Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice.

Fibroblast growth factor-19 (human FGF19; murine FGF15) suppresses bile acid synthesis. In FGF19 deficiency, diarrhea resulting from bile acid spillage into the colon mimics irritable bowel syndrome. To seek other consequences of FGF19/15 deficiency, we used Fgf15-/- and wild-type (WT) mice to assess gallbladder filling, the bile acid pool, fecal bile acid levels, and colon neoplasia. We fasted mice for six hours before assessing gallbladder size by magnetic resonance imaging (MRI). We measured bile acid levels in different compartments by enzymatic assay, and induced colon neoplasia with azoxymethane (AOM)/dextran sodium sulfate (DSS) and quantified epithelial Ki67 immunostaining and colon tumors 20 weeks later. In vivo MRI confirmed the gross finding of tubular gallbladders in FGF15-deficient compared to WT mice, but fasting gallbladder volumes overlapped. After gavage with a bile acid analogue, ex vivo MRI revealed diminished gallbladder filling in FGF15-deficient mice (P = 0.0399). In FGF15-deficient mice, the total bile acid pool was expanded 45% (P <0.05) and fecal bile acid levels were increased 2.26-fold (P <0.001). After AOM/DSS treatment, colons from FGF15-deficient mice had more epithelial cell Ki67 staining and tumors (7.33 ± 1.32 vs. 4.57 ± 0.72 tumors/mouse; P = 0.003 compared to WT mice); carcinomas were more common in FGF15-deficient mice (P = 0.01). These findings confirm FGF15, the murine homolog of FGF19, plays a key role in modulating gallbladder filling and bile acid homeostasis. In a well-characterized animal model of colon cancer, increased fecal bile acid levels in FGF15-deficient mice promoted epithelial proliferation and advanced neoplasia.

Should hot biopsy forceps be abandoned for polypectomy of diminutive colorectal polyps?

Standardized approach to polypectomy of diminutive colorectal polyps (DCPs) is lacking since cold biopsy forceps have been associated with high levels of recurrence, hot biopsy forceps are considered inadequate and risky and cold snaring is currently under investigation for its efficacy and safety. This has led to confusion and a gap in clinical practice. This article discusses the usefulness and contemporary practical applicability of hot biopsy forceps and provides well-intentioned criticism of the new European guidelines for the treatment of DCPs. Diminutive colorectal polyps are a source of frustration for the endoscopist since their small size is accompanied by a considerable risk of premalignant neoplasia and a small but non-negligible risk of advanced neoplasia and even cancer. Since the proportion of diminutive colorectal polyps is substantial and exceeds that of larger polyps, their effective removal poses a considerable workload and a therapeutic challenge. During the last decade, the introduction of cold snaring to routine endoscopy practice has attempted to overcome the use of prior techniques, such as hot biopsy forceps. It is important to recognize that with the exception of endoscopic methods that are obviously unsafe and inadequate to serve their purpose, all other interventional endoscopic methods are operator-dependent in the sense that specific expertise and training are obligatory for the success of any therapeutic intervention. Since relevant publications on hot biopsy forceps are still in favor of its careful use, as it has not yet demonstrated inferiority compared with newer techniques, it would be prudent for any medical practitioner to evaluate the available tools and judge any new proposed technique based on the evidence before it is adopted.

Differential expression of M3 muscarinic receptors in progressive colon neoplasia and metastasis.

M3 muscarinic receptor (M3R) activation promotes colon cancer cell proliferation, migration, and invasion in vitro. Although over-expression of CHRM3, the gene encoding M3R, is reported in primary colon cancers, expression of M3R itself has not been studied in colon neoplasia. We compared M3R expression in normal colon to colon adenomas, and primary and metastatic colon cancers. Compared to adjacent normal colon, CHRM3 expression was increased up to 128-fold in 10 of 18 consecutive surgical cancer specimens (56%) and associated with metastatic spread (P < 0.05). To analyze M3R protein expression we interrogated 29 consecutive paraffin-embedded colon adenocarcinomas and adjacent normal colon using a specific anti-M3R antibody and immunoperoxidase staining. This revealed weak M3R expression in normal colonocytes, primarily on basolateral surfaces. In contrast, in 25 of 29 cancer tissues (86%) we observed both cytoplasmic and plasma membrane over-expression of M3R; compared to normal epithelium, mean M3R staining intensity was increased more than two-fold in colon cancer (P < 0.001). M3R staining was also increased in 22 colon adenomas compared to adjacent normal colon (P < 0.001). In contrast, M3R staining intensity was not increased in lymph node or liver metastases. These findings suggest M3R expression plays an important role in early progression and invasion of colon neoplasia but is less important once tumors have spread.

Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer.

The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and microRNA expressions in colorectal cancer.

Primary sclerosing cholangitis and the risk of colon neoplasia in patients with Crohn's colitis.

