Kenta Nagai

The water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia (Designated as MAK) ameliorates murine colitis induced by trinitrobenzene sulphonic acid.

Ganoderma lucidum Karst is well known as ‘Reishi’, a traditional food in China and Japan. It contains a polysaccharide component known to induce granulocyte macrophage colony‐stimulating factor (GM‐CSF) production from murine splenocytes. Moreover, GM‐CSF may be a therapeutic agent for Crohn’s disease. In this study, we investigated the water‐soluble, polysaccharide components of Reishi (designated as MAK) in murine colitis induced by trinitrobenzene sulphonic acid (TNBS). We examined the concentration of GM‐CSF in peritoneal macrophage cells (PMs) of C57BL/6 mice during in vitro and in vivo stimulation with MAK. After feeding with chow or MAK for 2 weeks, 2 mg of TNBS/50% ethanol was administered to each mouse. After 3 days of TNBS treatment, intestinal inflammation was evaluated, and mononuclear cells of the mesenteric lymph nodes (MLNs) and colon were cultured for ELISA. To determine the preventive role of GM‐CSF, the mice were pre‐treated with or without anti‐GM‐CSF antibody before TNBS administration. In vitro and in vivo MAK‐stimulated PMs produced GM‐CSF in a dose‐dependent manner. Intestinal inflammation by TNBS was improved by feeding with MAK. MLNs of mice treated with TNBS produced IFN‐γ, which was inhibited by feeding with MAK. In contrast, MLNs of mice treated with TNBS inhibited GM‐CSF production, which was induced by feeding with MAK. The colon organ culture assay also revealed that IFN‐γ was decreased and GM‐CSF was increased by MAK. The preventive effect was blocked by the neutralization of GM‐CSF. We concluded that the induction of GM‐CSF by MAK may provide the anti‐inflammatory effect.

Is It Possible to Discriminate Between Neoplastic and Nonneoplastic Lesions in Ulcerative Colitis by Magnifying Colonoscopy

Background:Colitis-associated cancer/dysplasia is an intestinal tract condition that can affect the life expectancy of patients with ulcerative colitis. It is often difficult to detect neoplastic lesions. This study evaluated whether any endoscopic features are effective for distinguishing colitis-associated cancer/dysplasia from nonneoplastic lesions in patients with ulcerative colitis. Methods:The study involved 52 patients with 61 lesions treated at Hiroshima University Hospital between September 1999 and May 2012: 10 patients with 11 dysplastic lesions, 5 patients with 5 intramucosal carcinomas, 3 patients with 3 submucosal carcinomas, and 34 patients with 42 nonneoplastic lesions. All patients had undergone targeted biopsy. Endoscopic findings were compared between patients with biopsy-determined neoplasia and those with biopsy-determined nonneoplasia. Multivariate regression analysis was performed to identify magnifying chromocolonoscopy features predictive of neoplasia. Results:No significant difference was found in conventional endoscopy features between the neoplastic and nonneoplastic lesions. Under magnifying chromocolonoscopy, the pit density of the neoplastic lesions was found to be significantly greater than that of the nonneoplastic lesions (89% [17/19] versus 60% [25/42], respectively). Pit margins were more frequently irregular in the neoplastic lesions than in the nonneoplastic lesions (63% [12/19] versus 33% [14/42], respectively). Conclusions:In differentiating between colitis-associated neoplastic and nonneoplastic lesions, focus should be on the high residual density of pits and irregular pit margins observed under magnifying chromocolonoscopy.

