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Three subcategories of high-risk flat and depressed lesions (FDLs), laterally spreading tumors non-granular type (LST-NG), depressed lesions, and large sessile serrated lesions (SSLs), are highly attributable to post-colonoscopy colorectal cancer (CRC). Efficient and organized educational programs on detecting high-risk FDLs are lacking. We aimed to explore whether a web-based educational intervention with training on FIND clues (fold deformation, intensive stool/mucus attachment, no vessel visibility, and demarcated reddish area) may improve the ability to detect high-risk FDLs.This was an international web-based randomized control trial that enrolled non-expert endoscopists in 13 Asian countries. The participants were randomized into either education or non-education group. All participants took the pre-test and post-test to read 60 endoscopic images (40 high-risk FDLs, five polypoid, 15 no lesions) and answered whether there was a lesion. Only the education group received a self-education program (video and training questions and answers) between the tests. The primary outcome was a detection rate of high-risk FDLs.In total, 284 participants were randomized. After excluding non-responders, the final data analyses were based on 139 participants in the education group and 130 in the non-education group. The detection rate of high-risk FDLs in the education group significantly improved by 14.7% (66.6-81.3%) compared with -0.8% (70.8-70.0%) in the non-education group. Similarly, the detection rate of LST-NG, depressed lesions, and large SSLs significantly increased only in the education group by 12.7%, 12.0%, and 21.6%, respectively.Short self-education focusing on detecting high-risk FDLs was effective for Asian non-expert endoscopists. (UMIN000042348).

Fundic gland polyps (FGPs) are the most common gastric polyps and have been regarded as benign lesions with little malignant potential, except in the setting of familial adenomatous polyposis. However, in recent years, the prevalence of FGPs has been increasing along with the widespread and frequent use of proton pump inhibitors (PPIs). To date, several cases of FGPs with dysplasia or carcinoma (FGPD/CAs) have been reported. In this review, we evaluated the clinical and endoscopic characteristics of sporadic FGPD/CAs. Majority of the patients with sporadic FGPD/CAs were middle-aged women receiving PPI therapy and without Helicobacter pylori (H. pylori) infection. Majority of the sporadic FGPD/ CAs occurred in the body of the stomach and were sessile and small with a mean size of 5.4 mm. The sporadic FGPs with carcinoma showed redness, irregular surface structure, depression, or erosion during white light observation and irregular microvessels on the lesion surface during magnifying narrow-band imaging. In addition, sporadic FGPs, even with dysplasia, are likely to progress to cancer slowly. Therefore, frequent endoscopy is not required for patients with sporadic FGPs. However, histopathological evaluation is necessary if endoscopic findings different from ordinary FGPs are observed, regardless of their size. In the future, the prevalence of FGPs is expected to further increase along with the widespread and frequent use of PPIs and decreasing infection rate of H. pylori. Currently, it is unclear whether FGPD/CAs will also increase in the same way as FGPs. However, the trends of these lesions warrant further attention in the future.

In recent years, the serrated neoplasia pathway where serrated polyps arise as a colorectal cancer has gained considerable attention as a new carcinogenic pathway. Colorectal serrated polyps are histopathologically classified into hyperplastic polyps (HPs), sessile serrated lesions, and traditional serrated adenomas; in the serrated neoplasia pathway, the latter two are considered to be premalignant. In western countries, all colorectal polyps, including serrated polyps, apart from diminutive rectosigmoid HPs are removed. However, in Asian countries, the treatment strategy for colorectal serrated polyps has remained unestablished. Therefore, in this review, we described the clinicopathological features of colorectal serrated polyps and proposed to remove HPs and sessile serrated lesions ≥ 6 mm in size, and traditional serrated adenomas of any size.

Colorectal polyps are often detected during the insertion phase of colonoscopy but are commonly removed during the withdrawal phase. We aimed to investigate the clinical advantages of instant removal of colorectal polyps during the insertion phase to determine the appropriate strategy for polyps detected on insertion.This prospective, multicenter, randomized trial targeted patients with at least 1 left-sided polyp 10 mm in size detected unintentionally on endoscope insertion from April 2018 to March 2019. Patients were allocated to the following 2 groups: study group, consisting of patients who had polyp removal instantly on insertion, and control group, comprising patients who had the endoscope inserted to the cecum first and polyps removed subsequently on withdrawal. Carbon dioxide gas insufflation and cold polypectomy were applied to minimize the influences of polypectomy on endoscope insertion. Twenty advanced endoscopists from 7 community-based institutions participated in this trial.Of 1451 patients enrolled, 220 patients were eligible for full assessment. Mean total procedure time was significantly shorter in the study group (18.9 vs 22.3 minutes, P .001). Mean pure cecal intubation time and number of polyps per patient were similar between the 2 groups. In the control group, among 107 polyps found during insertion, 48 (45.8%) required reinspection and 7 (6.5%) were completely missed, with an average reinspection time of approximately 3 minutes.Polypectomy during the insertion phase in the colon and rectum significantly shortens the total procedure time and eliminates all missed polyps without experiencing any disadvantages.

