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Negative control for immunohistochemistry

Comparison of DCLK1 immunostaining scores between primary PNETs and metastatic sites (lymph nodes) in four cases. n.s., not significant.

Sphere formation assay.

Expression of DCLK1 in primary liver NET (LNET) tissues.

cDNA microarray analysis to compare DCLK1-overexpressing QGP1 cells (DCLK1) with empty vector-transfected control cells (EV).

Supplemental Figure Legends 1-5

The Japan Gastroenterological Endoscopy Society published the second edition of the "Guidelines for Colorectal Endoscopic Submucosal Dissection/Endoscopic Mucosal Resection" in 2019 to clarify the indications for colorectal endoscopic mucosal resection (EMR) and endoscopic submucosal dissection and to ensure appropriate preoperative diagnoses as well as effective and safe endoscopic treatment in front-line clinical settings. Endoscopic resection with electrocautery, including polypectomy and EMR, is indicated for colorectal polyps. Recently, the number of facilities introducing and implementing cold polypectomy without electrocautery has increased. Herein, we establish supplementary guidelines for cold polypectomy. Considering that the level of evidence for each statement is limited, these supplementary guidelines must be verified in clinical practice.

BACKGROUND Fecal calprotectin has been proposed as a useful biomarker of disease activity in inflammatory bowel disease (IBD). However, the role of calprotectin in systemic circulation is not well established. Thus, this study aimed to quantify serum calprotectin levels to identify a potential inflammatory marker for IBD. METHODS Ninety-eight patients with ulcerative colitis (UC) and 105 patients with Crohn's disease (CD) were prospectively enrolled and clinically scored. Ninety-two healthy, age-matched subjects served as controls. Blood samples from UC and CD patients and controls were analyzed for serum calprotectin levels and routine laboratory parameters. Disease activity was assessed by partial Mayo score and Harvey-Bradshaw index for UC and CD, respectively. RESULTS Serum calprotectin levels were higher in CD and UC patients than in controls and were higher during active disease than during inactive disease in CD but not in UC. In UC, serum calprotectin levels were correlated with C-reactive protein (CRP) but not with other laboratory parameters or disease activity. In CD, serum calprotectin levels were positively correlated with disease activity, serum CRP, and platelet count. In UC and CD, serum calprotectin and CRP levels increased during the acute phase and decreased towards remission. CONCLUSIONS Serum calprotectin is an inflammatory marker in IBD but might be more effective in evaluating patients with CD than those with UC. Further studies are needed to confirm these findings and to better determine the specific uses of serum calprotectin in routine practice.

Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also several types of precarcinomatous adenomas. It is important to establish practical guidelines wherein preoperative diagnosis of colorectal neoplasia and selection of endoscopic treatment procedures are appropriately outlined and to ensure that actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society compiled colorectal endoscopic submucosal dissection/endoscopic mucosal resection guidelines by using evidence-based methods in 2014. The first edition of these guidelines was published 5 years ago. Accordingly, we have published the second edition of these guidelines based on recent new knowledge and evidence.

Background The aim of this study was to address whether the therapeutic effect of leukocytapheresis (LCAP) depends on calcitonin gene– related peptide (CGRP) induction. Methods An HLA-B27 transgenic rat model was treated with an LCAP column. The effects of LCAP on clinical, endoscopic, and histologic disease activity, the colony-forming ability of colony-forming unit (CFU)–granulocyte macrophages (GMs), colonic blood flow, and tissue expression of tumor necrosis factor (TNF)–α and CGRP were examined. Changes in the effects of LCAP after pretreatment with the CGRP antagonist CGRP8–37 were also observed. A dextran sulfate sodium–induced colitis rat model included treatment with CGRP, and the effect was assessed based on clinical, endoscopic, and histologic disease activity, colonic blood flow, the colony-forming ability of CFU-GMs, and tissue expression of inflammatory cytokines and CGRP receptor families. Results LCAP improved disease activity, enhanced colonic blood flow, and induced the bone marrow colony-forming ability of CFU-GMs with an increase in CGRP mRNA levels. These effects were abolished by pretreatment with CGRP8–37. The administration of CGRP suppressed colitis, promoting colonic blood flow, inducing bone marrow–derived cells, downregulating inflammatory cytokines, and upregulating receptor activity–modifying protein–1. The mRNA and protein levels of inflammatory cytokines in lipopolysaccharide-stimulated mononuclear cells were also decreased after CGRP treatment. Conclusions The therapeutic effects of LCAP depend on CGRP induction. CGRP can effectively suppress colitis through the downregulation of inflammatory events and upregulation of protective events.

