Targeted suppression of beta-catenin blocks intestinal adenoma formation in APC Min mice.

INTRODUCTION: Mutations involving the adenomatous polyposis coli (APC) tumor suppressor gene leading to activation of beta-catenin have been identified in the majority of sporadic colonic adenocarcinomas and in essentially all colonic tumors from patients with Familial Adenomatous Polyposis. The C57BL/6J-APC(min) (Min) mouse, which carries a germ line mutation in the murine homolog of the APC gene is a useful model for intestinal adenoma formation linked to loss of APC activity. One of the critical downstream molecules regulated by APC is beta-catenin; molecular targeting of beta-catenin is, thus, an attractive chemopreventative strategy in colon cancer. Antisense oligodeoxynucleotides (AODNs) capable of downregulating murine beta-catenin have been identified. ANALYSIS OF beta-CATENIN PROTEIN EXPRESSION IN LIVER TISSUE AND INTESTINAL ADENOMAS: Adenomas harvested from mice treated for 7 days with beta-catenin AODNs demonstrated clear downregulation of beta-catenin expression, which was accompanied by a significant reduction in proliferation. There was no effect on proliferation in normal intestinal epithelium. Min mice treated systemically with beta-catenin AODNs over a 6-week period had a statistically significant reduction in the number of intestinal adenomas. These studies provide direct evidence that targeted suppression of beta-catenin inhibits the formation of intestinal adenomas in APC-mutant mice. Furthermore, these studies suggest that molecular targeting of beta-catenin holds significant promise as a chemopreventative strategy in colon cancer.

Acute thromboembolic events during carotid artery angioplasty and stenting: etiology and a technique of neurorescue.

PURPOSE: To review the protected carotid stenting experience at two major referral centers to evaluate the frequency of clinically significant intraprocedural thromboembolic events, use of neurorescue techniques, and ultimate clinical outcomes. METHODS: A retrospective review was conducted of 254 cases of protected transfemoral carotid stenting performed at the Washington University-Barnes Hospital and The Fleni Institute of Buenos Aires in a 6-year period. Medical records of patients with periprocedural thromboembolic events were reviewed to determine the type of complication, method of treatment, and outcome. RESULTS: Among the 254 cases in which a carotid protection device was used, 2 (0.79%) episodes of witnessed, symptomatic thromboembolism occurred. Both patients suffered thromboembolic occlusion of the M1 branch of the middle cerebral artery (MCA) immediately following crossing of the internal carotid lesion with the protection device. Neurological symptoms consisted of agitation, aphasia, and hemiplegia in both patients. After rapid stent deployment across the carotid lesion, the MCA was cannulated and the occlusion treated with balloon angioplasty. This was followed by selective intra-arterial delivery of urokinase and intravenous abciximab. These maneuvers resulted in excellent restoration of blood flow in the MCA and its branches. With the exception of minor word-finding difficulties in one, both patients demonstrated full neurological recovery within the perioperative period. CONCLUSIONS: In our experience, intraprocedural thromboembolic events occur despite the use of cerebral protection devices, but are rare. Notably these complications appeared to occur at the time of lesion crossing by distal cerebral protection devices. These thromboembolic events can be successfully treated if the complication is rapidly identified and the physician is adequately prepared and proficient in neurorescue techniques.

Prospective trial of a blood supply-based technique of pancreaticojejunostomy: effect on anastomotic failure in the Whipple procedure.

BACKGROUND: Anastomotic failure at the pancreaticojejunostomy after a Whipple procedure, manifested either as a pancreatic fistula or intraabdominal abscess, is still an unacceptably common postoperative complication. STUDY DESIGN: A prospectively collected series of 123 patients underwent a Whipple procedure. During the pancreaticojejunostomy, the blood supply at the cut surface of the pancreas was evaluated, and if deemed inadequate, the pancreas was cut back 1.5 to 2.0 cm to improve the blood supply. The anastomosis was performed under magnification with meticulous technique. RESULTS: There were 123 Whipple procedures performed. In 47 (38%), the blood supply was considered inadequate and the pancreas was cut back. Postoperatively, there were 2 pancreatic fistulas (1.6%) and 2 intraabdominal abscesses (1.6%). There was 1 (0.8%) postoperative death from aspiration pneumonia. CONCLUSIONS: Pancreatic fistula, the most serious complication of the Whipple procedure, can be almost entirely eliminated by a technique that combines meticulous attention to placement and tying of sutures under magnification with optimization of blood supply to the anastomosis.