Outcomes of cold snare piecemeal EMR for nonampullary small-bowel adenomas larger than 1 cm: a retrospective study.

BACKGROUND AND AIMS: Nonampullary small-bowel adenomas ≥10 mm are typically resected using cautery-based polypectomy, which is associated with significant adverse events. Studies have demonstrated the safety and efficacy of piecemeal cold snare EMR for removing large colon polyps. Our aim was to assess the safety and efficacy of cold snare EMR for removal of large adenomas in the small bowel. METHODS: A retrospective study of patients who underwent lift and piecemeal cold snare EMR of small-bowel adenomas ≥1 cm between January 2014 and March 2019 was conducted at a tertiary care medical center. Polyp characteristics at the time of index and surveillance endoscopy were collected. Primary outcomes were residual or recurrent adenoma (RRA) seen on surveillance endoscopy, polyp eradication rate, and number of endoscopic procedures required for eradication. Adverse events including immediate and delayed bleeding, perforation, stricture, pancreatitis, and postpolypectomy syndrome were assessed. RESULTS: Of 43 patients who underwent piecemeal cold snare EMR, 39 had follow-up endoscopy. Polyps ranged in size from 10 to 70 mm (mean, 26.5 mm). RRA was found in 18 patients (46%), with increased polyp size correlating with higher recurrence (P < .001). Polyp eradication was observed in 35 patients (89%), requiring a median of 2 (range, 1-6) endoscopic procedures. Only 1 patient (2.3%) had immediate postprocedural bleeding. No cases of perforation or postpolypectomy syndrome were seen. CONCLUSIONS: Piecemeal cold snare EMR may be a feasible, safe, and efficacious technique for small-bowel polyps >10 mm. Prospective, randomized studies are needed to assess how outcomes compare with traditional cautery-based polypectomy.

Calcium and dairy products in the chemoprevention of colorectal adenomas: a systematic review and meta-analysis.

The risk of transition to colorectal cancer (CRC) in advanced colorectal adenomas (ACAs) is about 2.5 times higher than the non-advanced ones. This systematic review and meta-analysis was performed to determine the effect of calcium and dairy products on the incidence of CAs and ACAs. Six databases were systematically searched and 37 relevant clinical trials and observational studies involving over 10,964 cases were selected for inclusion. The results showed that calcium consumption reduced the risk of CAs incidence by 8% (RR: 0.92; 95% CI: 0.89-0.96), and calcium intake as a food and dairy product reduced it about 21% (RR: 0.79; 95% CI: 0.72-0.86), and 12% (RR: 0.88; 95% CI: 0.78-0.98), respectively. However, calcium supplementation did not show a significant effect on CAs incidence (RR: 0.97; 95% CI: 0.89-1.05). Results also revealed that total calcium intake markedly reduced the risk of ACAs (RR: 0.79; 95% CI: 0.73-0.85) and the risk of recurrence of adenomas about 12% (RR: 0.88; 95% CI: 0.84-0.93). Our results suggest that natural sources of calcium such as dairy products and foods may have more effective role than supplementary calcium in terms of reducing the risk of incidence and recurrence of colorectal adenomas and advanced adenomas.

Dose-response meta-analysis of coffee consumption and risk of colorectal adenoma.

BACKGROUND: The association between coffee and colorectal adenoma risk remains controversial. We conducted a meta-analysis of cohort and case-control studies to sum up the existing proof about this matter. METHODS: We searched Pubmed, Medline, and Embase for studies published before 1 September 2018 on coffee consumption and colorectal adenoma in any language. The different ORs were calculated for cohort and case-control studies in this study, and we use a random-effects model to aggregate the relative risks of individual studies and conduct dose response, heterogeneity, and publication bias. RESULTS: A total of 8 studies (6 case-control studies, 2 cohort studies) were identified, including 7090 subjects. In a summary analysis of all studies, high coffee intake (compared the highest with the lowest categories) was associated with a reduced risk of colorectal adenoma (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.55-0.90). The results of subgroup analysis of adenoma location were similar with the pooled analysis, except for rectal adenoma. In the dose-response meta-analysis study, the estimated total odds ratio for increasing coffee consumption by 150 ml per day (about one cup) was 0.91 (95% CI = 0.87-0.95). CONCLUSIONS: The meta-analysis demonstrates possible evidence that increased coffee intake is related to a reduced risk of colon adenoma. However, because of latent confusion and different exposure classification, this finding should be carefully considered.

Effects of fish oil supplementation on eicosanoid production in patients at higher risk for colorectal cancer.

Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. The mechanism of action of fish oil is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on the levels of urinary and rectal eicosanoids. We conducted a randomized, double-blind, controlled trial of 2.5 g of fish oil per day compared with olive oil supplementation over a 6-month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. A total of 141 participants were randomized. Urinary prostaglandin E2 metabolite (PGE-M) was measured at baseline, 3, and 6 months and rectal prostaglandin E2 (PGE2) at baseline and 6 months. Repeated-measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared with olive oil (P=0.03). Fish oil did not reduce rectal PGE2 overall; however, it did significantly reduce PGE2 in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify effects of fish oil on PGE2 production. We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs.

Efficacy and Safety of Curcumin in Treatment of Intestinal Adenomas in Patients With Familial Adenomatous Polyposis.

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.

Calcium intake and colorectal adenoma risk: dose-response meta-analysis of prospective observational studies.

Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose-response relationship and influence on high-risk adenomas is limited. To address these issues, we conducted linear and nonlinear dose-response meta-analyses primarily based on prospective observational studies published up to July 2014 identified from PubMed and Embase. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated for total and supplemental calcium intake, respectively, using a random-effects model. For total calcium intake, summary RR for each 300 mg/day increase was 0.95 (95% CI = 0.92-0.98; I(2) = 45%; eight studies with 11,005 cases; range of intake = 333-2,229 mg/day). Evidence of nonlinearity was indicated: approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.92 (95% CI = 0.89-0.94) at 1,000 mg/day and 0.87 (95% CI = 0.84-0.90) at 1,450 mg/day (pnonlinearity < 0.01). Associations were stronger for high-risk adenomas (≥1 cm in diameter, (tubulo)villous histology, dysplasia, or multiplicity): approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.77 (95% CI = 0.74-0.81) at 1,000 mg/day and reduced to 0.69 (95% CI = 0.66-0.73) at 1,450 mg/da (pnonlinearity < 0.01). For supplemental calcium intake, summary RR of total adenoma risk for each 300 mg/day increase was 0.96 (95% CI = 0.93-0.99; I(2) = 0%; three studies with 4,548 cases; range of supplementation = 0-1,366 mg/day). In conclusion, calcium intake may continue to decrease the risk of adenomas, particularly high-risk adenomas, over a wide range of calcium intake.

Testing multiple biological mediators simultaneously.

MOTIVATION: Modern biomedical and epidemiological studies often measure hundreds or thousands of biomarkers, such as gene expression or metabolite levels. Although there is an extensive statistical literature on adjusting for 'multiple comparisons' when testing whether these biomarkers are directly associated with a disease, testing whether they are biological mediators between a known risk factor and a disease requires a more complex null hypothesis, thus offering additional methodological challenges. RESULTS: We propose a permutation approach that tests multiple putative mediators and controls the family wise error rate. We demonstrate that, unlike when testing direct associations, replacing the Bonferroni correction with a permutation approach that focuses on the maximum of the test statistics can significantly improve the power to detect mediators even when all biomarkers are independent. Through simulations, we show the power of our method is 2-5× larger than the power achieved by Bonferroni correction. Finally, we apply our permutation test to a case-control study of dietary risk factors and colorectal adenoma to show that, of 149 test metabolites, docosahexaenoate is a possible mediator between fish consumption and decreased colorectal adenoma risk. AVAILABILITY AND IMPLEMENTATION: R-package included in online Supplementary Material.

Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial.

Colorectal adenoma (CRA) is the precursor lesion of colorectal cancer (CRC). Several agents have been shown to be effective in the chemoprevention of CRA recurrence, but there has been little research on its primary prevention. Participants older than 50 years with no adenomas were recruited for our study and randomized to receive either 1 mg/day folic acid supplement or treatment without folic acid. After 3 years of follow-up, plasma folate and colonoscopy were evaluated. Seven hundred ninety-one participants (91.98%) completed the study. CRA occurred in 64 (14.88%) participants in the folic acid group and 132 (30.70%) in the control group [unadjusted risk ratio (RR), 0.49; 95% confidence interval (CI), 0.37-0.63; P < 0.01]; left-sided adenoma (unadjusted RR, 0.54; 95% CI, 0.38-0.76; P = 0.001) and advanced CRA (unadjusted RR, 0.36; 95% CI, 0.16-0.81; P = 0.01) were most common. There was no significance difference in the occurrence of three or more adenomas (unadjusted RR, 0.70; 95% CI, 0.36-1.77; P = 0.38) or right-sided adenoma (unadjusted RR, 0.55; 95% CI, 0.30-1.00; P = 0.07) between the two groups. Participants with low plasma folate may have a high risk of CRA. In conclusion, primary prevention with 1 mg/day folic acid supplementation could reduce the incidence of CRA, especially left-sided and advanced disease in those with no previous adenomas. People with differing baseline plasma folate levels should be given individualized treatment. Those with low plasma folate should be encouraged to take adequate supplements; plasma folate should be elevated to an effective therapeutic level, which may reduce the incidence of CRA.