Background Detailed endoscopic findings of the bile duct mucosa have not been fully established. This fundamental ex vivo study assesses the relationship between magnified endoscopic findings and pathological findings of the bile duct mucosa. Methods Forty-one surgically resected common bile duct mucosae were investigated. Each common bile duct was cut open longitudinally for ex vivo endoscopic observation. A magnifying endoscope commonly used for the gastrointestinal tract was used, using both white light imaging and narrowband imaging. After pathological diagnosis, the association between the magnifying endoscopic findings and histopathology was evaluated. Results Totally, 39 non-neoplastic mucosae and 13 neoplastic mucosae were evaluated. In 13 non-neoplastic mucosae without inflammation, an oval-shaped depressed area and a fine, regular network of microvessels were observed. These findings were not clearly seen or not seen at all in the non-neoplastic mucosae with inflammation. Although vessels with loop-like structure were observed on all eight papillary tumors of 13 neoplastic mucosae, no characteristic vessels were seen on the other five. Conclusions Ishida and colleagues assessed the association between magnifying endoscopic findings and histopathological findings of the bile duct mucosa ex vivo. Oval-shaped, depressed areas and a fine, regular network of microvessels are characteristic features of normal bile duct mucosa, while loop structures may be indicative of a type of tumor vessel.

The aim of the present study was to quantify calprotectin levels using an enzyme-linked immunosorbent assay (ELISA) and a point-of-care test (POCT) in patients with inflammatory bowel disease. Overall, 113 patients with ulcerative colitis (UC; 51 men and 62 women) and 42 patients with Crohn's disease (CD; 29 men and 13 women), who were scheduled to undergo a colonoscopy, were prospectively enrolled and scored endoscopically and clinically. An additional 96 healthy, age-matched subjects served as the normal controls. Feces and blood samples from the patients with UC and CD, and the normal controls were analyzed. These patients had received adequate medical treatment. The tissue distribution of calprotectin was investigated using immunohistochemistry. The fecal calprotectin levels, as measured using an ELISA, were correlated with the endoscopic and clinical disease activities and laboratory parameters, including serum levels of hemoglobin (Hb), albumin and C-reactive protein, and erythrocyte sedimentation rate, particularly among the patients with UC. The fecal Hb level was close to that of the fecal calprotectin level (r=0.57; P

Patients with longstanding ulcerative colitis have an increased risk of colorectal cancer. Mouse models for colitis-associated tumors are indispensable for the development of novel strategies for prevention and intervention, as well as an improved understanding of the mechanisms underlying tumor formation. The present study examined whether stereomicroscopic observations with dye-application were able to detect and discriminate tumors in a colitis-associated tumor model in mice. Colonic tumors were induced in C57BL/6 mice by 15 cycles of treatment with dextran sulfate sodium (DSS) in drinking water. The mice were then divided into 4 groups: normal mice fed a control diet, normal mice fed an iron-supplemented diet, 0.7% DSS mice fed an iron diet and 1.5% DSS mice fed an iron diet. The entire colons were characterized with respect to both morphology and histology. The pit pattern architecture was analyzed using stereomicroscopy with dye agents (0.2% indigo carmine or 0.06% crystal violet). The tumor histology was graded as negative, indefinite or positive for dysplasia. The positive category was divided into two subcategories: low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The tumor incidences and multiplicity were significantly higher in mice fed an iron diet and 1.5% DSS compared with in mice fed an iron diet and 0.7% DSS. Compared with LGD, HGD was predominantly located in the distal colon, was larger in size and had a higher incidence of elevated lesions (Is and IIa) and a lower incidence of flat lesions (IIb). In regards to the pit pattern, HGD had a high incidence of VI pits and a low incidence of IV, IIIL and II pits. In conclusion, evaluation of the pit pattern using stereomicroscopy with dye-application is useful for detecting and discriminating neoplastic changes in DSS mice and may further our understanding of the mechanisms that induce tumor formation in patients with ulcerative colitis and the characterization of pharmaceutical responses.

Daikenchuto (TU‑100) is a traditional Japanese medicine that is widely used to treat intestinal symptoms. The mechanisms underlying it effects on the circulating levels of adrenomedullin (ADM) are of interest. In addition, the effect of TU‑100 in the treatment of Crohn's disease (CD) in humans remains to be elucidated. The primary objective of the present study was to evaluate the effect of TU‑100 on the circulating ADM levels in patients with active CD. An additional objective was to assess the effect of the drug on the disease activity and its potential side effects. In an open‑label study, 10 patients with active CD received 15 g TU‑100 per day for 8 consecutive weeks, and baseline anti‑inflammatory therapy was continued. The pre‑ and post‑treatment blood plasma levels of total ADM (t‑ADM) and mature‑ADM (m‑ADM) were determined using enzyme‑linked immunosorbent assays. The response of patients to the treatment was evaluated clinically using the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) score. The plasma levels of t‑ADM (16.4±1.1 vs. 20.2±1.7 fmol/ml, P=0.0218) and m‑ADM (1.7±0.1 vs. 2.2±0.1 fmol/ml, P=0.0284) increased following 8 weeks of TU‑100 treatment, compared with control. The IOIBD score of patients also improved, with a significant decrease in the score from 3.9±0.5 at 0 weeks to 2.4±0.4 at 8 weeks (P=0.0284). Out of the 10 components of the IOIBD scoring system, the scores for abdominal pain and tenderness, decreased significantly (P=0.014 and P=0.046). Therefore, TU‑100 was safe and well‑tolerated by the patients that participated in the current study. The present study determined that the pharmacologic action of TU‑100 is associated with changes in the circulating ADM levels and that treatment with TU‑100 may aid in the management of CD. These promising findings warrant further investigation in larger, multicenter studies.

