Pathophysiology of superficial femoral artery in-stent restenosis.

Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drug-eluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis.

Unique demands of the femoral anatomy and pathology and the need for unique interventions.

With the aging of the population the incidence of peripheral artery disease (PAD) is increasing, which is histologically characterized by fibrocalcific intimal plaques as well as underlying Mönckeberg's medial calcinosis as compared to coronary and carotid artery disease. Superficial femoral artery (SFA) is one of the longest and most dynamically active vessels in the body undergoing torsion, compression, flexion, and extension from leg motion, and is known to be more susceptible to atherosclerosis because of low shear stress or spiral flow, best appreciated in the long segment in its lesser curvature. Endovascular interventions are now considered the first-line strategy for the treatment of PAD patients presenting with claudication or critical limb ischemia, where physiologic stresses on the arterial wall, anatomic considerations, and lesion characteristics impact on their success. Stent fracture and malapposition, are a common phenomenon in PAD which are attributed to severe calcification and fibrosis along with greater motion of the lower extremity, that result in the dampening of the efficacy of stenting and balloon angioplasty. Better designs of self-expanding stents have resulted in either reduction in stent fracture rates or its elimination at least in the short-term follow-up studies, to date. Although drug-eluting stents (DES) have reduced restenosis rates in the coronary circulation, this benefit has not been consistently observed in PAD. However, recent clinical studies utilizing novel Zilver-PTX self-expanding stent (DES) have demonstrated favorable patency rate. Also, in patients with critical limb ischemia, better outcomes have been reported for below-the-knee utilization of DES. Nevertheless, drawbacks of stent technology remain and interests in the greater use of drug-coated balloons (DCB) for PAD have emerged. Randomized controlled trials have consistently shown superiority of DCB over uncoated balloons in reducing neointimal formation in patients with SFA disease. Moreover, there is a growing interest in atherectomy as an alternative treatment strategy for PAD, thus decreasing plaque burden with possibly avoidance of barotrauma. The results from registries support the effectiveness of the atherectomy devices; however, prospective randomized controlled trials are needed to confirm their benefit.

Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease.

BACKGROUND: Several recent studies have reported on the overexpression of human epidermal growth factor receptor (HER)2 in extramammary Paget disease (EMPD). However, there are only a few cases in which both overexpression and gene amplification of HER2 have been examined. OBJECTIVES: To evaluate the overexpression and gene amplification of HER2 using a standardized method with a large number of cases of EMPD. METHODS: Immunohistochemically, the overexpression of the HER2 protein was examined in 104 cases of EMPD, including 31 intraepithelial cases and 73 invasive cases (35 superficially invasive and 38 deeply invasive). When the HER2 protein was overexpressed or potentially overexpressed, further analysis of amplification of the gene encoding HER2, ERBB2, was undertaken using fluorescence in situ hybridization. RESULTS: The HER2 protein was overexpressed in 16 cases (15%) in total, and in 13 of 73 cases (18%) of invasive EMPD. The ERBB2 gene was amplified in all cases with a HER2 score of 3+. A HER2 score of 3+ or 2+, and ERBB2 amplification were significantly more frequent in the cases of deeply invasive EMPD than in intraepithelial/superficially invasive EMPD (24% vs. 6%/3%, P=0·012) and were correlated with a larger number of lymph-node metastases (P=0·047). Log-rank tests for survival curves showed that lymph-node metastasis and ERBB2 amplification were significant prognostic factors (P=0·0001 and P=0·043, respectively). However, by a multivariate analysis, only lymph-node status was a significant indicator of Paget-disease-specific survival (P=0·0001). CONCLUSIONS: A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.