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Background & Aims Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. Oral administration of the spice curcumin has been followed by regression of polyps in patients with this disorder. We performed a double-blinded randomized trial to determine the safety and efficacy of curcumin in patients with familial adenomatous polyposis. Methods This study included 44 patients with familial adenomatous polyposis (18–85 years old) who had not undergone colectomy or had undergone colectomy with ileorectal anastomosis or ileal anal pouches, had at least 5 intestinal adenomatous polyps, and had enrolled in Puerto Rico or the United States from September 2011 through November 2016. Patients were randomly assigned (1:1) to groups given 100% pure curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months. The number and size of lower gastrointestinal tract polyps were evaluated every 4 months for 1 year. The primary outcome was the number of polyps in the curcumin and placebo groups at 12 months or at the time of withdrawal from the study according to the intention-to-treat principle. Results After 1 year of treatment, the average rate of compliance was 83% in the curcumin group and 91% in the placebo group. After 12 weeks, there was no significant difference in the mean number of polyps between the placebo group (18.6; 95% CI, 9.3–27.8) and the curcumin group (22.6; 95% CI, 12.1–33.1; P = .58). We found no significant difference in mean polyp size between the curcumin group (2.3 mm; 95% CI, 1.8–2.8) and the placebo group (2.1 mm; 95% CI, 1.5–2.7; P = .76). Adverse events were few, with no significant differences between groups. Conclusions In a double-blinded randomized trial of patients with familial adenomatous polyposis, we found no difference in the mean number or size of lower intestinal tract adenomas between patients given curcumin 3,000 mg/day and those given placebo for 12 weeks. Clinicaltrials.gov ID NCT00641147 .

The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease.

Background & aims: Loss of genomic imprinting (LOI) of insulin-like growth factor II gene ( IGF2 ) involves abnormal activation of the normally silent maternally inherited allele. LOI of IGF2 has been associated with personal and family history of colorectal neoplasia (CRN), supporting a role for LOI in colorectal carcinogenesis. Whether LOI of IGF2 is associated with known environmental risk factors for CRN is unknown. Methods: We performed quantitative hot-stop PCR for imprinting analysis of IGF2 on normal peripheral blood lymphocytes (PBL) of individuals. Environmental exposures including tobacco, alcohol, NSAIDs, and nutrient consumption (calcium, folate, selenium, fiber, and fat) were correlated with LOI expression in PBL. Odds ratios (OR) and 95% CI were calculated. Results: The prevalence of LOI of IGF2 was examined in 172 individuals. Persons with CRN (adenomas/cancer) had 5.1-fold (95% CI: 1.92–13.6) increased risk of having LOI of IGF2 in PBL compared with those without CRN. In contrast, tobacco smoking (OR = 0.96, 95% CI: 0.36–2.55), alcohol consumption (OR = 1.22, 95% CI: 0.45–3.3), and NSAIDs use (OR = 1.21, 95% CI: 0.38–3.94) were not significantly associated with LOI of IGF2 . Nutrient ingestion including calcium ( P = 0.61), folate ( P = 0.23), selenium ( P = 0.19), fiber ( P = 0.63), and fat ( P = 0.14) was not statistically correlated with LOI of IGF2 . Conclusions: Abnormal imprinting of IGF2 gene was strongly associated with CRN but not with any of the environmental exposures examined. LOI of IGF2 does not appear to be an environmentally acquired phenomenon but rather a hereditary risk factor for CRN.

Background & Aims: Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated. Methods: A randomized, double-blind, placebo-controlled study of 41 subjects genotypically affected with familial adenomatous polyposis but phenotypically unaffected was conducted. Patients received either sulindac or placebo for 48 months, and development of new adenomas was evaluated. The levels of 5 prostanoids, ornithine decarboxylase, and polyamines were measured serially in normal-appearing rectal mucosa. Results: There were no statistically significant differences between treatment groups in baseline levels of prostanoids, ornithine decarboxylase, or polyamines. At conclusion of the study, 4 of 5 prostaglandin levels were statistically significantly lower in the sulindac group than in the placebo group. Among the subset of patients taking sulindac, 3 of 5 prostaglandin levels were statistically significantly lower in patients who were polyp free than in those who developed polyps. By contrast, there were no statistically significant differences in ornithine decarboxylase or polyamines between treatment groups or in those on sulindac who were polyp free compared with those who developed polyps. Conclusions: Colorectal mucosal prostaglandin levels, but not ornithine decarboxylase or polyamines, may be valuable biomarkers to assess appropriate drug dosage and medication compliance in patients undergoing primary chemoprevention therapy with sulindac. Reduction of mucosal prostaglandin levels may be necessary to achieve chemopreventive benefit from this agent.

