A phase I clinical, pharmacologic, and biologic study of thrombopoietin and granulocyte colony-stimulating factor in children receiving ifosfamide, carboplatin, and etoposide chemotherapy for recurrent or refractory solid tumors: a Children's Oncology Group experience.

PURPOSE: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Children's Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 microg/kg per dose. EXPERIMENTAL DESIGN: Children received ifosfamide 1,800 mg/m2 on days 0 to 4, carboplatin 400 mg/m2 on days 0 to 1, and etoposide 100 mg/m2 on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 microg/kg per dose.RESULTS: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery > or =100,000/microL of rhTPO at 1.2, 2.4, and 3.6 microg/kg/d was 24 days (22-24 d), 25 days (23-29 d), and 22 days (16-37 d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (+/- SD) rhTPO maximum serum concentrations were 63.3 +/- 9.7 and 89.3 +/- 15.7 ng/mL and terminal half-lives were 47 +/- 13 and 64 +/- 42 hours after 2.4 and 3.6 microg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery. CONCLUSIONS: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).     

Pharmacokinetic and pharmacodynamic profiles of a novel phospholipid-aspirin complex liquid formulation and low dose enteric-coated aspirin: results from a prospective,randomized, crossover study

Journal of Thrombosis and Thrombolysis - Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which...     

Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial)

Drug-eluting stent failures were associated with various clinical factors. However, the clinical impact of stent deployment technique was unknown. This study was designed to evaluate the frequency and impact of suboptimal percutaneous coronary intervention on long-term outcomes of 1,557 patients treated with sirolimus-eluting stents (SESs) in 41 US hospitals. All steps of the interventional procedure were scrutinized by an independent core laboratory to determine the occurrence of geographic miss (GM). GM included longitudinal (LGM; injured or diseased segment not covered by SES) or axial GM (balloon-artery size ratio <0.9 or >1.3) mismatches. Patients with and without GM were stratified (GM vs no-GM group). Patients, investigators, and the independent clinical event adjudication committee were blind to study group assignments. The primary end point was 1-year target-vessel revascularization (TVR) rate. Incidences and predictors of GM and safety outcomes were secondary end points. GM occurred in 943 patients (66.5%): 47.6% had LGM, 35.2% had axial GM, and 16.5% had both. One-year TVR rates were 5.1% in the GM group versus 2.5% in the no-GM group (p=0.025). TVR was 6.1% in the LGM versus 2.6% in the no-LGM subgroups (p=0.001). The association of GM with 1-year TVR was independent of clinical or anatomic factors (hazard ratio 2.0, 95% confidence interval 1.0 to 4.02, p=0.05). There was a 3-fold increase in myocardial infarction rates associated with GM (2.4% vs 0.8%; p=0.04). In conclusion, GM occurred frequently during SES implantation and was associated with increased risk of TVR and myocardial infarction at 1 year. These results emphasized the need for improvement in contemporary percutaneous coronary intervention practices and technologies.     

Saphenous vein graft disease

Saphenous vein graft (SVG) disease has been an obstinate problem facing the cardiologist since the early days of coronary artery bypass grafting (CABG) surgery. SVG disease follows temporally distinct phases of thrombosis, intimal hyperplasia and progressive atherosclerosis leading to recurrent ischemia which can be treated with repeat operation or percutaneous revascularization. However, repeat operation is associated with high mortality and morbidity. Also, percutaneous treatment of SVG disease is complicated by a high rate of procedural and long term complications due to the interrelated phenomena of distal embolization, slow flow or no reflow, periprocedure myocardial infarction, and subsequent restenosis. Long-term patency is poor in this patient population regardless of the treatment modality. Many pharmaceutical and device based approaches have been tested to avert these complications, but few, such as the use of distal protection devices, have shown benefit. The novel drug-eluting stents show promise in reducing the occurrence of restenosis and solving one of the problems associated with the percutaneous treatment of SVG disease. The pathogenesis and therapeutic options for SVG disease is reviewed in this article.     

Quantitative magnetic resonance perfusion imaging detects anatomic and physiologic coronary artery disease as measured by coronary angiography and fractional flow reserve.

OBJECTIVES: To evaluate the ability of quantitative perfusion cardiac magnetic resonance (CMR) to assess the hemodynamic significance of coronary artery disease (CAD) compared with well-established anatomic and physiologic techniques. BACKGROUND: Fractional flow reserve (FFR) is considered by many investigators to be a reliable stenosis-specific method to determine hemodynamically significant CAD. Quantitative perfusion CMR is a promising noninvasive approach to detect CAD but has yet to be validated against FFR. METHODS: This is a prospective study in patients with suspected CAD who underwent coronary angiography, FFR, and CMR assessments. The quantitative myocardial perfusion reserve (MPR) was calculated in 720 myocardial sectors (8 sectors/slice). The MPR was calculated from the ratio between stress and rest myocardial flow based on signal intensity time curves using deconvolution analysis. Stress was simulated with adenosine for both FFR and MPR. The MPR assessments were compared to FFR (n = 44 coronary segments) and quantitative coronary angiography (n = 108 segments) in the corresponding coronary territories. RESULTS: The MPR was 1.54 +/- 0.36 in segments with FFR < or =0.75 (n = 14) and 2.11 +/- 0.68 in those with FFR >0.75 (n = 30; p = 0.0054). An MPR cutoff of 2.04 was 92.9% (95% CI 77.9 to 100.0) sensitive and 56.7% (95% CI 32.8 to 80.6) specific in predicting a coronary segment with FFR < or =0.75. The MPR was 1.54 +/- 0.49 in coronary segments with > or =50% diameter stenosis (DS) (n = 47) and 2.13 +/- 0.80 in segments with <50% DS (n = 61; p < 0.001). An MPR cutoff of 2.04 was 85.1% (95% CI 71.1 to 99.2) sensitive and 49.2% (95% CI 33.6 to 64.8) specific in predicting CAD with > or =50% DS. CONCLUSIONS: Quantitative perfusion CMR is a safe noninvasive test that represents a stenosis-specific alternative to determine the hemodynamic significance of CAD.