Overexpression of the focal adhesion kinase (p125FAK) in the vascular smooth muscle cells of intimal hyperplasia.

PURPOSE: The migration and proliferation of vascular smooth muscle cells (VSMCs) are important events in the development of intimal hyperplasia (IH). The focal adhesion kinase (FAK) gene encodes a protein tyrosine kinase (p125FAK) involved in signal transduction pathways used in cell adhesion, motility, and proliferation. Because alterations in these cellular processes are thought to occur in VSMCs during IH, we studied FAK expression in healthy arteries and veins in comparison with that in pathologic vessels containing IH. METHODS: To determine p125FAK expression at the cellular level, we developed a monoclonal antibody that specifically detected FAK in formalin-fixed, paraffin-embedded tissue sections (5 microm) and analyzed the levels of FAK expression in human arteries and veins. Specificity of monoclonal antibody 4.47 was demonstrated by means of immunofluorescence microscopy showing FAK-specific staining at focal adhesions of healthy human vascular smooth muscle cells (AoSMCs). By using immunohistochemistry techniques, we analyzed the expression of p125FAK in 25 adult human vascular tissue samples from individual patients, which contained a histologically confirmed healthy artery, vein, or IH. RESULTS: FAK expression in healthy and pathologic human vascular tissue was localized predominantly within VSMC cytoplasm. In healthy human artery and vein, borderline FAK expression was detected in the media of seven of 17 vessels and undetectable in the remainder of specimens. However, in vessels containing IH, FAK was overexpressed in the pathologic VSMC populations at moderate-to-strong levels in eight of eight specimens. The levels of FAK expression were directly correlated with structures containing IH, and the results of FAK staining intensity and the percentage of positive cells in these samples were significantly increased compared with normal vascular tissue levels (P <.05, Student t test). CONCLUSION: These results provide the first evidence that FAK is overexpressed in VSMCs involved in IH and suggest that FAK upregulation may be part of a mechanism for migration and proliferation of VSMCs during this process. Furthermore, the dramatic upregulation of FAK in IH and the relative lack of expression in healthy vessels suggest that FAK may be a rational target for controlling IH.

Distal thoracic aorta as inflow for the treatment of chronic mesenteric ischemia.

PURPOSE: Mesenteric revascularization for chronic mesenteric ischemia (CMI) traditionally involves antegrade or retrograde bypass graft originating from the supraceliac or infrarenal aorta. The distal thoracic aorta (DTA) may provide a better inflow source than the abdominal aorta. The purpose of this study was to evaluate the results with the DTA used as inflow for the surgical treatment of CMI. METHODS: All patients undergoing mesenteric revascularization for CMI with grafts originating from the DTA were identified from 1990 to 1999. A ninth interspace thoracoretroperitoneal incision was used for exposure, and distal aortic flow was maintained by use of a partial occlusion clamp. RESULTS: Eighteen consecutive patients with CMI underwent mesenteric bypass grafting with the DTA used as inflow. All patients were admitted with chronic abdominal pain or weight loss, with two (12%) requiring urgent revascularization because of acute exacerbation of chronic symptoms. Fourteen (78%) patients had both celiac and superior mesenteric artery bypass grafts placed, and three (17%) patients had superior mesenteric artery grafts alone. There was one (6%) perioperative death and three (17%) major complications. There was no kidney failure, mesenteric infarction, or spinal cord ischemia. The life-table survival rate was 89%, 89%, and 76% at 1, 3, and 5 years, respectively. All 18 patients remained symptom free and required no additional procedures to assist patency. There was no evidence of graft stenosis or occlusion (100% patency) for those grafts evaluated objectively during the mean follow-up of 34.8 months (range, 1-97 months). CONCLUSIONS: Antegrade mesenteric revascularization with the DTA used as inflow is associated with low morbidity and mortality rates. Furthermore, it provides excellent midterm patency and survival results and should be considered as a primary approach for reconstruction of patients with CMI.

The value of air plethysmography in predicting clinical outcome after surgical treatment of chronic venous insufficiency.

PURPOSE: The role of air plethysmography (APG) as a predictor of clinical outcome after surgery in venous disease is yet to be defined. The purpose of this study was to investigate the value of APG in predicting clinical outcome after venous surgery for chronic venous insufficiency (CVI). METHODS: Seventy-three extremities in 71 patients with Class 3 through 6 CVI were assessed preoperatively with CEAP (c linical, e tiologic, a natomic, p athophysiologic) criteria, standing reflux duplex ultrasound scan, and APG with measurements of preoperative venous filling index (VFI), venous volumes, ejection fraction, and residual volume fraction. After surgical treatment of the affected limbs, repeat APG studies were obtained within 6 weeks. Established venous reporting standards were used for follow-up to calculate clinical symptom scores (CSSs) in each patient. RESULTS: Superficial venous reflux occurred alone in 24 limbs or in conjunction with perforator incompetence in 26 limbs. Deep and superficial reflux, with or without perforator incompetence, was found in 16 limbs, and seven limbs had isolated deep insufficiency. Follow-up was available in 60 of 71 patients (mean period, 44.3 months). Postoperative APG demonstrated significant hemodynamic changes after surgery as measured with VFI, venous volumes, ejection fraction, and residual volume fraction. Mean CSSs decreased from 7.35 +/- 0.56 preoperatively to 1.79 +/- 0.32 at late follow-up after surgery (P <.001). With the use of logistic regression, the parameter correlating most closely with clinical outcome was the VFI. A normal postoperative VFI (

Prospective screening for postoperative deep venous thrombosis in patients undergoing infrainguinal revascularization.