Many clinical studies on narrow-band imaging (NBI) magnifying endoscopy classifications advocated so far in Japan (Sano, Hiroshima, Showa, and Jikei classifications) have reported the usefulness of NBI magnifying endoscopy for qualitative and quantitative diagnosis of colorectal lesions. However, discussions at professional meetings have raised issues such as: (i) the presence of multiple terms for the same or similar findings; (ii) the necessity of including surface patterns in magnifying endoscopic classifications; and (iii) differences in the NBI findings in elevated and superficial lesions. To resolve these problems, the Japan NBI Expert Team (JNET) was constituted with the aim of establishing a universal NBI magnifying endoscopic classification for colorectal tumors (JNET classification) in 2011. Consensus was reached on this classification using the modified Delphi method, and this classification was proposed in June 2014. The JNET classification consists of four categories of vessel and surface pattern (i.e. Types 1, 2A, 2B, and 3). Types 1, 2A, 2B, and 3 are correlated with the histopathological findings of hyperplastic polyp/sessile serrated polyp (SSP), low-grade intramucosal neoplasia, high-grade intramucosal neoplasia/shallow submucosal invasive cancer, and deep submucosal invasive cancer, respectively.

Previous data shows that colorectal serrated lesions are precursor of carcinogenesis. It has been advancing even molecular biological analysis, SSA/P become microsatellite instability (MSI) positive colon cancers and TSA become microsatellite stable (MSS) positive colon cancers. It is observed that redness and double elevation in conventional endoscopy, CP type II (Sano classification) in the NBI endoscopy, type III pit pattern in magnifying endoscopy, if SSA/P have cytological dysplastic change. Especially, if SSA/P have cancerous change, CP type III and type V pit pattern are observed.

AIM To determine the usefulness of assigning narrow-band imaging (NBI) scores for predicting tumor grade and invasion depth in colorectal tumors. METHODS A total of 161 colorectal lesions were analyzed from 138 patients who underwent endoscopic or surgical resection after conventional colonoscopy and magnifying endoscopy with NBI. The relationships between the surface and vascular patterns of the lesions, as visualized with NBI, and the tumor grade and depth of submucosa (SM) invasion were determined histopathologically. Scores were assigned to distinct features of the surface microstructures of tubular and papillary-type lesions. Using a multivariate analysis, a model was developed for predicting the tumor grade and depth of invasion based on NBI-finding scores. RESULTS NBI findings that correlated with a high tumor grade were associated with the “regular/irregular” (P < 0.0001) surface patterns and the “avascular area” pattern (P = 0.0600). The vascular patterns of “disrupted vessels” (P = 0.0714) and “thick vessels” (P = 0.0133) but none of the surface patterns were associated with a depth of invasion of ≥ 1000 μm. In our model, a total NBI-finding score ≥ 1 was indicative of a high tumor grade (sensitivity: 0.97; specificity: 0.24), and a total NBI-finding score ≥ 9 (sensitivity: 0.56; specificity: 1.0) was predictive of a SM invasion depth ≥ 1000 μm. Scores less than these cutoff values signified adenomas and a SM invasion depth < 1000 μm, respectively. Associations were also noted between selected NBI findings and tumor tissue architecture and histopathology. CONCLUSION Our multivariate statistical model for predicting tumor grades and invasion depths from NBI-finding scores may help standardize the diagnosis of colorectal lesions and inform therapeutic strategies.

Background aims Endoscopy is the gold standard for the diagnosis and follow-up of patients with Crohn disease (CD). However, a less invasive approach is now being sought for the management of these patients. The objective of this study was to examine whether 18 F–fluorodeoxyglucose (FDG)-positron emission tomography (PET) might be relevant for monitoring the disease activity in CD patients undergoing granulocyte/monocyte apheresis (GMA). Methods. This study was conducted in 12 patients with CD who were receiving treatment with 10 once-a-week GMA sessions with the Adacolumn. The response to treatment was monitored by measuring standard laboratory variables, Crohn's Disease Activity Index (CDAI) score, International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) score, and regional and global bowel uptakes on FDG-PET. Results. In 6 of the 12 patients, significant improvement of the CDAI was observed after the final session of GMA. The patients who showed clinical response to GMA had a decrease in the regional and global bowel uptakes on FDG-PET, whereas those who did not respond showed no change. In the patients who responded to the GMA, the decrease in regional bowel uptake on FDG-PET in each disease area of the same patient varied in parallel. There was a significant correlation between decrease in the global bowel uptake on FDG-PET and improvement of the CDAI and IOIBD scores. Conclusions. The longitudinal changes in FDG-PET uptakes are of potential clinical interest for assessing the regional and global bowel disease activity in CD patients undergoing GMA therapy.

Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein, is known to regulate neuronal differentiation, migration and neurogenesis. Recent evidence suggests that the protein is a putative marker for intestinal and pancreatic stem cells, including their cancer stem cell counterparts. The present study conducted immunohistochemical analyses for DCLK1 and the stemness marker, NANOG, in human intestinal neuroendocrine tumors (NETs), as their expression had not been previously investigated in these tumors. Eighteen patients with endoscopically resected rectal NETs were enrolled in the study. The mean age of the patients was 51 years old. The mean diameter of the resected tumors was 5.2 mm, and a histological diagnosis of NET grade G1 was formed for all tumors. Immunohistochemical analysis was performed not only for DCLK1, but also for the known NET markers, synaptophysin, chromogranin A and cluster of differentiation (CD)56. The intensity and distribution of staining were scored on a scale of 0–3 and 0–2, respectively. The sum of the scores was calculated for each specimen. Co-expression of DCLK1 and NANOG was also examined. The mean scores for DCLK1 and synaptophysin were significantly higher than those for chromogranin A (P

Serrated lesions, including hyperplastic polyps (HPs), traditional serrated adenomas (TSAs) and sessile serrated adenomas/polyps (SSA/Ps), are important contributors to colorectal carcinogenesis. The aim of the present study was to analyze the potential of conventional endoscopy and advanced endoscopic imaging techniques to delineate the characteristic features of serrated lesions with cancer. The present study was a retrospective analysis of the data of 168 patients who had undergone colonoscopy, and a total of 228 serrated lesions (77 HPs, 58 TSAs, 84 SSA/Ps, 9 SSA/P plus TSAs) have been identified in these patients. A cancer component was identified in 2.6% of HPs, 13.8% of TSAs and 10.7% of SSA/Ps, but none of SSA/P plus TSAs. Compared with the lesions without cancer, the lesions with cancer exhibited a larger size (HP, TSA and SSA/P), a reddish appearance (SSA/P), a two-tier raised appearance (HP and SSA/P), a central depression (HP, TSA and SSA/P), the type V pit pattern (HP, TSA and SSA/P), and/or the type III capillary pattern (TSA and SSA/P). Deep invasion was identified in 50.0% of HPs, 12.5% of TSAs and 55.6% of SSA/Ps with cancer. The Ki-67 proliferative zone was distributed diffusely within the area of the cancer, but partially within the non-cancer area of HPs, TSAs and SSA/Ps. The lesion types were also analyzed on the basis of mucin phenotype. The present study suggested that a detailed endoscopic analysis of serrated lesions with cancer is useful for delineating characteristic features, and the analysis aids treatment selection.

BACKGROUND AND AIM The Japan narrow-band imaging (NBI) Expert Team (JNET) was organized to unify four previous magnifying NBI classifications (the Sano, Hiroshima, Showa, and Jikei classifications). The JNET working group created criteria (referred to as the NBI scale) for evaluation of vessel pattern (VP) and surface pattern (SP). We conducted a multicenter validation study of the NBI scale to develop the JNET classification of colorectal lesions. METHODS Twenty-five expert JNET colonoscopists read 100 still NBI images with and without magnification on the web to evaluate the NBI findings and necessity of the each criterion for the final diagnosis. RESULTS Surface pattern in magnifying NBI images was necessary for diagnosis of polyps in more than 60% of cases, whereas VP was required in around 90%. Univariate/multivariate analysis of candidate findings in the NBI scale identified three for type 2B (variable caliber of vessels, irregular distribution of vessels, and irregular or obscure surface pattern), and three for type 3 (loose vessel area, interruption of thick vessel, and amorphous areas of surface pattern). Evaluation of the diagnostic performance for these three findings in combination showed that the sensitivity for types 2B and 3 was highest (44.9% and 54.7%, respectively), and that the specificity for type 3 was acceptable (97.4%) when any one of the three findings was evident. We found that the macroscopic type (polypoid or non-polypoid) had a minor influence on the key diagnostic performance for types 2B and 3. CONCLUSION Based on the present data, we reached a consensus for developing the JNET classification.

Recently in Japan, the morbidity of colorectal polyp has been increasing. As a result, a large number of cases of colorectal polyps that are diagnosed and treated using colonoscopy has now increased, and clinical guidelines are needed for endoscopic management and surveillance after treatment. Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Ten specialists for colorectal polyp management extracted the specific clinical statements from articles published between 1983 and September 2011 obtained from PubMed and a secondary database, and developed the CQs and statements. Basically, statements were made according to the GRADE system. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. The professional committee created 91CQs and statements for the current concept and diagnosis/treatment of various colorectal polyps including epidemiology, screening, pathophysiology, definition and classification, diagnosis, treatment/management, practical treatment, complications and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumor/carcinoma). After evaluation by the moderators, evidence-based clinical guidelines for management of colorectal polyps have been proposed for 2014.

