A Karrenbeld

Review article: anthranoid laxatives and their potential carcinogenic effects

Anthranoid laxatives are widely used laxatives of natural origin. Because of their chemical structure they are carried unabsorbed to the large bowel, where metabolism to the active aglycones takes place. These aglycones exert their laxative effect by damaging epithelial cells, which leads directly and indirectly to changes in absorption, secretion and motility. Damaged epithelial cells can be found as apoptotic bodies in the pigmented colonic mucosa, characteristic for pseudomelanosis coli. Pseudomelanosis coli is a condition caused by chronic (ab)use of anthranoid laxatives and has recently been associated with an increased risk of colorectal carcinoma. In vitro and animal studies have shown a potential role of anthranoid laxatives in both the initiation and promotion of tumorigenesis. Studies in humans have also suggested tumour promoting activities for these laxatives. Although the short‐term use of these substances is generally safe, long‐term use cannot be recommended.

Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes' C colon cancer

OBJECTIVE:It has been suggested that KRAS and TP53 mutated tumors might influence the phenotypic behavior of left- and right-sided colon tumors. We investigated the incidence of these mutations in left- and right-sided colon tumors and their possible influence on survival in a homogeneous group of patients with Dukes’ C colon cancers.METHODS:The primary tumors of 55 patients with a sporadic Dukes’ C colon cancer, all treated with adjuvant chemotherapy were analyzed for the presence of KRAS and TP53 mutations. Mutation detection of the KRAS and TP53 genes was performed on paraffin-embedded tumor material, using denaturating gradient gel electrophoresis. The 5-yr survival rates of KRAS and TP53 mutated tumors were analyzed regarding right-sided tumors (defined as tumors up to the splenic flexure) and left-sided tumors (defined as tumors from the splenic flexure to the rectosigmoid peritoneal reflection).RESULTS:KRAS mutations occurred more frequently in the right colon compared to the left colon (R = 38% (10/26); L = 10% (3/29); χ2 test: p = 0.014). KRAS mutations did not influence survival in patients with right-sided colon tumors. Patients with KRAS mutation–negative tumors in the right colon, however, had a significantly worse survival than patients with left-sided KRAS mutation–negative tumors (5-yr survival; R: 34% vs L: 65%, log-rank test: p = 0.007). TP53 mutations of a possible causative nature were found in 24 tumors (44%). Neither the incidence (R = 42% (11/26); L = 45% (13/29)) nor the survival of TP53 mutated tumors differed significantly between left- and right-sided tumors. Furthermore, survival of patients with TP53 mutation–negative tumors did not differ significantly between left- and right-sided tumors.CONCLUSIONS:There seems to be no difference in survival rate between patients with KRAS mutated and KRAS negative Dukes’ C colon tumors; however, KRAS mutations are more frequently found in the right colon compared to the left colon. TP53 mutations do not have predominance for either side of the colon, and there are no differences in survival in patients with left-sided versus right-sided tumors. Patients with KRAS-nonmutated tumors in the right colon did have a worse survival compared to those with such tumors in the left colon. This suggests that other genetic factors may play a role in tumor genesis in this subgroup of patients.

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: Case series, review and follow-up guidelines

BACKGROUND Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening. METHODS AND RESULTS The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression. CONCLUSIONS Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.

Impact of the number of histologically examined lymph nodes on prognosis in colon cancer : a population-based study in the Netherlands

PURPOSE: The impact of the reported number of lymph nodes at pathologic examination of colon specimens on survival was studied. METHODS: The data of 2,281 patients with localized colon cancer were retrospectively reviewed. The effect of tumor characteristics and surgical and pathologic factors on the number of lymph nodes and examined lymph node numbers on nodal status and survival were analyzed. RESULTS: The number of examined nodes increased with T stage, left-sided tumors, and mucinous morphology, but decreased with age. The proportion of node-positive patients increased with a larger number of nodes. A high number of examined nodes and high T stage affected nodal status. The five-year overall survival was 51.3 percent for node-positive patients vs. 68.2 percent for node-negative patients. Node-negative patients had a significantly higher five-year crude and relative survival when more lymph nodes were examined. This was not found for the node-positive group and for all patients combined. CONCLUSIONS: T stage, localization, and patient age were predictive for the number of nodes examined. A higher number of examined nodes was associated with an increase in node positivity. The survival benefit can be explained by stage migration. Eventually this may lead to an overall survival benefit, as more patients are classified as node-positive, and therefore will receive adjuvant therapy.