The endocytoscope with ultra-high magnification (x 520) allows us to observe the cellular structure of the colon epithelium during colonoscopy, known as virtual histopathology. We hypothesized that the endocytoscope could directly observe colorectal histopathological specimens and store them as endocyto-pathological images by the endoscopists without a microscope, potentially saving the burden on histopathologists.To assess the feasibility of endocyto-pathological images taken by an endoscopist as adequate materials for histopathological diagnosis.Three gastrointestinal pathologists were invited and asked to diagnose 40 cases of endocyto-pathological images of colorectal specimens. Each case contained seven endocyto-pathological images taken by an endoscopist, consisting of one loupe image, three low-magnification images, and three ultra-high magnification images. The participants chose hyperplastic polyp or low-grade adenoma for 20 cases of endocyto-pathological images (10 hyperplastic polyps, and 10 Low-grade adenomas in conventional histopathology) in study 1 and high-grade adenoma/ shallow invasive cancer or deep invasive cancer for 20 cases [10 tumor in situ/T1a and 10 T1b] in study 2. We investigated the agreement between the histopathological diagnosis using the endocyto-pathological images and conventional histopathological diagnosis.Agreement between the endocyto-pathological and conventional histopathological diagnosis by the three gastrointestinal pathologists was 100% (95%CI: 94.0%-100%) in studies 1 and 2. The interobserver agreement among the three gastrointestinal pathologists was 100%, and the κ coefficient was 1.00 in both studies.Endocyto-pathological images were adequate and reliable materials for histopathological diagnosis.

The serrated neoplasia pathway, in which serrated polyps develop as colorectal cancer, has received a lot of interest in recent years as a new carcinogenic process. Hyperplastic polyps (HPs), sessile serrated lesions, and classic serrated adenomas are histopathologically characterised colorectal serrated polyps; the latter two are considered premaligna in the serrated neoplasia pathway. Apart from diminutive rectosigmoid HPs, all colorectal polyps, including serrated polyps, are removed in Western countries. The treatment strategy for colorectal serrated polyps in Asian countries, on the other hand, has remained unestablished. As a result, we detailed the clinicopathological aspects of colorectal serrated polyps in this review and recommended eliminating HPs and sessile serrated lesions ≥ 6 mm in size, as well as traditional serrated adenomas of any size.

Endoscopic submucosal dissection (ESD) for remnant gastric cancer (RGC) after distal gastrectomy (DG) is considered technically challenging due to the narrow working space, and severe fibrosis and staples from the previous surgery. Technical difficulties of ESD for RGC after DG have not been thoroughly investigated. This study aimed to develop and validate a risk-scoring system for assessing the technical difficulty of ESD for RGC after DG in a large multicenter cohort. We investigated patients who underwent ESD for RGC after DG in 10 institutions between April 2008 and March 2018. A difficult case was defined as ESD lasting ≥ 120 min, involving piecemeal resection, or the occurrence of perforation during the procedure. A risk-scoring system for the technical difficulty of the procedure was developed based on multiple logistic regression analyses, and its performance was internally validated using bootstrapping. A total of 197 consecutive patients with 201 lesions were analyzed. There were 90 and 111 difficult and non-difficult cases, respectively. The scoring model consisted of four independent risk factors and points of risk scores were assigned for each as follows: tumor size > 20 mm: 2 points; anastomosis site: 2 points; suture line: 1 point; and non-expert endoscopist: 2 points. The C-statistics of the scoring system for technical difficulty was 0.72. We developed a validated risk-scoring model for predicting the technical difficulty of ESD for RGC after DG that can contribute to its safer and more reliable performance.

Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems.

Background:Helicobacter pylori eradication rates have decreased worldwide. Gastric acid inhibition during treatment is important to eradicate these bacteria successfully. A new potassium-competitive acid blocker, vonoprazan (VPZ), has been shown to achieve high eradication rates in a previous randomized controlled trial. Objective: To determine the efficacy of VPZ for H. pylori eradication. Methods: A total of 874 patients were enrolled; 431 received esomeprazole (EPZ) and 443 received VPZ. First-line regimens contained clarithromycin (CAM) 200 mg b.i.d., amoxicillin 750 mg b.i.d., and either EPZ 20 mg b.i.d. or VPZ 20 mg b.i.d. for 7 days. Metronidazole 250 mg b.i.d. replaced CAM in the second-line regimens. The eradication of H. pylori was assessed by 13C-urea breath tests 4-8 weeks after each therapy. Results: The overall first-line eradication rate was 79.9% (341/427) with EPZ vs. 86.3% (377/439) with VPZ (p = 0.019). The second-line eradication rate was 83.3% (45/51) with EPZ vs. 91.1% (41/45) with VPZ (p = 0.900). Conclusion: VPZ was significantly more effective than EPZ for first-line treatment. However, for second-line treatment, there was no significant difference between EPZ and VPZ.

