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Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice.
Hereditary nonpolyposis colorectal cancer is associated with defects in DNA mismatch repair. Here, we characterize tumor susceptibility of the recently described Msh2-deficient mouse model. Within the first year of observation, all homozygous mice succumbed to disease, with lymphomas observed in at least 80% of the cases. The majority (70%) of animals 6 months or older developed intestinal neoplasms associated with APC inactivation. Microsatellite instability was more common in carcinomas than in adenomas, but uncommon in normal tissues. Some animals (7%) developed a variety of skin neoplasms analogous to the Muir-Torre syndrome. Msh2-/- mice implicate a direct role for mismatch repair in several neoplasms with striking phenotypic similarities to humans.
Adenomatous Polyposis Coli Protein↗
The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(Min/+) mice.
Ranolazine was shown to improve exercise parameters in patients with chronic angina. It works by switching myocardial energy metabolism from fatty acids to glucose, thus increasing the efficiency of ATP production under hypoxic conditions. Tumors are hypoxic and may also respond to ranolazine. We found that ranolazine caused a dose-dependent increase in tumor number in APC(Min/+) mice, a model of spontaneous intestinal tumorigenesis. Tumors from drug-treated mice were also more dysplastic and invasive than those from untreated mice. These findings have implications for the use of ranolazine in patients with a history of malignant neoplasms or adenomatous polyps.
Acetanilides↗
Subcellular localization of the APC protein: immunoelectron microscopic study of the association of the APC protein with catenin.
Mutations in the APC gene are linked to the development of sporadic colorectal tumors as well as to familial adenomatous polyposis. Recently, the APC protein was reported to associated with catenins, proteins that bind to the cell adhesion molecule E-cadherin. In the present study, we examined the distribution and localization of the APC protein and alpha -catenin in the normal mouse intestine by light and immunoelectron microscopy using specific antibodies. The APC protein was found to be localized in microvilli and in the apical and lateral cytoplasm of the epithelial cells, whereas alpha-catenin was detected only in the lateral cytoplasm. Double-labeling immunoelectron microscopy showed colocalization of the APC protein with alpha-catenin in the lateral cytoplasm, especially along the lateral plasma membrane, although a certain portion of the APC protein in this region was distributed independently of alpha-catenin. These results suggest that a portion of the APC protein localized in the lateral cytoplasm of intestinal epithelial cells functions in cooperation with catenins, whereas the APC protein in microvilli and in the apical cytoplasm has other functions independent of catenins.
Adenomatous Polyposis Coli Protein↗
Molecular and biological analysis of carcinoma of the small intestine: beta-catenin gene mutation by interstitial deletion involving exon 3 and replication error phenotype.
The genetic mechanisms of carcinomas of the small intestine are not well understood. We report the results of analysis of genetic alterations in a case of small intestinal carcinoma. A tumor in the terminal ileum was resected in a 59-yr-old woman. Histologically, the tumor was classified as well-differentiated adenocarcinoma. We screened for genetic alterations in adenomatous polyposis coli (APC), beta-catenin, K-ras, and p53 genes, as well as microsatellite instability, which are known to be involved in colorectal tumorigenesis. The tumor exhibited somatic interstitial deletion of 425-bp, which included the entire exon 3 in beta-catenin gene. Immunohistochemical staining confirmed accumulation of aberrant beta-catenin protein in the cytoplasm and nuclei of the malignant tissue. Furthermore, a frameshift mutation in the transforming growth factor beta receptor type II gene with replication error phenotype was detected in the tumor DNA. In contrast, no genetic alterations were found in the APC, K-ras, and p53 genes. Our results suggested that both beta-catenin gene mutation and replication error phenotype might contribute to carcinogenesis of the small intestinal tumor in our case. This is the first report that activation of beta-catenin gene by somatic gene mutation is involved in the development of carcinoma of the small intestine.
Amino Acid Sequence↗
Effects of sodium valproate on various intestinal motor functions after ileal J pouch-anal anastomosis.
