Yasuharu Saito

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis

BackgroundInterleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs).MethodsIL-33 mRNA expression was determined by real-time polymerase chain reaction (PCR). IL-33 expression in the IBD mucosa was evaluated by immunohistochemical methods.ResultsIL-33 mRNA expression was significantly elevated in active lesions from patients with ulcerative colitis (UC), but was not detected in inactive lesions from UC patients or in lesions from patients with either active or inactive Crohn’s disease. Colonic SEMFs were identified as a major source of IL-33 in the mucosa. IL-1β and tumor necrosis factor-α (TNF-α) significantly enhanced IL-33 mRNA and protein expression in isolated colonic SEMFs. IL-1β and TNF-α did not affect IL-33 expression in intestinal epithelial cell lines (HT-29 and Caco-2 cells). This IL-1β- and TNF-α-induced IL-33 mRNA expression was mediated by p42/44 mitogen activated protein kinase (MAPK) pathway-dependent activation of nuclear factor (NF)-κB and activator protein (AP)-1.ConclusionsIL-33, derived from colonic SEMFs, may play an important role in the pathophysiology of UC.

Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn’s disease using terminal restriction fragment length polymorphism analysis

BackgroundTerminal restriction fragment length polymorphism (T-RFLP) analysis is a powerful tool to assess the diversity of a microbial community. In this study, we performed T-RFLP analysis of the fecal microbiota from patients with ulcerative colitis (UC) and those with Crohn’s disease (CD).MethodsThirty-one patients with UC, 31 patients with CD, and 30 healthy individuals were enrolled. The polymerase chain reaction (PCR) products obtained from the 16S rRNA genes of fecal samples were digested with BslI, and T-RF lengths were determined.ResultsThe fecal microbial communities were classified into 5 clusters. Twenty-eight of the 30 healthy individuals and 17 of the 18 patients with inactive UC were classified into clusters I, II, and III, but these clusters included a small number of patients with active UC and inactive/active CD. In contrast, 8 of the 13 patients with active UC and the majority of CD patients (12 of the 16 patients with inactive CD, and 11 of the 15 patients with active CD) were included in clusters IV and V. Based on the BslI-digested T-RFLP database, the bacteria showed a significant decrease in the Clostridium family in patients with active UC and inactive/active CD. In contrast, Bacteroides were significantly increased in CD patients. No significant differences were observed between patients with active UC and those with active CD.ConclusionThe fecal microbial communities of IBD patients were different from those of healthy individuals. The gut microbiota of patients with inactive UC tended to be closer to that of healthy individuals, suggesting different roles for the fecal microbiota in the pathophysiology of UC and CD.

Newly Developed Biodegradable Stents for Benign Gastrointestinal Tract Stenoses: A Preliminary Clinical Trial

We developed an Ultraflex-type stent by knitting polylactic acid monofilaments. The purpose of this study was to evaluate the stent’s clinical usefulness for treating benign stenoses in the gastrointestinal tract. The radial force of the biodegradable stent was compared with those of commercially available metallic stents. The measured radial force of the new biodegradable stent was higher than that of commercially available metallic stents. The biodegradable stents were applied in 2 patients with benign gastrointestinal stenoses. The first patient was a 19-year-old female with esophageal stenosis, due to drinking of caustic potash in an attempt to commit suicide. The second patient was a 75-year-old male who had a stenosis at the anastomotic site after esophageal cancer resection. In both cases, the placement of the stent was performed successfully, and the patients’ complaints improved immediately after stent placement. There were no complications during stent placement. The stenosis had not recurred at the six-month follow-up examination. In conclusion, the newly developed biodegradable stents were useful in treating benign stenoses of the alimentary tract.