ObjectiveTo investigate the efficacy of recombinant human soluble thrombomodulin (rTM) in preventing the development of walled-off necrosis (WON) in severe acute pancreatitis (SAP) patients.MethodsWe retrospectively analyzed 54 SAP patients divided into two groups: SAP patients treated by rTM (rTM group, 24 patients) and not treated by rTM (control group, 30 patients). rTM was administered to patients with disseminated intravascular coagulation (DIC). Initially, on the admission day, we recorded patient severity and pancreatic necrosis/ischemia positive or negative. Then we investigated development of WON using 4 weeks later CT/MRI. Finally we compared the proportions of patients developing WON in the rTM group and the control group.ResultsOn the admission day, the condition of patients treated by rTM was significantly worse than patients in the control group; rTM group vs. control: 71.8 ± 13.9 vs. 59.8 ± 15.3 years for age, 10.7 ± 3.5 vs. 8.0 ± 4.4 for Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and 3.3 ± 1.8 vs. 2.2 ± 1.8 for sequential organ failure assessment (SOFA) score (p

Background/Aims: Currently, there is no study evaluating the effect of acotiamide on transient lower esophageal sphincter relaxations (TLESRs). The aim of this study was to evaluate the effect of acotiamide on TLESRs using simultaneous high-resolution manometry (HRM) and impedance-pH monitoring. Methods: Ten healthy subjects were enrolled. On day 1, subjects underwent HRM and impedance-pH recordings as a baseline. Subjects ate a 750-kcal liquid meal; recording was continued for 2 h while the subjects were in a sitting position. After the administration of acotiamide 100 mg three times a day for 1 week, subjects underwent HRM and impedance-pH recording under the same protocol. Results: A total of 208 TLESRs were identified at baseline. Acotiamide decreased the total number of TLESRs from 208 to 143 (p < 0.05). The rate of reflux events during TLESRs after acotiamide administration was similar to that at baseline (57% after acotiamide vs. 58% at baseline). Bolus clearance time was significantly reduced by acotiamide. Conclusions: Acotiamide was believed to have the potential for reducing TLESRs and for enhancing esophageal bolus clearance in healthy volunteers. Future research is needed to determine whether the effects of acotiamide that reduce TLESRs and enhance esophageal motility could improve symptoms in patients with refractory gastroesophageal reflux disease.

Background/Aim: The effects of vonoprazan and proton pump inhibitors (PPIs) in patients with reflux esophagitis (RE) have not yet been compared using multichannel intraluminal impedance-pH (MII-pH). Methods: A total of 8 patients with persistent gastric mucosal injury, despite completing an 8-week standard PPI therapy, were enrolled in the study. While they were on standard PPI therapy, the baseline values of reflux parameters, holding time ratio (HTR) of gastric pH >4, and esophageal pH Results: The patients were found to be CYP2C19 extensive metabolizers and negative for Helicobacter pylori infection. In 7 patients (87.5%), the mucosal lesions had healed completely after vonoprazan therapy. A significant increase in gastric pH >4 HTR was observed, from 26.5 to 78.0% (p = 0.029). A reduction in esophageal pH Conclusion: Vonoprazan may be a better therapy for the treatment of patients with PPI-refractory RE.

Background Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA. Patients and methods This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20–80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0–2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety. Results Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31–79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7–40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0–10.2) and 17.3 months (95% CI 11.7–19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths. Conclusions Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

Gastrinomas mainly occur in the duodenum and pancreas. Primary hepatic gastrinoma is rare and difficult to diagnose because the liver is a frequent site of metastatic gastrinomas. Clinical factors were assessed in a 28-year-old man with diarrhea and heartburn who was hospitalized for recurrent duodenal ulcers. Abdominal ultrasound, endoscopic ultrasound and computed tomography (CT) could not detect a tumor in the duodenum or pancreas. His gastrin level was 846 pg/mL and magnetic resonance imaging showed a mass 12 mm in diameter in the right robe of the liver. A selective intra-arterial calcium injection (SACI) test and 68-gallium edotreotide positron emission tomography CT (Ga-DOTATOC PET-CT) were therefore performed. Calcium gluconate injection into the proper hepatic artery resulted in a marked increase in serum gastrin concentration in the right hepatic vein, with Ga-DOTATOC PET-CT showing uptake only by the liver mass. Following a diagnosis of primary hepatic gastrinoma, the tumor was resected. A histopathological examination indicated gastrinoma. Six months postoperatively, he has no symptoms, is not taking proton-pump inhibitors and his gastrin level remains within the normal range. The SACI test and the clinical course of this patient strongly suggest that the tumor was a primary hepatic gastrinoma. The SACI test is helpful in the diagnosis of primary hepatic gastrinoma.

Objective: To evaluate the feasibility of S-1 and high-dose cisplatin short hydration regimens for outpatients with unresectable metastatic gastric cancer. Methods: Data for individual outpatients treated in our institution were retrospectively pooled to assess the feasibility of an S-1 and highdose cisplatin short hydration regimen (S-1: 80 to 120 mg on Days 1 to 21; cisplatin: 60 mg/m2 on Day 8, every 5 weeks), which included 2250 ml of intravenous fluids and 1000 ml oral hydration. Ten consecutive patients were treated with S-1 and high-dose cisplatin short hydration for unresectable metastatic gastric cancer from July 2011 to May 2012 and were included in the analysis. Results: With a median of 3.5 medication cycles, unscheduled admission occurred in two patients for 5 days each due to paralytic ileus and cerebral infarction. Four patients required dose reduction, in both S-1 and cisplatin in two patients, and in S-1 alone and cisplatin alone in one patient each. Renal function transiently declined after administration of cisplatin, but serum creatinine level and estimated glomerular filtration rate were both improved by the time of the next administration. Conclusion: This study suggests that an S-1 and high-dose cisplatin short hydration strategy for outpatients with unresectable metastatic gastric cancer might be feasible.

