Francis M. Giardiello

Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas

BACKGROUND/AIMS Several clinical, epidemiological, and animal studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may alter the incidence of colorectal cancer. A likely target for NSAIDs is cyclooxygenase, a key enzyme in arachidonic acid metabolism. Two isoforms of this enzyme have been identified; cyclooxygenase (COX) 1 and COX-2. The present study was undertaken to determine if there is differential expression of these isoforms in colorectal neoplasia, and, if so, at what stage in malignant transformation this occurs. METHODS COX-1 and COX-2 messenger RNA (mRNA) levels were determined by Northern blot analysis of poly(A)+ RNA isolated from human colorectal cancers, adenomas, and accompanying normal mucosa. RESULTS There was a marked increase in COX-2 mRNA levels in 12 of 14 carcinomas (86%) compared with paired normal mucosa. In contrast, there was equivalent intensity of the COX-1 mRNA transcript between the normal mucosa and cancer in all 14 cases. In six pairs of colorectal adenomas and normal mucosa, three showed up-regulation of COX-2 in the adenoma compared with the normal mucosa. Because COX-2 expression is low to undetectable in normal colorectal mucosa, 14 unpaired adenomas were examined for COX-2 expression; a clearly detectable transcript was identified in six (43%). CONCLUSIONS COX-2, but not COX-1, gene expression is markedly elevated in most human colorectal cancers compared with accompanying normal mucosa. Furthermore, COX-2 expression seems to be increased in a subset of adenomas. COX-2 may provide an attractive therapeutic target in colorectal neoplasia.

Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.

In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults. In this update of each organizations guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that primarily is effective at early cancer detection and a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.

Treatment of Colonic and Rectal Adenomas with Sulindac in Familial Adenomatous Polyposis

BACKGROUND Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. METHODS We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. RESULTS A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted. CONCLUSIONS Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.

Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi‐Society Task Force on Colorectal Cancer, and the American College of Radiology*†

In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average‐risk adults. In this update of each organizations guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a screening test that primarily is effective at early cancer detection. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.

Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer

Screening for colorectal cancer (CRC) in asymptomatic patients can reduce the incidence and mortality of CRC. In the United States, colonoscopy has become the most commonly used screening test. Adenomatous polyps are the most common neoplasm found during CRC screening. There is evidence that detection and removal of these cancer precursor lesions may prevent many cancers and reduce mortality.1 Howver, patients who have adenomas are at increased risk for eveloping metachronous adenomas or cancer compared with atients without adenomas. There is new evidence that some atients may develop cancer within 3–5 years of colonoscopy nd polypectomy—so-called interval cancers. Ideally, screening and surveillance intervals should be ased on evidence showing that interval examinations preent interval cancers and cancer-related mortality. We have ocused on the interval diagnosis of advanced adenomas as surrogate marker for the more serious end point of cancer ncidence or mortality. In 2006, the United States Multiociety Task Force (MSTF) on CRC issued a guideline on ostpolypectomy surveillance,2 which updated a prior 1997 guideline. A key principle of the 2006 guideline was risk stratification of patients based on the findings at the baseline colonoscopy. The surveillance schema identified 2 major risk groups based on the likelihood of developing advanced neoplasia during surveillance: (1) low-risk adenomas (LRAs), defined as 1–2 tubular adenomas 10 mm, and (2) high-risk adenomas (HRAs), defined as adenoma with villous histology, high-grade dysplasia (HGD), 10 mm, or 3 or more denomas. The task force also published recommendations or follow-up after resection of CRC.3 More recently, the British Society of Gastroenterology updated their 2002 surveillance guideline in 2010.4 Their risk stratification differs from the US guideline, dividing patients into 3 groups: low risk (1–2 adenomas 10 mm), intermediate risk (3–4 small adenomas or one 10 mm), nd high risk ( 5 small adenomas or 3 with at least one 10 mm). They recommend that the high-risk group unergo surveillance at 1 year because of concerns about issed lesions at baseline. US guidelines place emphasis on erforming a high-quality baseline examination. In 2008, the STF published screening guidelines for CRC, which inluded recommendations for the interval for repeat colonocopy after negative findings on baseline examination.5 New issues have emerged since the 2006 guideline, including risk of interval CRC, proximal CRC, and the role of serrated polyps in colon carcinogenesis. New evidence suggests that adherence to prior guidelines is poor. The task force now issues an updated set of surveillance recommendations. During the past 6 years, new evidence has emerged that endorses and strengthens the 2006 recommendations. We believe that a stronger evidence base will improve adherence to the guidelines. The 2012 guidelines are summarized in Table 1 and are based on risk stratification principles used in the 2006 guideline. The ensuing discussion reviews the new evidence that supports these guidelines. This guideline does not address surveillance after colonoscopic or surgical resection of a malignant polyp.