PURPOSE: The incidence of deep venous thrombosis (DVT) in patients undergoing infrainguinal bypass graft procedures has not been well documented, and the need for routine prophylaxis remains controversial. The purpose of this study was to prospectively evaluate the risk of postoperative DVT complicating infrainguinal revascularization. METHODS: Seventy-four patients undergoing infrainguinal bypass graft procedures during a 12-month period were prospectively screened for DVT. Bilateral lower extremity venous duplex scan imaging was performed preoperatively and within 1 week and 6 weeks, postoperatively. Routine DVT prophylaxis was not used, with anticoagulation reserved for specific indications. RESULTS: Of the 74 patients screened, three patients (4.1%) had DVT identified on preoperative venous duplex scan imaging and were excluded from the study. Of the remaining 71 patients enrolled, only two patients (2.8%) had postoperative DVT. Postoperative DVT was ipsilateral to the bypass graft extremity in both patients, with involvement of the peroneal vein in one patient and the femoral vein in the other. Although routine prophylaxis was not used, 18 of these patients (25%) were anticoagulated for other indications, with DVT occurring in one patient (5.6%). Of the remaining 53 patients who did not receive postoperative anticoagulation, only one patient (1.8%) had DVT. CONCLUSIONS: According to this prospective study, the risk of postoperative DVT in patients undergoing infrainguinal revascularization is low. Routine prophylaxis is not recommended, with postoperative anticoagulation reserved for specific indications.

Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells.

The focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase implicated in integrin-mediated signal transduction pathways, oncogenic transformation by v-src, and the invasion of human tumors. The overexpression of p125FAK in a variety of human tumors and tumor cell lines in comparison to their nontransformed counterparts suggested that attenuation of p125FAK expression might have an effect on tumor cell proliferation. In this study, we have treated tumor cell lines that expressed high levels of p125FAK with different antisense oligonucleotides to FAK, and have specifically attenuated p125FAK expression. The cells treated with antisense oligonucleotides not only lost their attachment, but also underwent apoptosis. Extensive control oligonucleotide experiments suggested that this attenuation was highly FAK specific. Furthermore, normal human fibroblasts, which did not express high levels of p125FAK, did not lose their attachment or become apoptotic with FAK antisense treatment. These results suggested that FAK is involved in adhesion-mediated growth in tumor cells and that FAK may be a rational gene-directed target for disrupting tumor cell growth.

Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer.

BACKGROUND: The FAK gene encodes a 125-kDa tyrosine kinase (p125FAK) involved in signal transduction pathways used in cell adhesion, motility, and anchorage-independent growth. Because thyroid carcinomas have a wide variability in their propensity for invasion and metastasis, we studied the expression of FAK in a variety of thyroid tissues. METHODS: We synthesized a recombinant N-terminal fragment of the human FAK protein and developed a specific polyclonal antisera. Using Western blot analysis, we assessed the levels of p125FAK expression in 30 human thyroid tissue samples from 27 patients that included paired normal and malignant specimens. Levels of FAK protein in individual tumors were quantitated by densitometric scanning of the immunoblots, and the results were correlated with tumor histology and biologic behavior. RESULTS: The levels of FAK expression were directly correlated with thyroid carcinomas demonstrating the most aggressive phenotypes. The highest levels of p125FAK were seen in follicular carcinomas and tumors associated with distant metastatic foci. In contrast, neoplastic thyroid tissues with limited invasive potential, such as papillary carcinomas, follicular adenomas, and other nonmalignant thyroid lesions, showed minimal p125FAX expression. CONCLUSIONS: Overexpression of FAK may be part of a mechanism for invasion and metastasis of thyroid cancer. Furthermore, the levels of p125FAK may serve as a marker of biologic behavior in this disease.

Extrathoracic reconstruction of arterial occlusive disease involving the supraaortic trunks.

