Citations

Purpose To evaluate the impact of letrozole compared with placebo after adjuvant tamoxifen on quality of life (QOL) in the MA.17 trial. Methods Patients completed the Short Form 36-item Health Survey (SF-36) and the Menopause Specific Quality of Life Questionnaire (MENQOL) at baseline, 6 months, and annually. Mean change scores from baseline were compared between groups for summary measures and domains. A response analysis compared the proportion of patients who demonstrated an important change in QOL. Results Of 5,187 randomly assigned women in the trial, 3,612 (69.9%) participated in the QOL substudy: 1,799 were allocated to placebo and 1,813 were allocated to letrozole. No differences were seen between groups in mean change scores from baseline for the SF-36 physical and mental component summary scores at 6, 12, 24, and 36 months. Small (< 0.2 standard deviations) but statistically significant differences in mean change scores from baseline were seen for the SF-36 domains of physical functioning (12 months), bodily pain (6 months) and vitality (6 and 12 months), and the MENQOL vasomotor (6, 12, and 24 months) and sexual domains (12 and 24 months). On the response analysis, a significant difference was seen between groups for the bodily pain domain (percentage of patients reporting a worsening of QOL, 47% placebo v 51% letrozole; P = .009) and the vasomotor domain (22% placebo v 29% letrozole; P = .001). Conclusion Letrozole did not have an adverse impact on overall QOL. Small effects were seen in some domains consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis.

Extracellular proteolysis plays a key role in many pathophysiologic processes including cancer, inflammatory diseases, and cardiovascular conditions such as atherosclerosis and restenosis. Whereas matrix metalloproteinases are their best known member, many others are becoming better known. The extracellular proteases are a complex and heterogeneous superfamily of enzymes. They include metalloproteinases (matrix metalloproteinases, adamalysins, or pappalysins), serine proteases (elastase, coagulation factors, plasmin, tissue plasminogen activator, urokinase plasminogen activator), and the cysteine proteases (such cathepsins). In addition to their matrix degradation capabilities, they have other less well known biologic functions that include angiogenesis, growth factor bioavailability, cytokine modulation, receptor shedding, enhancing cell migration, proliferation, invasion, and apoptosis. This review discusses extracellular proteases relevant to the vasculature, their classification and function, and how protease disorders contribute to arterial plaque growth, including chronic atherosclerosis, acute coronary syndromes, restenosis, and vascular remodeling. These broad extracellular protease functions make them potentially interesting therapeutic targets.

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.

AbstractInsulinoma in patients with multiple endocrine neoplasia (MEN) is a rare condition that because of its usual multicentricity presents difficulties not encountered in sporadic patients. In contrast to gastrinoma, which is the most common pancreatic neoplasm associated with MEN I, malignancy and duodenal tumors are much less common for patients with insulinomas, and excellent palliative medication is not available. Accordingly, there is a much greater reliance on surgical therapy for this group of patients. Between 1970 and 1991 a total of 19 patients had surgical treatment of MEN I‐related insulinoma. Each patient had hyperinsulinemic hypoglycemia. One patient, with extensive metastases, had unresectable disease. Of the remaining 18, there were 16 (89%) multiple pancreatic tumors. Tumors were located in the neck, body, or tail in 17 cases, 10 of whom also had tumors in the head. Pancreatic resections performed were 1 total, 12 subtotal (7 also had enucleation of tumors from the pancreatic head), and 5 limited distal resections and/or enucleation (conservative resection). There was no operative mortality. One patient developed pancreatitis, fistula, and diabetes following subtotal resection and enucleation. Postoperative cure was achieved in 17 of 18 cases. Recurrent disease occurred in 2 of 5 conservative resections compared to 0 of 12 subtotal resections, with median follow‐up times of 10.4 and 10.3 years, respectively. During the follow‐up period, four patients died, possibly all due to MEN I‐related conditions. Hyperinsulinism in MEN I is associated with the occurrence of multiple, usually benign, pancreatic islet cell tumors, and surgery is an effective treatment modality. Surgical management should be guided by two principles: total removal of gross disease and safe prophylactic pancreatic resection. Acceptable morbidity, low recurrence rates, and a low risk of inducing diabetes lead us to recommend routine subtotal distal pancreatectomy. Meticulous evaluation of the pancreatic head using intraoperative ultrasonography to locate tumors and to locate the pancreatic duct, followed by precise enucleation of residual tumors, is essential to ensure cure.