Takuto Ikeda

Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice

Background and aims: Imbalance between pro- and anti-inflammatory cytokines produced by intestinal T cells induces inflammatory bowel diseases (IBD). However, the importance of regulation of cytokine signalling in IBD has not been fully clarified. We have demonstrated that suppressor of cytokine signalling 1 (SOCS1) is expressed in inflamed tissues in an experimental colitis model. In the present study, we investigated the role of SOCS1 in colitis models to clarify the mechanism of IBD development. Methods: Intestinal T cells in transgenic mice expressing high levels of SOCS1 in lymphocytes (SOCS1Tg mice) were characterised by flow cytometric analysis and cytokine production from intestinal T cells was determined by ELISA. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis was induced in SOCS1Tg mice and severity was compared with control littermates by measurement of survival rates. Intracellular signalling was assessed by western blotting analysis. Results: SOCS1Tg mice developed colitis spontaneously with age. Young SOCS1Tg mice less than 15 weeks of age, before the onset of colitis, were susceptible to TNBS induced colitis. Intestinal T cells of SOCS1Tg mice showed increased interferon γ and tumour necrosis factor α production and decreased transforming growth factor β production. Expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a negative regulator of T cell activation, in SOCS1Tg mice was severely impaired at the protein level although mRNA levels of CTLA-4 in SOCS1Tg mice were comparable with those in control mice. Conclusions: Our data suggest that SOCS1 plays an important role in the regulation of colitis by controlling intestinal T cell activation mediated through CTLA-4 expression.

Factors influencing outcome after surgery for stage IV colorectal cancer

PurposeAccording to the classification system of the Japanese Society for Cancer of the Colon and Rectum, Stage IV colorectal cancer is characterized by distant metastasis, which is defined by four factors: liver metastasis (H factor), metastasis to organs other than the liver (M factor), peritoneal dissemination (P factor), and distant lymph node metastasis (N factor). We conducted this study to investigate the postsurgical prognosis of patients with Stage IV colorectal cancer (CRC), in reference to each of these four factors.MethodsWe analyzed the medical records of 73 patients who underwent surgery for Stage IV CRC at our hospital between 1991 and 2001.ResultsUnivariate analysis revealed that P0 or P1 CRC (P < 0.001), absence of the M factor (P = 0.024), well or moderately differentiated adenocarcinoma (P < 0.001), resection of the primary tumor (P < 0.001), and curability B surgery (P < 0.0001) were associated with a better prognosis than other types of Stage IV CRC. Multivariate analysis revealed that tumor differentiation and surgical curability affected cancer-specific survival significantly.ConclusionSurgery with curative intent should be considered for patients with Stage IV CRC defined by the P1 factor or H factor.

Up-regulation of intestinal toll-like receptors and cytokines expressions change after TPN administration and a lack of enteral feeding.

BACKGROUND Total parenteral nutrition (TPN) increases the risk of severe infectious complications such as septic shock, which are believed to be the result of a breakdown of intestinal barrier function and subsequent bacterial translocation. Toll-like receptors (TLRs) comprise a family of membrane proteins that serve as pattern recognition receptors for a variety of microbe-derived molecules and stimulate innate immune responses to microbes. Alteration of intraepithelial lymphocytes (IELs) to TPN administration has been studied extensively. However, few studies have examined the effect of TPN administration on intestinal TLRs. We hypothesized that the expressions of intestinal TLRs and cytokines may change with TPN administration and a lack of enteral feeding. MATERIALS AND METHODS TPN-treated mice and sham operation mice (control) were killed at 10 days after operation. mRNA expression of intestinal cytokines and TLRs were analyzed with reverse transcription-polymerase chain reaction (RT-PCR) methods. Change in IEL populations was analyzed with flow cytometry. RESULTS RT-PCR showed varying expression levels of TLRs at different sites on the small intestine and colon. TLR4, TLR5, TLR7, and TLR9 mRNAs were up-regulated in response to TPN administration, particularly in the distal small intestine. CONCLUSIONS Up-regulation of TLRs in intestine in response to TPN administration and a lack of enteral nutrition may be associated with an increased risk of septic shock due to bacterial translocation caused by Interferon gamma-mediated intestinal epithelial cell apoptosis.