BACKGROUND AND AIM: Crohn's colitis (CC) is associated with primary sclerosing cholangitis (PSC). However the risk of colon cancer or dysplasia in CC and PSC is unclear. Our aim was to study the risk of colon neoplasia in CC in patients with and without PSC. METHODS: This is a nested, case-control cohort study of all patients diagnosed with concurrent CC and PSC, seen at the Cleveland Clinic between 1985 and 2012. Forty-three patients with both CC and PSC were compared with a random sample of 159 CC controls without PSC during the same period. RESULTS: Seven (16.3%) of 43 CC patients with PSC developed colon cancer or dysplasia, compared with 22 (13.8%) of 159 controls (P = 0.98). Of seven colon neoplasia cases in the PSC group, 100% occurred proximal to the splenic flexure, compared with 50% (11/22) cases of colon neoplasia in controls occurring in the proximal colon (P = 0.001). Based on Cox regression analysis, male gender independently increased the risk of neoplasia [hazard ratio (HR) = 2.68; 95% confidence interval (CI) 1.30-5.54; P = 0.008], as did age at CC diagnosis (HR = 1.29; 95% CI 1.14-1.47; P < 0.001), while the use of azathioprine/6-mercaptopurine was protective (HR = 0.30; 95% CI 0.13-0.70; P = 0.005). The presence of PSC did not increase the risk for colon neoplasia (HR = 0.45; 95% CI 0.18-1.13; P = 0.09). CONCLUSIONS: CC patients with PSC appear not to be at increased risk of developing colon neoplasia. Among patients in our cohort with colon neoplasia and concurrent PSC, the neoplasia occurred in the proximal colon in all cases.

Comparison of outcomes for patients with primary sclerosing cholangitis associated with ulcerative colitis and Crohn's disease.

BACKGROUND: The comparative outcomes of ulcerative colitis (UC) and Crohn's disease (CD) in patients with primary sclerosing cholangitis (PSC) are unclear; the aim of our study was to make an objective comparison. METHODS: A total of 273 patients with PSC and inflammatory bowel disease (223 with UC and 50 with CD) were included. Clinical and demographic variables were obtained. RESULTS: The PSC risk score was similar for both groups. The median follow-up period in patients with PSC-UC was 12 years (range 0-38) and that for PSC-CD was 14 years (range 1-36). The median number of disease flares per year was higher in PSC-UC patients than in the PSC-CD group [1vs.0 (ranges 0-20 and 0-9, respectively); P < 0.001]. More patients with UC developed colon neoplasia than CD (35.9% vs.18%; P = 0.009). On proportional hazards analysis for the risk of colectomy, UC patients had a 12% higher risk for colectomy [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.51-1.51; P = 0.64]. Liver transplantation for PSC was associated with decreased risk (HR = 0.57; 95% CI 0.37-0.89; P = 0.013), while colon neoplasia increased the risk (HR = 3.83; 95% CI 2.63-5.58; P < 0.001) for colectomy. On proportional hazards analysis for the risk of colon neoplasia, UC patients had 56% higher risk of developing colon neoplasia than CD (HR = 0.44; 95% CI 0.16-1.25; P = 0.12). CONCLUSIONS: PSC patients with CD appear to be associated with a lower risk of colon neoplasia and colectomy than PSC patients with UC.

High-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps.

Colorectal cancer is one of the leading causes of death worldwide. The progression from adenoma to cancer is a well known phenomenon. Current clinical practice favors colonoscopy as the preferred modality for colorectal cancer screening. Many novel endoscopic technologies are emerging for the purposes of performing "optical biopsy" to allow real-time histologic diagnosis of polyps. High resolution microendoscopy is a low-cost endoscopic technology that has demonstrated high sensitivity and specificity in differentiating neoplastic and non-neoplastic polyps. With the ability to make real-time conclusions based on the endoscopic appearance of polyps, it is becoming increasingly possible to decrease the rate of unnecessary polypectomies and utilize a "resect and discard" strategy to decrease costs of pathology evaluation. Future directions for this technology include surveillance of premalignant conditions such as inflammatory bowel disease. Moreover, the low cost and relative ease of use of this technology lends itself to widespread applicability.

New isolated bovine colon model dedicated to colonic ESD hands-on training: development and first evaluation.

INTRODUCTION: ESD is the reference method to achieve en bloc resections for large digestive lesions. Nevertheless, it is a difficult and risky technique. Animal models exist to teach the initial skills, particularly in Japan, where pigs' stomachs are dedicated models to gastric ESD. In Europe, we have to develop different strategies of teaching with dedicated colon models. A pig colon is a good model but thinner and narrower than a human's. In this present work, we evaluated a bovine colon model to perform rectal ESD in retroflexion. METHODS: First, we prepared six bowels to precise the preparation protocol. Then, two endoscopists unexperienced in ESD performed 64 procedures on eight models. Learning curves and factors of variation were studied. RESULTS: A precise protocol to prepare the colon was defined. The two students achieved en bloc resection in 89.1 % of cases with a rate of 6.2 % of perforations. A large heterogeneity appeared between the speed and the success rate depending mainly on the age of the animal bowel. Using calf colons, the failure rates were higher (p = 0.002) and the speed was lower (p < 0.001) than for adult bovine ones. A learning curve appeared with, respectively, 0.49 and 0.59 cm(2)/min throughout the study. No significant difference appeared between measured and calculated specimen areas. DISCUSSION: Bovine colon is a new model to teach ESD in colorectal conditions. The bovine age is important to homogenize the model. A learning curve existed with a time procedure decreasing throughout the study. Further studies are needed to evaluate the precise learning curve with more students. CONCLUSION: A bovine colon model is a suitable model to teach colorectal ESD. Nevertheless, an adult bovine colon model is more homogeneous than a calf one.

