Tatsushi Kitagawa

Impact of elemental diet on mucosal inflammation in patients with active Crohn's disease: Cytokine production and endoscopic and histological findings

Background: The aim of this study was to examine the impact of elemental diet on mucosal inflammation in Crohns disease (CD), mainly by cytokine measurements. Methods: Twenty‐eight consecutive patients with active CD were treated with an elemental diet (Elental) for 4 weeks. The mucosal biopsies were obtained from the terminal ileum and large bowel before and after treatment. As a control group, mucosal biopsies were obtained from 20 patients without inflammation. Mucosal cytokine concentrations were measured by enzyme‐linked immunosorbent assay. Results: After treatment, clinical remission was achieved in 20 patients (71%). Endoscopic healing and improvement rates were 44% and 76% in the terminal ileum and 39% and 78% in the large bowel, respectively. Histologic healing and improvement rates were 19% and 54% in the terminal ileum and 20% and 55% in the large bowel, respectively. Before treatment, the mucosal concentrations of interleukin (IL)‐1&bgr;, IL‐1 receptor antagonist (IL‐1ra), IL‐6, IL‐8, and tumor necrosis factor‐&agr; in the ileum and large bowel were significantly higher than in controls. These cytokine concentrations decreased to the levels of control after treatment. IL‐1ra/IL‐1&bgr; ratio in the ileum and large bowel was significantly lower than in controls before treatment. The ratio increased to the level of controls after treatment. The endoscopic and histologic healing of the mucosal inflammation was associated with a decline of the mucosal cytokines and an increase of the IL‐1ra/IL‐1&bgr; ratio. Conclusions: The elemental diet (Elental) reduced mucosal cytokine production and corrected an imbalance between proinflammatory and anti‐inflammatory cytokines in CD.

Systemic and local cytokine production in quiescent ulcerative colitis and its relationship to future relapse: A prospective pilot study

Background: The main aim of this prospective study was to examine whether systemic (plasma) and local (mucosal) cytokine production is a predictor of future relapse in patients with quiescent ulcerative colitis (UC). The impact of other clinical and laboratory parameters on relapse was also studied. Methods: Fifty consecutive patients with quiescent UC were included. At enrollment, blood and mucosal (rectal biopsies) samples were collected. All patients were followed up regularly for 1 year after enrollment. Plasma and mucosal cytokine levels were measured by enzyme‐linked immunosorbent assay. To identify independent significant predictive factors for relapse, time‐dependent analyses using the Kaplan‐Meier method and the Cox proportional hazard model were performed. Results: Thirty‐four patients remained in remission, and 16 patients relapsed during the 1‐year follow‐up. Higher interleukin (IL)‐8 levels in the rectal mucosa were significantly associated with relapse. In contrast, IL‐1&bgr;, IL‐6, and tumor necrosis factor‐&agr; levels in the rectal mucosa were not associated with relapse. Conventional blood markers and plasma cytokines (IL‐1&bgr;, IL‐6, IL‐8, and tumor necrosis factor‐&agr;) did not correlate with relapse. Among clinical factors, age and number of prior relapses were significantly associated with relapse. In multivariate analysis, a higher rectal mucosal IL‐8 level (≥160 pg/mg of tissue; hazard ratio, 4.7), younger age (<30 yr; hazard ratio, 7.3), and a greater number of prior relapses (≥5; hazard ratio, 4.3) were independent significant risk factors for future relapse. Conclusions: Rectal mucosal IL‐8 measurement might be an additional objective diagnostic tool that can predict relapse in patients with quiescent UC.