Dietary supplement use is not associated with recurrence of colorectal adenomas: a prospective cohort study.

Diet and lifestyle influence colorectal adenoma recurrence. The role of dietary supplement use in colorectal adenoma recurrence remains controversial. In this prospective cohort study, we examined the association between dietary supplement use, total colorectal adenoma recurrence and advanced adenoma recurrence. Colorectal adenoma cases (n = 565) from a former case-control study, recruited between 1995 and 2002, were prospectively followed until 2008. Adenomas with a diameter of ≥1 cm and/or (tubulo)villous histology and/or with high grade dysplasia and/or ≥3 adenomas detected at the same colonic examination were considered advanced adenomas. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dietary supplement users (use of any supplement during the past year) compared to nonusers and colorectal adenoma recurrence were calculated using stratified Cox proportional hazard models for counting processes and were adjusted for age, sex, educational level and number of colonoscopies during follow-up. Robust sandwich covariance estimation was used to adjust for the within subject correlation. A number of 165 out of 565 adenoma patients had at least one colorectal adenoma recurrence during a median person-time of 5.4 years and of these, 37 patients had at least one advanced adenoma. One-third of the total study population (n = 203) used a dietary supplement. Compared to no use, dietary supplement use was neither statistically significantly associated with total colorectal adenoma recurrence (HR = 1.03; 95% CI 0.79-1.34) nor with recurrent advanced adenomas (HR = 1.59; 95% CI 0.88-2.87). This prospective cohort study did not suggest an association between dietary supplement use and colorectal adenoma recurrence.

Evaluation of removable statistical interaction for binary traits.

This paper is concerned with evaluating whether an interaction between two sets of risk factors for a binary trait is removable and, when it is removable, fitting a parsimonious additive model using a suitable link function to estimate the disease odds (on the natural logarithm scale). Statisticians define the term 'interaction' as a departure from additivity in a linear model on a specific scale on which the data are measured. Certain interactions may be eliminated via a transformation of the outcome such that the relationship between the risk factors and the outcome is additive on the transformed scale. Such interactions are known as removable interactions. We develop a novel test statistic for detecting the presence of a removable interaction in case-control studies. We consider the Guerrero and Johnson family of transformations and show that this family constitutes an appropriate link function for fitting an additive model when an interaction is removable. We use simulation studies to examine the type I error and power of the proposed test and to show that, when an interaction is removable, an additive model based on the Guerrero and Johnson link function leads to more precise estimates of the disease odds parameters and a better fit. We illustrate the proposed test and use of the transformation by using case-control data from three published studies. Finally, we indicate how one can check that, after transformation, no further interaction is significant.

Vanadium pentoxide: use of relevant historical control data shows no evidence for a carcinogenic response in F344/N rats.

The National Toxicology Program (NTP) chronic inhalation bioassay of vanadium pentoxide (V(2)O(5)) produced "clear" evidence of lung tumors in B6C3F1 mice, but only "some" and "equivocal" evidence in male and female F344/N rats, respectively. No significant pairwise differences or trends with V(2)O(5) concentration in male or female rat poly-3-adjusted tumor incidence were reported. The "some" and "equivocal" evidence descriptors arose from comparisons of V(2)O(5)-exposed group incidence rates with NTP-2000- and NIH-07-fed historical control (HC) group incidence ranges. NTP acknowledged that use of data from NIH-07-fed HC groups could be inappropriate because the V(2)O(5) study used the NTP-2000 diet, but few studies using this newer diet were available then. We supplemented the early NTP-2000 diet HC data with data from 25 additional NTP-2000 diet studies conducted subsequent to the V(2)O(5) bioassay. This widened the HC tumor incidence ranges, thereby weakening the limited evidence for the carcinogenicity of inhaled V(2)O(5) in rats relative to HCs. The male rat control group in the V(2)O(5) study also appeared to be a near-"outlier" relative to the expanded HC database, potentially invalidating any comparisons of exposed group incidence rates with those for HCs. We conclude that there is "no" evidence of V(2)O(5) carcinogenicity in male or female F344/N rats.

