1·58)] was smaller and non‐significant but not different from CVD patients ( P = 0·30). Combining all CVD and non‐CVD patients, a liberal strategy decreased MACE [0·59, (0·39–0·91); P = 0·02]. Conversely, among studies reporting mortality, a liberal strategy decreased mortality in CVD patients (11·7% vs·13·3%) but increased mortality (19·2% vs 18·0%) in patients without known CVD [interaction P = 0·05; ratio of RR 0·73, (0·53–1·00)]. A liberal strategy also did not benefit patients undergoing cardiac surgery; data were insufficient for percutaneous cardiac procedures. Conclusions In patients hospitalised for non‐cardiac indications, liberal transfusion strategies are associated with a decreased risk of MACE in both those with and without known CVD. However, this only provides a survival benefit to CVD patients not admitted for CVD‐corrective procedures.

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.