Background and Aims: Although patients with early colorectal cancer invading the submucosa (CRC-sm) may be treated with endoscopic mucosal resection alone, they generally undergo additional surgery because of the risk of lymph node metastasis. The aims of the present study were to examine the roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in tumor vascularization and to investigate whether COX-2 and VEGF expression and tumor vascularity are useful markers for predicting lymph node metastasis in CRC-sm. Methods: Twenty-seven resected specimens of CRC-sm with lymph node dissection were examined, and expression of COX-2 and VEGF was evaluated immunohistochemically and scored. Microvessel density (MVD) in CRC-sm tissues was estimated using a Macscope system after CD34 immunostaining. The relationships among clinicopathological parameters, COX-2 and VEGF expression, and MVD in CRC-sm tissues were then analyzed. Results: Scores for COX-2, VEGF and MVD were all significantly higher in patients with CRC-sm with lymphatic invasion or lymph node metastasis. COX-2 score (P

A 70-year-old man was referred to our hospital because of elevated CA19-9. Magnetic resonance imaging revealed a jejunal tumor having duct and retention cyst-like structures, which suggested ectopic pancreatic cancer. We resected that part of the jejunum and the lymph nodes around the tumor. Pathological examination revealed an adenocarcinoma originating from a Heinrich type I ectopic pancreas in the jejunum. Adjuvant chemotherapy with gemcitabine was performed for half a year. After 8 months, CA19-9 remained elevated, and liver metastasis occurred. We began treatment with tegafur/gimeracil/oteracil potassium (S-1) and particle beam therapy. After 7 months, CA19-9 was normal, and the patient has remained in partial remission with S-1 treatment. Ectopic pancreas tissues typically occur in the stomach and duodenum and rarely become cancerous. Here, we report the features of a rare and illustrative case of jejunal ectopic pancreatic cancer.

Background: It is still not clear which parameters are important for predicting the metastatic potential of superficial esophageal squamous cell carcinoma (SESCC). The purpose of the present paper was thus to investigate tumor cell dissociation (TCD) in SESCC as a predictive factor of lymph node metastasis. Methods: Thirty-three SESCC were classified into four groups based on the depth of tumor invasion. Carcinomas not invading as far as the muscularis mucosa were classified as group A; carcinomas invading to the muscularis mucosa or less than one-third of the upper submucosa were classified as group B; those invading to the middle layer of the submucosa were classified as group C; and those invading one-third of the lower submucosa were classified as group D. The TCD score was calculated by dividing the length of the TCD region by the maximal longitudinal length of the area of invasion into or beyond the lamina propria, and multiplying by 100. E-cadherin expression of the carcinomas was investigated in the TCD area and the successive area of mucosal invasive carcinoma (SAM). Results: The incidence of lymph node metastasis was 0% in group A, 10% in group B, 36.4% in group C and 57.1% in group D. The mean TCD scores (±SEM) of SESCC with lymph node metastasis were higher than that without (85.3 ± 5.7, 16.3 ± 3.9, respectively; P

Acupuncture has been used to treat gastrointestinal symptoms in China for more than 3000 years. However, the mechanism of the beneficial effects of acupuncture remains unknown. Strain gauge transducers were implanted on the serosal surface of the stomach to record circular muscle contractions in thiobutabarbital-anesthetized rats. Acupuncture on the right lower abdomen caused a transient relaxation of the stomach. Acupuncture-induced gastric relaxations were abolished by guanethidine, propranolol, splanchnic ganglionectomy, spinal cord transection, and spinomedullary transection. In contrast, N G-nitro-l-arginine, phentolamine, truncal vagotomy, and pontomedullary transection had no effect. Acupuncture increased the number of c-Fos immunopositive cells at the ventrolateral medulla (VLM). It is concluded that acupuncture-induced gastric relaxations are mediated via the somatosympathetic reflex. Its afferent limb is composed of abdominal cutaneous and muscle afferent nerves. Its efferent limb is the gastric sympathetic nerve and the reflex center is within the medulla. VLM neurons may play an important role in mediating this reflex.

Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.

