Management of Dietary Habits and Diarrhea in Fap Individuals: A Mediterranean Low-Inflammatory Dietary Intervention.

BACKGROUND: A total colectomy and a frequent life-long endoscopic surveillance are guaranteed to patients with Familial Adenomatous Polyposis (FAP) to reduce their risk of duodenal and rectal stump cancers. However, after surgery, individuals with FAP suffer from an increased number of diarrheal discharges that force them to dietary restrictions. A non-randomized pilot study was conducted to assess whether a three-month low-inflammatory Mediterranean dietary intervention reduces gastro-intestinal markers of inflammation in FAP individuals. The aim of the present work is to evaluate the participant's adherence to the proposed dietary recommendations and the change in their number of diarrheal discharges. METHODS: 26 FAP individuals aged >18 years, who underwent a total colectomy with ileo-rectal anastomosis and were involved in the surveillance program at the Fondazione IRCCS Istituto Nazionale Tumori of Milan, were included in the present analysis. RESULTS: FAP individuals significantly reduced the Not recommended foods (p-value: 0.002) and increased the consumption of the Recommended ones (p-value: 0.075). The adherence to the proposed dietary recommendations was accompanied by a significant decrease in the number of diarrheal discharges (p-value: 0.008). CONCLUSIONS: This study suggests that adhering to a low-inflammatory Mediterranean diet has a potential protective effect on the number of diarrheal discharges in FAP individuals.

Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study.

Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil-lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. PREVENTION RELEVANCE: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.

Supplementation with phytoestrogens and insoluble fibers reduces intestinal carcinogenesis and restores ER-ß expression in Apc-driven colorectal carcinogenesis.

Supplementation with phytoestrogens and insoluble fibers has been reported to reduce duodenal polyps in colectomized familial adenomatous polyposis patients, with a mechanism involving, at least in part, upregulation of estrogen receptor-ß subtype, whose expression is lowered during intestinal tumorigenesis. These data suggest a protective effect also in the colon, the main target organ for tumorigenesis in familial adenomatous polyposis and a major cancer type in non-familial (sporadic) cancers. Therefore, we tested whether a similar preparation might reduce tumorigenesis in the colon of Pirc rats (F344/NTac-Apc) mutated in the Apc gene and thus, like familial adenomatous polyposis patients, spontaneously developing multiple tumors in the colon. We first demonstrate that estrogen receptor-ß expression in Pirc rat colon is significantly down-regulated compared to age-matched wt rats. Then, Pirc rats aged 1 month were treated for 3 months with Adipol (Adi), a patented preparation containing phytoestrogens and insoluble fibers. Colon tumorigenesis was significantly reduced by Adi treatment (colon tumors/rat were 5.3 ± 0.8 and 2.9 ± 0.3, Mucin Depleted Foci/rat 127 ± 6.6 and 97.1 ± 8.6 in Controls and Adi-treated rats, respectively, means ± SE, P < 0.01). The treatment also normalized colon proliferation pattern along the crypt and significantly increased apoptosis in colon tumors. Estrogen receptor-ß expression was increased by Adi treatment, especially in the tumors. These positive effects suggest that Adipol may be exploited as a chemopreventive agent to reduce cancer risk in familial adenomatous polyposis patients and to postpone prophylactic colectomy. Moreover, given the similarities between familial adenomatous polyposis and sporadic colorectal cancer, it might also be used as chemopreventive agent in colorectal cancer patients at risk.

Can supplementation of phytoestrogens/insoluble fibers help the management of duodenal polyps in familial adenomatous polyposis?