Intraperitoneal Cytokine Productions and Their Relationship to Peritoneal Sepsis and Systemic Inflammatory Markers in Patients With Inflammatory Bowel Disease

PURPOSEThis prospective, blinded study was designed to assess intraperitoneal cytokine productions and their relationship to clinical presentations and systemic inflammatory markers in patients with inflammatory bowel disease.METHODSFifty patients who required abdominal surgery for active inflammatory bowel disease (ulcerative colitis, 27; and Crohn’s disease, 23) were investigated. Interleukin-1β, interleukin-6, and tumor necrosis factor-α levels in intraperitoneal fluid (obtained by intraoperative lavage) and plasma were measured by enzyme-linked immunosorbent assay. To compare intraperitoneal cytokine productions between diseases with a different degree of inflammation, intraperitoneal cytokine measurement also was performed for patients who required surgery for colorectal cancer (n = 25) and acute appendicitis (n = 25).RESULTSThe median intraperitoneal cytokine (interleukin-1β, interleukin-6, and tumor necrosis factor-α) levels were significantly higher in patients with inflammatory bowel disease than in patients with colorectal cancer and acute appendicitis. In patients with inflammatory bowel disease, intraperitoneal cytokine levels were significantly higher in patients with intraperitoneal sepsis (abscess/fistula) than in patients without intraperitoneal sepsis at laparotomy. Intraperitoneal cytokine levels did not correlate with type of disease (ulcerative colitis/Crohn’s disease), age, gender, duration of disease before surgery, preoperative medical treatment, and the extent or site of disease. There were no significant correlations between intraperitoneal cytokine levels and the following systemic inflammatory markers: plasma cytokine levels, white blood cell count, platelet count, erythrocyte sedimentation rate, and C-reactive protein levels. Postoperative intraperitoneal septic complications (anastomotic leak/abscess/enterocutaneous fistula) more frequently occurred in patients with higher intraperitoneal cytokine levels.CONCLUSIONSIntraperitoneal cytokine productions were greatly elevated in patients with inflammatory bowel disease, and their levels correlated with the presence of intraperitoneal sepsis at laparotomy and development of postoperative intraperitoneal septic complications. Intraperitoneal cytokine levels showed no correlations with systemic inflammatory markers.

Hepatic Infarction as a Complication of Gastric Cancer Surgery: Report of Four Cases

Four cases of patients who developed hepatic infarction caused by an operative injury to the hepatic circulation during gastric cancer surgery are reported herein. In two patients, the hepatic infarction resulted from accidental injury to the proper hepatic artery, and in the other two, it was possibly due to persistent pressure on the folded liver by a retractor during surgery. In the former two patients, the proper hepatic artery had been collapsed by the spread of enlarged metastatic lymph nodes before the onset of the arterial injury. In the latter two patients, postoperative laboratory data and computed tomography scanning revealed hepatic infarction even though preservation of the proper hepatic artery was confirmed by angiography. Elevated serum levels of hepatic enzymes released from the infarcted tissue recovered to the normal range within three weeks in all four patients. In conclusion, when an operative injury to the hepatic artery is encountered, the hepatoduodenal ligament should not be manipulated any more than necessary to preserve the collaterals, and the gallbladder should be removed to prevent necrotic perforation. Although close observation is mandatory, conservative therapy seems to be sufficient when an infarcted area is restricted to the lateral segment and a small part of the medial segment of the liver.

The impact of the fecal stream and stasis on immunologic reactions in ileal pouch after restorative proctocolectomy for ulcerative colitis: a prospective, pilot study.

OBJECTIVE:The etiology of pouch inflammation after restorative proctocolectomy is unknown. The fecal stream and immunological reactions are potential pathological factors. This study was performed to examine the impact of the fecal stream and stasis on immunological reactions in the pouch.METHODS:Patients who underwent a restorative proctocolectomy with a covering ileostomy for ulcerative colitis were studied. Mucosal biopsy specimens were obtained from both the pouch and the proximal ileum at the time of ileostomy closure, and 3, 6, and 12 months after ileostomy closure. As a control group, normal ileal biopsies were obtained from patients with colonic polyps.RESULTS:At the time of ileostomy closure, mucosal interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor-α levels in the pouch and the proximal ileum were not significantly different from those in the normal control group. At 3 months after ileostomy closure, the mucosal cytokine levels in the pouch increased significantly compared with those at ileostomy closure, and their levels were significantly higher than those in the proximal ileum. At 6 and 12 months after ileostomy closure, the mucosal cytokine levels in the pouch did not change significantly compared with those at 3 months after ileostomy closure. The mucosal cytokine levels in the proximal ileum did not change significantly during the entire study.CONCLUSIONS:The immunological reactions in the pouch occurred soon after ileostomy closure, and continued for at least 1 yr. The fecal stream and stasis play an important part in the pathogenesis of immunological reactions in the ileal pouch.