It has been shown that centrally administered neuropeptide Y (NPY) delays gastric emptying. To determine the receptor subtypes of NPY mediating the inhibitory effects on gastric emptying, effects of intracerebroventricular injection of NPY, [Leu31,Pro34]NPY (a Y1agonist) and NPY-(3–36) (a Y2agonist) on solid gastric emptying and postprandial antropyloric motility were studied in conscious rats. Intracerebroventricular injection of NPY and NPY-(3–36), but not [Leu31,Pro34] NPY, delayed solid gastric emptying in a dose-dependent manner (0.03–3 nmol). After the feeding (40 min), contractions with low frequency and high amplitude of the antrum were frequently observed, and the peak contraction of the antrum occurred most often 3–6 s before the peak contraction of the pylorus. Intracerebroventricular injection of NPY and NPY-(3–36) (3 nmol), but not [Leu31,Pro34]NPY, significantly reduced antral contractions and the number of antropyloric coordination events. It is suggested that centrally administered NPY impairs postprandial antral contractions and antropyloric coordination via Y2receptors, resulting in delayed gastric emptying.

Background and Aims: Cyclooxygenase (COX)-2 has a trophic effect on gastrointestinal epithelial cells and is associated with the progression of colorectal adenomas. Mutation of the K-ras gene is also associated with the progression of colorectal adenomas and has recently been suggested to play an important role in the induction of COX-2. In the present study, we investigated the relationship between COX-2 expression and K-ras mutation in colorectal adenomas. Methods: Twenty-nine colorectal adenomas were obtained from specimens resected by the use of surgery or endoscopic mucosal resection and analyzed clinicopathologically. Immunohistochemistry was performed to analyze COX-2 expression in the adenoma specimens. The K-ras codon 12 mutations were detected by using the polymerase chain reaction-restriction fragment length polymorphism method. Results: An increase of COX-2-positive cells in adenoma was observed in 11 (37.9%) lesions, 10 (90.9%) of which had a K-ras gene mutation, suggesting a significant correlation between COX-2 expression and K-ras gene mutation in colorectal adenomas. Morphologically, COX-2-positive adenomas (13.8 ± 2.6 mm) were significantly larger than COX-2-negative ones (5.8 ± 0.9 mm). In addition, the increase of COX-2-positive cells in the lesion was observed more frequently in tubulovillous (63.6%) than in tubular (36.4%) adenoma. Conclusions: Cycloxygenase-2 expression in colorectal adenoma cells is strongly correlated with K-ras gene mutation, suggesting that COX-2 and mutated K-ras are connectively associated with the progression of colorectal adenoma.

Background and Study Aims: Photodynamic therapy (PDT) has proved effective in the treatment of gastric cancer, but there is room for improvement. To achieve the technical goal of carrying out endoscopic PDT, endoscopists need to determine the precise area for laser irradiation at adequate dosages. This report describes the use of a shapememory alloy (SMA) loop snare as a useful tool in endoscopic PDT. Patients and Methods: Eleven patients with biopsyproved early gastric cancer were treated with endoscopic PDT after intravenous injection of Photofrin II (2 mg/kg b.w.). Five patients underwent PDT using the SMA loop snare, and six underwent PDT without the use of the device. Cancer lesions smaller than 2 cm in diameter were irradiated with an excimer-dye laser (4 mJ, 80 Hz, 630 nm) for 20 min. Results: All five patients (100%) treated with PDT using the SMA loop snare, and four of the six patients (67%) treated with PDT without use of the SMA loop snare, showed complete remission. Conclusions: The SMA loop snare routinely forms a circle 2 cm in diameter, covering an area of 3.14 cm 2 , and makes it possible to mark and calculate the precise area of cancerous lesions for irradiation at appropriate dosages. The findings of this study suggest that the SMA loop snare is an effective tool for PDT in early gastric cancer.

Dans la presente etude, nous comparons et confrontons l’image reconstituee a partir de coupes histologiques seriees et l’image obtenue par l’examen au microscope apres coloration au bleu alcian-hematoxyline (methode BAH), ceci en tant que methode d’evaluation de la nature et de l’extension des cellules tumorales. La performance diagnostique de l’endoscopie dans le diagnostic des mini et petites lesions s’eat averee correcte dans 16 foyers sur 28, alors que le diagnostic par BAH etait concordant pour toutes les lesions grâce aux techniques d’agrandissement et de coloration qui facilitent l’identification des traits caracteristiques des carcinomes gastriques plats et deprimes; a savoir la marge effilee a terminaison abrupte (Type Cliff, differences Niveu), le bord erode de la berge des plis (type Rias coat) a la fois sur des lesions plates et deprimees. En cas de dysplasie. l’erreur concernant l’extension de la lesion determinee par le pouvoir d’amplification du microscope a dissection et l’image reconstruite a partir de coupes seriees, etait superieure ou egale a 1 mm. Selon ces observations, l’evaluation histologique de l’extension et de la diffusion intra-murale des lesions de dysplasie ou de carcinome intra-muqueux ou a envahissement limite, resequees par RME (Resection muqueuse endoscopique) beneficient de la methode BAH. En revanche la methode BAH ne permet pas l’evaluation correcte de la profondeur de l’envahissement carcinomateux: ceci revient a dire que le microscope a dissection ou l’observation de coupes seriees apres BAH ne contribuent pas au diagnostic differenciel entre dysplasie et carcinome moderement invasif. Sur des echantillons gastriques reseques par RME, la methode BAH est efficace dans le diagnostic de la nature de la lesion et celui de l’extension intra-muqueuse du processus tumoral.