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disorder, and prophylactic colectomy has been shown to decrease the incidence of colorectal cancer (CRC). Duodenal cancer and desmoids are now the leading causes of death in FAP. We evaluate whether 3 months of oral supplementation with a patented blend of phytoestrogens and indigestible insoluble fibers (ADI) help the management of FAP patients with ileal pouch-anal anastomosis (IPAA). In a prospective open label study, we enrolled 15 FAP patients with IPAA and duodenal polyps who underwent upper gastrointestinal endoscopy at baseline and after 3 months of treatment. The primary endpoint was the change in gene expression in polyp mucosa, whereas the secondary endpoint was the reduction in polyp number and size. After 3 months of ADI treatment, all patients showed a reduction in the number and size of duodenal polyps (P = 0.021). Analysis of the expression of CRC promoting/inhibiting genes in duodenal polyps biopsies demonstrated that different CRC-promoting genes (PCNA, MUC1 and COX-2) were significantly downregulated, whereas CRC-inhibiting genes (ER-ß and MUC2) were significantly upregulated after ADI treatment. In conclusion, ADI proved to be safe and effective, and its long-term effects on FAP patients need further investigation. Judging from the results we observed on COX-2 and miR-101 expression, the short-term effects of ADI treatment could be comparable with those obtained using COX-2 inhibitors, with the advantage of being much more tolerable in chronic therapies and void of adverse events.

Eviendep® reduces number and size of duodenal polyps in familial adenomatous polyposis patients with ileal pouch-anal anastomosis.

AIM: To evaluate if 3 mo oral supplementation with Eviendep® was able to reduce the number of duodenal polyps in familial adenomatous polyposis (FAP) patients with ileal pouch-anal anastomosis (IPAA). METHODS: Eleven FAP patients with IPAA and duodenal polyps were enrolled. They underwent upper gastrointestinal (GI) endoscopy at the baseline and after 3 mo of treatment. Each patient received 5 mg Eviendep twice a day, at breakfast and dinner time, for 3 mo. Two endoscopists evaluated in a blinded manner the number and size of duodenal polyps. Upper GI endoscopies with biopsies were performed at the baseline (T0) with the assessment of the Spigelman score. Polyps > 10 mm were removed during endoscopy and at the end of the procedure a new Spigelman score was determined (T1). The procedure was repeated 3 mo after the baseline (T2). Four photograms were examined for each patient, at T1 and T2. The examined area was divided into 3 segments: duodenal bulb, second and third portion duodenum. Biopsy specimens were taken from all polyps > 10 mm and from all suspicious ones, defined by the presence of a central depression, irregular surface, or irregular vascular pattern. Histology was classified according to the updated Vienna criteria. RESULTS: At baseline the mean number of duodenal detected polyps was 27.7 and mean sizes were 15.8 mm; the mean Spigelman score was 7.1. After polypectomy the mean number of duodenal detected polyps was 25.7 and mean sizes were 7.6 mm; the mean Spigelman score was 6.4. After 3 mo of Eviendep bid, all patients showed a reduction of number and size of duodenal polyps. The mean number of duodenal polyps was 8 (P = 0.021) and mean size was 4.4 mm; the mean Spigelman score was 6.6. Interrater agreement was measured. Lesions > 1 cm found a very good degree of concordance (kappa 0.851) and a good concordance was as well encountered for smaller lesions (kappa 0.641). CONCLUSION: Our study demonstrated that short-term (90 d) supplementation with Eviendep® in FAP patients with IPAA and with recurrent adenomas in the duodenal mucosa, resulted effective in reducing polyps number of 32% and size of 51%.

Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: modification by dietary curcumin and implications for clinical trials.

The natural polphenol, curcumin, retards the growth of intestinal adenomas in the Apc(Min+) mouse model of human familial adenomatous polyposis. In other preclinical models, curcumin downregulates the transcription of the enzyme cyclooxygenase-2 (COX-2) and decreases levels of two oxidative DNA adducts, the pyrimidopurinone adduct of deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We have studied COX-2 protein expression and oxidative DNA adduct levels in intestinal adenoma tissue from Apc(Min+) mice to try and differentiate between curcumin's direct pharmacodynamic effects and indirect effects via its inhibition of adenoma growth. Mice received dietary curcumin (0.2%) for 4 or 14 weeks. COX-2 protein, M1dG and 8-oxo-dG levels were measured by Western blot, immunochemical assay and liquid chromatography-mass spectrometry, respectively. In control Apc(Min+) mice, the levels of all three indices measured in adenoma tissue were significantly higher than levels in normal mucosa. Lifetime administration of curcumin reduced COX-2 expression by 66% (P = 0.01), 8-oxo-dG levels by 24% (P < 0.05) and M1dG levels by 39% (P < 0.005). Short-term feeding did not affect total adenoma number or COX-2 expression, but decreased M1dG levels by 43% (P < 0.01). COX-2 protein levels related to adenoma size. These results demonstrate the utility of measuring these oxidative DNA adduct levels to show direct antioxidant effects of dietary curcumin. The effects of long-term dietary curcumin on COX-2 protein levels appear to reflect retardation of adenoma development.