Aim To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. Methods The present study evaluated consecutive patients aged ≤ 15 years who had undergone their first colonoscopy in Kurume University between January 2007 and February 2015. Data were retrospectively analyzed. We identified 110 pediatric patients who had undergone colonoscopy that had reached the cecum, allowing the observation of the total colon. Results Hematochezia, abdominal pain, and diarrhea were the most common symptoms. For bowel-cleansing preparation, pediatric patients aged ≤ 12 years were treated with magnesium citrate, and patients aged 13-15 years were treated with polyethylene glycol 4000. For sedation, thiamylal with pentazocine, which has an analgesic effect, was used in patients aged ≤ 6 years, and midazolam with pentazocine was used in patients aged ≥ 7 years. Regarding the choice of endoscope, short and thin endoscopes were selected for younger patients, particularly patients aged ≤ 3 years. Positive diagnoses were made in 78 patients (70.9%). Inflammatory bowel disease (n = 49, 44.5%), including ulcerative colitis (n = 37, 33.6%) and Crohn's disease (n = 12, 10.9%), was the most common diagnosis. Conclusion Colonoscopy offers a high diagnostic capability for pediatric patients with gastrointestinal symptoms. The selection of appropriate management the performance of colonoscopy is important in pediatric patients.

Conventional endoscopic resection (CER) includes polypectomy and endoscopic mucosal resection. The most common complications related to these techniques are post procedure bleeding and perforation. The aim of this study was to evaluate the outcomes of CER for colorectal neoplasms ≧20 mm and to clarify predictive factors for complications. We conducted a multicenter prospective study at 18 specialized institutes. From October 2007 to December 2010, 1,029 CERs were performed at participating institutes. We collected the data prospectively and analyzed gender, age, tumor size, gross appearance, mode of resection, etc. The mean size of polyps resected was 26.4 ± 8.6 mm (range 20–120 mm). The final pathology was Vienna classification category 1 or 2 in 24, category 3 in 502, and category 4 or 5 in 503 lesions. Post procedure bleeding and intra procedure perforation occurred, respectively, in 16 (1.6 %) and 8 cases (0.78 %). The overall complication rate was 2.3 %. Risk factors for bleeding in multivariate analysis were only patients under 60 years of age. Risk factors for perforation in multivariate analysis were en bloc resection and Vienna classification category 4–5. The difference of complication rate was not statistically significant regarding gender, size, tumor location, gross appearance, treatment method, and kind of insufflation. CER is a safe, efficient, and effective minimally invasive therapy for large colorectal lesions. However, care should be taken for post procedure bleeding in patients under 60 years of age and for perforation in cases of Vienna classification category 4–5 or when an en bloc resection is tried.

Colorectal endoscopic submucosal dissection (C-ESD) is a promising but challenging procedure. We aimed to evaluate the factors associated with technical difficulties (failure of en bloc resection and procedure time, ≥2 h) and adverse events (perforation and bleeding) of C-ESD. We conducted a retrospective exploratory factor analysis of a prospectively collected cohort in 15 institutions. Eight-hundred sixteen colorectal neoplasms larger than 20 mm from patients who underwent C-ESD were included. We assessed the outcomes of C-ESD and risk factors for technical difficulties and adverse events. Of the 816 lesions, 767 (94 %) were resected en bloc, with a median procedure time of 78 min. Perforation occurred in 2.1 % and bleeding in 2.2 %. Independent factors associated with failure of en bloc resection were low-volume center (

Diagnosis of the bile duct cancer still needs more accuracy. Studies on endoscopic retrograde cholangiopancreatography (ERCP)-guided brushing cytology were carried to evaluate the role of the endoscopic transpapillary brushing cytology for the diagnosis of bile duct cancer.The study involved 76 consecutive patients who underwent ERCP-guided bile duct cytology for the diagnosis of bile duct cancer from 2008 to August 2012. Three types of cytological specimens were obtained using different sampling methods, i.e., bile aspiration cytology (BAC), brush tip cytology (BTC), and post brushing bile cytology (PBC), to investigate their diagnostic abilities, and comparatively studied with each macroscopic type of the surgically resected specimens.The cancer-positive rate was 67.1 % (BAC alone: 41.9 %), and the use of BTC and PBC in addition to BAC yielded a statistically significant increase of the cancer-positive rate (p = 0.0031). In 34 resected cases, the cancer-positive rate in relation to the macroscopic type was improved by the addition of BTC and PBC to BAC alone for the papillary (87.5 vs. 40.0 %, p = 0.071) and nodular (100 vs. 70.0 %, p = 0.0603) types, but not for the flat type (62.5 vs. 57.1 %; p = 0.7651).The diagnostic ability of ERCP-guided brushing cytology could be improved by the addition of PBC. However, the cancer-positive rate was the lowest for the flat type of bile duct cancer.

