Citations

Purpose Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. Methods Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. Results Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. Conclusion This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.

Background— Sirolimus-eluting stents (SESs) reduce angiographic restenosis in patients with focal, native coronary artery stenoses. This study evaluated the usefulness of SESs in complex native-vessel lesions at high risk for restenosis. Methods and Results— Angiographic follow-up at 240 days was obtained in 701 patients with long (15- to 25-mm) lesions in small-diameter (2.5- to 3.5-mm) native vessels who were randomly assigned to treatment with SESs or bare-metal stents (BMSs) in the SIRIUS trial. Quantitative angiographic measurements of minimal lumen diameter and percent diameter stenosis were obtained within the treated segment, within the stent, and within its 5-mm proximal and distal edges. Patients treated with SESs had lower rates of binary (>50% diameter stenosis) angiographic restenosis within the segment (8.9% versus 36.3% with the BMS; P <0.001) and within the stent (3.2% versus 35.4% with the BMS; P <0.001). SESs were associated with significantly less late lumen loss within the treated segment, within the stent, and within its 5-mm proximal and distal edges (all P <0.001). The reduction of restenosis with the SES was consistent in patients at risk for restenosis, including those with small vessels, long lesions, and diabetes mellitus. The frequency of late aneurysms was similar in the 2 groups. Conclusions— Compared with BMSs, SESs reduced angiographic late lumen loss within the stent and its adjacent 5-mm margins in patients with complex native-vessel lesions.

Background The diagnosis of a painful partial tear of the medial collateral ligament in overhead-throwing athletes is challenging, even for experienced elbow surgeons and despite the use of sophisticated imaging techniques. Hypothesis The “moving valgus stress test” is an accurate physical examination technique for diagnosis of medial collateral ligament attenuation in the elbow. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods Twenty-one patients underwent surgical intervention for medial elbow pain due to medial collateral ligament insufficiency or other abnormality of chronic valgus overload, and they were assessed preoperatively with an examination called the moving valgus stress test. To perform the moving valgus stress test, the examiner applies and maintains a constant moderate valgus torque to the fully flexed elbow and then quickly extends the elbow. The test is positive if the medial elbow pain is reproduced at the medial collateral ligament and is at maximum between 120 ° and 70 °. Results The moving valgus stress test was highly sensitive (100%, 17 of 17 patients) and specific (75%, 3 of 4 patients) when compared to assessment of the medial collateral ligament by surgical exploration or arthroscopic valgus stress testing. The mean shear range (ie, the arc within which pain was produced with the moving valgus stress test) was 120 ° to 70 °. The mean angle at which pain was at a maximum was 90 ° of elbow flexion. Conclusions The moving valgus stress test is an accurate physical examination technique that, when performed and interpreted correctly, is highly sensitive for medial elbow pain arising from the medial collateral ligament.

Objective— Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic cytokines. Ability of VEGF to stimulate formation of superoxide anion in vivo has not been studied. We hypothesized that in vivo expression of recombinant VEGF in the rabbit carotid artery increases production of superoxide anion. Methods and Results— Plaque-forming units (10 9 ) of adenovirus-encoding human VEGF 165 (AdVEGF) or β-galactosidase (AdLacZ) were delivered into the lumen of rabbit carotid arteries. Three days after gene delivery, expression of recombinant proteins was detected in endothelium and smooth muscle cells. Endothelium-dependent relaxations to acetylcholine were impaired in AdVEGF-transduced arteries ( P <0.01; n=5). Treatment with superoxide dismutase mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10 −5 mol/L), improved relaxations to acetylcholine ( P <0.01; n=5). Western blot analysis demonstrated increased expression of p47 phox in AdVEGF-transduced arteries ( P <0.05; n=8). Lucigenin chemiluminescence showed significantly higher production of superoxide anion in AdVEGF-transduced arteries ( P <0.05; n=5 to 10). Conclusions— Our results suggest that in vivo expression of recombinant VEGF in the vascular endothelium increases local production of superoxide anion. Superoxide anion appears to be an important mediator of vascular effects of VEGF in vivo.