Postoperative Change of Mucosal Inflammation at Strictureplasty Segment in Crohn’s Disease: Cytokine Production and Endoscopic and Histologic Findings

PURPOSEThis study was designed to examine postoperative change of mucosal inflammation at strictureplasty segment in Crohn’s disease mainly by cytokine measurements.METHODSPatients who underwent strictureplasty for Crohn’s disease in the terminal ileum were investigated. Mucosal samples at the strictureplasty site were obtained during operation. At 3, 6, and 12 months after operation, biopsy specimens were taken from the strictureplasty site and macroscopically normal ileum at endoscopy. Mucosal cytokine concentrations were measured by enzyme-linked immunosorbent assay.RESULTSThe mucosal concentrations of proinflammatory cytokines (interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor-α) and anti-inflammatory mediator (interleukin-1 receptor antagonist) at the strictureplasty segment greatly increased at the time of operation. Interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-8, and tumor necrosis factor-α concentrations at the strictureplasty segment decreased during a 12-month period after operation. Twelve months after operation there was no significant difference in each cytokine concentration between the strictureplasty and macroscopically normal segments. The mucosal interleukin-1 receptor antagonist/interleukin-1β ratio at the strictureplasty segment increased during a 12-month period after operation. Twelve months after operation there was no significant difference in the ratio between the strictureplasty and macroscopically normal segments. The endoscopic and histologic severities of mucosal inflammation at the strictureplasty site also decreased; however, their findings were not normalized during the study.CONCLUSIONSDuring one year after strictureplasty for Crohn’s disease, cytokine production at the strictureplasty segment was decreased to the level of the macroscopically normal ileum and an imbalance between proinflammatory and anti-inflammatory cytokines was corrected.

Serum Cell Adhesion Molecules in Patients with Colorectal Cancer

The serum levels of intercellular adhesion molecule-1 (sICAM-1) and endothelial leukocyte adhesion molecule-1 (sELAM-1) were determined in 40 patients with colorectal cancer. The sICAM-1 and sELAM-1 levels in the drainage venous blood adjacent to a tumor were significantly correlated with those in the peripheral venous blood in patients without evident hematogenous dissemination of tumor cells. The sICAM-1 levels in peripheral venous blood were significantly higher in patients with hepatic metastases, while the sELAM-1 levels were significantly higher in those with pulmonary metastases. An immunohistochemical study of metastatic sites in the liver revealed that ICAM-1 was expressed in cancer stroma, but not in the cancer cells. In conclusion, the sICAM-1 and sELAM-1 levels in the peripheral venous blood in colorectal cancer patients without any distant metastasis are likely to reflect the topical production of these cell adhesion molecules, and appear to be instructive in predicting hematogenous dissemination in patients with colorectal cancer.

Nonoperative treatment for a ruptured pseudoaneurysm of the celiac trunk: Report of a case