Quality of life after ileal pouch-anal anastomosis: an evaluation of diet and other factors using the Cleveland Global Quality of Life instrument.

PURPOSE: Although functional results after ileal pouch-anal anastomosis are excellent, imperfections of function do occur. In this setting, quality-of-life assessment is an invaluable tool in determining overall therapeutic efficacy. We evaluated the impact of dietary restrictions, preoperative diagnosis (ulcerative colitis vs. familial adenomatous polyposis), and pregnancy (after pouch insertion) on quality of life. METHODS: After ethical approval, 64 patients were reviewed (mean age, 31 (range, 15-54) years). Long-term quality of life in patients after ileal pouch-anal anastomosis was assessed using the Cleveland Global Quality of Life instrument or Fazio score. The Cleveland Global Quality of Life score is a novel quality-of-life instrument specifically designed for patients with ileal pouches. Stool frequency and continence were recorded to establish the functional status of this group. RESULTS: Sixty-one patients (95.3 percent) complained of some form of dietary restriction and adopted a fixed dietary regimen. All such patients felt that a breach of this regimen would impinge significantly on their quality of life. Late eating and alcohol were associated with diarrhea, whereas smoking was not. Constipation was infrequently reported. The mean Cleveland Global Quality of Life score of patients with ulcerative colitis (0.81 +/- 0.13) was greater than that of patients with ulcerative colitis and a background of pouchitis (0.78 +/- 0.16; P = 0.042). Whereas postoperative stool frequency in patients with familial adenomatous polyposis was always higher than the preoperative level (4 vs. 2 movements per day; P = 0.04), the Cleveland Global Quality of Life score of this group was lower than that of ulcerative colitis patients (0.77 vs. 0.81; P = 0.047). The Cleveland Global Quality of Life score of females who had had pregnancies after pouch formation was 0.70, significantly lower (P = 0.039) than that of ulcerative colitis patients, although pouch function was similar to the general group (7 vs. 6 daily bowel movements with full continence in all parous patients). CONCLUSIONS: Most patients suffered dietary restrictions, forcing them to adopt a fixed dietary regimen. Breach of this regimen would impact on their quality of life. Hence composition of diet and timing of intake are important determinants of quality of life after ileal pouch formation. Patients with familial adenomatous polyposis and those with a history of pouchitis had poorer Cleveland Global Quality of Life scores than ulcerative colitis patients without a background of pouchitis. This indicates that they also had poorer quality of life. Parous patients had the lowest Cleveland Global Quality of Life scores, indicating the poorest quality of life. These differences did not correlate with poorer pouch function, highlighting the influence of non-pouch-related factors in quality of life after ileal pouch formation.

Wheat bran fiber and development of adenomatous polyps: evidence from randomized, controlled clinical trials.

Mutations in oncogenes and tumor suppressor genes are thought to initiate and promote the pathway to colorectal cancer, leading to hyperproliferation, the development of adenomas, and progression to gross malignancy. Intervention at any of these steps can potentially prevent the development of cancer. Several randomized, controlled trials have investigated the effect of dietary interventions, including the addition of wheat bran fiber, on the development of adenomatous polyps. In a familial adenomatous polyposis trial, patients were treated with 4 g of ascorbic acid plus 400 mg of alpha-tocopherol per day alone or with a grain fiber supplement (22.5 g/day) over a 4-year period. On an actual-intake basis, the combined intervention inhibited the development of rectal polyps. However, the Toronto Polyp Prevention Trial found no significant differences in polyp recurrence rates between patients who were counseled to follow a low-fat, high-fiber diet and patients consuming a typical Western diet with placebo fiber. A 9-month study of patients with resected colon adenomas found that dietary wheat bran fiber significantly reduced total, primary, and secondary fecal bile acid concentrations and excretion rates. Such bile acid levels are thought to be related to the risk of developing cancer. The Australian Polyp Prevention Project reported that the combination of fat reduction and a supplement of wheat bran reduced the incidence of large colorectal adenomas. These latter results suggest that intervention with a low-fat wheat bran supplemented diet inhibits the transition from smaller to larger adenomas, which may be a critical step in determining which adenomas progress to malignancy.

