Citations

Incidental findings pose considerable management dilemmas for the treating physician and psychological burden for the respective patient. With an aging population, more patients will be diagnosed with asymptomatic internal carotid artery stenosis. Patients will have to be counseled with regard to treatment options according to their individual risk profile and according to professionals' knowledge of evidence-based data derived from large randomized control trials. Treatment consensus has long been lacking for patients with asymptomatic carotid artery stenosis prior to any randomized controlled trials. Additionally, an individual's risk profile may be hard to assess according to knowledge gained from randomized controlled trials. Moreover, while earlier studies compared carotid endarterectomy and medical therapy, in the past years, a new therapeutic modality, carotid artery angioplasty and stenting, has emerged as a possible alternative. This has been evaluated in a recent randomized controlled trial, the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), which compared carotid endarterectomy with angioplasty and stenting in both symptomatic and asymptomatic patients. The following review summarizes current knowledge of the natural history, diagnosis, and treatment strategies to counsel patients with asymptomatic carotid artery stenosis.

Vascular endothelial growth factor (VEGF) acts primarily as an endothelial cell mitogen via the specific receptors Flk-1 and Flt-1. To help further define the possible role of VEGF in the control of pituitary cell function, we examined Flk-1 expression in normal rat pituitaries and in GH3 cells. Flk-1 expression was studied by immunohistochemistry, in situ hybridization, and double-labeling immunofluorescence combined with confocal laser microscopy. In normal rat pituitaries, Flk-1-immunoreactive cells appeared widely distributed only in the anterior lobe and were not detected in the intermediate or posterior lobe. Apart from the adenohypophysial cells, Flk-1 immunopositivity was also evident in endothelial cells of many capillaries distributed throughout the gland. Immunohistochemistry also showed that majority of GH3 cells expressed Flk-1 protein. In situ hybridization showed conclusive staining with the antisense probe and confirmed the immunohistochemical results. The double immunofluorescence method revealed Flk-1 expression in all types of hormone-producing adenohypophysial cells but not in folliculostellate cells. The percentage of immunopositive cells varied among the various cell types. The present study demonstrates that pituitary cells are not only sources of VEGF but also targets of this multifunctional substance, supporting the concept that VEGF functions as an autocrine/paracrine factor in the pituitary.

Leptin is a key mediator in the maintenance of neuroendocrine homeostasis. Recently, leptin and leptin receptor expression were demonstrated in non-tumorous and adenomatous human pituitaries. This study was performed to determine the subcellular localization of leptin in human adenohypophyses ( n = 3) and in various types of pituitary adenoma ( n = 16). Immunoelectron microscopy showed leptin immunolabeling in most hormone-producing cells of the human non-tumorous adenohypophysis, but not in stellate cells. Labeling was noted over secretory granules. Immunocytochemistry using double labeling revealed leptin expression in GH-, ACTH-, TSH-, and FSH/LH-containing cells but not in PRL cells. The percentage of immunopositive cells and the intensity of immunostaining varied considerably among the various cell types. Immunoelectron microscopy with double gold labeling showed co-localization of leptin and adenohypophysial hormones in the same secretory granules. Among pituitary tumors, leptin immunolabeling was evident only in corticotroph adenomas. Compared to non-tumorous corticotrophs, leptin immunoexpression was less abundant in corticotroph adenomas. The presence of leptin and adenohypophysial hormones in the same secretory granules suggests that leptin is secreted concomitantly with various adenohypophysial hormones and that its release is under the control of hypothalamic stimulating and inhibiting hormones. (J Histochem Cytochem 48:1147–1152, 2000)

The purpose of this study was to evaluate the incidence and durability of additional proximal cuffs during endovascular abdominal aortic aneurysm repair (EVAR). A retrospective review of 90 EVAR patients was conducted. Postoperative survival, proximal sealing zone–related complications, and secondary procedures were analyzed. Additional proximal cuffs were used in 11%. Their use did not affect postoperative survival ( p = .58), type I endoleak rate (4.4%; p = .19), or the need for sealing zone–related secondary procedures (6.3%; p = .38) compared with patients without cuff placement but was related to a higher cumulative graft migration rate (2.2% overall p = .02). Two patients (2.5%; p = .79) underwent conversion to open surgery, both for proximal sealing zone–related complications. Application of proximal cuffs appears to be an effective intraoperative adjunctive procedure to achieve a proximal seal during EVAR, with favorable midterm results. However, the risk of late endograft migrations may be elevated in this group.

