Faculty Publications

Context The established relationship between lymph node metastasis and prognosis in colorectal cancer suggests that recurrence in 25% of patients with lymph nodes free of tumor cells by histopathology ( pN0) reflects the presence of occult metastases. Guanylyl cyclase 2C ( GUCY2C) is a marker expressed by colorectal tumors that could reveal occult metastases in lymph nodes and better estimate recurrence risk. Objective To examine the association of occult lymph node metastases detected by quantifying GUCY2C messenger RNA, using the reverse transcriptase - polymerase chain reaction, with recurrence and survival in patients with colorectal cancer. Design, Setting, and Participants Prospective study of 257 patients with pN0 colorectal cancer enrolled between March 2002 and June 2007 at 9 US and Canadian centers ( 7 academic medical centers and 2 community hospitals) provided 2570 fresh lymph nodes measuring 5 mm or larger for histopathology and GUCY2C messenger RNA analysis. Patients were followed up for a median of 24 months ( range, 2- 63 months) for disease recurrence or death. Main Outcome Measures Time to recurrence ( primary outcome) and diseasefree survival ( secondary outcome) relative to expression of GUCY2C in lymph nodes. Results Thirty- two patients ( 12.5%) had lymph nodes negative for GUCY2C ( pN0 [ mol-]), and all but 2 remained free of disease during follow- up ( recurrence rate, 6.3%; 95% confidence interval [ CI], 0.8%- 20.8%). Conversely, 225 patients ( 87.5%) had lymph nodes positive for GUCY2C ( pN0 [ mol +]), and 47 developed recurrent disease ( 20.9%; 95% CI, 15.8%- 26.8%) ( P=. 006). Multivariate analyses revealed that GUCY2C in lymph nodes was an independent marker of prognosis. Patients who were pN0 ( mol +) exhibited earlier time to recurrence ( adjusted hazard ratio, 4.66; 95% CI, 1.11- 19.57; P=. 04) and reduced disease- free survival ( adjusted hazard ratio, 3.27; 95% CI, 1.15-9.29; P=. 03). Conclusion Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease- free survival in patients with pN0 colorectal cancer.

For individuals meeting Bethesda criteria for hereditary nonpolyposis colorectal cancer syndrome, the microsatellite instability (MSI) test is recommended as a screening evaluation before proceeding to genetic testing. The MSI test is new to the medical setting, but will be increasingly used to screen patients at high risk for hereditary nonpolyposis colorectal cancer. The main goals of this study were to examine knowledge about and exposure to the MSI test among individuals considering the test, to evaluate perceived benefits and barriers to undergoing the MSI test, and to identify the demographic, medical, and psychosocial correlates of the perceived benefits and barriers to undergoing the test. One hundred and twenty-five patients completed a survey after being offered the test, but prior to making the decision whether to pursue MSI testing. Results indicated low levels of knowledge about and previous exposure to the MSI test. Participants held positive attitudes about!

Colorectal cancer (CRC) screening is widely recommended as part of standard preventive care. All average risk persons over the age of 50 y are eligible. Various authorities have advocated fecal occult blood teesting, flexible sigmoidoscopy, barium enema and colonoscopy at varying intervals as acceptable screening options. Despite the array of choices, CRC screening lags in frequency behind other cancer screening maneuvers like mammography or Pap smear. Of late, there is growing interest in CT colonography (CTC) as another screening option. CTC, or virtual colonoscopy, may represent an attractive, non-invasive method of CRC screening that provides images akin to traditional colonoscopy. Improvements in CTC performance, especially when coupled with declining costs, suggest that CTC's role in average risk screening will increase in the future. This review summarizes available data about the efficacy of CTC in average and high risk screening populations. Current indications as well as limitations to this technology are discussed, as are practical issues like the cost-effectiveness of CTC for widespread use.

Colorectal cancer is common in Ashkenazi Jews. The I1307K APC mutation occurs in 6-7% of Ashkenazi Jews and increases the risk of colorectal cancer. This study aimed to describe the clinical, pathologic and epidemiologic features of colorectal cancer in I1307K carriers to determine whether there were any features which might warrant individual screening for the mutation. In all, 215 Ashkenazi Jews with a personal history of colorectal cancer were enrolled. Clinical and family history, pathology reports, and slides were obtained and blood drawn for I1307K determination. The presence of the mutation was determined by PCR from white blood cell DNA. Colorectal cancer pathology slides were read in a blinded fashion. Of the 215 enrolled patients, 26 (12.1%) tested positive for I1307K. There was no difference in the pathologic features between colorectal cancers in Ashkenazi carriers compared to noncarriers. There was no difference in the age at diagnosis or history of second or ot! her primaries. Carriers had an increased likelihood of having a first-degree relative with colorectal cancer (50%) compared to noncarriers (28%, P < 0.04). We could find no distinguishing feature other than family history that characterizes I1307K positive colorectal cancers. We could find no group of Ashkenazi Jews with colorectal cancer for whom screening for I1307K would be clinically useful. (c) 2006 Elsevier Inc. All rights reserved.

