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Biomedical subjects

Francis M Giardiello

Publications and source records attributed to Francis M Giardiello.

11 recordsLinked to original sources
PubMed2003

Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas.

PURPOSE: Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debate exists about the premalignant potential of hamartomas. Also, treatment options other than surveillance are not available. Therefore, molecular alterations in hamartomas and PJS carcinomas were studied. The objective was (a) to evaluate expression of cyclooxygenase (COX)-2 as target for chemopreventive treatment and (b) to define the neoplastic potential of hamartomas at the molecular level. EXPERIMENTAL DESIGN: Paraffin-embedded samples of 24 PJS hamartomas, including 2 hamartomas with dysplastic changes, and 11 PJS carcinomas were available. Slides were stained with antibodies against COX-2, beta-catenin, cyclin D1, p21(waf1/cip1), Ki-67, and p53. DNA was studied for loss of heterozygosity (LOH) at 19p (STK11), 5q (APC), and 17p (TP53); mutations in beta-catenin, APC, and K-RAS; and microsatellite instability. RESULTS: Moderate or strong epithelial COX-2 was present in 25% of hamartomas, including two hamartomas with dysplastic changes, and 64% of carcinomas. Several hamartomas showed focal nuclear beta-catenin (18%) and cyclin D1 overexpression (29%), both unrelated to dysplasia at histological examination. Disturbed topographical expression of Ki-67 in relation to p21(waf1/cip1) was focally present in 27% of hamartomas, including those with dysplastic changes. Most carcinomas showed nuclear beta-catenin (71%), cyclin D1 overexpression (71%), and aberrant Ki-67 staining (100%). There was LOH at 19p in 32% of hamartomas and 82% of carcinomas. p53 staining was present in four (36%) carcinomas, one of which showed LOH at 17p. No beta-catenin mutations were found. APC mutations were present in two carcinomas, but LOH at 5q was not found. Two carcinomas had K-RAS mutations, and one carcinoma had microsatellite instability. CONCLUSIONS: The presence of COX-2 expression in PJS carcinomas and dysplastic hamartomas provides a rationale for chemoprevention with nonsteroidal anti-inflammatory drugs or COX-2 inhibitors. Focal immunohistochemical changes, which may indicate a premalignant potential, were present in some nondysplastic PJS hamartomas. Molecular changes in carcinomas and dysplastic hamartomas in PJS are distinct from the usual adenoma-carcinoma sequence.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Loss of IGF2 imprinting: a potential marker of colorectal cancer risk.

Loss of imprinting (LOI), an epigenetic alteration affecting the insulin-like growth factor II gene (IGF2), is found in normal colonic mucosa of about 30% of colorectal cancer (CRC) patients, but it is found in only 10% of healthy individuals. In a pilot study to investigate the utility of LOI as a marker of CRC risk, we evaluated 172 patients at a colonoscopy clinic. The adjusted odds ratio for LOI in lymphocytes was 5.15 for patients with a positive family history [95% confidence interval (95% CI), 1.70 to 16.96; probability P = 0.002], 3.46 for patients with adenomas (95% CI, 1.14 to 11.37; P = 0.026), and 21.7 for patients with CRC (95% CI, 3.48 to 153.6; P = 0.0005). LOI can be assayed with a DNA-based blood test, and it may be a valuable predictive marker of an individual's risk for CRC.

Adolescent↗
PubMed2003

Genetic testing for hereditary colorectal cancer in children: long-term psychological effects.

