Relationship Between Immunophenotypes, Genetic Profiles, and Clinicopathologic Characteristics in Small Bowel Adenocarcinoma.

Small bowel adenocarcinoma (SBA) is rare, and scant data exist regarding its molecular and clinicopathologic characteristics. This study aimed to clarify the correlation between immunophenotypes, DNA mismatch repair status, genomic profiling, and clinicopathologic characteristics in patients with SBA. We examined 68 surgical resections from patients with primary SBA for immunohistochemical analyses of CK7, CK20, CD10, CDX2, MUC1, MUC2, MUC4, MUC5AC, and MUC6 expression as well as mismatch repair status. Genomic profiling was performed on 30 cases using targeted next-generation sequencing. Tumor mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null based on MUC2, MUC5AC, MUC6, and CD10 immunostaining. The expression of these proteins was categorized into 3 classifications according to their relationship to: (1) tumor location: CK7/CK20, MUC4, and MUC6; (2) histologic type: mucinous adenocarcinoma was positive for MUC2 and negative for MUC6; and (3) TNM stage: CD10 was downregulated, whereas MUC1 was upregulated in advanced TNM stages. CDX2 was a specific marker for SBA generally expressed in the small intestine. MUC1 and MUC4 expression was significantly associated with worse prognosis. MUC2 expression correlated with better prognosis, except for mucinous adenocarcinoma. Although the difference was not statistically significant, gastric-type tumors were more frequently located in the duodenum and were absent in the ileum. APC and CTNNB1 mutations were not found in the gastric-type tumors. The SBA immunophenotype correlated with tumor location, biological behavior, and genomic alterations. Our results suggest that the molecular pathway involved in carcinogenesis of gastric-type SBA differs from that of intestinal-type SBA.

Trypsin may be associated with duodenal eosinophils through the expression of PAR2 in early chronic pancreatitis and functional dyspepsia with pancreatic enzyme abnormalities.

BACKGROUND: Early chronic pancreatitis (ECP) has been reported to advance into chronic pancreatitis, it may be critical to differentiate the pathophysiology of ECP and functional dyspepsia (FD) in patients with pancreatic enzyme abnormalities (FD-P). This study aimed to clarify differences in the pathophysiology of ECP and FD-P and to determine whether duodenal inflammatory responses in the two diseases were associated with protease-activated receptor (PAR) 2, as the trypsin receptor. METHODS: Eighty patients who presented with FD-P and ECP were enrolled. In duodenal specimens, PAR2 mRNA levels were determined using real-time PCR. Using immunostaining, CD68-, GLP-1-, PRG2-, and CCR2-positive cells, tight junction proteins, and PAR 2 were evaluated. RESULTS: There were no significant differences in clinical symptoms and gastric motility between ECP and FD-P patients. The CD68-positive cells infiltrations and occludin expression levels in the duodenal mucosa of patients with FD-P were significantly (p<0.001 and p = 0.048, respectively) lower than those in patients with ECP. Although serum trypsin levels in ECP and FD-P patents were significantly (p<0.05 and p<0.001, respectively) associated with duodenal eosinophils counts, elevated trypsin levels were not significantly associated with degranulated eosinophils, occludin, claudin-1 and ZO-1 expression levels in the duodenum of either group. PAR2 mRNA levels were increased in the duodenum of patients with ECP and FD-P. PAR2 was localized in the epithelial cells of the duodenal mucosa and the surface of degranulated eosinophils in ECP and FD-P patients. CONCLUSIONS: Elevated trypsin levels might be partly associated with duodenal inflammatory responses through PAR2-related degranulated eosinophils and the reduction of occludin in patients with ECP and FD-P.

Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing.