With the advances in the multidisciplinary treatment of pancreatic cancer (PC) over the last few years, it is crucial to obtain a histopathological diagnosis prior to treatment. Histopathological diagnosis for unresectable PC is currently performed with endoscopic retrograde cholangiopancreatography (ERCP) in combination with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). We retrospectively assessed the results of these two methods and investigated diagnostic performance according to the location of the lesion and the complications. This study was conducted on a series of 263 consecutive cases of unresectable PC diagnosed with endoscopic cytology. Up to 2006, ERCP-guided cytology (group A) was performed as the first choice for the diagnosis of PC. EUS-FNA was introduced in 2007 and became the first choice thereafter (group B), except in cases with obstructive jaundice, in which ERCP-guided cytology during endoscopic biliary stenting (EBS) remains the first choice. There were statistically significant differences in the overall cancer-positive rate between groups A and B (60.4 vs. 75.3%, P=0.01). The cancer-positive rate in the pancreatic body and tail was significantly higher in group B (59.5 vs. 83.3%, P=0.005), whereas there were no significant differences regarding cancer of the pancreatic head. The complication rate was 4.95% in group A and 3.09% in group B (P=0.448). The endoscopic cytology cancer-positive rate in unresectable PC cases was increased as a result of the introduction of EUS-FNA. In conclusion, we recommend performing EUS-FNA in combination with ERCP-guided cytology in cases with a lesion in the pancreatic head that requires EBS.

There are two major hurdles to carrying out endoscopic retrograde cholangiopancreatography (ERCP) in patients with altered gastrointestinal anatomy (Billroth II gastrectomy [B-II], Roux-en-Y anastomosis [R-Y] etc.), post-pancreatoduodenectomy or post-choledochojejunostomy. These are: (i) the endoscopic approach to the afferent loop, blind end, and the site of bilio-pancreatic anastomosis; and (ii) bile duct and/or pancreatic duct cannulation. Balloon-assisted enteroscopy (BAE) became available in recent years and is now being actively used to overcome the first hurdle and, at least, the success rate has improved. However, room for improvement still remains in regards to the second hurdle (i.e. the success rate of cannulation of the bile duct and/or pancreatic duct), and there has been a desire for the development of dedicated devices (ERCP catheters, hoods etc.) and for improvement in the functionality of the enteroscopes etc. In the present review, we explain the basic procedure for bile duct and/or pancreatic duct cannulation with conventional endoscopes and BAE, and modifications of the basic procedure.

The usefulness of magnifying endoscopy with narrow-band imaging (ME-NBI) for the diagnosis of early gastric cancer is well known, however, there are no evaluation criteria. The aim of this study was to devise and evaluate a novel diagnostic algorithm for ME-NBI in depressed early gastric cancer. Between August, 2007 and May, 2011, 90 patients with a total of 110 depressed gastric lesions were enrolled in the study. A diagnostic algorithm was devised based on ME-NBI microvascular findings: microvascular irregularity and abnormal microvascular patterns (fine network, corkscrew and unclassified patterns). The diagnostic efficiency of the algorithm for gastric cancer and histological grade was assessed by measuring its mean sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Furthermore, inter- and intra-observer variation were measured. In the differential diagnosis of gastric cancer from non-cancerous lesions, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 86.7, 48.0, 94.4, 26.7, and 83.2%, respectively. Furthermore, in the differential diagnosis of undifferentiated adenocarcinoma from differentiated adenocarcinoma, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 61.6, 86.3, 69.0, 84.8, and 79.1%, respectively. For the ME-NBI final diagnosis using this algorithm, the mean κ values for inter- and intra-observer agreement were 0.50 and 0.77, respectively. In conclusion, the diagnostic algorithm based on ME-NBI microvascular findings was convenient and had high diagnostic accuracy, reliability and reproducibility in the differential diagnosis of depressed gastric lesions.

Background and Aims Bleeding from esophageal and gastric varices is a fatal event in patients with liver cirrhosis and portal hypertension. However, the effects of Helicobacter pylori (H. pylori) infection on esophagogastric variceal bleeding are not known. The present study was aimed to elucidate the role of H. pylori infection in esophagogastric variceal bleeding. Methods The subjects were 196 cirrhotic patients who were admitted to the Kurume University Hospital to treat their esophagogastric varices consisted of 95 with acute bleeding and 101 with nonbleeding but high risk of bleeding. For the diagnosis of H. pylori infection, a 13C-urea breath test was used, and serum pepsinogen (PG) I and II levels and the PG I/II ratio were also measured. Results Esophagogastric variceal bleeding was seen in 34.9% (n = 30) of the H. pylori-infected patients (n = 86) and in 59.1% (n = 65) of the noninfected patients (n = 110) (P

A novel series of pyrrolidine derivatives as Na + channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na + channels. Structure–activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na + channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