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. GASTROENTEROLOGY 2002;122:641-645

17 The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the offi ce or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3 - 6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

Background & Aims: Patients with hyperplastic polyposis are reported to have multiple and/or large hyperplastic polyps (HPs) and an increased risk of colorectal cancer, but the phenotype and genetic alterations in hyperplastic polyposis have not been studied in detail. Methods: We evaluated clinical-pathological and molecular characteristics of 129 HPs, 6 serrated adenomas, and 3 admixed hyperplastic-adenomatous polyps from 13 patients with hyperplastic polyposis (more than 20 HPs), 5 patients with a large HP (≥1 cm in diameter), and 5 patients with multiple HPs (5–10 HPs). Results: HPs in the right colon in contrast to the left colorectum had more frequent topographic dysregulation of p21 Waf-1/Cip1 expression (94% vs. 76%, P = 0.03) and of proliferation (92% vs. 53%, P = 0.0001), but less frequent allelic loss of chromosome 1p (4% vs. 17%, P = 0.03). K- ras mutation was present in 8% of HPs, p53 gene product overexpression in none, and microsatellite instability in 3% without relationship to microsatellite instability in synchronous cancer. Patients with a large HP differed from those with multiple HPs in having a high frequency of right-sided HP (63% vs. 22%, P = 0.01) and of right-sided colon cancer (100% vs. 8%, P = 0.003). Hyperplastic polyposis was associated with a family history of colorectal cancer ( P = 0.01) and with loss of chromosome 1p in HP (21% vs. 0%, P = 0.001). Conclusions: A hyperplastic polyp/dysplasia–to–adenocarcinoma sequence can be manifested in 3 distinct phenotypes consisting of patients with hyperplastic polyposis and chromosome 1p allelic loss in some HPs, in contrast to patients who have large, right-sided HPs or small numbers of HPs that lack 1p loss. GASTROENTEROLOGY 2000;119:323-332

Background & Aims: The Peutz–Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary. Methods: We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications. Results: For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old. Conclusions: Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers. GASTROENTEROLOGY 2000;119:1447-1453

Background & Aims: The mechanism by which sulindac causes regression of adenomas in patients with familial adenomatous polyposis (FAP) is unclear. Conflicting data on the drug's effects on colorectal epithelial proliferation have been reported. An alternative mechanism, and one not previously studied, is via induction of colorectal epithelial cell apoptosis (programmed cell death). This hypothesis was tested by studying the effects of sulindac on colorectal epithelial proliferation and apoptosis in patients with FAP. Methods: Cell proliferation was studied via immunohistochemistry for proliferating cell nuclear antigen in a group of 22 patients randomized to either sulindac (150 mg twice a day) or placebo in a previously published trial. The rectal epithelium from 7 additional patients with FAP treated with sulindac was examined by flow cytometry to assess changes in cell-cycle distribution and apoptosis. Results: Although sulindac caused a significant decrease in polyp size and number, there was no significant change in cytokinetic variables or cell cycle distribution 3 months after treatment. However, the subdiploid apoptotic fraction was increased significantly 3 months after treatment with sulindac (31.3% ± 4.8% compared with 10% ± 4.3% at baseline; P = 0.01). Conclusions: Our findings suggest that sulindac does not affect colorectal epithelial proliferation and that its effects in patients with FAP may instead result from induction of apoptosis.

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.

