Hiroki Taguchi

Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma.

Objectives The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). Methods Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features. Results The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002). Conclusions Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.

Human neutrophil peptides induce interleukin-8 in intestinal epithelial cells through the P2 receptor and ERK1/2 signaling pathways

Human neutrophil peptides (HNPs) are antimicrobial peptides produced predominantly by neutrophils. We have previously reported that HNP 1-3 levels are increased in the sera and plasma of patients with active ulcerative colitis. The increased expression of interleukin-8 (IL-8) has also been demonstrated in the colonic mucosa of patients with active ulcerative colitis. HNPs induce IL-8 in lung epithelial cells and monocytes through the P2Y6 signaling pathway. However, the association between HNPs and IL-8 in the intestinal mucosa has not yet been investigated. In the present study, we investigated the effects of HNP-1 on the production of IL-8 by human intestinal epithelial cells and the underlying signaling mechanisms. We observed a significant increase in IL-8 expression in the human colon carcinoma cell line, Caco-2, following treatment with HNP-1. The non-selective P2 receptor antagonists, suramin and pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium salt hydrate (PPADS), significantly blocked the HNP-1-induced expression of IL-8 in the Caco-2 cells. The P2Y6-specific antagonist, MRS2578, led to a significant but partial decrease in IL-8 expression, suggesting that P2 receptors in addition to P2Y6 are involved in the HNP-1-induced production of IL-8 by Caco-2 cells. In agreement with this finding, HNP-1 also significantly increased IL-8 production in the P2Y6-negative human colon cancer cell line, HT-29, and this increase was blocked by treatment with suramin and PPADS. HNP-1 significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in the HT-29 cells. However, the HNP-1-induced production of IL-8 was suppressed by the ERK1/2 inhibitor, U0126, but not by the p38 MAPK inhibitor, SB203580. In conclusion, our data demonstrate that HNP-1 induces IL-8 production not only through P2Y6, but also through additional P2 receptors via an ERK1/2-dependent mechanism in intestinal epithelial cells.

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

Effect of Endoscopic Submucosal Dissection for Superficial Esophageal Neoplasms and Risk Factors for Postoperative Stricture

AbstractEndoscopic submucosal dissection (ESD) enables wider tumor resection compared with endoscopic mucosal resection and en bloc resection of superficial esophageal neoplasms. However, ESD may cause difficult-to-treat stricture of the esophagus, and therefore, prediction of and measures against postoperative esophageal stricture are critical. The aim of this study was to evaluate the effect of ESD on superficial esophageal neoplasms and identify risk factors associated with esophageal stricture after ESD.This study included 165 lesions in 120 patients with superficial esophageal neoplasms, including cancer and neoplasia, who underwent ESD from 2009 to 2013.The complete resection rate of superficial esophageal neoplasms by ESD was 90.9%. After ESD, 22 subjects (18.3%) had symptomatic esophageal stricture, 12 (10.0%) had aspiration pneumonia of grade 2, and 7 (5.8%) had mediastinal emphysema of grade 2. Comparison of the 22 subjects with stricture with the 98 subjects without stricture showed significant differences in the rate of resection of >75% of the esophageal circumference, rate of whole circumference resection, and the required time for resection. The tumor size and the size of the resected tissue sample also differed between the 2 groups. The groups did not differ in age, sex, alcohol intake, and smoking; location, macroscopic, and histological tumor findings; chest pain; or use of anticoagulants for comorbidities. In multivariate analysis, tumor size and whole circumference resection were independent risk factors for stricture. Furthermore, in 45 subjects with resection of >75% of the esophageal circumference, whole resection of the esophagus was the only independent risk factor for stricture.This study suggests that ESD has a strong therapeutic effect on superficial esophageal neoplasms; however, a greater extent of resection of the esophagus increases the risk of postoperative esophageal stricture. Preventive measures against development of postoperative stricture require further study.

NEW TECHNIQUE FOR DIRECT PERCUTANEOUS ENDOSCOPIC JEJUNOSTOMY USING DOUBLE-BALLOON ENDOSCOPY AND MAGNETIC ANCHORS IN A PORCINE MODEL

Direct percutaneous endoscopic jejunostomy (D-PEJ) is not yet globally carried out because of two technical difficulties in the procedure.The first is difficulty in reaching the jejunum with good maneuverability by conventional endoscopy. The second involves the anatomical features of the jejunum. The jejunal lumen is much smaller than that of the stomach. In addition, the location of the jejunal loop is not stable in relation to the abdominal wall. To solve these problems, we developed a new technique for D-PEJ using double-balloon endoscopy (DBE) and magnetic anchors. DBE was used for the access to the jejunum.Two magnetic anchors were prepared for the inside and outside anchors. The inside anchor was tied to the tip of the endoscope. Two anchors were used to fix the jejunal wall to the abdominal wall. Puncture was carried out from the abdominal wall beside the outside anchor without fluoroscopy. The jejunal wall was fixed to the abdominal wall by suturing the fixing thread. Percutaneous endoscopic gastrostomy (PEG) tube was placed through the overtube of DBE (Fig. 1). To evaluate the feasibility and safety, placement of D-PEJ using DBE and magnetic anchors was carried out on eight pigs with survival. Procedure of the animal experiments was investigated and permitted by The Judging Committee of Experimental Animal Ethics of Jichi Medical University. D-PEJ was successfully placed in all eight pigs. DBE and magnetic anchors were useful for stabilization of the maneuvers. PEG tube placement through the overtube was useful for preventing contamination of the tube and trauma of the intestinal wall. The mean procedure time was 89 min. There were no complications. D-PEJ using DBE and magnetic anchors was feasible and safe in the porcine model.

Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival. Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed. Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035). Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625–32. ©2017 AACR.

Diagnostic efficacy of liquid-based cytology for solid pancreatic lesion samples obtained with endoscopic ultrasound-guided fine-needle aspiration: Propensity score-matched analysis

There is a paucity of data on the diagnostic efficacy of liquid‐based cytology (LBC) for pancreatic samples obtained by endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA). Using propensity score matching, we retrospectively analyzed the additional diagnostic value of LBC compared to a conventional Papanicolaou smear (CPS) for samples of solid pancreatic lesions obtained by EUS‐FNA.

Preoperative classification of submucosal fibrosis in colorectal laterally spreading tumors by endoscopic ultrasonography.

Background and study aims: Although endoscopic submucosal dissection (ESD) is an established therapy for colon neoplasms including laterally spreading tumors (LSTs), its application to advanced fibrotic lesions is very difficult owing to the thin walls of the large intestine. We examined the ability of preoperative endoscopic ultrasonography (EUS) to predict lesion fibrosis in patients undergoing colorectal ESD. Patients and methods: From 2009 to 2013, 58 LSTs were evaluated retrospectively with EUS and treated using colorectal ESD. The degree of submucosal fibrosis was determined during ESD and classified as F0 (no fibrosis), F1 (mild fibrosis), or F2 (severe fibrosis). Results: The sensitivity and specificity of fibrosis prediction by preoperative EUS of all cases were 77.8 % and 57.1 %, respectively. However, there was a high accuracy (97.2 %, 35/36) for only the 36 LSTs with clear and visible images. In one case, EUS diagnosed no fibrosis but significant fibrosis was found during ESD, the result of colon cancer invasion into the submucosa. Conclusions: Preoperative EUS before colorectal ESD successfully predicted the degree of fibrosis in a number of cases.

Evaluation of a Proton Pump Inhibitor for Sleep Bruxism A Randomized Clinical Trial

Bruxism is a repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. Recent advances have clarified the relationship between gastroesophageal reflux and sleep bruxism (SB). However, the influence of pharmacological elimination of gastric acid secretion on SB has not been confirmed. The authors aimed to assess the efficacy of a proton pump inhibitor (PPI) on SB and to examine the gastrointestinal (GI) symptoms and endoscopic findings of the upper GI tract in SB patients. The authors performed a randomized double-blind placebo-controlled crossover study at Kagoshima University Hospital. Twelve patients with polysomnography (PSG)–diagnosed SB underwent an assessment of GI symptoms using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) and esophagogastroduodenoscopy. At baseline (i.e., before interventions), the mean frequencies of electromyography (EMG) bursts and rhythmic masticatory muscle activity (RMMA) episodes were 65.4 ± 49.0 bursts/h and 7.0 ± 4.8 episodes/h, respectively, and at least 1 RMMA episode with grinding noise was confirmed in all participants. The mean FSSG score was 8.4 ± 5.6, and 41.7% of patients were diagnosed with gastroesophageal reflux disease. Mild reflux esophagitis was confirmed in 6 patients. PSG, including EMG of the left masseter muscle and audio-video recording, was performed on days 4 and 5 of administration of 10 mg of the PPI (rabeprazole) or placebo. PPI administration yielded a significant reduction in the frequency of EMG bursts, RMMA episodes, and grinding noise. No significant differences were observed regarding the swallowing events and sleep variables. Since the clinical application of PPI for SB treatment should remain on hold at present, the results of this trial highlight the potential application of pharmacological gastroesophageal reflux disease treatment for SB patients. Larger scale studies are warranted to corroborate these findings. (UMIN Clinical Trials Registry: UMIN000004577).

Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis

Background/Aim: Fecal markers have recently been found to provide convenient and noninvasive assessment of intestinal inflammation in inflammatory bowel disease (IBD). In this study, we examined the clinical significance of fecal human neutrophil peptides (F-HNP) in the evaluation of IBD disease activity. Methods: This study enrolled 70 patients with IBD, consisting of 45 patients with ulcerative colitis (UC), 25 patients with Crohns disease (CD), and 11 non-IBD controls. Stools samples were evaluated for the association between F-HNP concentration and disease and endoscopic activity in each group and the correlation between F-HNP and fecal calprotectin (F-CP) concentrations. Results: Median F-HNP levels were as follows: UC: 25.6 ng/ml; CD: 20.1 ng/ml; and non-IBD controls: 4.9 ng/ml. F-HNP levels were significantly higher in each IBD group, especially in the UC group, than in the control group. In the UC group, both F-HNP and F-CP levels were significantly higher during active disease compared to the remission phase. Both markers were significantly correlated with the Mayo endoscopic score, although the correlation was stronger for F-HNP than for F-CP (r = 0.66 vs. r = 0.54). Conclusion: F-HNP is a noninvasive marker that is useful for evaluating UC endoscopic activity.