Linfoma primário de cólon: relato de caso / Primary colorectal lymphoma: case report

O linfoma colorretal primário é uma doença rara (0.2 a 0.6 por cento de todas as neoplasias colônicas), apresentando pior prognóstico quando comparado com o linfoma gástrico primário ou com o adenocarcinoma do cólon. É uma doença com sintomatologia inespecífica, o que dificulta o diagnóstico precoce. O objetivo deste relato é mostrar um caso de linfoma primário do cólon, revisar critérios diagnósticos e tratamento.

The primary colorectal lymphoma is a rare disease (0.2 to 0.6 percent of all colonic neoplasias), that has a worse prognosis than primary gastric lymphoma or colon adenocarcinoma. The poor signals makes the early diagnosis difficult. The objectives of this report is to describe a case of primary colon lymphoma, revise diagnosis criteria and treatment.

Estudo da relação entre a imunoexpressão das proteínas caderina-E e DCC com o grau de diferenciação celular e o estadiamento TNM do adenocarcinoma colorretal / Study of the expression of E-cadherin and DCC proteins with cell differentiation degree and staging in colorectal adenocarcinoma

OBJETIVO: Avaliar a relação de duas proteínas que participam do mecanismo de adesão celular com o grau de diferenciação celular e os estadiamentos TNM (T: tumor, N: linfonodo, M: metástase) I e IV no câncer de cólon e reto. MÉTODOS: Foram estudados cem pacientes (54 homens e 46 mulheres) tratados por adenocarcinoma colorretal, estádios I (44) e IV (56). Os cortes histológicos do tecido tumoral foram examinados por técnica de imuno-histoquímica em relação à imunoexpressão das proteínas caderina-E e delect in colon cancer (DCC), sendo classificados como positivos quando se detectou a imunoexpressão dessas proteínas em 50 por cento ou mais das células tumorais. RESULTADOS: Para o TNM, imunoexpressão da caderina-E estádio I: positiva em 72,7 por cento e negativa em 35,7 por cento ; estádio IV: positiva em 64,3 por cento e negativa em 35,7 por cento. Proteína DCC: 43,2 por cento positiva e 56,8 por cento negativa no estádio I, e 50 por cento positiva e 50 por cento negativa no estádio IV. Em relação ao grau de diferenciação celular, imunoexpressão da caderina-E - GI: positiva em 70 por cento e negativa em 30 por cento; GII: positiva em 68,4 por cento e 31,6 por cento negativa; GIII: 63,6 por cento positiva e 36,4 por cento negativa. Imunoexpressão da DCC - GI: 40 por cento positiva e 60 por cento negativa; GII: 46,8 por cento positiva e 53,2 por cento negativa; GIII: 54,5 por cento positiva e 45,5 por cento negativa. Não houve diferença significativa entre os grupos. CONCLUSÃO: Os resultados dessa pesquisa permitem concluir que não há relação da imunoexpressão das proteínas caderina-E e DCC com o estadiamento TNM (I e IV) e o grau de diferenciação celular no carcinoma colorretal.

OBJECTIVE: Evaluate the relationship of two proteins, which take part in the same mechanism of cell adhesion, with the cell differentiation degree and TNM staging I and IV in colorectal cancer. METHODS: One-hundred patients (54 men and 46 women), who have received treatment for colorectal cancer, stages I (44) and IV (56), have been studied. Histological cuts of tumor tissue were examined by the immunohistochemical technique as to the expression of E-cadherin and delect in colon cancer (DCC) proteins, being classified as positive whenever it was detected immunoexpression of such proteins in 50 percent or more tumor cells. RESULTS: For TNM, E-cadherin immunoexpression for stage I: positive in 72.7 percent and negative in 35.7 percent; stage IV: positive in 64.3 percent and negative in 35.7 percent. For DCC protein: 43.2 percent positive and 56.8 percent negative in stage I, and 50 percent positive and 50 percent negative in stage IV. Regarding the cell differentiation degree, the immunoexpression of E-cadherin - GI: positive in 70 percent and negative in 30 percent; GII: positive in 68.4 percent and negative in 31.6 percent; GIII: positive in 63.6 percent and negative in 36.4 percent. The immunoexpression of DCC - GI: 40 percent positive and 60 percent negative; GII: 46.8 percent positive and 53.2 percent negative; GIII: 54.5 percent positive and 45.5 percent negative. There was no significant difference among groups. CONCLUSION: The results of this research make it possible to come to the conclusion that there is no relationship between the immunoexpression of E-cadherin and DCC proteins with TNM staging (I and IV) and cell differentiation degree in colorectal cancer.