Role of Natural Killer T Cells in the Mouse Colitis‐Associated Colon Cancer Model

Invariant natural killer T (iNKT) cells are considered innate‐like lymphocytes, and regulate the immunity against inflammation and tumorigenesis. However, the impact of iNKT cells in inflammation‐associated tumorigenesis remains unclear. In this study, we examined the physiological role of iNKT cells in a mouse colitis‐associated colorectal cancer model. C57BL/6 (B6) and Jα18 NKT cell‐deficient KO (KO) mice were used. Colitis‐associated colorectal cancer was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). The resulting inflammation and tumours were examined. The surface markers of mononuclear cells from the liver and the colon were assessed by FACS. The levels of IL‐13 from the colon were measured by ELISA. α‐galactosylceramide (GC), or its close analog OCH, was administered intraperitoneally on the first day of each cycle of DSS‐administration. In the AOM/DSS model, hepatic iNKT cells were significantly decreased. In KO mice there were significantly greater numbers of colon tumours and more severe inflammation than in B6 mice. FACS analysis revealed that the population of NK1.1 + T cells (non‐invariant NKT cells) in the colon was increased when compared to B6 mice. The secretion of IL‐13 was increased in the colon of KO mice after AOM/DSS. The number of colon tumours was significantly decreased in the GC‐treated group compared to the control group. GC‐treatment significantly inhibited IL‐13 secretion from the colonic mononuclear cells and the number of colonic NK1.1 + T cells was significantly decreased. These results suggest that iNKT cells may play a critical role in the prevention of tumour progression and inflammation in the AOM/DSS model.

Clinical usefulness of classification by transabdominal ultrasonography for detection of small-bowel stricture.

Abstract Objective. To assess the clinical usefulness of transabdominal ultrasonography (TUS) for detection of small-bowel stricture. Patients and methods. Subjects were 796 patients undergoing double-balloon endoscopy (DBE), December 2003–October 2011. All underwent TUS prior to DBE. The TUS findings were classified by type as intestinal narrowing and distension at the oral side (Type A); extensive bowel wall thickening (Type B); focal bowel wall thickening (Type C) or no abnormality detected (Type D). We compared TUS findings against DBE findings with respect to small-bowel stricture, defined as failure of the enteroscope to pass through the small bowel. Results. Small-bowel stricture was detected by DBE in 11.3% (90/796) of patients. Strictures resulted from Crohns disease (n = 36), intestinal tuberculosis (n = 24), malignant lymphoma (n = 9), ischemic enteritis (n = 6), NSAID ulcer (n = 5), radiation enteritis (n = 2), surgical anastomosis (n = 2) and other abnormalities (n = 6). Stricture was detected by TUS in 93.3% (84/90) of patients, and each such stricture fell into one of the three types of TUS abnormality. The remaining 6 strictures were detected only by DBE. DBE-identified strictures corresponded to TUS findings as follows: 100% (43/43) to Type A, 59.1% (29/49) to Type B, 14.8% (12/81) to Type C and 1% (6/623) to Type D. Correspondence between stricture and the Type A classification (vs. Types B, C and D) was significantly high, as was correspondence between stricture and Type B (vs. Types C and D). Conclusions. TUS was shown to be useful for detecting small-bowel stricture. We recommend performing TUS first when a small-bowel stricture is suspected.

Successful Use of Adalimumab for Treating Pyoderma Gangrenosum with Ulcerative Colitis under Corticosteroid-tapering Conditions.

A 52-year-old woman with ulcerative colitis was admitted to our hospital for an ulcerative colitis flare-up under salazosulfapyridine therapy. The symptoms improved with high-dose corticosteroids. After prednisolone was tapered to 10 mg, the frequency of diarrhea increased. The diarrhea was accompanied by joint pain and a skin ulcer with abscess formation, which was diagnosed to be pyoderma gangrenosum. The patient was started on adalimumab. A positive response to the adalimumab therapy was observed after 2 weeks, during which time the ulcerative skin lesion healed completely, however, colonic mucosal healing was achieved at 2 months. Therefore, adalimumab appears to be an effective therapeutic option for patients with ulcerative colitis-associated pyoderma gangrenosum.