Children who carry a gene mutation for familial adenomatous polyposis are virtually certain to develop colorectal cancer without annual endoscopic screening and a colectomy when polyps appear. Predictive genetic testing can identify children who need regular surveillance. While the medical benefits of genetic testing are clear, the psychological effects have not been well studied. We evaluated the long-term psychological effects of genetic testing in 48 children and their parents. In each family, one parent was a known APC gene mutation carrier. Before genetic testing, and three times afterward, participants completed measures of psychological functioning, which, for children, included depression and anxiety symptoms, and behavior problems and competencies. Parents completed a measure of depression symptoms. Data were collected at 3-, 12-, and 23-55 months after disclosure. Twenty-two children tested positive; 26 children tested negative. Mean length of follow-up was 38 months. There were no clinically significant changes in mean psychological test scores in children or parents, regardless of the children's test results or the sex of the affected parent. However, the group of children who tested positive and had a mutation-positive sibling showed significant, but subclinical, increases in depression symptoms. Furthermore, several individual mutation-negative children with a positive sibling had clinical elevations in anxiety symptoms at one or more follow-up. Behavior problems declined for all groups, and behavior competence scores remained unchanged. We conclude that most children do not suffer clinically significant psychological distress after testing. However, because some children showed clinically significant anxiety symptoms, long-term psychological support should be available to those families with both mutation-positive and mutation-negative children, and with multiple mutation-positive children. Our findings should call for a multidisciplinary approach to genetic testing for children.

Anxiety↗
PubMed2003

High incidence of microsatellite instability in colorectal cancer from African Americans.

PURPOSE: Colorectal carcinoma (CRC) is the second most common cause of cancer death in the United States, and the rate of CRC is nearly 1.5 times higher in African-Americans (AA) than in Caucasians. Microsatellite instability (MSI) is observed in sporadic CRC reflecting promoter hypermethylation of the DNA mismatch repair gene hMLH1, and anecdotal evidence suggests an increased incidence of MSI among AAs. Additionally, p16 can be inactivated by hypermethylation of the promoter region, abrogating its ability to regulate cell proliferation. The objective of this study is to determine the frequency of MSI and p16 gene methylation in CRC from AA patients. EXPERIMENTAL DESIGN: Experiments were conducted on serially collected archival samples of colon cancer and adjacent normal tissue (n = 22). Five microsatellite markers were used to measure MSI in tumors with direct comparison to normal tissue from the same patient. p16 promoter methylation status was determined by methylation-specific PCR. RESULTS: Ten cancers (45%) demonstrated high MSI (MSI-H), 1 demonstrated low MSI, and the remaining 11 tumors were microsatellite stable. Most of the MSI-H tumors were proximal, well differentiated, and showed high levels of mucin production. Most patients in the MSI-H group were female (70%), whereas most of the microsatellite-stable group (81%) were male. Five of the 22 tumors (22%) had methylation of the p16 promoter. CONCLUSION: Data provided here demonstrated that the incidence of MSI-H tumors was 3-fold higher in our study group of AA patients compared with data reported in nonracially selected but serially collected studies. Odds ratio analysis indicates that the chance of female patients having MSI-H was 11.7 times more than male patients (P < 0.03). The reason for this gender difference is unknown. These findings might reflect dietary differences or genetic polymorphisms that may be common in the AA population. Additional investigation in a larger patient population is needed before strong conclusion can be drawn.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Primary chemoprevention of familial adenomatous polyposis with sulindac.

BACKGROUND: Familial adenomatous polyposis is caused by a germ-line mutation in the adenomatous polyposis coli gene and is characterized by the development of hundreds of colorectal adenomas and, eventually, colorectal cancer. Nonsteroidal antiinflammatory drugs can cause regression of adenomas, but whether they can prevent adenomas is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled study of 41 young subjects (age range, 8 to 25 years) who were genotypically affected with familial adenomatous polyposis but phenotypically unaffected. The subjects received either 75 or 150 mg of sulindac orally twice a day or identical-appearing placebo tablets for 48 months. The number and size of new adenomas and side effects of therapy were evaluated every four months for four years, and the levels of five major prostaglandins were serially measured in biopsy specimens of normal-appearing colorectal mucosa. RESULTS: After four years of treatment, the average rate of compliance exceeded 76 percent in the sulindac group, and mucosal prostaglandin levels were lower in this group than in the placebo group. During the course of the study, adenomas developed in 9 of 21 subjects (43 percent) in the sulindac group and 11 of 20 subjects in the placebo group (55 percent) (P=0.54). There were no significant differences in the mean number (P=0.69) or size (P=0.17) of polyps between the groups. Sulindac did not slow the development of adenomas, according to an evaluation involving linear longitudinal methods. CONCLUSIONS: Standard doses of sulindac did not prevent the development of adenomas in subjects with familial adenomatous polyposis.

