Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas.

BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV: NCT00844649.

The effects of Carmeda Bioactive Surface on human blood components during simulated extracorporeal circulation.

Postoperative morbidity after cardiopulmonary bypass most commonly manifests as bleeding diatheses or pulmonary dysfunction. The pathophysiology has been attributed to the activation of cellular and humoral components of blood after contact with an artificial surface. Development of a surface that would be nonthrombogenic and also would constitute a less potent inflammatory stimulus would therefore be beneficial. In the following experiments, we evaluated the heparin-bonded Carmeda Bioactive Surface (Medtronics Cardiopulmonary, Anaheim, Calif.) in an in vitro model of extracorporeal circulation at standard-dose heparin (5 U/ml), to examine the effects of the surface treatment on activation of blood elements, and at reduced-dose heparin (1 U/ml), to determine whether surface-bound heparin would serve as an effective anticoagulant. During the initial recirculation period, platelet counts in the Carmeda (n = 12) circuits were preserved at both doses of heparin and compared with control values (n = 12): At 5 U/ml, control 36% +/- 4% (mean +/- standard error of the mean) versus Carmeda 81% +/- 5%; at 1 U/ml, 43% +/- 3% versus 61% +/- 10%, expressed as a percent of baseline at 30 minutes, p < 0.05. Furthermore, plasma levels of platelet factor 4 and beta-thromboglobulin were significantly reduced in the Carmeda circuits throughout the experiment: At heparin 5 U/ml, 2500 +/- 340 ng/ml versus 604 +/- 191 ng/ml; at 1 U/ml, 2933 +/- 275 ng/ml versus 577 +/- 164 ng/ml of platelet factor 4 at 2 hours (p < 0.05). The pattern of beta-thromboglobulin release was similar, with effects more pronounced at the lower dose of heparin. Surface modification also reduced leukocyte depletion (p < 0.05) and release of elastase at both concentrations of heparin (5 U/ml, 0.72 +/- 0.29 ng/ml versus 0.33 +/- 0.23 ng/ml; 1 U/ml, 0.85 +/- 0.08 ng/ml versus 0.20 +/- 0.05 ng/ml, at 2 hours, p < 0.05). Moreover, as heparin concentration was reduced, Carmeda surface treatment significantly decreased generation of C3a des Arg (1 U/ml, 14,410 +/- 3558 ng/ml versus 3053 +/- 1039 ng/ml at 2 hours, p < 0.05). Although heparin bonding was originally intended to obviate the need for systemic heparinization, Carmeda treatment did not reduce fibrinopeptide A generation at the lower dose of heparin. In summary, Carmeda treatment failed to exhibit anticoagulant efficacy in this model; however, the data suggest that surface modification may have a role in ameliorating the typical inflammatory response initiated by blood contact with an artificial surface.

Iloprost reduces procoagulant activity in the extracorporeal circuit.

Although activation of formed blood elements during cardiopulmonary bypass has been examined, its presumed procoagulant role has not been identified or quantified. We evaluated the effects of iloprost, an inhibitor of platelet and leukocyte function, on subclinical coagulation during simulated extracorporeal circulation. We determined that a heparin dose of 1 U/ml prevented clot formation in this model, but resulted in elevated plasma levels of fibrinopeptide A, the first cleavage product of fibrinogen. Human blood was recirculated with 1 U/ml heparin using a roller pump and pediatric reversed hollow fiber oxygenator (0.8 m2) for 2 hr at 37 degrees C. Iloprost (1 ng/ml, n = 5) reduced platelet adhesion, with platelet counts of 78 +/- 7% (mean +/- SEM) of baseline during 2 hr of simulated extracorporeal circulation, compared to 36 +/- 6% in control circuits (CONT: n = 6, P < 0.05). Plasma levels of platelet factor 4 and beta-thromboglobulin were also reduced by iloprost (486 +/- 116 ng/ml vs CONT, 2933 +/- 275 ng/ml, P < 0.05, and 938 +/- 274 ng/ml vs CONT, 5700 +/- 1109 ng/ml, P < 0.05, respectively). Circulating leukocyte counts were maintained in iloprost circuits (6.4 +/- 0.6 x 10(3)/mm3 vs CONT, 4.2 +/- 0.3 x 10(3)/mm3, P < 0.05), and neutrophil elastase levels rose to only 0.4 +/- 0.1 ng/ml in iloprost circuits, compared to 0.8 +/- 0.1 ng/ml in CONT (P < 0.05). Finally, iloprost treatment reduced fibrinopeptide A levels to 102 +/- 28 ng/ml (CONT, 793 +/- 337 ng/ml, P < 0.05) after 2 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Coaxial transthoracic fine-needle biopsy in patients with a history of malignant lymphoma.

