Dendritic cell populations in colon and mesenteric lymph nodes of patients with Crohn's disease.

Dendritic cells (DCs) are key cells in innate and adaptive immune responses that determine the pathophysiology of Crohn's disease. Intestinal DCs migrate from the mucosa into mesenteric lymph nodes (MLNs). A number of different markers are described to define the DC populations. In this study we have identified the phenotype and localization of intestinal and MLN DCs in patients with Crohn's disease and non-IBD patients based on these markers. We used immunohistochemistry to demonstrate that all markers (S-100, CD83, DC-SIGN, BDCA1-4, and CD1a) showed a different staining pattern varying from localization in T-cell areas of lymph follicles around blood vessels or single cells in the lamina propria and in the MLN in the medullary cords and in the subcapsular sinuses around blood vessels and in the T-cell areas. In conclusion, all different DC markers give variable staining patterns so there is no marker for the DC.

Genotype-phenotype correlations as a guide in the management of familial adenomatous polyposis.

BACKGROUND & AIMS: The options for prevention of colorectal cancer in familial adenomatous polyposis are either a colectomy with ileorectal anastomosis (IRA) or a total proctocolectomy with ileal pouch-anal anastomosis (IPAA). Rectal cancer risk is eliminated by IPAA, but complication rate is higher than in IRA. Mutation analysis might predict severity of polyposis and be helpful in the surgical decision. METHODS: Patients from the Dutch Polyposis Registry with an IRA were subdivided according to the site of adenomatous polyposis coli gene mutation into the attenuated (1), intermediate (2), and severe (3) genotype groups. Cumulative risks of secondary rectal excision and rectal cancer were calculated for each group. RESULTS: A total of 174 patients underwent an IRA: 26 patients from group 1, 121 from group 2, and 27 from group 3. Cumulative risks of rectal cancer 15 years after surgery were 6%, 3%, and 8% in groups 1, 2, and 3, respectively. Cumulative risks of rectal excision 20 years after IRA were 10%, 43%, and 74%, respectively. The risk of rectal excision was significantly higher in group 3 than in the other groups (P < .05). CONCLUSIONS: The risk of secondary rectal excision after IRA can be predicted on the basis of the adenomatous polyposis coli mutation site. An IRA appears to be the appropriate treatment in patients with the attenuated genotype. Patients with a severe genotype are good candidates for an IPAA.

A prospective evaluation of anorectal function after total mesorectal excision in patients with a rectal carcinoma.

BACKGROUND: Rectum resection with total mesorectal excision (TME) and neorectal anastomosis often compromises anorectal function. Insight into the underlying mechanisms is lacking. Therefore, a prospective study was designed to investigate the relationship between clinical and functional outcomes preoperatively and postoperatively. METHODS: Eleven patients with rectal cancer were examined before and 4 and 12 months after surgery and compared with 11 healthy volunteers (HVs). Anorectal (neorectal) function was examined by clinical outcome questionnaire, anal manometry, rectal compliance, and sensation. Six HVs also underwent barostat measurements in the sigmoid colon. RESULTS: Clinical parameters of soiling and passive incontinence (loss of stool without sensation) increased significantly until 12 months postoperatively, whereas urgency and tenesmus increased temporarily, returning to preoperative values at 12 months. In anorectal measurements, anal sphincter function was grossly preserved; however, rectal-anal inhibitory reflex (RAIR) was decreased at 4 months but recovered after 1 year. Neorectal compliance was similar to that of HV sigmoid, increasing slightly after 12 months but still significantly lower than that of normal rectum. Neorectal sensation to pressure distention was similar to that of normal rectum, however accompanied by smaller volumes. Neorectal distention induced contractions of large amplitude at 4 months, returning to normal after 12 months. CONCLUSIONS: Our results suggest that the transient increase in urgency and tenesmus after surgery results from a temporary increase in neorectal "irritability" accompanied by some adaptation of compliance in time. In contrast, episodes of incontinence and soiling are increased after 1 year most likely because of reduced neorectal capacity and RAIR recovery in the presence of a low basal anal sphincter pressure.

Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging--a meta-analysis.

PURPOSE: To perform a meta-analysis to compare endoluminal ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging in rectal cancer staging. MATERIALS AND METHODS: Relevant articles published between 1985 and 2002 were included if more than 20 patients were studied, histopathologic findings were the reference standard, and data were presented for 2 x 2 tables; articles were excluded if data were reported elsewhere in more detail. Two reviewers independently extracted data on study characteristics and results. Bivariate random-effects approach was used to obtain summary estimates of sensitivity and specificity for invasion of muscularis propria, perirectal tissue, and adjacent organs and for lymph node involvement. Summary receiver operating characteristic (ROC) curves were fitted for perirectal tissue invasion and lymph node involvement. RESULTS: Ninety articles fulfilled all inclusion criteria. For muscularis propria invasion, US and MR imaging had similar sensitivities; specificity of US (86% [95% confidence interval [CI]: 80, 90]) was significantly higher than that of MR imaging (69% [95% CI: 52, 82]) (P =.02). For perirectal tissue invasion, sensitivity of US (90% [95% CI: 88, 92]) was significantly higher than that of CT (79% [95% CI: 74, 84]) (P <.001) and MR imaging (82% [95% CI: 74, 87]) (P =.003); specificities were comparable. For adjacent organ invasion and lymph node involvement, estimates for US, CT, and MR imaging were comparable. Summary ROC curve for US of perirectal tissue invasion showed better diagnostic accuracy than that of CT and MR imaging. Summary ROC curves for lymph node involvement showed no differences in accuracy. CONCLUSION: For local invasion, endoluminal US was most accurate and can be helpful in screening patients for available therapeutic strategies.

The 'just-right' signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade.

According to the classical interpretation of Knudson's 'two-hit' hypothesis for tumorigenesis, the two 'hits' are independent mutation events, the end result of which is loss of a tumor suppressing function. Recently, it has been shown that the APC (adenomatous polyposis coli) gene does not entirely follow this model. Both the position and type of the second hit in familial adenomatous polyposis (FAP) polyps depend on the localization of the germline mutation. This non-random distribution of somatic hits has been interpreted as the result of selection for more advantageous mutations during tumor formation. However, the APC gene encodes for a multifunctional protein, and the exact cellular function upon which this selection is based is yet unknown. In this study, we have analyzed somatic APC point mutations and loss of heterozygosity (LOH) in 133 colorectal adenomas from six FAP patients. We observed that when germline mutations result in truncated proteins without any of the seven beta-catenin downregulating 20-amino-acid repeats distributed in the central domain of APC, the majority of the corresponding somatic point mutations retain one or, less frequently, two of the same 20-amino-acid repeats. Conversely, when the germline mutation results in a truncated protein retaining one 20-amino-acid repeat, most second hits remove all 20-amino-acid repeats. The latter is frequently accomplished by allelic loss. Notably, and in contrast to previous observations, in a patient where the germline APC mutation retains two such repeats, the majority of the somatic hits are point mutations (and not LOH) located upstream and removing all of the 20-amino-acid repeats. These results indicate selection for APC genotypes that are likely to retain some activity in downregulating beta-catenin signaling. We propose that this selection process is aimed at a specific degree of beta-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all of the beta-catenin downregulating motifs in APC.