Abstract Abstract #2149 Background: Inhibitors of the insulin-like growth factor 1 receptor (IGF-1R) are currently undergoing clinical testing. Preclinical investigations have identified IGF-1 signaling as a key mechanism for breast cancer growth and resistance to clinically useful therapies, including tamoxifen and trastuzumab. Thus, agents targeting IGF-1R have promise in the treatment of breast cancer. Determining mechanisms that can confer resistance to these agents may aid their clinical development.
 Methods: To understand factors may be important in predicting sensitivity to targeting the IGF-1 signaling pathway, we developed a cell line (MCF-7R4) that is resistant to BMS-554417, a small molecule, dual-kinase inhibitor of IGF-1R and insulin receptor (InsR). Compared with the parental MCF-7 cells, MCF-7R4 cells are 40- to 50-fold resistant to BMS-554417 and cross-resistant to the similar compound BMS-536924. The expression profiles of MCF-7R4 and that of MCF-7 were compared using Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Intracellular concentrations of BMS-536924 were examined by reverse phase high performance liquid chromatography. BMS-536924 cellular accumulation in vitro was visualized by fluorescence microscopy using a DAPI filter set. MCF-7 cells stably transfected with either the empty mammalian expression vector pcDNA (MCF-EV) or full length BCRP (MCF-BCRP) were examined for sensitivity to BMS 536924 by MTS assays.
 Results: Compared to MCF-7 cells, BCRP expression was increased 9-fold in MCF-7R4, which was highly statistically significant by t-test (p= 7.13E-09). Little change was observed in other ABC transporter proteins, including ABCB1. No change was observed in IGF-1R or InsR expression. BCRP overexpression in MCF-7R4 cells was confirmed by western blotting. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared to MCF-7 cells. Confirming these results, MCF-BCRP cells were significantly less sensitive to the cytoxic effects of BMS-536924 cells than MCF-EV cells.
 Conclusions: BCRP expression was stimulated by prolonged exposure of MCF-7 cells to BMS-554417. Upregulation of BCRP is one of the most significant changes observed in MCF-7R4 cells in comparison to parental cells. BCRP expression decreased cellular exposure to BMS-536924 and was sufficient to confer resistance. These data suggest that BSM-536924 is a substrate for BCRP-mediated efflux. Expression of BCRP may be important in de novo and acquired resistance to benzimidazole –based inhibitors of IGF-1R/InsR. Supported in part by the Mayo Clinic Breast SPORE (CA116201-03), NIH K12 (CA090628-05) and the Mayo Clinic Cancer Center (CA15083). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2149.

Background: Historical outcomes in anaplastic thyroid carcinoma (ATC) are poor, with a median survival of only 5 months and <20% of patients surviving 1 year from diagnosis. We hypothesized that survival in newly diagnosed patients with stages IVA and IVB locoregionally confined ATC might be improved by utilizing an aggressive therapeutic approach, prioritizing both the eradication of disease in the neck and preemptive treatment of occult metastatic disease. Methods: Between January 1, 2003, and December 31, 2007, 25 new ATC patients were evaluated at our institution. Of these 25 patients, 10 (40%) had metastatic disease at diagnosis and therefore underwent palliative treatment, whereas 5 (20%) had regionally confined disease and desired treatment at their local medical facilities. The remaining 10 consecutive patients (40%) had regionally confined ATC and elected aggressive therapy combining individualized surgery (where feasible), intensity-modulated radiation therapy (IMRT), and radiosensitizing + adjuvant chemotherapy intending four cycles of docetaxel + doxorubicin. Outcomes were assessed on an intention to treat basis. Results: There were no deaths from therapy, but hospitalization was required in two patients (20%) because of treatment-related adverse events. Five patients (50%) are alive and cancer-free, all having been followed >32 months (range: 32–89 months; median: 44 months) with a median overall Kaplan–Meier survival of 60 months. Overall survival at 1 and 2 years was 70% and 60%, respectively, compared to <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation at our and other institutions. Conclusions: Although based upon a small series of consecutively treated patients, an aggressive approach combining IMRT and radiosensitizing plus adjuvant chemotherapy appears to improve outcomes, including survival in stages IVA and IVB regionally confined ATC, but remains of uncertain benefit in patients with stage IVC (metastatic) disease. Also uncertain is the optimal chemotherapy regimen to use in conjunction with IMRT. Further multicenter randomized trials are required to define optimal therapy in this rare but deadly cancer.

Background— Coronary artery bypass graft surgery with cardiopulmonary bypass is a safe, routine procedure. Nevertheless, significant morbidity remains, mostly because of the body’s response to the nonphysiological nature of cardiopulmonary bypass. Few data are available on the effects of off-pump coronary artery bypass graft surgery (OPCAB) on cardiac events and long-term clinical outcomes. Methods and Results— In a single-center randomized trial, 308 patients undergoing coronary artery bypass graft surgery were randomly assigned: 155 to OPCAB and 153 to on-pump CAB (ONCAB). Primary composite end points were death, myocardial infarction, further revascularization (surgery or angioplasty), or stroke. After 5-year follow-up, the primary composite end point was not different between groups (hazard ratio 0.71, 95% CI 0.41 to 1.22; P =0.21). A statistical difference was found between OPCAB and ONCAB groups in the duration of surgery (240±65 versus 300±87.5 minutes; P <0.001), in the length of ICU stay (19.5±17.8 versus 43±17.0 hours; P <0.001), time to extubation (4.6±6.8 versus 9.3±5.7 hours; P <0.001), hospital stay (6±2 versus 9±2 days; P <0.001), higher incidence of atrial fibrillation (35 versus 4% of patients; P <0.001), and blood requirements (31 versus 61% of patients; P <0.001), respectively. The number of grafts per patient was higher in the ONCAB than the OPCAB group (2.97 versus 2.49 grafts/patient; P <0.001). Conclusions— No difference was found between groups in the primary composite end point at 5-years follow-up. Although OPCAB surgery was related to a lower number of grafts and higher episodes of atrial fibrillation, it had no significant implications related to long-term outcomes. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66068876.