Inflammatory bowel disease after liver transplantation: a role for cytomegalovirus infection

Objective. Despite the use of immunosuppressive drugs, recurrent and de novo inflammatory bowel disease (IBD) can develop after orthotopic liver transplantation (OLT). Cytomegalovirus (CMV) infection has been suggested to play a role in the pathogenesis of IBD. The aim of this study was to investigate the role of CMV infection in the development of IBD after OLT. Material and methods. All 84 patients who underwent transplantation for primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) in our center between May 1987 and June 2002 and who survived the first year after transplantation were included in the study. Diagnosis of active CMV infection was made using the pp65–antigenemia assay. Results. Thirty-one of the 84 patients (37%) had IBD prior to OLT. Eighteen patients (21%) experienced IBD after OLT, either as flare-up (n=12) or de novo (n=6), at a median of 1.4 years (range 0.3 to 6.3) after OLT. Forty-eight percent of all patients experienced CMV infection after OLT, at a median of 27 days (range 8 to 193). CMV infection was primary in half the patients. At 1, 3, and 5 years after OLT, active IBD-free survival without CMV infection was 91, 88, and 88%, respectively. With CMV infection these figures were 93, 82, and 67%. De novo IBD was seen only in those who had experienced a CMV infection (p=0.02). Conclusions. In patients transplanted for end-stage PSC or AIH, active IBD, especially de novo IBD, occurred more often in patients who experienced CMV infection in the postoperative period. This finding supports a pathogenic role for CMV in the development of IBD.

Dysplasia in fundic gland polyps is associated with nuclear beta-catenin expression and relatively high cell turnover rates

Background: Fundic gland polyps (FGPs) occur in both syndromic and sporadic form. Syndromic FGPs arise through mutations in the adenomatous polyposis coli (APC) gene, whereas sporadic FGPs are caused by

Prognostic significance of K-ras and TP53 mutations in the role of adjuvant chemotherapy on survival in patients with Dukes C colon cancer

-catenin gene mutations. Dysplasia in sporadic FGPs, found less often than in syndromic FGPs, was recently associated with APC rather than

Molecular Fluorescence Endoscopy Targeting Vascular Endothelial Growth Factor A for Improved Colorectal Polyp Detection

-catenin mutations. These data suggest different functional consequences of APC and

Residual Tumor After Neoadjuvant Chemoradiation Outside the Radiation Therapy Target Volume: A New Prognostic Factor for Survival in Esophageal Cancer

-catenin mutations. To investigate this hypothesis, we examined proliferative activity, degree of apoptosis, # -catenin expression and p53 expression in syndromic and sporadic FGPs. Methods: Syndromic FGPs ( n r = r 9) from familial adenomatous polyposis (FAP) patients and sporadic FGPs ( n r = r 18) were studied. Proliferative activity, apoptotic cell death and expression of # -catenin and p53 were examined by immunohistochemistry. In FGPs containing dysplasia, areas with and without dysplasia were compared. Results: Syndromic and sporadic FGPs without dysplasia exhibited similar proliferative activity, degree of apoptosis, # -catenin and p53 expression. Dysplasia was observed more often in syndromic (4/9) than in sporadic FGPs (1/18). Within FGPs containing dysplasia, dysplastic areas showed abnormal nuclear # -catenin staining in 3/5 cases and higher rates of cell proliferation and apoptosis than non-dysplastic areas. Overexpression of p53 was not observed. Conclusion: The finding of similar rates of proliferation and apoptosis in syndromic and sporadic FGPs does not support the hypothesis that APC and

Abdominal angina in patients with a midgut carcinoid, a sign of severe pathology

-catenin gene mutations have different functional consequences in FGPs. The association of dysplasia with relatively high cell turnover rates and nuclear expression of