[DNA methylation defects in sporadic and hereditary colorectal cancer]. / Defectos de la metilación del ADN en el cáncer colorrectal esporádico y hereditario.

DNA methylation is a fundamental epigenetic mechanism in regulating the expression of genes controlling crucial cell functions in cancer development. Methylation defects (both global hypomethylation and hypermethylation of CpG islands) are implicated in colorectal carcinogenesis. Some nutrients have a clear effect on methylation, suggesting that some dietary-associated differences in the incidence of colorectal cancer could be due to the effect of diet on methylation. The presence of methylation defects has clear diagnostic and prognostic implications. Thus, several tests are being used for colorectal cancer screening based on methylated gene analysis, whether in feces or blood. In addition, the reversibility of methylation processes allows the development of chemotherapies that regulate this process through their antineoplastic activity.

A multi-mineral natural product inhibits liver tumor formation in C57BL/6 mice.

C57BL/6 mice were maintained for up to 18 months on high-fat and low-fat diets with or without a multi-mineral supplement derived from the skeletal remains of the red marine algae Lithothamnion calcareum. Numerous grossly observable liver masses were visible in animals on the "western-style" high-fat diet sacrificed at 12 and 18 months. The majority of the masses were in male mice (20 out of 100 males versus 3 out of 100 females; p = 0.0002). There were more liver masses in animals on the high-fat diet than on the low-fat diet (15 out of 50 on high-fat versus 5 out of 50 on low-fat; p = 0.0254). The multi-mineral supplement reduced the number of liver masses in mice on both diets (3 out of 25 male mice in the low-fat diet group without the supplement versus 1 out of 25 mice with supplement; 12 of 25 male mice in the high-fat diet group without the supplement versus 3 of 25 mice with supplement [p = 0.0129]). Histological evaluation revealed a total of 17 neoplastic lesions (9 adenomas and 8 hepatocellular carcinomas), and 18 pre-neoplastic lesions. Out of eight hepatocellular carcinomas, seven were found in unsupplemented diet groups. Steatosis was widely observed in livers with and without grossly observable masses, but the multi-mineral supplement had no effect on the incidence of steatosis or its severity. Taken together, these findings suggest that a multi-mineral-rich natural product can protect mice against neoplastic and pre-neoplastic proliferative liver lesions that may develop in the face of steatosis.

Meat consumption and the risk of incident distal colon and rectal adenoma.

BACKGROUND: Most studies of meat and colorectal adenoma have investigated prevalent events from a single screening, thus limiting our understanding of the role of meat and meat-related exposures in early colorectal carcinogenesis. METHODS: Among participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who underwent baseline and follow-up sigmoidoscopy (n=17,072), we identified 1008 individuals with incident distal colorectal adenoma. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between meat and meat-related components and incident distal colorectal adenoma using multivariate logistic regression. RESULTS: We observed suggestive positive associations for red meat, processed meat, haeme iron, and nitrate/nitrite with distal colorectal adenoma. Grilled meat (OR=1.56, 95% CI=1.04-2.36), well or very well-done meat (OR=1.59, 95% CI=1.05-2.43), 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) (OR=1.75, 95% CI=1.17-2.64), benzo[a]pyrene (OR=1.53, 95% CI=1.06-2.20), and total mutagenic activity (OR=1.57, 95% CI=1.03-2.40) were positively associated with rectal adenoma. Total iron (diet and supplements) (OR=0.69, 95% CI=0.56-0.86) and iron from supplements (OR=0.65, 95% CI=0.44-0.97) were inversely associated with any distal colorectal adenoma. CONCLUSION: Our findings indicate that several meat-related components may be most relevant to early neoplasia in the rectum. In contrast, total iron and iron from supplements were inversely associated with any distal colorectal adenoma.

Determination of the minimal essential serum folate concentration for reduced risk of colorectal adenoma.