Ampullary tumors are diagnosed by endoscopic biopsy of the ampulla of Vater. We encountered a rare case of acute pancreatitis following endoscopic biopsy of the ampulla. A 53-year-old man referred to our hospital for detailed examination of a suspected tumor of the ampulla of Vater. We conducted endoscopic biopsy from the ampulla. He developed severe abdominal pain four hours after the procedure. The serum amylase and serum lipase were elevated and abdominal computed tomography (CT) revealed pancreatic enlargement and diffuse stranding of the peri-pancreatic fat, compatible with the findings of acute pancreatitis. We diagnosed the patient as having acute pancreatitis caused by endoscopic biopsy of the ampulla of Vater. Conservative therapy improved his condition, however, a large pancreatic walled-off necrosis (WON) developed. Therefore, we performed endoscopic ultrasonography (EUS)-guided cyst drainage on the 74th day after admission. The WON diminished gradually in size and the symptoms disappeared, and the patient was discharged in good physical condition on the 137th day after admission. In this case, the ampullary biopsy may have caused mucosal edema or intraductal hematoma, resulting in pancreatic duct obstruction. It is important for endoscopists both to be aware of this potential complication following endoscopic biopsy of the ampulla and to inform the patients about possible complications of this procedure.

Doublecortin-like kinase 1 (DCLK1), a marker for intestinal and pancreatic cancer stem cells, is highly expressed in neuroblastomas. This study was conducted to assess DCLK1 expression levels in pancreatic neuroendocrine tumor (PNET) tissues and to explore the roles of this molecule in clinical tissue from multiple PNET patients, cells (BON1, QGP1, and CM) and tumor xenografts. Immunohistochemically, all PNET tissues highly and diffusely expressed DCLK1 as a full-length isoform, identical to that detected in primary liver NETs. A DCLK1-overexpressing PNET cell line (QGP1-DCLK1) exhibited epithelial–mesenchymal transition (EMT)-related gene signatures, and robust upregulation of Slug (SNAI2), N-Cadherin (CDH2), and Vimentin (VIM) was validated by real-time PCR and immunoblotting. QGP1-DCLK1 cells had increased cell migration in a wound-healing assay and formed significantly larger xenograft tumors in nude mice. The factors involved in the formation of the fast-growing tumors included p-FAK (on Tyr925), p-ERK1/2, p-AKT, Paxillin, and Cyclin D1, which upon knockdown or pharmacologic inhibition of DCLK1 abolished the expression of these molecules. In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1. Implications: Evidence here reveals that human PNETs diffusely and robustly express the cancer stem cell marker DCLK1, which drives SLUG-mediated EMT, and suggests that NETs share biological features for druggable targets with other tumors, including neuroblastoma that also highly expresses DCLK1. Mol Cancer Res; 15(6); 744–52. ©2017 AACR.

Background and Aim Detailed endoscopic findings of the bile duct mucosa, even of the non-neoplastic mucosa, have not yet been established. The aim of the present study was to compare a currently used video cholangioscope (CCS) with a magnifying endoscope (ME) that is commonly used for the gastrointestinal tract, for visualization of the bile duct mucosa. Methods Ten freshly resected common bile ducts were used in this study. We observed the non-neoplastic bile duct mucosa with CCS and ME, and carried out both conventional white light imaging and narrow band imaging. After histological diagnosis, the 10 specimens were classified into three categories according to the degree of histological inflammation: normal to mild, moderate, and severe. Then, we examined the relationship between the magnifying endoscopic findings and the histopathological findings. Results In eight of the 10 cases, the visualization obtained with CCS was inferior to that obtained by ME. Five specimens were classified as normal to mild inflammation, and many oval-shaped, depressed areas and a fine, regular network of the microvessels were observed by ME on the mucosal surfaces of these specimens. The remaining specimens were classified as moderate or severe inflammation, and the aforementioned findings could not be clearly visualized. Conclusion CCS does not allow visualization of the bile duct mucosa with high sensitivity. Oval-shaped depressed areas and a fine, regular network of microvessels are characteristic endoscopic features of non-neoplastic bile duct mucosa without inflammation.

The patient was a 69 year old man who had been diagnosed with alcoholic chronic pancreatitis and lower common bile duct (CBD) stricture. He subsequently developed cholangitis 2-3 times a year, and we replaced the endoscopic biliary stent (EBS) each time. In April 2010, he was admitted because of complication by a liver abscess and acute cholangitis. We performed percutaneous transhepatic liver abscess drainage. The inflammatory findings then rapidly improved, but the patient developed acute cholangitis due to the sludge and the stones. Then, we placed a partially covered self-expandable metallic stent (C-SEMS) in the lower CBD and performed endoscopic lithotripsy through the C-SEMS, and the cholangitis subsequently improved. Two weeks after, we removed the C-SEMS endoscopically and replaced it with a 10 Fr plastic stent; since then there have been no recurrences of cholangitis. Our experience in this case suggested that when a plastic stent is placed long-term to treat a biliary stricture associated with chronic pancreatitis, it might be useful to also control biliary sludge and stones using a C-SEMS.