BACKGROUND: We investigate the effects of sodium valproate, a gamma-aminobutyric acid transaminase inhibitor, on the clinico-physiologic state after ileoanal anastomosis. METHODS: Twelve patients (five with ulcerative colitis and seven with familial adenomatous polyposis coli) were studied in a placebo-controlled trial. RESULTS: Placebo had no effect, but valproate increased the resting anal pressure by 22.4% and the maximum tolerable pouch volume by 20.7%. It also prolonged pouch emptying by 47.3%, with an associated improvement in stool frequency and incontinence. These results suggested that valproate improved both reservoir continence and sphincter continence. CONCLUSIONS: Only minimal side effects were noted, so the administration of sodium valproate appears to be a safe and useful adjunct for patients with ileoanal anastomosis in the early postoperative period.
4-Aminobutyrate Transaminase↗
Long-term results of abdominal salvage surgery following restorative proctocolectomy.
BACKGROUND: This study evaluated outcomes of patients who underwent abdominal salvage ileal pouch redo surgery and identified factors associated with pouch failure following restorative proctocolectomy. METHODS: Data on patients who underwent abdominal salvage surgery in a tertiary referral centre between 1985 and 2003 were collected. Outcomes studied included failure of salvage and bowel function of patients with an intact intestine. RESULTS: One hundred and twelve patients underwent 117 pouch salvage procedures for ulcerative colitis (86), indeterminate colitis/ulcerative colitis (eight), indeterminate colitis/Crohn's disease (three), familial adenomatous polyposis (ten) and other conditions (five). The most common indications for pouch salvage were intra-abdominal sepsis (45 patients), anastomotic stricture (13) and retained rectal stump (35). Median follow-up was 46 (range 1-147) months. Twenty-four patients (21.4 per cent) experienced pouch failure, the incidence of which increased with time. The pouch failed in all patients with Crohn's disease. Successful salvage at 5 years was significantly associated with non-septic (85 per cent) rather than septic (61 per cent) indications (P = 0.016). Frequency of night-time defaecation and faecal urgency improved after salvage surgery (P = 0.036 and P = 0.016 respectively at 5-year follow-up; n = 32). CONCLUSION: Abdominal salvage surgery was associated with a failure rate of 21.4 per cent. A successful outcome was less likely when the procedure was carried out for septic compared with non-septic indications. The rate of pouch failure increased with length of follow-up.
Adolescent↗
Adenocarcinoma of the rectum with associated colorectal adenomatous polyps in tuberous sclerosis: a case report.
The authors present the case of a 17-year-old girl with tuberous sclerosis (TS) who presented with symptoms of intussusception. Although endoscopically diagnosed with multiple colonic polyps, presumed to be hamartomas, and an invasive rectal adenocarcinoma, postoperative pathology findings confirmed the rectal cancer and showed multiple colonic adenomas. Multiple colonic adenomatous polyps in a young girl with tuberous sclerosis is extremely rare. Furthermore, we believe that this is the first report of an invasive adenocarcinoma of the large intestine occurring in a patient with TS.
Adenocarcinoma↗
Studies on schistosomal rectal and colonic polyposis.
Anatomic and digestion studies were done on rectal and colonic schistosomal polyps from 30 patients. Results indicate that schistosomal colonic polyposis is principally due to high, localized egg burdens of Schistosoma mansoni or S. haematobium resulting in damage to the muscularis mucosa of the colon. Furthermore, atypically focal oviposition by S. mansoni is probably more important in genesis of rectocolonic polyposis than is schistosomiasis haematobium.
Adult↗
Gardner's syndrome.
A 22-year-old woman had multiple osteomas of the facial skeleton that were thought to represent Gardner's syndrome. At the first examination, however, other symptoms were not present. The diagnosis was established when colonic polyposis developed four years later.
Adult↗
Familial juvenile polyposis of the stomach.
Innumerable polyps of the stomach were recognized in a 13-yr old girl. She had no extragastric polyps on roentgenographic and endoscopic studies. Her elder brother received a subtotal gastrectomy because of gastric polyposis at 14 yr of age. Their mother died of gastric cancer at 37 yr of age. Only these three subjects in this family had unusual brown hair and were low in normal intelligence. Polyps produced chronic and severe loss of both blood and protein, which resolved after a subtotal gastrectomy at 18 yr of age. Macroscopic and histologic observations of polyps in the resected stomach confirmed the diagnosis of juvenile polyposis. Both siblings are now in good health. Classification of this hereditary syndrome as a newly recognized entity, familial juvenile polyposis of the stomach, is proposed.
Adolescent↗
Mouse models for hereditary nonpolyposis colorectal cancer.