Chronic intestinal nematode infection induces Stat6‐independent interleukin‐5 production and causes eosinophilic inflammatory responses in mice

The role of Stat6 (signal transducers and activators of transcription) in the recruitment and activation of eosinophils has been studied in detail in asthma and other allergic diseases. In this study, we demonstrated that eosinophil responses occur in a Stat6‐independent manner in mice infected with the intestinal nematode, Nippostrongylus brasiliensis. Stat6‐deficient (Stat6–/–) mice cannot expel N. brasiliensis and establish chronic infections. Prominent blood and intestinal eosinophilia were induced after day 14 postinfection (p.i.) and maintained at this level in Stat6–/– mice, whereas in wild‐type mice eosinophil responses reached a peak on day 10 p.i. and declined thereafter. The introduction of a secondary infection of N. brasiliensis into wild‐type mice induced rapid and exaggerated eosinophilia, whereas secondary infection in Stat6–/– mice resulted in almost the same eosinophil responses as those of the primary infection, suggesting a lack of memory responses. Blood eosinophilia was also induced in Stat6–/– mice implanted with N. brasiliensis in the small intestine, suggesting that intestinal exposure to parasitic antigen is sufficient to induce eosinophil responses. Furthermore, this prominent eosinophil response of Stat6–/– mice after day 14 was closely associated with an increase of interleukin (IL)‐5 production in serum and intestine. Neither IL‐4 nor eotaxin were significantly induced in Stat6–/– mice after infection with N. brasiliensis. We also found that mRNA for IL‐5, GATA‐3 and eosinophil peroxidase (EPO) are induced in the intestine of Stat6–/– mice on day 14 p.i. Taken together, these results provide evidence for Stat6‐independent IL‐5 production and subsequent eosinophil responses after chronic infection with N. brasiliensis.

Results of seton drainage and infliximab infusion for complex anal Crohn's disease.

BACKGROUND/AIMS To investigate the efficacy of infliximab for complicated perianal Crohns disease with special reference to maintenance therapy. METHODOLOGY Between June 2002 and April 2009, 20 patients (15 men and 5 women, aged 31.4±2.9 years old (mean ± standard error)) with complicated fistulizing anal Crohns disease underwent seton placement. For the induction therapy, intravenous infusion of infliximab was given 3 times after surgical treatment. Thereafter, infliximab was given every 8 weeks as maintenance therapy. Patients were followed-up for 31.8±4.2 months after the first infliximab infusion. The number of the infliximab treatments given was 13.6±2.5. RESULTS After induction therapy, complete response (CR) was observed in 8 patients (40%), partial response (PR) in 9 and progress disease (PD) in 3. With (n=17) or without (n=3) maintenance therapy following the induction therapy, CR was observed in 15 of 20 patients (75%). Of the 17 patients who received maintenance therapy, CR was of observed in 13 patients, of whom 7 patients showed PR or PD before maintenance therapy. CONCLUSIONS Seton drainage and infliximab therapy is effective in the patients with fistulizing perianal Crohns disease. Maintenance infliximab therapy might be effective in patients with perianal Crohns disease.

Side-to-side-to-end strictureplasty for Crohn's disease.

PURPOSE: Side-to-side strictureplasty is a useful procedure for preserving the bowel in patients with Crohn’s disease. However, bowel resection is required in some patients, and diseased proximal bowel and disease-free distal bowel exist after resection. We performed a modified new technique called side-to-side-to-end strictureplasty. METHODS: Four patients with Crohn’s disease underwent this procedure. After resection of the diseased bowel that was not suitable for strictureplasty, side-to-side strictureplasty was performed with use of the proximal diseased loop. Thereafter, the distal end of the side-to-side stricture was anastomosed to the distal disease-free bowel in a side-to-side-to-end manner. RESULTS: The length of the small intestine requiring surgical intervention was 69.8 ± 26.4 (mean ± standard deviation) cm, and the length of the small intestine necessitating resection was 31.8 ± 12.6 cm. Side-to-side stricture was performed by use of 48.8 ± 20.2 cm of the diseased proximal bowel, which was anastomosed to the disease-free distal bowel. Intra-abdominal abscess, which was not associated with this procedure, was observed in one patient, but was treated by drainage. The recoveries of all four patients were uneventful, without recurrence, after a follow-up of 21.5 ± 16.2 months. CONCLUSIONS: Side-to-side-to-end strictureplasty may be a useful procedure when diseased proximal bowel and disease-free distal bowel are present after bowel resection in patients with Crohn’s disease.