Decreased life expectancy may occur after remote peptic ulcer surgery, but the cause of shortened survival is unclear. A 50-year follow-up study of an Amsterdam cohort of postgastrectomy patients who underwent ulcer surgery between 1931 and 1960 showed a statistically significant decrease in survival after a postoperative interval of 12 years or more compared with the general population. The shortened life expectancy mainly reflected decreased survival in men. In women, no significant difference in survival compared with the general population was observed. The excess mortality in men was predominantly due to a statistically significant increase in cancer-related deaths. Carcinoma of the lung accounted for the majority of excess mortality. No time relationship between lung cancer death and interval since surgery was observed. Thus, smoking, primarily in men who had undergone surgery for gastric ulcers, seems an important factor contributing to excess mortality and shortened life expectancy. Excess mortality due to tobacco use has also been observed in postmarketing surveillance of H2-receptor antagonists. Therefore, smoking cessation may provide the greatest improvement in the long-term prognosis of peptic ulcer patients, regardless of the treatment.

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 organization's 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.

Background Lynch Syndrome is an inherited form of colorectal cancer caused by germline mutations in the Mismatch Repair (MMR) genes. It accounts for approximately 5% of all colorectal cancers. The prevalence of Lynch Syndrome among US Hispanics is unknown. The objective of this studywas to describe the germlinemutation spectrum and clinicopathological associations of Lynch Syndrome in Caribbean Hispanics from Puerto Rico and Dominican Republic. Methods Subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry between January 2010 to June 2014 and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. Results 89 CRC Caribbean Hispanic patients, with suspected LS were referred to the Hereditary Cancer Clinic. Nine-teen (21.3%) patients met Amsterdam Criteria (I/II) and 70 (78.7%) met Bethesda guidelines. From the 89 patients who received genetic counseling, 31 had direct MMR germline analysis and 21 (71.0%) had a germline mutation in one of the MMR genes. The mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7 %) mutations, followed by MLH1 (25.0 %). Only one mutation was identified in MSH6 (8.3 %). A previously unidentified mutation inMLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutationpositive individuals were more likely to have a prominent family history of CRC and tumors located at the proximal colon compared to MMR mutation-negative CRC patients. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC, earlier age at diagnosis and LS-associated cancers. Insurance coverage for genetic testing was found to be limited in the study population with most patients (66%) of the individuals been denied coverage. Conclusions This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 mutations, followed by MLH1. Due to genetic ancestry background differences among Caribbean Hispanics, compared to other Hispanics groups, there is potential for identifying novel MMR mutations associated with LS and Variables of unknown significance (VUS). Future studies should be directed towards understanding the differences in the mutation spectrum of Hispanic LS patients and implementation of widespread clinical guidelines for LS screening according to the National Comprehensive Cancer Network.

Epidemiologic and experimental reports suggest that female hormones protect against the development of colorectal cancer, but studies are limited. We describe a patient in the placebo arm of a 4-year primary chemoprevention trial who developed adenomatous polyps and then had eradication of polyps after the administration of oral contraceptives. No change in the prostaglandin levels in the colonic mucosa was noted after polyp elimination, making nonsteroidal anti-inflammatory drug ingestion unlikely as a cause. This report represents the regression of colorectal adenomas with the use of estrogen/progesterone compounds.

There is limited data on the spectrum and risk for cancer associated with germline serine/threonine protein kinase 11 (STK11) mutations that cause Peutz-Jeghers syndrome (PJS).We analyzed the incidence of cancer in 240 individuals with PJS possessing germline mutations in STK11.Fifty-four cancers were found among carriers. Overall, the risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 1%, 3%, 19%, 32%, 63%, and 81%, respectively. Kaplan-Meier analysis showed similar cancer risks between missense and truncating mutation carriers (log-rank chi(2) = 2.48; P = 0.12). There was some evidence that mutations in exon 3 of STK11 were associated with a higher cancer risk than mutations within other regions of the gene. We found no difference in overall cancer risk between male and female carriers (log-rank chi(2) = 1.31; P = 0.25) or between familial and sporadic cases (log-rank chi(2) = 1.16, with 1 df; P = 0.28). The most common cancers represented 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%, 10%, 18%, and 42%, respectively. In women, the risk for breast cancer was substantially increased, being 32% by age 60 years.These results quantitatively show the spectrum of cancer risk associated with STK11 germline mutations in the context of PJS and provide a valuable reference for defining surveillance regimens.

This literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice and Practice Economics Committee. The paper was approved by the Committee on March 20, 2001, and by the AGA Governing Board on April 18, 2001.