A 74-year-old woman was noted to have a mass lesion near the right elbow joint during medication for pulmonary tuberculosis. After discontinuation of medication, the mass gradually became enlarged with swelling and tenderness of the joint. Radiological evaluation disclosed tenosynovitis with an encapsulated abscess. Microscopic examination and culture of an aspiration biopsy specimen from the abscess showed no microorganisms. However, DNA extracted from the specimen contained mycobacterium tuberculosis DNA, permitting a diagnosis of tuberculous tenosynovitis. Mycobacterium is not always detected in biopsy specimens of tuberculous arthritis and tenosynovitis. In such cases, genetic diagnosis may be of great use.

A 72-year-old man was admitted with obstructive jaundice. Computed tomography revealed a 4cm tumor with multiple cystic components obstructing the common bile duct. Endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography and intraductal ultrasonography demonstrated the tumor, which derived from the lower bile duct, grew into the bile duct lumen. Peroral cholangioscopy revealed distended tumor vessels on the surface of the tumor. Signet ring cell carcinoma of the bile duct was diagnosed by biopsy. The patient died 3 months after the first hospital admission despite chemotherapy.

polyposis or cancer. In all subjects basal GH, Insulin Growth Factor-I (IGF-I), maximal suppresion of GH (maxGH) and plasma insulin after a standarized meal were measured and a colonoscopy was performed . All patients had been diagnosed by tipical symptoms, increased GH (greater than 2 nglml after oral glucose overload) and increased levels of IGF-l. Results: 19 patients(50%) had polyps (8 mill 1):15 (39,5 %) adenomatous and 4 (10,5%) hyperplasic . 19 patients (50 %) had no polyps (9 milO I) . One patient with adenomatous polyps had colonic carcinoma (2.6 %). In a control group (subjects referred to colonoscopy for other reasons with the same age and sex) the prevalence of polyps was 25 %. Conclusions: The prevalence of polyps and colon cancer in active acromegaly patients is higher than in the general population and in the subjects referred to colonoscopy for other reasons. Except for age, no significant differences were observed in the risk factors studied. We recommend a colonoscop y examination in acromegalic patients, especially those over 50 years of age.

A 77-year-old man, who underwent segmental pancreatectomy for intraductal papillary mucinous adenoma in 2001, was referred to our hospital with complaints of hematemesis and melena on January, 2004. Emergency upper gastrointestinal endoscopy showed a pulsating submucosal protrusion in the duodenal bulb, which was identified as a gastroduodenal arterial aneurysm measuring 1.5cm on abdominal CT imaging. Transcatheter arterial embolization of the aneurysm with metallic coils was successfully performed. Periodically repeated endoscopic examination has revealed the coils protruding into the duodenal lumen without any serious complication.

Background and Aim: Colonic perforation is the serious accidental complication. The aim of this study is to analyze the clinical presentation and management of recent iatrogenic perforations during therapeutic colonoscopy. Methods: Consecutive patients referred to four academic cancer centers in Japan were retrospectively reviewed using each center's endoscopy database of medical records. Data was obtained by means of an extensive data collection sheet. Since we evaluated the data including iatrogenic perforation during newly developed therapeutic procedure such as endoscopic submucosal dissection (ESD) or hemoclips, the collection of patient data was set from the period of the beginning of ESD technique in each hospital in this study. Results: The overall rate of occurrence of perforation was 0.15% (23/15, 160). Perforation rate for EMR (0.58%) showed a significantly higher rate (P

430 Background: Small bowel adenocarcinoma (SBA) is a rare disease. Previous studies suggested several prognostic factors of unresectable SBA, including age, performance status (PS), primary site, resection of primary tumor, histology, and tumor marker (CEA and CA19–9) levels. However, prognostic factors of the patients treated with oxaliplatin–fluoropyrimidine combination therapy were unknown, while these drugs were reported as a promising chemotherapy regimen for SBA. Methods: Previously untreated SBA patients were treated with an mFOLFOX6 regimen, and a post hoc analyses for prognostic factors were performed. Results: Between April 2010 and November 2012, 24 patients were included in this study. The overall response rate was 45% (9/20). The median progression-free survival and overall survival (OS) were 5.4 months (95% CI, 4.8–6.0) and 17.3 months (95% CI, 11.7–19.0), respectively. Univariate analysis revealed that lower PS (HR= 0.27; 95% CI, 0.10–0.77; p= 0.014), primary disease of the jejunum (HR= 0.35; 95% CI, 0.11–1.12; p=0.077), and serum CEA in the normal range (HR= 0.40; 95% CI, 0.14–1.11; p= 0.079) were potential prognostic factors of longer OS (threshold, p< 0.10). Although resection of the primary tumor was not a predictive factor of survival in this study, 54% and 21% of the patients needed surgery (primary resection or bypass) because of stenosis before and during chemotherapy, respectively. It is considered that bowel obstruction should be addressed before and during treatment. Conclusions: PS, primary site, and serum CEA levels are potential prognostic factors of unresectable SBA. There is a higher incidence of bowel stenosis or obstruction caused by the primary tumor before and during the treatment of SBA.

