Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study.

Several cytogenetic abnormalities are associated with poor outcomes in multiple myeloma (MM). We prospectively analyzed the impact of cytogenetic abnormalities on outcomes during the phase 2 PX-171-003-A1 study of single-agent carfilzomib for relapsed and refractory MM. In the response-evaluable population (257/266), fluorescence in situ hybridization (FISH)/conventional cytogenetic profiles were available for 229 patients; 62 (27.1%) had high-risk cytogenetics--del 17p13, t(4;14) or t(14;16) by interphase FISH or deletion 13 or hypodiploidy by metaphase cytogenetics--and 167 (72.9%) had standard-risk profiles. Generally, baseline characteristics were similar between the subgroups, but International Staging System stage III disease was more common in high- vs standard-risk patients (41.9% vs 27.5%) as was Eastern Cooperative Oncology Group performance status 1/2 (85.5% vs 68.3%). Overall response was comparable between the subgroups (25.8% vs 24.6%, respectively; P=0.85), while time-to-event end points showed a trend of shorter duration in high-risk patients, including median duration of response (5.6 months (95% confidence interval (CI) 3.7-7.8) vs 8.3 months (95% CI 5.6-12.3)) and overall survival (9.3 (95% CI 6.5-13.0) vs 19.0 months (95% CI 15.4-NE); P=0.0003). Taken together, these findings demonstrate that single-agent carfilzomib is efficacious and has the potential to at least partially overcome the impact of high-risk cytogenetics in heavily pre-treated patients with MM.

Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety.

This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50-80 ml/min, 30-49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2) and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.

Use of ATP-MgCl2 in the evaluation and treatment of children with pulmonary hypertension secondary to congenital heart defects.

BACKGROUND: Pulmonary hypertension results in increased morbidity and mortality in children after surgical repair of congenital heart defects. Various vasodilators have been unsuccessful in providing preferential pulmonary vasodilation in these patients. Identification of a more preferential pulmonary vasodilator would improve the assessment, management, and outcome of these children. To determine whether ATP-MgCl2 is a preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects, ATP-MgCl2 was administered during routine cardiac catheterization, and the effects were compared with tolazoline. In addition, ATP-MgCl2 was infused intravenously during episodes of postoperative pulmonary hypertension. METHODS AND RESULTS: During cardiac catheterization in 28 children, the effect of ATP-MgCl2 on the pulmonary artery pressure (PAP) and pulmonary vascular resistance index (Rp) was compared with tolazoline. ATP-MgCl2 (0.1 mg of ATP per kilogram per minute) decreased mean PAP by 24% (P < .05) and Rp by 47% (P < .05) without changing mean systemic arterial pressure or systemic vascular resistance. These effects were comparable to those of tolazoline (1 mg/kg). ATP-MgCl2 produced no significant side effects; tolazoline caused tachycardia, nausea, and vomiting. After cardiac surgery in 7 patients, ATP-MgCl2 decreased PAP by 14% (P < .05) and systemic arterial pressure by 6% (P < .05) and eliminated pulmonary hypertensive crises in 3 of 3 patients. CONCLUSIONS: ATP-MgCl2 is a safe, effective, and preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects. It is useful for evaluating pulmonary vasoreactivity during cardiac catheterization and for treating pulmonary hypertension after cardiac surgery.

Antifungal agents and their renal implications in the neonate.

The incidence of superficial or systemic fungal infections has been increasing in neonates. The cause of this increased susceptibility to fungal infections is due to the increased use of mechanical ventilation, indwelling catheters, broad-spectrum antibiotic therapy, parenteral nutrition, and steroid therapy. The most common organism encountered in neonatal infections is Candida species. This article will cover the etiology, signs, symptoms, diagnosis, and treatment of the usual neonatal fungal infections. Each of the antifungal agents used to treat neonates will be discussed with regard to its mechanism of action, pharmacokinetics, indications, normal and renal functional impairment dosing, and adverse effects.

Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates.

Four neonates had resolution of peripheral tissue ischemia after the application of 2% nitroglycerin ointment. A dosage of 4 mm nitroglycerin ointment per kilogram of body weight was applied to two patients with ischemia caused by vasospasm from indwelling radial artery catheterization and to two patients with ischemia resulting from dopamine extravasation. No adverse effects were noted except mild episodes of decreased blood pressure in two of the patients.

Complications of home parenteral nutrition.

The complications associated with home parenteral nutrition (HPN) and their relationship to length of therapy were studied. The medical records of 56 patients treated with HPN (age range, 6 months to 82 years) were retrospectively reviewed to study complications associated with HPN. Of the 56 study patients, 30 (53.6%) had complications related to HPN, 18 (32.1%) had complications not related to HPN, and 8 (14.3%) had no complications. Of the 365 total complications noted, 125 (34.2%) were related to HPN. The mean +/- S.D. interval between initiation of HPN and occurrence of a complication was 1.25 +/- 1.73 years (mean +/- S.D.). Patients were more likely to have fluid or electrolyte complications or glucose intolerance in the first year of therapy and catheter-related complications later in the course of treatment. The first episode of septicemia occurred 2.1 +/- 1.8 years (mean +/- S.D.) after the initiation of HPN. The risk of developing catheter-related septicemia was higher for patients on long-term HPN therapy and for young patients. Patients receiving HPN should be carefully monitored for complications such as fluid and electrolyte abnormalities and glucose intolerance, which commonly occur early in the course of therapy; later complications of HPN include catheter-related infection, thrombosis, and breakage or dislodgement.

Evaluation of cost-effectiveness research: a survey of recent publications.

Because of interest in cost containment, a series of basic guidelines for performing cost-effectiveness research has evolved in the past decade. These guidelines advise that the perspective of the cost study be clarified, that all applicable costs, benefits, and health outcomes be included, and that discounting and sensitivity analyses be performed where appropriate. A survey of 47 recent cost-effectiveness publications selected via MEDLINE and manual searches confirms our hypothesis that many studies do not adhere to these guidelines. Since such short-comings can lead to misleading or ill-founded conclusions, attention must be paid to the principles of cost-effectiveness research to avoid making major, inappropriate health policy decisions.