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.

Naringin, a natural dietary compound, prevents intestinal tumorigenesis in Apc (Min/+) mouse model.

PURPOSE: Naringin is a natural dietary flavonoid compound. We aimed to evaluate the effects of naringin on intestinal tumorigenesis in the adenomatous polyposis coli multiple intestinal neoplasia (Apc (Min/+)) mouse model. METHODS: Apc (Min/+) mice were given either naringin (150 mg/kg) or vehicle by p.o. gavage daily for 12 consecutive weeks. Mice were killed with ether, and blood samples were collected to assess the concentrations of IL-6 and PGE2. Total intestines were removed, and the number of polyps was examined. Tissue samples of intestinal polyps were subjected to the assays of histopathology, immunohistochemical analysis and Western blotting analysis. RESULTS: Apc (Min/+) mice fed with naringin developed less and smaller polyps in total intestines. Naringin prevented intestinal tumorigenesis without adverse effects. Histopathologic analysis revealed the reduction of dysplastic cells and dysplasia in the adenomatous polyps. The treatments' effects might arise from its anti-proliferation, induction of apoptosis and modulation of GSK-3ß and APC/ß-catenin signaling pathways. Naringin also exerted its effects on tumorigenesis through anti-chronic inflammation. CONCLUSION: Naringin prevented intestinal tumorigenesis likely through a collection of activities including anti-proliferation, induction of apoptosis, modulation of GSK-3ß and APC/ß-catenin pathways and anti-inflammation. Naringin is a potential chemopreventive agent for reducing the risk of colonic cancers.

Olive oil and omega-3 polyunsaturated fatty acids suppress intestinal polyp growth by modulating the apoptotic process in ApcMin/+ mice.

The promotion and progression of carcinogenesis are susceptible to nutritional interventions aimed at counteracting cancer development. Lipid metabolism is essential in the onset and progression of tumors and for cancer cell survival. In this study, we tested the effects of diets enriched with natural compounds, such as olive oil and salmon oil, in mice that spontaneously develop intestinal polyps (Apc(Min/+) mice). For this purpose, we evaluated polyp number and volume, intestinal mucosa proliferation/apoptosis, estrogen receptors (ERs) expression, fatty acid synthase and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase gene expression and enzymatic activity. Compared with the standard diet, the salmon oil-enriched diet, containing a high percentage of omega-3 polyunsaturated fatty acids, and, to a lesser extent, olive oil-enriched diet reduced polyp number and volume through a reduction of proliferation and a marked proapoptotic effect. These biological effects were mediated by an inhibition of fatty acid synthase and HMGCoA reductase gene expression and activity and an increase of ERß/ERα ratio. Our findings suggest that a proper dietary lifestyle could contribute to primary cancer prevention.

Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown. METHODS: NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months. RESULTS: Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020). CONCLUSION: High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.

Filiform polyposis in a patient without inflammatory bowel disease.

Filiform polyposis is a rare condition of uncertain pathogenesis that is usually found in patients with a history of inflammatory bowel disease. Here I report a case of filiform polyposis with no associated inflammatory bowel disease. Numerous finger-like polypoid lesions with the appearance of stalactites were noted in the transverse colon at the time of colonoscopy. Filiform polyps may be misinterpreted on colonoscopy as unusual villous adenomas or small carcinomas. Endoscopists should be familiar with the varied morphology of filifform polypsis in order to arrive at a correct diagnosis, and to ensure proper management.

Modifying effect of diallyl sulfide on colon carcinogenesis in C57BL/6J-ApcMin/⁺ mice.

Diallyl sulfide (DAS), a flavoring compound derived from garlic, is considered to have cancer chemopreventive potential in experimental animals and humans. This study was designated to examine possible chemopreventive effects of DAS on colon carcinogenesis using genetically engineered transgenic ApcMin/⁺ mice, a well-established animal model for familial adenomatous polyposis (FAP) and sporadic colorectal cancer. Male C57BL/6J-ApcMin/⁺ mice were divided into three groups. Animals of group 1 were placed on the basal diet (AIN-76A) as non-treated controls. Animals of groups 2 and 3 were given DAS- containing diets (in doses of 100 and 300 ppm, respectively). All mice were sacrificed at the end of week 10 of the experiment. Histopathological investigation revealed that the incidence of colonic polyps was decreased dose-dependently by 19% (13/16) in group 2 and by 32% (13/20) in group 3 compared to the 100% incidence (10/10) in group 1. The multiplicity of colonic polyps per mouse was also slightly decreased by DAS treatment (1.88 ± 0.35 in group 2 and 1.63 ± 0.36 in group 3) compared to 2.00 ± 0.39 in group 1. On the other hand, there were no significant differences in the numbers of total polyps per mouse in the small intestine between the groups. Taken together, we suggest that DAS may exert promising inhibitory effects on colon carcinogenesis in the transgenic ApcMin/⁺ mice.

Ileal Vanek's tumor mimicking cecal carcinoma.