Hemizygous germ-line defects in mismatch repair (MMR) genes underlie hereditary nonpolyposis colorectal cancer (HNPCC). Loss of the wild-type allele results in a mutator phenotype, accelerating tumorigenesis. Tumorigenesis specifically occurs in the gastrointestinal and genitourinary tracts; the cause of this tissue specificity is elusive. To understand the etiology and tissue distribution of tumors in HNPCC, we have developed mouse models carrying a deficiency in the MMR gene Msh2. Most of the completely Msh2-deficient mice succumbed to lymphomas at an early age; lymphomagenesis was synergistically enhanced by exposure to ethylnitrosourea. Lymphomas were absent in immunocompromised Tap1-/-;Msh2-/- mice; these mice generally succumbed to HNPCC-like tumors. Together, these data suggest that the HNPCC tumor spectrum is determined by exposure of MMR-deficient cells to exogenous mutagens, rather than by tissue-specific loss of the wild-type MMR allele or by immune surveillance. Msh2 hemizygous mice had an elevated tumor incidence that, surprisingly, was rarely correlated with loss of the Msh2+ allele. To develop a model for intestinal tumorigenesis in HNPCC, we introduced the Min allele of the Apc tumor suppressor gene. We observed loss of the wild-type Msh2 allele in a significant fraction of intestinal tumors in Apc+/Min;Msh2+/- mice. In some of the latter tumors, one area of the tumor displayed loss of the Msh2+ allele, but not of the Apc+ allele, whereas another area displayed the inverse genotype. This apparent biclonality might indicate a requirement for collaboration between independent tumor clones during intestinal tumorigenesis.
Adenomatous Polyposis Coli Protein↗
Gastric and small bowel polyps in Gardner's syndrome and familial polyposis coli.
The adenomas of Familial Polyposis Coli and of Gardner's syndrome are widely thought to affect the large bowel only. However, this report and a critical review of the literature shows that of the few hundred reported cases of these diseases, at least thirty-six have also shown gastric and/or small bowel polyps. The majority have been concentrated in stomach, duodenum and ampulla of Vater and the latter two areas have shown the highest incidence of carcinoma. It seems that gastric polyps are especially associated with Familial Polyposis Coli, and duodeno-ampullary ones with Gardner's syndrome.
Adult↗
Restorative proctocolectomy: the Irish experience. Irish Association of Coloproctology.
Between January 1982 and March 1990, 106 patients underwent restorative proctocolectomy in eight separate surgical departments. The indication for operation was ulcerative colitis in 86%, familial adenomatous polyposis in 12% and megacolon in 2%. The age at operation was 33 +/- 2 years (mean +/- sem) (range 15-55 years). There were no perioperative deaths. The principal causes of post-operative morbidity were intra-abdominal sepsis (15%), anastomotic stricture (10%) and intestinal obstruction (8%). Intestinal continuity has been restored in 99 patients. All were grossly continent, but 32% experienced occasional soiling. The mean stool frequency was 5/day and 1/night. The overall failure rate was 6%. Eighty-nine percent of patients were happy with the outcome. We conclude that restorative proctocolectomy is safe and provides acceptable functional results. It should be the operation of choice in most patients with ulcerative colitis or familial adenomatous polyposis.
Adolescent↗
Prevention of early-onset familial/hereditary colon cancer: new models and mechanistic biomarkers (review).
Human colon cancer is a multi-factorial, multi-step disease wherein genetic and dietary factors represent important regulators of initiation, promotion and progression. While the etiology of sporadic colon cancer remains largely unidentified, familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) represent predisposing genetic syndromes for early-onset familial/hereditary colon cancer. These syndromes are characterized by germ-line mutations in the adenomatous polyposis coli (APC) and/or DNA mismatch repair genes, respectively. Currently available preclinical animal models for human FAP and HNPCC syndromes, expressing clinically relevant germ-line mutations, exhibit adenomas in the small intestine rather than in the colorectum. These models are, therefore, subject to extrapolation for direct clinical translatability of the data for colon carcinogenesis and chemoprevention. Experimental models expressing clinically relevant genetic defects (APC and/or DNA mismatch repair gene mutations) in an appropriate target site (colon) may represent novel approaches that reduce extrapolation of the data for their clinical relevance. This report provides an overview on carcinogenesis and chemoprevention in preclinical models of FAP and HNPCC syndromes, and summarizes recent data on i) development of new cell culture models for FAP and HNPCC syndromes; and ii) validation of developed models for rapid, mechanism-based screening of new pharmacological or naturally occurring chemopreventive agents.