BACKGROUND & AIMS: There are no data regarding basal folate levels in patients without colorectal adenoma. This study aimed to determine the minimum serum folate concentration that associates with reduced risk of colorectal adenoma. METHODS: 1510 consecutive patients underwent total colonoscopy for suspected colorectal lesions after barium enema examination. Prior to colonoscopy, history of alcohol consumption was noted and blood serum analyzed for folate and vitamin B12 levels. Polypoid lesions were evaluated histologically. We excluded patients with anemia, history of colonoscopy, overconsumption of alcohol, or malignancies. In all, 458/1510 patients (male/female; 258/200, 40-75 years) were determined eligible. Variables were compared between patients with adenoma and those without adenoma. RESULTS: Serum folate concentration was the variable with the most significant statistical variation between males with adenoma (8.0 ng/ml) and males without adenoma (9.2) (p = 0.001). Serum folate concentrations in females with adenoma did not differ significantly from those in females without adenoma (10.7 versus 10.9). When subjects were stratified into groups according to serum folate, we found no significant difference in the prevalence of adenoma in patients with folate levels greater than 8.0 ng/ml. CONCLUSION: Patients with serum folate concentrations above 8.0 ng/ml had the lowest risk of developing colorectal adenoma.

Circulating 25-hydroxyvitamin-D and risk of colorectal adenomas and hyperplastic polyps.

Colorectal adenomas are clear precursors of cancer; hyperplastic polyps may also have malignant potential. An inverse association between circulating vitamin D metabolites and adenoma risk has been reported, but less is known about vitamin D and hyperplastic polyps. We conducted a case-control study of adenomas and hyperplastic polyps among 459 members of an integrated health plan evaluated via colonoscopy. Questionnaires provided information on colorectal polyp risk factors, and plasma samples were assayed for 25-hydroxyvitamin-D [25(OH)D]. Polytomous regression was used to estimate odds ratios for adenomas (n = 149) and hyperplastic polyps (n = 85) compared to polyp-free controls (n = 225) by tertile of 25(OH)D. An inverse association between 25(OH)D and adenomas was suggested after adjustment for potential confounding factors [comparing upper to lower tertiles, OR (95%CI): 0.71 (0.38-1.30)]. After restriction of the analyses to study participants with no history of polyps, this OR estimate was reduced further [adjusted OR (95%CI): 0.52 (0.23-1.20)]. In comparison, no inverse association between hyperplastic polyps and 25(OH)D was observed among the full study participants [adjusted OR (95%CI): 1.17 (0.55-2.51)] or among those without prior polyps [adjusted OR (95%CI): 1.42 (0.55-3.65)]. Our study suggests that the established inverse association between circulating 25(OH)D and adenoma may not apply to hyperplastic polyps.

Non-malignant thyroid diseases after a wide range of radiation exposures.

The thyroid gland is one of the most radiosensitive human organs. While it is well known that radiation exposure increases the risk of thyroid cancer, less is known about its effects in relation to non-malignant thyroid diseases. The aim of this review is to evaluate the effects of high- and low-dose radiation on benign structural and functional diseases of the thyroid. We examined the results of major studies from cancer patients treated with high-dose radiotherapy or thyrotoxicosis patients treated with high doses of iodine-131, patients treated with moderate- to high-dose radiotherapy for benign diseases, persons exposed to low doses from environmental radiation, and survivors of the atomic bombings who were exposed to a range of doses. We evaluated radiation effects on structural (tumors, nodules), functional (hyper- and hypothyroidism), and autoimmune thyroid diseases. After a wide range of doses of ionizing radiation, an increased risk of thyroid adenomas and nodules was observed in a variety of populations and settings. The dose response appeared to be linear at low to moderate doses, but in one study there was some suggestion of a reduction in risk above 5 Gy. The elevated risk for benign tumors continues for decades after exposure. Considerably less consistent findings are available regarding functional thyroid diseases including autoimmune diseases. In general, associations for these outcomes were fairly weak, and significant radiation effects were most often observed after high doses, particularly for hypothyroidism. A significant radiation dose-response relationship was demonstrated for benign nodules and follicular adenomas. The effects of radiation on functional thyroid diseases are less clear, partly due to the greater difficulties encountered in studying these diseases.

Dietary-induced ERbeta upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice.

Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ERbeta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERbeta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ERbeta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERbeta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ERbeta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ERbeta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ERbeta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.

Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancer.

Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer.

A rare association of hyperparathyroidism and Turner's syndrome--a case report.

We present the clinical, laboratory, radiological and pathological findings in the case and review the literature. Our patient, a 37-year-old woman of short stature, was referred because of musculoskeletal pain. After primary evaluation, she underwent treatment with calcium and vitamin D supplement with the diagnosis of osteomalacia in Turner's syndrome. The rise of serum calcium during medical therapy, which was an unusual finding, attracted the clinician's attention to another underlying disorder. Further evaluation revealed primary hyperparathyroidism due to an adenoma of the parathyroid gland. Even though this is a rare diagnosis, its presence should be considered in any patient with Turner's syndrome presenting with severe osteoporosis and a rise in serum calcium during treatment.