Inflammatory fibroid polyps or Vanek's tumors are rare benign pseudotumoral lesions with morphological characteristics similar to those of submucosal mesenchymal tumors. They have been described in the gastrointestinal tract, most frequently in the gastric antrum. We present a case of ileal Vanek's tumor associated with a raised carcinoembryonic antigen level and with radiological and endoscopic features mimicking cecal carcinoma.

The use of digital photos and video images taken by a parent in the diagnosis of anal swelling and anal protrusions in children with normal physical examination.

PURPOSE: The purpose of this study is to demonstrate that digital photos and video images taken by a parent can provide a definite diagnosis and makes some diagnostic procedures (eg, air contrast enema, sigmoidoscopy) unnecessary for anal swelling and anal protrusions in children with normal physical examination. METHODS: In a 41-month period (September 2007-January 2011), 23 parents brought their children to the clinic, stating that they saw a swelling in the anal region and/or that something protruded from the anus while their children were defecating. If the visual inspection of the anal region and digital rectal examination of the patients were normal, parents were asked to take photos or record videos when the lesion occurred to make a diagnosis and avoid the need for air contrast enema and/or sigmoidoscopy. The parents were also asked either to send these images to the surgeon via e-mail or bring an image or the camera to the surgeon's office. The patients age, sex, symptoms, medical history, results of their first physical examination, photos and video records, and the diagnosis and treatment were recorded. All of these information were retrospectively reviewed. RESULTS: The photos provided by 20 parents and the video records from 3 parents were assessed, and the diagnoses of all patients were confirmed. Of these 23 patients, a definitive diagnosis of rectal prolapse in 8, hemorrhoids in 10, rectal polyps in 3, and sentinel skin tag in 2 was made. In addition, the photographic and video evidence gave the clinicians an idea of the degree of rectal prolapse in patients for whom this was a problem. Three patients diagnosed with a rectal polyp underwent polyp excision. One patient with rectal prolapse who was unresponsive to medical treatment underwent laparoscopic posterior rectopexy, and all other patients received medical treatment. CONCLUSION: When a swelling or protruding anal lesion in a child is discovered by parents and visual inspection of the anal region and digital rectal examination is normal, parents should be encouraged to take photos or videos of the anal region before performing air contrast enema and/or sigmoidoscopy. These photos and videos can provide a definitive diagnosis and prevent unnecessary diagnostic procedures.

Unexplained iron deficiency anaemia: Is it worthwhile to perform capsule endoscopy?

BACKGROUND: In around 30% of iron deficiency anaemia (IDA) cases a definite diagnosis cannot be made. AIM: To investigate the role of capsule endoscopy (CE) in detecting lesions in patients with unexplained IDA after a negative endoscopic, serologic and haematologic diagnostic work up and its possible role in influencing clinical outcome. METHODS: 138 patients suffering from IDA were identified among 650 consecutive patients undergoing CE at our unit. RESULTS: CE revealed the following positive findings in 91/138 patients: angiodysplasias in 51 patients; jejunal and/or ileal micro-ulcerations in 12; tumours/polyps in 9; erosive gastritis in 4; Crohn's disease in 5; jejunal villous atrophy in 5; a solitary ileal ulcer in 1 and active bleeding in the last 4 patients. Follow up data were available for 80/91 patients (87.9%). In 15 out of 46 patients with angiodysplasias IDA spontaneously resolved without any treatment; 9 patients required iron supplementation; 10 patients healed after lanreotide administration; APC was performed in 9 out of 46 patients and 3 patients underwent regular blood transfusion without any success on IDA. 10 out of the 12 patients with small bowel micro-ulcers spontaneously recovered from IDA whilst 2 patients after iron supplementation. All 9 patients affected by tumours/polyps were surgically addressed. In all erosive gastritis cases, patients recovered from IDA after PPI and Helicobacter pylori eradication. Four patients with Crohn's disease diagnosis restored to health with medical therapy. One out of the 4 patients with jejunal villous atrophy and the sole patient with a solitary ileal ulcer spontaneously healed. In 1 out of 3 patients with active bleeding IDA resolved without further treatment after blood transfusion whilst 2 patients were referred for surgical treatment. At follow up, complete resolution of IDA was achieved in 96.25%. CONCLUSIONS: Small bowel investigation is a matter of great importance in IDA patients after negative upper and lower gastrointestinal endoscopy.

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.

Endoscopic polypectomy resection of blue rubber bleb nevus lesions in small bowel.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by cutaneous and gastrointestinal (GI) venous malformations. The treatment of BRBNS is primarily supportive and ablative. Ablative therapy involves endoscopic or surgical treatment of GI venous malformations. We describe a 20-year-old woman who had multiple venous malformations all over the GI tract as well as cutaneous lesions. She had suffered from several episodes of melena, chronic anemia and fatigue for 10 years, which were treated temporarily by iron supplementation and blood transfusion. The endoscopic examination of the GI tract and total colonoscopy revealed multiple bluish sessile and polypoid venous malformations 2-3 cm in size throughout the GI tract. Argon plasma coagulation (APC) and polypectomy was done for all gastric and colonic lesions, respectively. Ileoscopy showed a large wide base vascular polypoid lesion at about 70 cm from the ileocecal valve with active bleeding; this was removed by snare polypectomy. One week later, she was discharged in good condition. At about 6 months' follow up she did not report any bleeding attack. Endoscopic polypectomy can be useful in patients with large and polypoid lesions of BRBNs which are not controlled with supportive therapy. Further experience is needed to evaluate the risks versus benefits of this approach.

