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BackgroundInfants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age.ResultsNine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious.ConclusionSebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Off-label use of drug-eluting stents was found to cause higher incidence of adverse clinical events. Stent thrombosis was observed predominantly in patients who had drug-eluting stents implanted for an off-label indication.

Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for patients with hematologic malignancies, yet the impact of transplanted CD34+ cell dose on clinical outcomes is unresolved. We conducted post hoc analyses of transplanted CD34+ cell dose and hematopoietic recovery following ASCT in 438 patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), using data from 2 multicenter phase 3 clinical studies that compared plerixafor plus granulocyte-colony stimulating factor (G-CSF) versus placebo plus G-CSF as stem cell mobilization regimens. Days to engraftment and the proportion of patients who reached predetermined blood count thresholds were compared across 3 CD34+ cell dose levels: 2-4 × 106 cells/kg, 4-6 × 106 cells/kg, and >6 × 106 cells/kg, regardless of mobilization treatment. Short-term neutrophil and platelet engraftment times were similar regardless of cell dose. A significant linear trend was observed between transplanted CD34+ cell dose and the proportion of patients with platelet count >150 × 109/L at 100 days (P < .001), 6 months (P = .026), and 12 months (P = .020) in patients with NHL, and at 100 days in patients with MM (P = .004). A linear trend was also observed between transplanted cell dose and the proportion of patients with platelet count >100 × 109/L at 100 days (P < .001) and 6 months (P = .023) in patients with NHL. A higher cell dose was associated with a lower percentage of NHL patients requiring red blood cell transfusions (P = .006). Our analyses confirm previous findings that transplanted CD34+ cell dose may be associated with better long-term platelet recovery after ASCT. [Copyright &y& Elsevier]

Background: In the first year after coronary stent implantation, clinical failures are driven mainly by procedural complications and restenosis, but the subsequent relative contributions of restenosis and disease progression to late failures are less clear., Methods and Results: We observed 1228 patients for 5 years after the implantation of stents as part of pivotal second-generation coronary stent trials. Clinical events of death, myocardial infarction, repeat revascularization, and repeat hospitalization for acute coronary syndrome or congestive heart failure were attributed to the index stented (target) lesion or other distinct sites (either in the target or other coronary vessels) and further classified as procedural, restenosis, or nonrestenosis. During the first year the hazard rate was 18.3% for target-lesion events and 12.4% for events unrelated to the target lesion. After the first year the average annual hazard rate was 1.7% for target-lesion events and 6.3% for nontarget-lesion events. By the fifth year, restenosis events occurred in 20.3% of patients, whereas 30-day procedural complications or later nonrestenosis events occurred in 37.9%, including 11.4% who also experienced a restenosis event, for a combined cumulative event rate of 46.4%. Diabetes mellitus and multivessel disease were independently associated with increased risk for both restenosis and nonrestenosis events., Conclusions: In a low-risk clinical trial population, the clinical outcome beyond 1 year after stenting is determined by a high rate of events related to disease progression in segments other than the stented lesion, which itself remains relatively stable.