Recently, according to increasing gastroesophageal reflux disease (GERD), the patients with Barrett's esophagus (BE) are increasing. Since Barrett have reported cases of esophageal ulcers surrounding by columnar epithelium, the various criteria of the BE have been proposed. In 1998, practice guidelines for BE were developed under the auspices of the American College of Gastroenterology. They proposed that BE was a chance in the esophageal epithelium of any length that can be recognized at endoscopy, and confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia. Endoscopically, BE is determined, when 'gastric-appearing mucosa' or apparent 'columnar lined esophagus' is evident proximal to the esophagogastric junction. Histologically, BE has double muscularis mucosae, and contains a mixture cell types; gastric-fundic type epithelium, junctional type epithelium, and specialized columnar epithelium (SCE). Especially SCE is distinctive features of BE, available for diagnosis. On the other hand, BE is premalignant condition for the adenocarcinoma of the esophagus, therefore the features of the BE are researched to prevent and find out earlier development of adenocarcinoma. In this review, we referred to the definition of BE with some topics.

Background: Surveillance colonoscopy is widely recommended in patients with longstanding and extensive ulcerative colitis (UC) in order to detect colorectal neoplasia at an early stage. However, it still remains questionable whether surveillance colonoscopy effectively enables early detection of UC associated neoplasia. There is a great need for sensitive markers to identify individuals at increased risk of neoplasia. The oestrogen receptor (OR) gene shows age related methylation in the colorectal epithelium and is methylated frequently in sporadic colorectal neoplasia, suggesting that OR methylation may predispose to colorectal neoplasia. Aim: To clarify whether analysis of methylation of the OR gene in non-neoplastic epithelium can contribute to prediction of increased neoplasia risk in UC patients. Materials and methods: A total of 165 non-neoplastic colorectal epithelia from 30 patients with longstanding and extensive UC, including 13 UC patients with neoplasia and 17 patients without, were evaluated. Methylation specific polymerase chain reaction was performed to determine the methylation status of the OR gene. Results: Methylation of the OR gene was detected in 54 of 70 (77.1%) non-neoplastic colorectal epithelia in UC with neoplasia but in only 23 of 95 (24.2%) without neoplasia. Methylation of the OR gene was significantly more frequent in non-neoplastic epithelium from UC with neoplasia than in chronic colitic epithelium from UC without neoplasia. Furthermore, in UC with neoplasia, the OR gene was extensively methylated in non-neoplastic epithelia throughout the colorectum compared with those in UC without neoplasia. Conclusion: These results suggest that analysis of OR gene methylation may have potential as a useful marker for identifying individuals at increased risk of neoplasia among those with longstanding and extensive UC.

Gemcitabine (GEM) is currently considered a standard drug for advanced pancreatic cancer and widely used for patients with this carcinoma. We report on 2 patients with unresectable pancreatic cancer who were able to survive for more than 2 years after GEM treatments. Case 1 was a 82-year-old woman with invasion to celiac artery and who was inoperable. During GEM administration, she had no symptoms and the tumor did not progress. However, because of the toxicities of heart failure, GEM administration was stopped after she took a total of 16,800 mg. After GEM administration was stopped, symptoms appeared and the tumor progressed. Case 2 was a 39-year-old man with obstructive jaundice with liver and lymph node metastases. He was treated with metallic stent in order to reduce cholestasis. During GEM administration, he had no symptoms and the tumor did not progress. As an adverse event, rash occurred after he took a total of 51,800 mg. GEM administration was then stopped. This patient sometimes developed cholestasis due to tumor ingrowths and sludge and was treated successful by endoscopy. GEM has shown to improve survival and show a clinically beneficial response in patients with advanced pancreatic cancer. However, toxic events can be expected to occur with long term GEM administration. We consider that management of complications such as obstructive jaundice is very important in the treatment of pancreatic cancer.

Acupuncture has been used to treat gastrointestinal symptoms in China for more than 3000 years. However, the mechanism of the beneficial effects of acupuncture remains unknown. Strain gauge transducers were implanted on the serosal surface of the stomach to record circular muscle contractions in thiobutabarbital-anesthetized rats. Acupuncture on the right lower abdomen caused a transient relaxation of the stomach. Acupuncture-induced gastric relaxations were abolished by guanethidine, propranolol, splanchnic ganglionectomy, spinal cord transection, and spinomedullary transection. In contrast, N(G)-nitro-L-arginine, phentolamine, truncal vagotomy, and pontomedullary transection had no effect. Acupuncture increased the number of c-Fos immunopositive cells at the ventrolateral medulla (VLM). It is concluded that acupuncture-induced gastric relaxations are mediated via the somatosympathetic reflex. Its afferent limb is composed of abdominal cutaneous and muscle afferent nerves. Its efferent limb is the gastric sympathetic nerve and the reflex center is within the medulla. VLM neurons may play an important role in mediating this reflex.