Progress report: the Arizona phase III study of the effect of wheat bran fiber on recurrence of adenomatous colon polyps.

A double-blind, placebo-controlled Phase III cancer prevention trial in subjects with previous resection of adenomatous colon polyps is nearing completion. The study's primary objective is to evaluate the effects of daily dietary supplementation with large (13.5 g/day) versus small (2.0 g/day) doses of wheat bran fiber for 3 years. A summary of the study design and a progress report are presented.

Modulation of abnormal colonic epithelial cell proliferation and differentiation by low-fat dairy foods: a randomized controlled trial.

CONTEXT: Before the development of human colonic neoplasms, colonic epithelial cells showed altered growth and differentiation. These alterations characterized mucosa at risk for cancer formation and were termed intermediate biomarkers of risk. Modifications of the mucosa toward more normal features by nutrients or drugs are putative approaches to chemoprevention of colon cancer. OBJECTIVE: To determine whether increasing calcium intake via dairy products alters colonic biomarkers toward normal. DESIGN: Randomized, single-blind, controlled study. SETTING: Outpatient clinic. PARTICIPANTS: Seventy subjects with a history of polypectomy for colonic adenomatous polyps. INTERVENTION: Low-fat dairy products containing up to 1200 mg/d of calcium. Subjects were randomized to 4 strata by diet (control vs higher calcium) and age (<60 vs > or = 60 years). MAIN OUTCOME MEASURES: Changes in total colonic epithelial cells and number and position of thymidine-labeled epithelial cells and changes in the ratio of sulfomucins (predominantly secreted by distal colorectal epithelial cells) to sialomucins and expression of cytokeratin AE1, 2 markers of colonic cell differentiation. RESULTS: During 6 and 12 months of treatment, reduction of colonic epithelial cell proliferative activity (P<.05), reduction in size of the proliferative compartment (P<.05), and restoration of acidic mucin (P<.02), cytokeratin AE1 distribution (P<.05), and nuclear size (P<.05) toward that of normal cells occurred. Control subjects showed no differences from baseline proliferative values at 6 and 12 months (P>.05). CONCLUSION: Increasing the daily intake of calcium by up to 1200 mg via low-fat dairy food in subjects at risk for colonic neoplasia reduces proliferative activity of colonic epithelial cells and restores markers of normal cellular differentiation.

A generalized estimating equations approach for testing ordered group effects with repeated measurements.

In repeated measures studies, we are often interested in comparing group effects in which groups are associated with a certain order relation. We propose testing procedures for ordered group effects using the generalized estimating equations (GEE) approach of Liang and Zeger (1986, Biometrika 73, 13-22). The order-constrained GEE estimators of group effects are approximated by the isotonic regression of the unconstrained GEE estimators. Based on these constrained estimators, we construct test statistics for detecting ordered group effects. The limiting distributions of the test statistics are mixtures of chi-square distributions. A Monte Carlo experiment shows improved performances of the proposed tests over the usual chi-square tests in detecting ordered group effects. The proposed test procedures are illustrated by familial polyposis supplementation trial data.

Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps.

