Stereomicroscopic features of colitis-associated tumors in mice: Evaluation of pit pattern.

Patients with longstanding ulcerative colitis have an increased risk of colorectal cancer. Mouse models for colitis-associated tumors are indispensable for the development of novel strategies for prevention and intervention, as well as an improved understanding of the mechanisms underlying tumor formation. The present study examined whether stereomicroscopic observations with dye-application were able to detect and discriminate tumors in a colitis-associated tumor model in mice. Colonic tumors were induced in C57BL/6 mice by 15 cycles of treatment with dextran sulfate sodium (DSS) in drinking water. The mice were then divided into 4 groups: normal mice fed a control diet, normal mice fed an iron-supplemented diet, 0.7% DSS mice fed an iron diet and 1.5% DSS mice fed an iron diet. The entire colons were characterized with respect to both morphology and histology. The pit pattern architecture was analyzed using stereomicroscopy with dye agents (0.2% indigo carmine or 0.06% crystal violet). The tumor histology was graded as negative, indefinite or positive for dysplasia. The positive category was divided into two subcategories: low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The tumor incidences and multiplicity were significantly higher in mice fed an iron diet and 1.5% DSS compared with in mice fed an iron diet and 0.7% DSS. Compared with LGD, HGD was predominantly located in the distal colon, was larger in size and had a higher incidence of elevated lesions (Is and IIa) and a lower incidence of flat lesions (IIb). In regards to the pit pattern, HGD had a high incidence of VI pits and a low incidence of IV, IIIL and II pits. In conclusion, evaluation of the pit pattern using stereomicroscopy with dye-application is useful for detecting and discriminating neoplastic changes in DSS mice and may further our understanding of the mechanisms that induce tumor formation in patients with ulcerative colitis and the characterization of pharmaceutical responses.

Increased levels of circulating adrenomedullin following treatment with TU­100 in patients with Crohn's disease.

Daikenchuto (TU­100) is a traditional Japanese medicine that is widely used to treat intestinal symptoms. The mechanisms underlying it effects on the circulating levels of adrenomedullin (ADM) are of interest. In addition, the effect of TU­100 in the treatment of Crohn's disease (CD) in humans remains to be elucidated. The primary objective of the present study was to evaluate the effect of TU­100 on the circulating ADM levels in patients with active CD. An additional objective was to assess the effect of the drug on the disease activity and its potential side effects. In an open­label study, 10 patients with active CD received 15 g TU­100 per day for 8 consecutive weeks, and baseline anti­inflammatory therapy was continued. The pre­ and post­treatment blood plasma levels of total ADM (t­ADM) and mature­ADM (m­ADM) were determined using enzyme­linked immunosorbent assays. The response of patients to the treatment was evaluated clinically using the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) score. The plasma levels of t­ADM (16.4±1.1 vs. 20.2±1.7 fmol/ml, P=0.0218) and m­ADM (1.7±0.1 vs. 2.2±0.1 fmol/ml, P=0.0284) increased following 8 weeks of TU­100 treatment, compared with control. The IOIBD score of patients also improved, with a significant decrease in the score from 3.9±0.5 at 0 weeks to 2.4±0.4 at 8 weeks (P=0.0284). Out of the 10 components of the IOIBD scoring system, the scores for abdominal pain and tenderness, decreased significantly (P=0.014 and P=0.046). Therefore, TU­100 was safe and well­tolerated by the patients that participated in the current study. The present study determined that the pharmacologic action of TU­100 is associated with changes in the circulating ADM levels and that treatment with TU­100 may aid in the management of CD. These promising findings warrant further investigation in larger, multicenter studies.