Intestinal Tuberculosis with Hoarseness as a Chief Complaint due to Mediastinal Lymphadenitis

A 68-year-old woman was admitted to our hospital complaining of hoarseness. A chest X-ray detected an abnormal shadow on the upper right lung. Bronchoscopic examination revealed that the left vocal cord was fixed in the paramedian position, and therefore left recurrent nerve paralysis was suspected. Lymphadenopathy was found in the left supraclavicular area. Chest computed tomography showed that the pretracheal and subaortic lymph nodes were swollen. Gastroendoscopy showed a 2-cm protruding lesion with ulceration on the upper esophagus. Histological examination of the supraclavicular lymph nodes and biopsy specimens from the esophagus revealed non-specific inflammation. PET-CT showed abnormal accumulations not only on the upper right lung but also on the lower right of the abdomen. Colonoscopy was performed and multiple erosions on the terminal ileum were found. Polymerase chain reaction analysis of a specimen biopsied from the erosion of the terminal ileum was positive for Mycobacterium tuberculosis and intestinal tuberculosis was diagnosed. The patient was then treated with anti-tuberculous therapy. After treatment, the erosions on the terminal ileum, the swelling of the mediastinal lymphadenopathy, and the esophageal ulcer were all improved. The hoarseness was subsequently relieved. This is the first report of intestinal tuberculosis with hoarseness as a chief complaint due to mediastinal lymphadenitis.

Two Cases of Severe Ulcerative Colitis with Colonic Dilatation Resolved with Tacrolimus Therapy

We report 2 cases of ulcerative colitis (UC) with intestinal tract dilatation treated with tacrolimus. They were 53- and 64-year-old males, who had been admitted to local hospitals for increasing severity of their UC symptoms. Treatment for severe UC was immediately started, but both cases were refractory to corticosteroid therapy; they were then transferred to our hospital. When they were referred to our hospital, they had frequent bloody diarrhea, fever, severe abdominal pain, and even dilatation of the transverse colon on abdominal X-ray test. They were treated with oral tacrolimus medication, and their symptoms improved immediately. Dilatation of the transverse colon was improved on plain X-ray at 2 weeks after starting therapy, and emergency colectomy could be avoided. These 2 cases may suggest that tacrolimus is effective for UC with colonic dilatation as a rescue therapy.

Abstract LB-296: Involvement of T-cell immunity in changes in the plasma amino acid profiles of patients with colorectal cancer

Metabolic changes in patients with various disorders, including liver disease and cancer, lead to alterations in amino acid balance, and plasma amino acid profiles can be used to discriminate between non-malnourished patients with cancer and healthy individuals. Not with standing, the mechanisms of amino acid imbalance are not well understood. In patients with cancer, various factors including metabolic changes in the tumor itself and immune responses may affect plasma amino acid levels. To investigate involvement of the immune system, we measured plasma amino acid levels in an orthotopic transplant model of colon cancer established in both conventional BALB/c mice and athymic BALB/c nude mice (T-lymphocyte-deficient mice). CT26 colon cancer cells (murine colon cancer cell line) were implanted into the cecal wall of the BALB/c mice (n=10) and nude mice (n=10). Plasma samples were collected from the tumor-bearing mice at 7 and 14 days after transplantation, and changes in plasma amino acid profiles were compared. Plasma was also collected from mice that underwent sham operation (control mice, n=10). Plasma amino acid concentrations were measured by LC/MS/MS. The plasma concentrations of several amino acids changed significantly in tumor-bearing mice compared to concentrations in control mice. Although cells from the same line were injected into the cecal wall of BALB/c mice and nude mice, a difference was noted in the change in plasma amino acid levels. Plasma Val, Ile, Leu, and Met levels decreased in BALB/c mice but increased in nude mice. There was no difference in the amino acid profile of CT26 tumor tissues between BALB/c mice and nude mice. We then injected antiCD3-antibody into the peritoneal cavity of tumor-bearing BALB/c mice (n=5) to eliminate T-cell function. We also injected IgG into tumor-bearing BALB/c mice (n=5) for control. The pattern of change in amino-acid profiles differed between the two groups of mice. Our findings suggest that T-lymphocyte-mediated immunoreactions are involved in changes in the plasma amino acid profile in patients with colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-296. doi:10.1158/1538-7445.AM2011-LB-296