Background: Because of the low prevalence of hepatitis C virus (HCV) infection in the general population, mass screening would be expensive and of low yield. Some researchers advocate targeted screening of persons at elevated HCV risk.Methods: This cross-sectional study aimed to develop a patient-administered tool to assess HCV infection risk. Two hundred seven patients with unknown HCV status from a general medicine practice and 222 HCV-positive patients from a hepatology practice completed a 72-item survey about demographic, social, and clinical risk factors for HCV infection. General medicine patients also underwent HCV serologic testing.Results: Three (1.5%) of 207 general medicine patients had positive HCV antibody test results. These patients plus the 222 hepatology patients were significantly more likely than HCV-negative patients to report an array of factors. In a multivariable model, 7 factors remained significantly associated with HCV infection: sex with a prostit ute or an injecting drug user, exposure to blood products, refusal as a blood donor or as a life insurance applicant, witnessing illicit drug use, and self-reported HBV infection. A simplified model that assigned 1 point for each factor present predicted HCV infection as well as a weighted model (based on chi(2) testing and receiver operating characteristic curve comparison). In a population with a 2% prevalence of HCV infection, people who identified 2 risk factors had a 10% chance of HCV infection, whereas those with 4 or more risk factors had a 50% chance.Conclusions: A self-administered 72-item questionnaire can stratify patients into HCV risk groups. If validated in other primary care populations, this instrument could help target HCV screening.

Gastrointestinal (GI) tumors continue to be major causes of cancer-related mortality, in part, reflecting metastases that escape detection by histopathology. Moreover, although approximately 10% of carcinomas arise from unknown locations, these tumors frequently originate in the GI tract. Guanylyl cyclase C (GC-C) is a receptor selectively expressed by intestinal epithelial cells whose persistent expression by colorectal carcinomas and ectopic expression by adenocarcinomas of the upper GI tract suggest its use as a marker for GI malignancies. Here, expression of GC-C protein, identified by immunohistochemistry, was examined in tissues and tumors arising from the human GI tract. Guanylyl cyclase C protein was expressed by epithelial cells from the duodenum to the rectum, but not by those in normal esophagus and stomach. Expression was retained in tubular adenomas, inflammatory bowel disease, premalignant lesions, and in primary and metastatic adenocarcinomas from the colon, i ncluding metastases to lymph nodes and liver. Moreover, GC-C was ectopically expressed in all cases of dysplasia and adenocarcinomas arising from intestinal metaplasia in esophagus and stomach. Thus, GC-C appears to be an immunohistochemical marker for identifying adenocarcinomas of unknown origin, metastases in patients undergoing staging for GI adenocarcinomas, and intestinal metaplasia, dysplasia, and tumors arising therein in the upper GI tract. (c) 2005 Elsevier Inc. All rights reserved.

Staging patients with colorectal cancer defines their prognosis and therapeutic management. Unfortunately, histopathology, the current standard for staging, is relatively insensitive for detecting occult micrometastases and a significant fraction of patients are understaged and, consequently, undertreated. Similarly, current approaches to postoperative surveillance of patients with colorectal cancer detect disease recurrence at a point when interventions have little impact on survival. The detection of rare cells in tissue, for accurately staging patients, and in blood, for detecting disease recurrence, could be facilitated by employing sensitive and specific markers of disease. Guanylyl cyclase C (GCC), the receptor for the diarrheagenic bacterial heat-stable enterotoxin, is expressed selectively by cells derived from intestinal mucosa, including normal intestinal cells and colorectal tumor cells, but not by extragastrointestinal tissues and tumors. The nearly uniform expression of relatively high levels by metastatic colorectal tumors suggests that GCC may be a sensitive and specific molecular marker for metastatic colorectal cancer cells. Employing GCC reverse transcriptase PCR, occult colorectal cancer micrometastases were detected in lymph nodes that escaped detection by histopathology. Moreover, marker expression correlated with the risk of disease recurrence. Similarly, GCC reverse transcriptase PCR revealed the presence of tumor cells in blood of all patients examined with metastatic colorectal cancer and, in some studies, was associated with an increased risk of disease recurrence and mortality. These observations suggest that GCC reverse transcriptase PCR is a sensitive and specific technique for identifying tumor cells in extraintestinal sites and may be useful for staging and postoperative surveillance of patients with colorectal cancer.

(from the journal abstract) Background: Complete diagnostic evaluation or CDE (i.e., colonoscopy or combined flexible sigmoidoscopy plus barium enema X-ray) is often not performed for persons with an abnormal screening fecal occult blood test (FOBT+) result. Method: This study evaluated the impact of a reminder-feedback and educational outreach intervention on primary care practice CDE recommendation and performance rates. Four hundred seventy primary care physicians (PCPs) in 318 practices participated in the study. Patients were mailed an FOBT kit annually as part of a screening program. Practices were randomly assigned to a Control Group (N = 198) or an Intervention Group (N= 120). During an 18-month pre-randomization period and a 9-month post-randomization period, 2,992 screening FOBT+ patients were identified. Intervention practices received the screening program and the intervention. Control practices received only the screening program. Study outcomes were baseline-adjusted CDE recommendation and performance rates. Results: At baseline, about two-thirds of FOBT+ patients received a CDE recommendation, and about half had a CDE performed. At endpoint, CDE recommendation and performance rates were both significantly higher for the Intervention as compared to the Control practices (OR = 2.28; 95% CI: 1.37, 3.78, and OR = 1.63; 95% CI: 1.06, 2.50, respectively). Conclusions: The reminder-feedback plus educational outreach intervention significantly increased CDE recommendation and performance. (PsycINFO Database Record (c) 2005 APA, all rights reserved).