Re-evaluation of Histogenesis of Gastric Carcinomas: A Comparative Histopathological Study Between Helicobacter pylori-Negative and H. pylori-Positive Cases

We histopathologically re-evaluated the histogenesis of gastric carcinomas from comparative studies between Helicobacter pylori-positive and H. pylori-negative cases using the gastritis score from the Updated Sydney System. The incidence of H. pylori-negative gastric carcinomas was 3.11% (12/386); they are likely to develop in the fundic gland mucosa, and show a gastric phenotype by mucin immunohistochemistry. Even in cases of completely gastric and predominantly gastric phenotypes, CDX2 protein was expressed in most cases (90.9% of pT1 and 100% of pT2-3), indicating a possibility that intestinalization of carcinoma cells occurs independently of the background mucosa. Regarding the degree of gastritis of background mucosa surrounding 143 H. pylori-positive differentiated-type adenocarcinomas, the mean score ranged from 1.497 to 1.713. Our data support the hypothesis that intestinal metaplasia is not a precancerous but a paracancerous lesion, and most gastric adenocarcinomas develop in mildly to moderately atrophic mucosa with H. pylori-infection, i.e., ongoing atrophy.

Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease

Background and Aim:  There have been no reports on 6‐thioguanine nucleotide (6‐TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6‐mercaptopurine (6‐MP) therapy. The aim of this study was to assess 6‐TGN concentrations in Japanese IBD patients.

Hepatic reactive lymphoid hyperplasia in a patient with primary biliary cirrhosis

Reactive lymphoid hyperplasia (RLH) of the liver is an extremely rare lesion characterized by the proliferation of non-neoplastic lymphocytes forming follicles. Hepatic RLH is known to be associated with gastrointestinal carcinoma and autoimmune diseases including primary biliary cirrhosis (PBC). We report a case of hepatic RLH in a patient with PBC and gastric cancer. A 68 year old Japanese woman with a 10 year history of liver enzyme abnormality was admitted. Laboratory testing revealed that her anti-mitochondrial antibody was markedly elevated. Five mo after the diagnosis of PBC, she was found to have gastric cancer. Abdominal computed tomography disclosed a liver nodule in S8, suggesting metastatic gastric carcinoma. Histopathologically, the resected liver lesion comprised of a nodular proliferation of small lymphocytes with lymphoid follicles. This is the first reported case of hepatic RLH in a patient with both PBC and gastric cancer. Pre-operative diagnosis of hepatic RLH by clinical imaging is extremely difficult. Therefore, a needle biopsy could be useful to make a diagnosis of hepatic RLH, especially to differentiate from metastatic gastrointestinal carcinoma.

Non-Epstein-Barr virus associated lymphoepithelioma-like carcinoma of the inferior common bile duct

A carcinoma displaying undifferentiated features with dense lymphoplasmacytic infiltration is defined as a lymphoepithelioma-like carcinoma (LEC), and some of LEC is associated with Epstein-Barr virus (EBV). All of the 13 previously reported cases of LEC of the biliary system were intrahepatic in location. Herein, we describe the first case of LEC of the inferior common bile duct. A 68-year-old Japanese man, who had been previously treated for hepatocellular carcinoma using microwave coagulation therapy, was found to have tumors of the common bile duct and pancreas head. Histopathological study of the resected tumor showed solid or cohesive nests of large undifferentiated cells with irregular large vesicular nuclei and nucleoli. Around the tumor cell nests, dense lymphoplasmacytic infiltration was observed. Focal glandular differentiation (approximately 5%) was also present. These histopathological features corresponded morphologically to LEC. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) 7, CK 19 and CA19-9, but negative for CK 20 and Hep Par 1. In situ hybridization for Epstein Barr virus early small RNAs disclosed no nuclear signal in tumor cells. Therefore, a diagnosis of non-EBV-associated LEC of the inferior common bile duct was made. Although the prognosis of the biliary LEC is thought to be better than that of conventional cholangiocarcinoma, the differences in prognosis between EBV-positive and -negative cases have not yet been established. Therefore, additional case studies will be needed to clarify the clinicopathological features of LEC of the biliary tract.

Mannan-Binding Protein, a C-Type Serum Lectin, Recognizes Primary Colorectal Carcinomas through Tumor-Associated Lewis Glycans