Efficacy and safety of coaxial transthoracic fine-needle biopsy were evaluated in 54 patients with a history of malignant lymphoma and new chest lesions. Twenty-one patients had recurrent lymphoma. Correct diagnosis was made in 17 of the 21 patients (81%) after one biopsy. The sensitivity increased to 95% with repeat needle biopsy in three patients. Immunophenotyping (determining phenotype by means of immunologic examination) was essential for a definitive diagnosis of lymphoma in three patients. Non-lymphomatous malignancies were correctly diagnosed in 14 patients. An infectious organism was identified in 11 of 19 patients (58%) with benign lesions. Pneumothorax occurred in eight patients (15%), necessitating placement of a chest tube in two (4%). Mild hemoptysis was observed in four patients (7%). The authors conclude that coaxial transthoracic fine-needle biopsy in patients with a history of lymphoma is safe and accurate. The use of large cutting needles or surgical biopsy can be restricted to patients with false-negative findings at percutaneous biopsy and to patients in whom histologic transformation of lymphoma is suspected.

The effects of heparin bound surface modification (Carmeda Bioactive Surface) on human platelet alterations during simulated extracorporeal circulation.

To determine if treatment with covalently bound heparin (Carmeda Bioactive Surface (CBAS)) to the synthetic surface of the extracorporeal circuit (ECC) would alter the stereotypic pattern of adverse platelet alterations, 450 ml of heparinized blood (lU/ml) was recirculated at a flow rate of twice the circulating volume (L/min) for 2 hrs at 37 degrees C through either untreated (CONT,n=7) or treated (CBAS,n=7) circuits constructed of identical components including a pediatric (0.8m 2) reversed hollow fiber membrane oxygenator. In CONT circuits, platelet count maintained 88+1% (x+/-SEM) of its initial level in the circuit prime sample, dropped to 36+/-6% after 5 min, and returned to 56+/-2% following 2 hrs of ECC. In CBAS circuits, platelet count in the circuit prime sample demonstrated 90+/-4%, decreased to 68+/-10% after 5 min (p less than 0.05) and declined further to 45+/-5% after 2 hrs (NS). Although platelets from both groups retained reactivity to ADP after priming the circuit, only at 5 min of recirculation did CBAS circuits significantly preserve this responsiveness. In CONT circuits, baseline plasma levels of platelet factor 4 rose from 24+/-3 to 581+/-82 ng/ml in the primed circuit and continued to rise to 2933+/-276 ng/ml by 2 hrs of ECC. In contrast, CBAS circuits markedly reduced this release after 2 hrs (577+/-165 ng/ml). Furthermore by 2 hrs of ECC, plasma levels of thromboxane B 2 in the CBAS circuits were significantly reduced when compared to CONT circuits (3035+/-1529 vs 29916+/-16293 pg/ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intracoronary verapamil administration in a sheep model of acute myocardial ischemia and reperfusion.

We evaluated the efficacy of intracoronary administration of verapamil hydrochloride in reducing myocardial injury during acute ischemia and reperfusion. Ischemia was induced by 30% and 45% reductions of circumflex arterial blood flow for successive 2-hour periods. A reperfusion period (1 hour and 45 minutes) followed ischemia upon deflation of a pneumatic occluder. Verapamil (30 micrograms/kg) was slowly injected into the circumflex artery as a bolus 15 minutes after each blood flow reduction step. To prevent verapamil-induced decreases in heart rate, ventricular pacing was established at 170 beats/min before a baseline period and maintained throughout the protocol. Creatine kinase activities (international units per milligram protein) measured in samples obtained from posterior papillary muscles were 15 +/- 1 (mean +/- SEM) and 10 +/- 2 for animals receiving verapamil or its saline vehicle, respectively (p less than 0.05). Quantitative morphometry was performed on left ventricular myocardium after staining with p-nitro blue tetrazolium. Intracoronary administration of verapamil reduced the extent of left ventricular infarction, as disclosed by positive tetrazolium staining of the tissue, from 34 +/- 4% of the left ventricle in vehicle-treated animals to 21 +/- 4% of the left ventricle in verapamil-treated animals (p less than 0.05). We conclude that intracoronary administration of verapamil reduced the extent of myocardial infarction acutely, independent of increases in blood flow through the circumflex coronary artery or decreases in heart rate. Administration of verapamil was not associated with decreases in ventricular afterload, the pressure-rate index, cardiac output, or the maximum rate of pressure development in the left ventricle. Verapamil treatment of animals subjected to ischemia was not associated with sustained elevations of left atrial pressure to values above those measured in animals receiving the vehicle.