BACKGROUND: Ongoing epidemiologic and nutritional studies suggest that colorectal carcinogenesis is consistent with complex interactions between genetic susceptibility and environmental and dietary factors. Among the dietary components found to reduce colon cancer risk are high intakes of dietary fiber and calcium. PURPOSE: We designed and conducted a randomized, double-blinded, placebo-controlled trial involving supplementation of the customary dietary intake with fiber and calcium and measurements of fecal bile acids to examine the potential mechanisms by which added dietary interventions might reduce colorectal cancer risk. METHODS: In a randomized, double-blinded, phase II study, we used a factorial design to measure the effects of dietary wheat bran fiber (2.0 or 13.5 g/day) in the form of cereal and supplemental calcium carbonate (250 or 1500 mg/day elemental calcium) taken as a tablet on fecal bile acid concentrations and excretion rates. Measurements were made at base-line randomization (i.e., after a 3-month placebo run-in period using 2.0 g wheat bran fiber plus 250 mg calcium carbonate) and after 3 and 9 months on treatment in a randomly selected 52-patient subsample of the 95 fully assessable study participants who had a history of colon adenoma resection. Concentrations of fecal bile acids, total, primary (i.e., chenodeoxycholic and cholic), and secondary (i.e., deoxycholic, lithocholic, and ursodeoxycholic), were measured in 72-hour stool samples by gas-liquid chromatography. All P values resulted from two-sided tests. RESULTS: All geometric mean fecal bile acid concentrations and excretion rates were lower at 9 months than at 0 months or 3 months on treatment in the high-dose fiber, high-dose calcium, and high-dose fiber/high-dose calcium treatment groups. The high-dose fiber effect at 9 months of supplementation was statistically significant with respect to virtually all geometric mean fecal bile acid concentrations and excretion rates. For example at 9 months versus 0 months, high-dose fiber supplementation caused a reduction in fecal concentrations of total bile acids (52% reduction; P = .001) and deoxycholic acid (48% reduction; P = .003). High-dose calcium supplementation also had a significant, but lower, effect at 9 months versus 0 months on the geometric mean total bile acid (35% reduction; P = .044) and deoxycholic fecal bile acid (36% reduction; P = .052) concentrations. CONCLUSIONS: High-dose wheat bran fiber and calcium carbonate supplements given for 9 months are associated with statistically significant reductions in both total and secondary fecal bile acid concentrations and excretion rates in patients with resected colon adenomas. This study supports the hypothesis that one of the important ways in which a high intake of wheat bran fiber and calcium may reduce the risk of colorectal neoplasia and cancer is by reduction of the concentrations of fecal bile acids. IMPLICATION: Phase III studies of these agents in the prevention of adenoma recurrence are necessary to confirm this hypothesis and have now been initiated at multiple institutions.

Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas.

BACKGROUND/AIMS: Fish oil supplementation can reduce cytokinetic anomalies in the flat rectal mucosa of patients with sporadic colorectal adenoma. This study attempted to identify an optimum dose for fish oil supplementation and evaluate the persistence of its effects during long-term administration. METHODS: In a double-blind study, 60 patients with sporadic adenomas received 2.5, 5.1, or 7.7 g of fish oil per day or placebo for 30 days. [3H]thymidine autoradiographic labeling indices were calculated in flat rectal mucosal biopsy specimens collected before and after supplementation. In a subsequent study, 15 patients with polyps received 2.5 g of fish oil per day. Proliferative parameters, mucosal fatty acids, and mucosal and plasma alpha-tocopherol levels were evaluated before, during, and after 6 months of supplementation. RESULTS: Mean proliferative indices and mucosal arachidonic acid levels decreased significantly (and to similar degrees) in all treated groups, whereas mucosal eicosapentaenoic and docosahexaenoic acid levels increased. Significantly reduced proliferation was observed only in patients with abnormal baseline patterns. These effects persisted during long-term, low-dose treatment. A transient reduction in mucosal (but not plasma) alpha-tocopherol levels was observed after 1 month of treatment. Side effects were insignificant. CONCLUSIONS: Low-dose fish oil supplementation has short-term and long-term normalizing effects on the abnormal rectal proliferation patterns associated with increased colon cancer risk.

Familial polyposis coli: the spectrum of ocular and other extracolonic manifestations.

Familial polyposis coli (FPC) is hereditary condition that conveys a virtual 100% risk for the development of colon cancer in the untreated patient. A total of 56 patients with FPC underwent complete ophthalmic examination. Highly pleomorphic pigmented retinal lesions were identified bilaterally in 52% (n = 29) and unilaterally in 14% (n = 8) of our subjects. In all, 33 patients had one or more extracolonic expressions associated with FPC, including desmoids, osteomas, epidermoid cysts, lipomas, fibromas, and upper gastrointestinal tract polyps. In 15 patients, pigmented fundus lesions were the only extracolonic manifestations. No significant association between eye findings and other extracolonic manifestations could be established. The presence or absence of pigmented fundus lesions was found to cluster within families. Pigmented fundus lesions are probably a variably penetrant expression of the polyposis gene and do not appear to be specifically associated with subgroups of inherited polyposis syndromes such as Gardner's syndrome.