PURPOSE: The purpose of this study was to review the various extrathoracic reconstruction options in patients with occlusive disease of the supraaortic trunks and to define the efficacy of these procedures in maintaining graft patency and relieving symptoms. METHODS: Forty-four consecutive patients underwent 47 extrathoracic bypass procedures of the supraaortic trunks for correction of symptomatic subclavian (SCA), common carotid (CCA) or innominate (INA) artery occlusive disease between July 1975 and May 1994. SCA stenosis (n = 27) was associated with upper extremity claudication (55%), vertebrobasilar insufficiency (15%), or both (30%). CCA stenosis (n = 14) was accompanied by hemispheric symptoms in 86% and global ischemia in 14%, whereas INA stenosis (n = 3) was associated with transient ischemic attacks (67%) and right arm ischemia (33%). RESULTS: SCA revascularization included carotid-subclavian or carotid-axillary bypass (n = 19), axilloaxillary bypass (n = 8), and subclavian-carotid transposition (n = 3). CCA reconstructions included subclavian-carotid (SC) bypass (n = 13) and carotid-carotid bypass (n = 1). INA procedures included three axilloaxillary bypasses. Six patients had an associated carotid endarterectomy, and three underwent concomitant vertebral artery transpositions. Intraluminal shunts were not routinely used. Vein was used as a conduit in five procedures, and a prosthetic graft (23 Dacron, 16 polytetrafluoroethlyene) was used in the remainder. The average postoperative intensive care unit and hospital and hospital stay were 1 and 5 days, respectively. Follow-up was available in 43 of 44 patients (mean = 26.2 months). The perioperative mortality rate was 2.2% (one axilloaxillary). There were five graft occlusions in procedures involving the axillary artery (3 of 11 axilloaxillary, 2 of 7 carotid-axillary) as compared with one of 29 thromboses when the operation was confined to the supraclavicular fossa (p < 0.05) Relief of symptoms was achieved in all patients with patent grafts. There were no perioperative strokes in the series. Other complications included one brachial plexus neuropraxia (axilloaxillary) and four patients with phrenic nerve neuropraxia. CONCLUSION: Extrathoracic revascularization of the supraaortic trunks is well tolerated and durable when operations are confined to the supraclavicular fossa and do not involve the axillary artery.

Retroperitoneal fibrosis treated with tamoxifen.

Retroperitoneal fibrosis, although histologically benign, has a malignant course due to encasement and compression of tubular retroperitoneal structures, particularly the urinary system. The etiology of this neoplastic process is unclear, but clinical symptoms result from fibroblast proliferation with excessive collagen deposition. Because of the diffuse nature of this disease, surgical resection is technically impossible, and past medical therapies have been inconsistent. Tamoxifen has been shown to be effective in the treatment of desmoid tumors, and we present a patient with retroperitoneal fibrosis who was treated successfully with this anti-estrogen. Because of its minimal side effects and simplicity of dosing, tamoxifen may be a useful treatment in this disease.

Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors.

The focal adhesion kinase (FAK) gene encodes a tyrosine kinase (p125FAK) thought to be involved in signal transduction pathways used in cell adhesion, motility, and anchorage-independent growth. Because alterations in these cellular processes occur in tumor invasion and metastasis, we studied the protein expression of FAK in a variety of human tumors and found that in the 119 samples studied, increased levels of p125FAK correlated with the invasive potential of a tumor. By comparing FAK expression in tumors with normal tissue from the same patient, we found that p125FAK was significantly elevated in 17 (100%) of 17 invasive and metastatic colonic lesions and in 22 (88%) of 25 invasive and metastatic breast tumors. Additional studies of FAK expression in 13 high grade sarcomas showed high levels in all samples compared to benign, noninvasive mesenchymal specimens. Furthermore, FAK protein levels were elevated in preinvasive lesions, such as large (> 2 cm) colonic villous adenomas, whereas noninvasive, yet hypercellular, neoplastic tissues such as parathyroid and hepatocellular adenomas did not overexpress FAK. These data provide evidence that both epithelial and mesenchymal tumor progression are accompanied by increased p125FAK expression and suggest that the level of FAK expression might be a marker for the invasive potential of a tumor.

Insulinoma: pitfalls in preoperative localization.

In patients with biochemical evidence of insulinoma, many techniques have been advocated as the procedures of choice for diagnostic localization without a clear-cut consensus as to their utility. Despite the small size of insulinomas, 90% are solitary and nearly 100% are intrapancreatic. A commonly held belief is that once the diagnosis of autonomous hyperinsulinism is confirmed, it is necessary to secure as much information as possible about the precise location prior to surgery. Although frequently used, preoperative localization studies are expensive, potentially morbid, and worse yet, may be misleading. We present a case study in which the preoperative studies falsely localized the insulinoma to the pancreatic head. Since the introduction of intraoperative ultrasound (IOUS), it is now unusual not to identify and excise the insulinoma in patients undergoing exploration for functioning beta-islet cell lesions. Our experience, along with support from the literature, led us to recommend a simplified localization approach, namely IOUS combined with surgical palpation.

Laparoscopic salvage of Tenckhoff catheters.

Laparoscopic abdominal surgery has opened many previously unexploited diagnostic and therapeutic options. At our institution, we have used laparoscopic techniques in several patients to successfully salvage dysfunctional Tenckhoff catheters. Peritoneal dialysis has gained widespread approval as an acceptable alternative to hemodialysis. Unfortunately, following surgical placement of the catheter, mechanical complications are all too common and usually result in unnecessary removal or replacement. To illustrate the usefulness of laparoscopy in preventing this unnecessary patient morbidity, we present a case study of an easily correctable cause of Tenckhoff catheter outflow obstruction that would have avoided detection under normal circumstances.