The molecular basis of Turcot's syndrome

BACKGROUND Turcots syndrome is characterized clinically by the concurrence of a primary brain tumor and multiple colorectal adenomas. We attempted to define the syndrome at the molecular level. METHODS Fourteen families with Turcots syndrome identified in two registries and the family originally described by Turcot and colleagues were studied. Germ-line mutations in the adenomatous polyposis coli (APC) gene characteristic of familial adenomatous polyposis were evaluated, as well as DNA replication errors and germline mutations in nucleotide mismatch-repair genes characteristic of hereditary nonpolyposis colorectal cancer. In addition, a formal risk analysis for brain tumors in familial adenomatous polyposis was performed with a registry data base. RESULTS Genetic abnormalities were identified in 13 of the 14 registry families. Germ-line APC mutations were detected in 10. The predominant brain tumor in these 10 families was medulloblastoma (11 of 14 patients, or 79 percent), and the relative risk of cerebellar medulloblastoma in patients with familial adenomatous polyposis was 92 times that in the general population (95 percent confidence interval, 29 to 269; P < 0.001). In contrast, the type of brain tumor in the other four families was glioblastoma multiforme. The glioblastomas and colorectal tumors in three of these families and in the original family studied by Turcot had replication errors characteristic of hereditary nonpolyposis colorectal cancer. In addition, germ-line mutations in the mismatch-repair genes hMLH1 or hPMS2 were found in two families. CONCLUSIONS The association between brain tumors and multiple colorectal adenomas can result from two distinct types of germ-line defects: mutation of the APC gene or mutation of a mismatch-repair gene. Molecular diagnosis may contribute to the appropriate care of affected patients.

Increased risk of cancer in the Peutz-Jeghers syndrome

The Peutz-Jeghers syndrome is an autosomal dominant hereditary disease characterized by hamartomatous polyps of the gastrointestinal tract and by mucocutaneous melanin deposits. The frequency of cancer in this syndrome has not been studied extensively. Therefore, we investigated 31 patients with the Peutz-Jeghers syndrome who were followed from 1973 to 1985. All cases of cancer were verified by histopathological review. Cancer developed in 15 of the 31 patients (48 percent)--gastrointestinal carcinomas in 4, nongastrointestinal carcinomas in 10, and multiple myeloma in 1. In addition, adenomatous polyps of the stomach and colon occurred in three other patients. The cancers were diagnosed when the patients were relatively young, but after the Peutz-Jeghers syndrome had been diagnosed (interval between diagnoses, 25 +/- 20 years; range, 1 to 64). According to relative-risk analysis, the observed development of cancer in the patients with the syndrome was 18 times greater than expected in the general population (P less than 0.0001). Our results suggest that patients with the Peutz-Jeghers syndrome have an increased risk for the development of cancer at gastrointestinal and nongastrointestinal sites.

Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome

Background: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited. Experimental Design: We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations. Results: Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference χ2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk. Conclusions: The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.

The use and interpretation of commercial APC gene testing for familial adenomatous polyposis

BACKGROUND The use of commercially available tests for genes linked to familial cancer has aroused concern about the impact of these tests on patients. Familial adenomatous polyposis is an autosomal dominant disease caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene that causes colorectal cancer if prophylactic colectomy is not performed. We evaluated the clinical use of commercial APC gene testing. METHODS We assessed indications for APC gene testing, whether informed consent was obtained and genetic counseling was offered before testing, and the interpretation of the results through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995. RESULTS Of the 177 patients tested, 83.0 percent had clinical features of familial adenomatous polyposis or were at risk for the disease-both valid indications for being tested. The appropriate strategy for presymptomatic testing was used in 79.4 percent (50 of 63 patients). Only 18.6 percent (33 of 177) received genetic counseling before the test, and only 16.9 percent (28 of 166) provided written informed consent. In 31.6 percent of the cases the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3 percent (1 of 44). CONCLUSIONS Patients who underwent genetic tests for familial adenomatous polyposis often received inadequate counseling and would have been given incorrectly interpreted results. Physicians should be prepared to offer genetic counseling if they order genetic tests.

The Risk of Upper Gastrointestinal Cancer in Familial Adenomatous Polyposis

Adenomas with potential for malignancy occur frequently in the upper gastrointestinal tract of patients with familial adenomatous polyposis. However, an assessment of relative risk of upper gastrointestinal cancer in patients with adenomatous polyposis has never been performed. Therefore, the incidence rate of upper gastrointestinal cancer in patients with familial adenomatous polyposis in The Johns Hopkins Registry was compared with the rate of the general population through person-year analysis with adjustment for demographics. There was an increased relative risk of duodenal adenocarcinoma (relative risk, 330.82; 95% confidence limits, 132.66 and 681.49; P less than 0.001) and ampullary adenocarcinoma (relative risk, 123.72; 95% confidence limits, 33.65 and 316.72; P less than 0.001). No significant increased risk was found for gastric or nonduodenal small intestinal cancer. These results indicate that periodic surveillance of the upper gastrointestinal tract for duodenal and periampullary cancer is needed in patients with familial adenomatous polyposis. Prophylactic duodenectomy is a consideration when large adenoma(s) with high-grade dysplasia are identified but awaits risk benefit analysis.