Background and Aim: Type 1 autoimmune pancreatitis (AIP) is characterized by the increase of serum immunoglobulin (Ig)G4 and abundant IgG4 plasma cell infiltration in the pancreas and various extrapancreatic lesions (EPL), which are proposed as IgG4-related disease. We assessed the correlation between serum IgG4 and the number of EPL, and the association between serum IgG4 and the distribution of EPL in type 1 AIP patients. Methods: Serum IgG4 was measured in 35 type 1 AIP patients and 71 non-AIP patients. The clinical characteristics and distribution of eight EPL were determined in 35 type 1 AIP patients. Results: Serum IgG4 in type 1 AIP was significantly higher than in non-AIP (P

In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

Summary. Ischaemic colitis is known to be a severe emergency complication of interferon (IFN) therapy. However, as ischaemic colitis is an infrequent complication of IFN therapy, limited information is available regarding the safety of resuming IFN therapy after resolution of ischaemic colitis and subsequent recurrence. Here, we report two cases of ischaemic colitis during IFN therapy for chronic hepatitis C. Ischaemic colitis was fully healed within 1 week after its onset and IFN withdrawal, and IFN therapy was resumed following patients’ wishes to do so. Ischaemic colitis did not recur after the resumption of IFN therapy, and sustained virological response was achieved in both patients. In this report, we also summarize the findings of 11 cases of IFN-associated ischaemic colitis (nine previously published cases plus our two cases) and review the clinical characteristics of ischaemic colitis during IFN therapy in patients with chronic hepatitis C.

Background and Aim: Germinated barley foodstuff (GBF) is a prebiotic product that reduces colonic mucosal inflammation and the clinical symptoms observed in ulcerative colitis (UC). The risk of contracting colorectal cancer is higher in patients with UC than in that of the general population. The aim of this study is to apply this prebiotic approach to control chronic colitis and to reduce the incidence of colitic cancer. Methods: Repeated and intermitted dextran sulfate sodium administration to male Sprague–Dawley rats was used for the chronic and subacute colitis models. GBF was added as the diet (10% w/v). The incidence of adenomatous high-grade dysplasia, and pathophysiological observations, including the proliferative cell nuclear antigen (PCNA) labeling index, and clinical score, cecal organic acid profile, and the accompanying β-glucosidase activity were determined. Results: In the chronic phase, the incidence of adenomatous dysplasia was only confirmed in the control group, and the GBF group had no dysplasia in the entire colon; the stratified squamous epithelium area of GBF was significantly lower than that of the controls. GBF treatment significantly lowered the cecal succinate content and significantly increased β-glucosidase activity compared to the controls. In addition, colonic mucosal inflammatory damage was comparable between the two groups, while the PCNA labeling index of the colonic mucosa in the GBF group was significantly lower than that of the control group. However, in the subacute phase, the mucosal damage score of GBF was significantly attenuated, and the PCNA labeling index of the colonic mucosa in the GBF group was significantly higher than that of the control group. Conclusion: This preliminary study demonstrated that GBF effectively prevents colitis-related dysplasia and inflammatory change in chronic and subacute colitis models by modulating the intestinal environment as a prebiotic. This prebiotic might contribute to the prevention of mucosal damage, to show different proliferative effects on the epithelium in the regeneration and steady states.

Diagnosis of cystic lesions of the pancreas is made by clinical history taking, physical examination, blood biochemical tests and diagnostic imaging, such as transabdominal ultrasound, endoscopic ultrasound (EUS), cross-sectional imaging (computed tomography and/or magnetic resonance imaging) and endoscopic retrograde cholangiopancreatography, bearing in mind the known characteristic features of the various cystic lesions that can occur in this organ. Among others, EUS, endowed with a sharp local resolving power, has been described as a highly useful examination method, because it enables concurrent fine-needle aspiration (FNA). EUS has an important role in the differential diagnosis and tumor grading (benign, premalignant or malignant) of cystic lesions. Although the differential diagnosis of cystic lesions of the pancreas based on EUS morphology is practicable to some extent, there have also been reports showing that the diagnosis might vary with the endosonographer and that the diagnostic performance of this method for tumor grading is not necessarily high. In countries overseas, differential diagnosis and tumor grading of cystic lesions of the pancreas are actively undertaken not merely by EUS morphology, but also by cyst-fluid EUS-guided FNA (EUS-FNA) cytology and measurements of pancreatic enzymes and tumor markers, and importance is attached to EUS-FNA in the latest version of the American Society for Gastrointestinal Endoscopy Guideline and in the diagnostic strategies for cystic diseases of the pancreas. Meanwhile, the current Japanese consensus is that EUS-FNA is not recommended in cases of mucinous cystic lesions suspected as being intraductal papillary mucinous neoplasm or mucinous cystic neoplasm.