Improving the outcomes of carotid endarterectomy: Results of a statewide quality improvement project

AbstractObjective: The purpose of this study was to establish the statewide outcomes for carotid endarterectomy (CEA) and to facilitate improvement in outcomes through feedback, peer discussion, and ongoing process and outcome measurement. Methods: The Medicare Part A claims files were used to identify all Medicare patients undergoing CEA in Iowa during two 12-month time periods (January 1994–December 1994 and June 1995–May 1996). Medical record abstraction was used to obtain surgical indications, perioperative care process, and outcome information. Confidential reports were provided to each hospital (N = 30) where the procedure was performed. Surgeons performing the procedure (N = 79) were invited to meetings to discuss care process variation and outcomes. Voluntary participation was solicited in a standardized program of ongoing hospital-based data collection of CEA process and outcome data. Results: The statewide combined stroke or mortality rate decreased from 7.8% in 1994 to 4.0% in the 1995 to 1996 time period (P <.001). Fourteen hospitals, accounting for 74% of the statewide cases, participated in ongoing data collection. The combined stroke or mortality rate in these hospitals decreased significantly (P <.05) over time from 6.5% (1994) to 3.7% (1995-1996) to 1.8% (June 1997–May 1998). The use of intraoperative assessment of the operative site (20% in 1994, 46% in 1997-1998) and patch angioplasty (14% in 1994, 30% in 1997-1998) increased significantly during this time in the participating hospitals. Conclusions: Confidential feedback of outcome and process data for CEA may lead to change in perioperative care processes and improved outcomes. Standardized community-based outcome analysis should become routine for CEA to ensure that optimum results are being achieved. (J Vasc Surg 2000;31:918-26.

Stage-specific sensitivity to p53 restoration during lung cancer progression

2011 May 25Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1, 2, 3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)American Cancer Society (New England Area Fellow)Leukemia & Lymphoma Society of America (Fellow)Massachusetts Institute of Technology. Undergraduate Research Program (John Reed Fund)Damon Runyon Cancer Research Foundation (Merck Fellow)Genentech, Inc. (Postdoctoral Fellow)Howard Hughes Medical Institut

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a super-phagocytic subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance. SIGNIFICANCE: mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress-dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types