Frequency of CD4+CD161+ T Cell and Interleukin-10 Expression in Inflammatory Bowel Diseases

Mucosal immune dysregulation associated with T cells plays a critical role in the development of inflammatory bowel diseases (IBD). However, the definite significances of these cells in IBD still remain unclear. Therefore, we investigated the population and expression of CD4+CD161+ T cells in the colonic lamina propria mononuclear cells (LPMCs) in patients with IBD by analyses using flow cytometry and immunohistochemistry. Interleukin-10 (IL-10) mRNA levels in both LPMCs and CD4+ T cells in lamina propria (LP-CD4+ T cells) were measured using a real-time quantitative reverse transcription-polymerase chain reaction. IL-10 production was investigated with immunohistochemistry. The results revealed that the population of CD4+CD161+ T cells was significantly decreased in active ulcerative colitis (UC) compared with inactive UC (P < 0.05). The CD4+CD161+ T cell population was inversely correlated with disease activity in patients with UC (r = −0.6326, P = 0.0055), but there was no significant correlation in those with Crohn’s disease. Over-expression of IL-10 mRNA in both LPMCs and LP-CD4+ T cells were detected in active UC. Immunohistochemistry revealed decreased frequency of CD161+ cells and increased IL-10 positive cells in active UC. The frequency of CD4+CD161+ T cells and IL-10 expression was supposed to be associated with the pathological status of mucosal immunoregulation in IBD.

Laparoscopic anterior pelvic exenteration for locoregionally advanced rectal cancer directly invading the urinary bladder: A case report of low anterior resection with en bloc cystectomy for sphincter preservation

Laparoscopic multi‐visceral resection in patients with T4 colorectal cancer remains controversial. A 73‐year‐old man was admitted to the hospital for rectosigmoid cancer directly invading the urinary bladder trigone without distant metastasis. We successfully performed complete resection by laparoscopic anterior pelvic exenteration while preserving the anus. After laparoscopic mobilization of the rectum, urinary bladder, and prostate, the urethra and urethral catheter were dissected to reveal the lower rectum. By pulling the urethral catheter toward the head, the prostate was excised retrogradely from the lower rectum anterior wall. The lower rectum was resected and anastomosed by the double stapling technique with a safe distal margin from the tumor. Pathological findings of the resected specimen indicated no residual tumor in the surgical margin. There was no evidence of recurrence 34 months after surgery. En bloc, R0, laparoscopic anterior pelvic exenteration for T4 rectal cancer is feasible. However, further studies with long‐term follow‐up are required to resolve oncological outcomes.

Jejunogastric intussusception after distal gastrectomy with Roux-en-Y reconstruction: A case report

Highlights • We report a case of jejunogastric intussusception after distal gastrectomy.• Diagnosis and management of the condition are discussed with a literatures review.• The authors suggest ways to prevent jejunogastric intussusception after gastrectomy.

Accompanying role of hepato-biliary-pancreas surgeon in urological surgery

Highlights • Accompanying support by full use of procedure of general or cardiovascular surgeons for urological surgery in malignancies provide curability.• Cardiovascular intervention should be necessary to remove long extension of tumor thrombus into the vena cava or right atrium.• Hepatic or pancreatic mobilization or combined resection is required for invasive or metastatic urological malignancies.• Operative safety is also required by precise preoperative planning and arrangement of procedure during operation by the good combination in each.