Adenomatous Polyposis Coli↗
Inverted hyperplastic polyposis of the colon.
AIMS: To describe and evaluate two apparently unique cases of inverted hyperplastic (metaplastic) polyposis of the colon. METHODS: The cases were analysed by standard histopathological, histochemical, and immunohistochemical techniques and the findings compared with those of regular hyperplastic polyps of the colorectum. RESULTS: Both patients were middle-aged men with concurrent adenocarcinoma of the proximal large intestine. The inverted polyps numbered 18 and 12, measured between 0.4 and 2.5 cm in diameter, and all were present in the proximal ascending colon. The polyps had characteristic macroscopic features: they were positioned on the apex of mucosal folds and demonstrated surface pitting and mucus hypersecretion. Histologically, inversion and misplacement of hyperplastic epithelium was related to lymphoglandular complexes. The polyps showed all the histochemical and immunohistochemical features of regular hyperplastic polyps. CONCLUSIONS: Inverted hyperplastic polyps are an unusual but distinctive polyp of the proximal colon, may be multiple, and share the phenotypic changes of regular hyperplastic polyps. The pathogenesis of epithelial inversion probably relates to misplacement of epithelium through anatomical defects in the muscularis mucosae due to mechanical forces. The polyps may mimic both adenomas and carcinomas. The neoplastic potential of inverted hyperplastic polyposis is likely to be very low: one polyp only showed adenomatous change.
Adenocarcinoma↗
Gastrointestinal lymphoma.
Primary gastrointestinal lymphoma comprises a group of distinctive clinicopathological entities, most of which are not included in current lymph node-based lymphoma classifications. They may be of B- or T-cell type, with primary gastrointestinal Hodgkin's disease being extremely uncommon. Most low grade B-cell gastrointestinal lymphomas are of mucosa-associated lymphoid tissue (MALT) type, so called because they recapitulate the features of MALT rather than those of lymph nodes. Paradoxically, however, most MALT lymphomas arise in the stomach, which normally contains no organized lymphoid tissue. These gastric MALT lymphomas appear to arise in MALT acquired as a reaction to infection of the stomach by Helicobacter pylori and their growth can be influenced by eradication of this organism from the stomach. Low grade MALT lymphomas, which usually have a very favorable clinical course, may undergo high grade transformation; high grade tumours also may arise de novo and these probably also belong to the MALT group. Immunoproliferative small intestinal disease (IPSID) is a special form of MALT lymphoma with a restricted geographic distribution, which is characterized by synthesis of alpha heavy-chain immunoglobulin. Other gastrointestinal B-cell lymphomas include mantle cell lymphoma, which presents as lymphomatous polyposis, and Burkitt's or Burkitt-like lymphoma. Enteropathy (celiac disease)-associated T-cell lymphoma (EATL) is the most common primary gastrointestinal T-cell lymphoma. This is a clinically aggressive tumor that arises from the intraepithelial T-cell population, which is increased in celiac disease.
Gastrointestinal Neoplasms↗
Familial polyposis coli. Results of mucosal proctectomy with ileoanal anastomosis.
The outcome of mucosal proctectomy with ileoanal anastomosis in patients with polyposis coli has not been well studied. A series of 25 patients with polyposis treated at the Mount Sinai Hospital over a period of ten years is reported. The mean age of the patients was 23 years. Early postoperative complications were present in seven patients and consisted of thrombophlebitis (three), pelvic sepsis (three), and retraction of the anastomosis (one). Intestinal obstruction requiring laparotomy occurred in another five patients. Twenty-three patients were followed for a mean of 47 months after closure of the ileostomy. Ninety-one percent are satisfied with the operative results. The mean number of bowel movements per 24 hours is 6.0. All patients are continent, but eight have occasional episodes of rectal seepage at night. Nearly 50 percent require some antidiarrheal medication. New adenomatous polyps have developed just above the dentate line in four patients. Patients with polyposis coli seem to have fewer serious complications requiring excision of the ileoanal anastomosis than patients with ulcerative colitis. They also should have lifelong surveillance of the entire gastrointestinal tract even after total colectomy with ileoanal anastomosis.
Adolescent↗