We report the case of a 67-year-old man in whom hemorrhage from a ruptured celiac trunk pseudoaneurysm, which occurred as a consequence of leakage at the site of gastroduodenostomy, was successfully controlled by transcatheter arterial embolization (TAE) with stainless steel coils and N-butyl cyanoacrylate (NBCA). The occurrence of a pseudoaneurysm of the celiac trunk associated with anastomotic leakage is etiologically rare. We compiled reports from the literature on TAE for ruptured aneurysms of the celiac trunk, and compared its therapeutic value with that of surgical treatment. Operative death occurred in 4 of a series of 43 patients with aneurysms of the celiac trunk that were surgically treated (9.3%). In 5 patients with ruptured aneurysms, the operative mortality rate was 40% (2/5). Conversely, while the unsuccessful rate of TAE therapy was 17% (1/6), the mortality rate was nil. The patient whose case is presented here was affected by methicillin-resistant staphylococcus aureus (MRSA) at the site of leakage and in the lung. Under septic conditions such as hemorrhage secondary to pancreatitis, the mortality rate of surgical therapy was 23%–29%, whereas the success rate of TAE therapy was 79% and the mortality rate was 4%. Based on these findings, it is suggested that TAE therapy is a viable alternative to surgery for patients even with ruptured pseudoaneurysms of the celiac trunk.

The Value of Plasma Cytokine Measurement for the Detection of Strangulation in Patients With Bowel Obstruction: A Prospective, Pilot Study

PURPOSEThe aim of this prospective blinded study was to examine whether measurement of plasma cytokines is a predictor of strangulation in patients with bowel obstruction.METHODSSeventy-seven consecutive patients diagnosed with bowel obstruction were included. Blood samples were obtained at enrollment in all patients and at surgery (immediately before operation) if patients required surgery.RESULTSForty-three patients were managed conservatively (group 1) and 34 patients required surgery, of whom 20 had no bowel strangulation (group 2) and 14 had bowel strangulation (group 3). The mean plasma interleukin (IL)-6 levels at enrollment were significantly higher in group 3 (107.8 pg/ml) than in groups 1 (11.3 pg/ml, P < 0.0001 vs. group 3) and 2 (23.6 pg/ml, P < 0.0001 vs. group 3). The sensitivity and specificity of plasma IL-6 level (≥40 pg/ml) in predicting strangulation were 86 percent (95 percent confidence interval, 60–97 percent) and 86 percent (95 percent confidence interval, 80–88 percent), respectively. The plasma IL-6 levels at surgery significantly increased compared to those at enrollment (from 107.8 pg/ml to 205.8 pg/ml, P = 0.0003) in group 3, however, they did not increase significantly in group 2. Among other clinical and laboratory parameters, plasma lactic acid levels (≥15 mg/dl) at enrollment were significantly associated with strangulation. In the multivariate analysis, both plasma IL-6 (</≥40 pg/ml) and lactic acid (</≥15 mg/dl) levels at enrollment were significant predictive factors for strangulation. IL-1β and tumor necrosis factor-α were not detected in the plasma of most patients during the study.CONCLUSIONPlasma IL-6 measurement might be an additional diagnostic tool that can predict strangulation in patients with bowel obstruction.

Co-expression of E-cadherin and α-catenin molecules in colorectal cancer

Immunohistochemical staining for epithelial (E)-cadherin and α-catenin was performed using frozen sections taken from fresh operative specimens, by the avidin-biotin-peroxidase complex method. Tumors were classified into three types according to the expression modality. Cancer cells with expression at the cell-cell boundaries were defined as normal; when the expression was positive, but not concentrated at the cell-cell boundaries, they were defined as cytoplasmic; and when the tumor showed no staining, they were defined as lost. The relationship between these three expression types and the clinicopathological features of colorectal cancer was investigated. In all 50 normal mucosa samples, E-cadherin and α-catenin were coexpressed normally. The expression type of E-cadherin and α-catenin was normal in 11 and 13 of the cancer tissue specimens, respectively, cytoplasmic in 26 and 29, respectively, and lost in 13 and 8, respectively. Cytoplasmic or lost expression was observed in cancer demonstrating an advanced clinical stage (E-cadherin,P=0.0065; α-catenin,P=0.0069), advanced tumor penetration (P=0.0003,P=0.0001), undifferentiated tumor histology (P=0.0196,P=0.0343), widespread lymph node involvement (P=0.0204,P=0.0343), and liver metastasis (P=0.0063,P=0.0299). In conclusion, the expression type of E-cadherin is significantly correlated to that of α-catenin, and the loss of their expression indicates the metastatic potentiality of colorectal cancer.