Mannan (mannose)-binding protein (MBP) is a C-type serum lectin that plays a key role in innate immunity. MBP forms large multimers (200–600 kDa) and exhibits broad specificity for mannose, N-acetylglucosamine, and fucose. MBP exhibits high affinity for unique oligosaccharides that have been isolated from human colorectal carcinoma (SW1116) cells and characterized as highly fucosylated high m.w. type 1 Lewis glycans. In this study, we first demonstrated that MBP recognizes human primary colorectal carcinoma tissues through tumor-associated MBP ligands. We performed fluorescence-based histochemistry of MBP in human colorectal carcinoma tissues and showed that MBP clearly stained cancer mucosae in a Ca2+-dependent manner. Coincubation with plant (Aleuria aurantia) lectin, but not Con A, blocked MBP staining, indicating that fucose, rather than mannose, is involved in this interaction. The expression of MBP ligands was detected in 127 of 330 patients (38.5%), whereas, most significantly, there was no expression in 69 nonmalignant tissues. The MBP-staining pattern in cancer mucosae significantly overlapped with that of Lewis b [Fucα1-2Galβ1-3(Fucα1-4)GlcNAc] staining, but the Lewis b staining in normal tissues was not associated with MBP staining. In addition, the MBP staining correlated inversely with the expression of CA19-9 Ag, and MBP stained 11 of 25 (44%) CA19-9 (sialyl Lewis a [NeuAc(α2-3)Galβ1-3(Fucα1-4)GlcNAc])− colorectal carcinoma tissues. We found a favorable prognosis in patients with MBP ligand+ tumors. These results suggest that selective recognition of cancer cells by endogenous MBP seems to be associated with an antitumor effect and that tissue staining with MBP in combination with CA19-9 may serve as a novel indicator of colorectal carcinoma tissues.

Evaluation of mucin expression patterns in gastric borderline (group III) lesions

BackgroundRecommendations for diagnosis and treatment of gastric borderline (group III) lesions remain controversial. We examined mucin expression patterns in endoscopically resected and forceps biopsy samples.MethodsSixty-three gastric lesions were histopathologically identified as belonging to group III on the basis of an endoscopic forceps biopsy. All of the patients underwent endoscopic resection, and the lesions were classified into group A (final diagnosis, adenocarcinoma) or group B (final diagnosis, adenoma). Immunostaining for MUC2, MUC5AC, MUC6, and CD10 was performed and the mucin phenotype determined. An additional 26 forceps biopsy samples from the above 63 patients were similarly evaluated.ResultsThe proportion of complete gastric (positive for MUC5AC and MUC6) plus gastric-predominant phenotypes was significantly higher in group A (58.0%) than in group B (18.7%) lesions (P < 0.05). The proportion of the complete intestinal (positive for MUC2 and CD10) phenotype was significantly higher in group B (68.8%) than in group A (19.4%) (P < 0.05). Similar results were also observed in the 26 forceps biopsy samples histopathologically diagnosed as group III lesions. The proportion of samples with a diffuse Ki-67 immunostaining pattern was significantly higher in group A than in group B (P < 0.05). p53 expression was significantly higher in group A (29.2%) than in group B (4.3%) (P < 0.05).ConclusionsImmunostaining of forceps biopsy samples for the mucin phenotype may be helpful for diagnosing gastric borderline (group III) lesions.

Threaded biliary inside stents are a safe and effective therapeutic option in cases of malignant hilar obstruction

BackgroundAlthough endoscopic biliary stents have been accepted as part of palliative therapy for cases of malignant hilar obstruction, the optimal endoscopic management regime remains controversial. In this study, we evaluated the safety and efficacy of placing a threaded stent above the sphincter of Oddi (threaded inside plastic stents, threaded PS) and compared the results with those of other stent types.MethodsPatients with malignant hilar obstruction, including those requiring biliary drainage for stent occlusion, were selected. Patients received either one of the following endoscopic indwelling stents: threaded PS, conventional plastic stents (conventional PS), or metallic stents (MS). Duration of stent patency and the incident of complication were compared in these patients.ResultsForty-two patients underwent placement of endoscopic indwelling stents (threaded PS = 12, conventional PS = 17, MS = 13). The median duration of threaded PS patency was significantly longer than that of conventional PS patency (142 vs. 32 days; P = 0.04, logrank test). The median duration of threaded PS and MS patency was not significantly different (142 vs. 150 days, P = 0.83). Stent migration did not occur in any group. Among patients who underwent threaded PS placement as a salvage therapy after MS obstruction due to tumor ingrowth, the median duration of MS patency was significantly shorter than that of threaded PS patency (123 vs. 240 days).ConclusionsThreaded PS are safe and effective in cases of malignant hilar obstruction; moreover, it is a suitable therapeutic option not only for initial drainage but also for salvage therapy.