Adenomatous Polyposis Coli↗
PubMed2002

Diagnosis and management of hereditary colon cancer.

Colorectal cancer is the third leading cause of cancer and the second leading cause of cancer death in the United States. About 130,000 new cases are diagnosed each year in North America, and 56,600 persons die annually from this disease. Approximately 5% of patients with colorectal cancer have clearly defined inherited syndromes such as familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. These conditions are well described both genetically and phenotypically, and are characterized by autosomal dominant inheritance, high penetrance, and high risk of colorectal cancer. We review the current recommendations for the diagnosis and management of these two hereditary forms of colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed2002

Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study.

BACKGROUND & AIMS: Management of patients with familial adenomatous polyposis (FAP) can consist of colectomy with ileorectal anastomosis (IRA). Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of colorectal adenomas in the retained rectal segment of FAP patients, although long-term use of this therapy has not been studied. We evaluated the long-term effectiveness and toxicity of sulindac in attempting to maintain retained rectal segments free of adenomas. METHODS: Twelve FAP patients (5 women), mean age 37.1 years, with IRA received sulindac (mean dosage, 158 mg/day) for a mean period of 63.4 +/- 31.3 months (range, 14-98 months). Number, size, and histologic grade of polyps, side effects, and medication compliance were assessed every 4 months. RESULTS: Seven of 12 patients (58%) remained in the study (6 of these polyp-free) for a mean of 76.9 +/- 27.5 months. Five of 12 patients (42%) withdrew from the trial after a mean follow-up period of 44 +/- 28 months (range, 14-89 months). A significant regression of polyp number was observed in all patients at 12 months (P = 0.039) and at a mean of 63.4 +/- 31.3 months (P = 0.006). Prevention of recurrence of higher-grade adenomas (tubulovillous, villous adenomas) was also observed (P = 0.004). At 35 months of follow-up, 1 patient developed stage III cancer in the rectal stump. The most common side effect was rectal mucosal erosions in 6 patients. CONCLUSIONS: Long-term use of sulindac seems to be effective in reducing polyp number and preventing recurrence of higher-grade adenomas in the retained rectal segment of most FAP patients. Erosions at the IRA site can preclude adequate dose maintenance.

Adenomatous Polyposis Coli↗
PubMed2002

Impact of genetic counseling and testing on colorectal cancer screening behavior.

One goal of cancer genetic counseling is to improve early detection and prevention of cancers by identifying individuals at risk and providing screening recommendations. This study determined the impact of genetic counseling and testing on patient's post-genetic risk assessment colorectal cancer screening behaviors. Follow-up data from patients seen August, 1996, through May, 1998, at the Johns Hopkins Cancer Risk Assessment Clinic were analyzed. Eligible patients included those without cancer who were due for a colon examination by the time of follow-up, based on recommendations given during genetic risk assessment (GRA). We analyzed the role of gender, age, time since GRA, prior screening, genetic testing decision, mutation status, and post-GRA screening. Of 65 patients evaluated, 50 (76.9%) had undergone at least one endoscopic colon exam prior to visiting the Cancer Risk Assessment Clinic. At the time of GRA, 37 of 65 (56.9%) were overdue for a colon exam and at the time of follow-up, 15/65 (23.1%) were past due (p < 0.001). Patients with mutation-positive genetic tests were more likely to adhere to screening guidelines than those with negative gene tests (100% vs. 40.5%, p = 0.05). Genetic counseling and testing increases overall patient adherence with recommended colon screening, especially for those with positive genetic test results. However, patients with negative results may receive false reassurance about cancer risks and fail to follow recommended screening. Emphasis should be placed on the importance of screening even when genetic test results are negative.

Colorectal Neoplasms↗