Conjugated linoleic acids differentially alter polyp number and diameter in the Apc(min/+) mouse model of intestinal cancer.

OBJECTIVE: Dietary conjugated linoleic acids (CLA) have had many health benefits claimed for them, including antineoplastic actions. MATERIALS AND METHODS: The effects of the predominant forms of CLA, namely the c9t11 and t10c12 isomers, or a mixture of these on polyp development, were investigated in the Apc(Min/+) mouse. CLAs have also been linked to altered rates of cell renewal and cell proliferation so this was also studied, as was a further means of increasing tissue mass, namely crypt fission. RESULTS: The stomach and small intestine were significantly heavier in the t10c12, and in the mixture-treated groups (P < 0.001). Crypt fission was increased in the middle small intestine by the t10c12 diet while colonic weight was reduced by c9t11 provision and crypts were 20% shorter. The t10c12 and the mixture significantly reduced polyp number in the proximal small intestine but they increased polyp diameter in the middle and distal small intestine, to an extent that the polyp burden was significantly increased at these sites. All CLAs significantly reduced polyp number in the colon, but the mixture significantly increased polyp diameter in the colon. CONCLUSION: Increased polyp diameter associated with t10c12 diet and especially with the mixture is a cause of concern, as this is the commercially available form. The naturally occurring isomer, c9t11 decreased colonic polyp number and did not increase diameter, suggesting that this natural isomer is the most likely to be protective.

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.

CONTEXT: Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. OBJECTIVE: To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results. DESIGN, SETTING, AND PATIENTS: Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. MAIN OUTCOME MEASURES: Molecular, clinical, and histopathological findings in patients with unexplained polyposis. RESULTS: Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen. CONCLUSIONS: Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

Juvenile colorectal polyps in children: experience in Pakistan.

Juvenile colorectal polyps are the most common cause of pediatric hematochezia and contribute to significant morbidity if not treated early. This report describes an experience with juvenile colorectal polyps in children (< or =14 years) from Pakistan. In a 3-year period, 154 polyps were documented in 129 children. The mean age at presentation was 5.2 years, with a male predominance. Most children presented with painless rectal bleeding (+/-13 months) associated with other symptoms, such as protrusion of a mass through the anus, diarrhea, and recurrent abdominal pain. Anemia was observed in 54 children, of whom 14 (26%) required blood transfusion before intervention. Diagnosis was made by digital rectal examination, proctosigmoidoscopy, and barium enema. The average distance of a colorectal polyp was 4 cm from the anal verge. In 108 (84%) children the polyps were solitary, whereas 21 patients had more than one polyp (maximum three) at different locations in the rectosigmoid area. All polyps were successfully removed by proctosigmoidoscopy. Histological examination revealed dysplastic changes in one case, while the rest were inflammatory. Recurrence occurred in seven children within 1 year of initial removal. Juvenile colorectal polyps contribute to a substantial morbidity in children and do carry a minimal risk of developing dysplastic changes, and therefore should be removed early.

Intestinal polyp formation in the Apcmin mouse: effects of levels of dietary calcium and altered vitamin D homeostasis.

This study evaluated the effects of various levels of dietary calcium on polyp formation, vitamin D homeostasis, and fecal bile acids in the Apcmin mouse. Female Apcmin mice were randomized to three groups and fed a purified diet with either half or double the level of calcium in control AIN-93G. Serum 25-OH-D and fecal bile acids were measured at weeks 0 and 12 of treatment. Mice were killed for polyp scoring by two observers blinded to treatment after 12 weeks. Results show there was no difference in polyp number or tumor load with dietary calcium in any treatment group. Serum 25-OH-D was reduced and total fecal bile acids were increased in animals that received the high calcium diet. We have previously shown that vitamin D supplementation diminishes polyp load; the lack of effect of an altered calcium diet seen here may be due to a disturbance in vitamin D homeostasis.

[Diagnosis of a high-grade B-cell lymphoma of the small bowel by means of wireless capsule endoscopy]. / Diagnostik eines hochmalignen B-Zell-Lymphoms des Dünndarms mit der Kapselendoskopie.

Wireless capsule endoscopy is a new diagnostic procedure to detect diseases of the small bowel, in particular in patients with obscure gastrointestinal bleeding. We report on a 76-year-old patient who presented at our hospital with signs of gastrointestinal bleeding and hypochromic anaemia. Bidirectional endoscopy, push enteroscopy, angiography as well as small bowel barium enema rendered no pathologic findings. Wireless capsule endoscopy demonstrated a polypous space in the cantral area of the small bowel. Subsequent intraoperative endoscopy revealed a subtotal stenosing tumour of the upper jejunum which was resected. Based on the histology a high-grade B-Cell lymphoma was diagnosed. The postoperative staging examinations did not indicate any further extranodal involvement.