Gastric carcinoid tumors associated with chronic atrophic gastritis type A have been reported to show good prognosis, because invasion and metastasis are rare. We report a case of gastric carcinoid tumor associated with hypergastrinemia that showed no malignant changes for 12 years. A 15-year-old man with abdominal discomfort underwent endoscopic examination. A polypoid lesion was detected on the atrophic mucosa of the fundus, and was diagnosed as a carcinoid tumor. Serological examination revealed a high level of anti-parietal-cell antibody, suggesting that the patient had chronic atrophic gastritis type A. The tumor was treated by endoscopic mucosal resection. Follow-up examinations were performed for 12 years, but showed no recurrence. This case confirms that gastric carcinoid tumors associated with chronic atrophic gastritis type A may have a good prognosis.

3646 Background: Several prospective and retrospective studies have suggested that chemotherapy prolongs survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA). However,...

After polypectomy, the cut end of the polyp is usually examined by light microscopy to assess the risk of recurrent cancer. Here, we report a recurrent tumor that appeared in the colon 6 years after polypectomy, although cancer cells were not observed in hematoxylin and eosin-stained sections of the cut end of the primary polyp. Retrospectively, the primary polyp and the recurrent tumor were analyzed for mutations of the p53 gene. We detected p53 mutations in the primary polyp, even in the cut end of the polyp. The same set of two p53 mutations was detected in the recurrent tumor. These observations indicate a common origin of the primary tumor and the recurrent tumor. We conclude that it is important to analyze p53 mutations in colonic polyps, especially when the cut end of the polyp is difficult to evaluate histologically, in order to predict recurrence.

The human haptoglobin (HP) HP*2 allele contains a 1.7-kilobase (kb) intragenic duplication that arose after a unique nonhomologous recombination between the prototype HP*1 alleles. During a genetic screening of 13,000 children of survivors exposed to atomic-bomb radiation and 10,000 children of unexposed persons, two children suspected of carrying de novo mutations at the haptoglobin locus were identified (one in each group). DNA analyses of single-cell-derived colonies of Epstein–Barr virus-transformed B cells revealed that the two children were mosaics comprising HP*2/HP*2 and HP*2/HP*1 cells at a ratio of ≈3:1. We infer that the latter cells are caused by reversion of one HP*2 allele to HP*1 through an intramolecular homologous recombination between the duplicated segments of the Hp*2 allele that excised one of the segments. Because the mosaicism is substantial (≈25%), this recombination must have occurred in early embryogenesis. The frequency of finding these children and the extent of their mosaicisms corresponds to an HP*2 to HP*1 reversion rate of 8 × 10 −6 per cell during development. This leads to the prediction that the HP*1 allele also will be represented, although usually at a very low frequency, in any HP2-2 person. We tested this prediction by using PCR for a single individual and found the HP*1 allele at frequencies of 4 × 10 −6 and 3 × 10 −6 in somatic and sperm cells. The HP*1 allele was detected by PCR in all four other HP2–2 individuals, which supports the regular but rare occurrence somatically of homologous recombination within duplicated regions in humans, in agreement with previous observations in mouse and Drosophila .

Purpose: PDT is an effective treatment for early gastric cancer, where patients cannot undergo surgery or show no indication for other endoscopic treatment, or both; nevertheless, its efficacy is limited in case of advanced gastric cancer. In this study, we assessed the efficacy of our new approach of reducing tumor volume before PDT in the treatment of advanced gastric cancer. Methods: The procedure comprises several steps as follows: 1. Saline containing epinephrine (0.05 mg/ml) is injected endoscopically under the tumor to prevent bleeding. 2. Part of the tumor is resected by electric-cautery to reduce volume; in the case of bleeding, Nd:YAG laser is applied. 3. The patient is then subjected to PDT.A photosensitizer, hematoporphyrin derivative, is injected intravenously at a dosage of 2.5-3.0 mg/kg. After 48 and 72 hours, the cancerous lesion is irradiated as extensively as possible with a pulsed laser (a gold vapor laser; 200-380 mW or an excimer-dye laser; 320 mW). 4. If the cancerous lesion appears reduced, a hot biopsy is carried out. 5. If one course of the therapy is not effective or if recurrence occurs, additional therapy is an alternative according to the appearance of the remnant tumor: when polypoid lesions appear, the treatment from step 1 is repeated; when ulcerated lesions appear, the treatment from step 3 is repeated. Follow-up endoscopic examination is conducted 3, 6, and 12 months after treatment, and complications are also checked. This therapy was applied to 10 cancerous lesions in 10 patients (10 men; average, 77 years old) who could not undergo surgery and/or chemotherapy because of complications or other factors. Results: Two of the ten (20%) cancerous lesions disappeared completely by a single course of treatment, and no recurrence was found over two years of follow-up examinations. Six of the ten (60%) lesions showed over 50% reduction in tumor volume; 5 of these 6 patients lived for 2 to 6 years after several courses of the treatment. The main complication of sunburn in 9 of the 10 patients was entirely eliminated; no other significant complications appeared. Conclusion: The new treatment, PDT combined with tumor reduction, is effective in the treatment of advanced gastric cancer and could be an alternative treatment for patients who may be at risk from surgery or chemotherapy, or both.