Mesenteric lymph node (ln) metastasis is the single most important prognostic characteristic in colorectal cancer (CRC). The ln status is used for staging and is a decisive selection criterion for postoperative adjuvant therapy. However, it is difficult to accurately determine ln status by routine histopathology (H&E). Thus, ~25% of CRC patients, who by H&E are considered to lack tumor cells in their lns, i.e. stage I+II, die from CRC. To explore the utility of biomarker mRNA analysis for staging and prognosis of CRC, lns were collected at surgery and mRNA levels for fourteen biomarkers, including carcinoembryonic antigen (CEA), kallikrein 6 (KLK6), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CEACAM1-S, CEACAM6 and mucin 2 (MUC2), were determined by quantitative RT-PCR with RNA copy standards. Results were compared to routine H&E analysis. The biomarkers were analyzed for capacity to detect disseminated tumor cells in lns. mRNA levels were determined in CRC- and control lns, primary tumor, normal colon, immune cells and fibroblasts. Lack of expression in immune cells and fibroblasts and high and homogenous expression in primary tumors showed to be the determining factors. CEA fulfilled these criteria best, followed by KLK6, CK20, GCC, and MUC2. Utility of the biomarker mRNAs for staging and prognosis was examined in 174 CRC patients. CEA was the best predictor of disease-free survival time after surgery with a 71 months difference between CEA(+) and CEA(-) patients and a hazard ratio of 5.1 for risk of recurrence for CEA(+) patients. CEA, CK20 and MUC2 were more sensitive than H&E in that these biomarkers identified patients who succumbed from recurrent CRC although H&E analysis had failed to detect the disseminated tumor cells. Combined analysis of CEA and MUC2 mRNAs improved prediction of outcome. Patients with high risk for recurrence had low MUC2/CEA ratios. KLK6 mRNA was identified as a potential progression marker by genome-wide microarray analysis of gene expression. It was found to be ectopically expressed in CRC tumor cells. KLK6(+) lns was an indicator of poor prognosis (hazard ratio 3.7). Notably, the actual level was of importance for outcome. The higher the KLK6 mRNA levels the greater the risk of recurrence. At the 90 thpercentile the hazard risk ratio for KLK6(+) patients was 5.6. KLK6 positivity in lns with low numbers of tumor cells, as indicated by low CEA mRNA levels, indicated poor prognosis (hazard ratio 2.8). Thus, KLK6 adds prognostic information to CEA analysis. Increased levels of mRNA for the proinflammatory cytokine interferon- and the down-regulatory cytokine interleukin-10 in lns of CRC patients suggested ongoing immune reactions against the infiltrating tumor cells. Elevated TGF-1 levels correlated weakly with survival, suggesting protection by the antiproliferative effect of TGF-1 in sporadic cases. CEA mRNA was the best single biomarker for staging and prediction of disease-free survival time and risk of recurrence after surgery. In addition to CEA, KLK6 positivity and low MUC2/CEA ratio correlate with poor prognosis. Thus, CEA, MUC2 and KLK6 mRNAs form a strong "trio" for staging and prediction of outcome for CRC patients.

Degree awarded (2003): EdDHRD, Counseling, Human and Organizational Studies, George Washington University / ABSTRACT OF DISSERTATION<p>The Effect of Patient Race upon Physicians Colorectal Cancer Screening: A Retrospective Medical Record Review and Physician Pattern Variable Analysis<p>There is a significant disparity in the health status of African-Americans and whites in the United States. Studies have revealed that African-Americans have higher mortality rates from colorectal cancer than whites. Differences in colorectal cancer screening of African-Americans compared to whites may account for a proportion of the excess mortality. This study evaluated internal medicine resident physicians colorectal cancer screening practices in African-American and white patients. Additionally, an analysis of physicians pattern variable orientation was performed to determine if there was a relationship between physicians orientation and adherence to colorectal cancer screening guidelines.<p>A retrospective review of medical records from January 2002 through March 2002 was conducted to assess internal medicine resident physicians performance of colorectal cancer screening. Univariate analysis revealed that there were statistically significant differences in the rate at which physicians performed rectal examinations (p=0.0039), fecal occult blood testing (p=0.0006) and colonic examinations (p<0.0001) in African-American compared to white patients. Multivariate analysis, evaluating patient race, patient gender, patient age and physician gender, demonstrated that patient race was the only factor significant for not performing colorectal cancer screening tests.<p>Physicians perspectives about the medical profession and the delivery of medical services were assessed by evaluating pattern variable orientations. Integrative, value and motivational orientations of the physicians were determined by using semi-structured interviews. All of the physicians had a self-orientation (integrative pattern variable), a universalistic-achievement orientation (value pattern variables) and a specificity orientation (motivational pattern variable). However, the physicians differed in their affectivity-affective neutrality orientation (motivational pattern variable). All of the physicians who had an affective orientation toward their patients adhered to colorectal cancer screening recommendations. The physicians who expressed affective neutrality toward their patients did not adhere to colorectal cancer screening recommendations.<p>This study revealed significant differences in the performance of colorectal cancer screening in African-American compared to white patients. Additionally, physicians pattern variable orientations correlated with adherence to practice guidelines. This study is important because it provides information about physician practice patterns. The results of this study can serve as the basis for the development of educational interventions for physicians that can improve health care delivery. / Advisory Committee: Dr. John Williams, Dr. David Schwandt (Chair), Dr. Andrea Casey, Dr. Jeffrey Lenn, Dr. Victor Scott

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