BACKGROUND: Small bowel adenocarcinomas (SBAs) are rare and there is little comprehensive data on SBA genomic alterations for Asian patients. This study aimed to profile genomic alterations of SBA in Japanese patients using targeted next-generation sequencing (NGS). METHODS: We examined 22 surgical resections from patients with primary SBA. SBA genomic alterations were analyzed by NGS. Mismatch repair (MMR) status was determined by immunohistochemical analysis. Mucin phenotypes were classified as gastric (G), intestinal (I), gastrointestinal (GI), and null (N) types on MUC2, MUC5AC, MUC6, and CD10 immunostaining. RESULTS: The most common genomic alterations found in SBA tumors were TP53 (n = 16), followed by KRAS (n = 6), APC (n = 5), PIK3CA (n = 4), CTNNB1 (n = 3), KIT (n = 2), BRAF (n = 2), CDKN2A (n = 2), and PTEN (n = 2). Deficient MMR tumors were observed in 6 out of 22 patients. Tumor mucin phenotypes included 2 in G-type, 12 in I-type, 3 in GI-type, and 5 in N-type. APC and CTNNB1 mutations were not found in G-type and GI-type tumors. KRAS mutations were found in all tumor types except for G-type tumors. TP53 mutations were found in all tumor types. Although no single gene mutation was associated with overall survival (OS), we found that KRAS mutations were associated with significant worse OS in patients with proficient MMR tumors. CONCLUSIONS: SBA genomic alterations in Japanese patients do not differ significantly from those reports in Western countries. Tumor localization, mucin phenotype, and MMR status all appear to impact SBA gene mutations.

State of anxiety may be associated with exocrine pancreatic insufficiency in functional dyspepsia patients with pancreatic enzyme abnormalities.

We have reported that refractory functional dyspepsia patients with pancreatic enzyme abnormalities (FD-P). We tried to analyze the prevalence of exocrine pancreatic insufficiency (EPI) in FD-P patients to clarify whether the pathophysiology of FD patients including clinical symptoms and quality of life were associated with EPI. We enrolled forty-nine patients presenting with typical symptoms of FD-P patients (n = 20) and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 29). Five pancreatic enzymes (p-amylase, lipase, elastase-1, trypsin, and PLA2) were measured and STAI-state/-trait and SF-8 were evaluated. Pancreatic exocrine function was analyzed using N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA). There were no significant differences in patient background between FD-P and AP-P patients. BT-PABA test scores for FD-P patients (61.67 ±â€…5.55) were significantly (p = 0.01) lower than in AP-P patients (95.38 ±â€…2.36). Physical component scale (PCS) in FD-P patients was significantly (p = 0.002) lower than that in AP-P patients. STAI-state was relatively (p = 0.054) associated with BT-PABA test in FD-P and AP-P patients by multiple logistic regression analysis. The prevalence of EPI in FD-P patients was significantly higher than that in AP-P patients and was relatively associated with state of anxiety. Further studies will be needed to clarify how EPI or pancreatic enzyme abnormalities are associated with the pathophysiology of FD-P patients.

Impact of clinical characteristics of colonic diverticular bleeding in extremely elderly patients treated with direct oral anti-coagulant drugs: a retrospective multi-center study.

Since there were no available data about colonic diverticular bleeding in extremely elderly patients (>80 years old) treated with direct oral anticoagulants (DOACs), we tried to determine clinical characteristics in those with colonic diverticular bleeding taking DOACs and to compare clinical outcomes of those in DOAC-treated to those in warfarin-treated . We enrolled DOAC-treated (n = 20) and warfarin-treated (n = 23) extremely elderly patients with diverticular bleeding diagnosed by colonoscopy. We performed a retrospective review of patients' medical charts and endoscopic findings. We classified colonic diverticular bleeding based on endoscopic features due to modified previous study following three groups, type A (active bleeding), type B (non-active bleeding) and type C (bleeding suspected). Clinical outcomes such as number of recurrent bleeding, thrombotic events and mortality were estimated. There were no differences in endoscopical features and clinical characteristics between patients treated with DOAC and warfarin therapy. However, the number of recurrent bleeding, frequency of required blood transfusions and units of blood transfusion in warfarin-treated patients were significantly higher (p<0.05) compared to those in DOAC-treated groups. In addition, mortality and thrombotic events did not differ between DOAC- and warfarin-treated patients. Clinical outcomes suggest that DOACs can be recommended for extremely elderly patients with colonic diverticular disease.

Endosonographic features in patients with non-alcoholic early chronic pancreatitis improved with treatment at one year follow up.

Since the prevention of early chronic pancreatitis (ECP) into chronic pancreatitis might be critical for the reduction of pancreatic cancer, we tried to clarify the pathophysiology of ECP patients, focusing on ECP patients without alcoholic chronic pancreatitis. 27 ECP patients without alcoholic chronic pancreatitis and 33 patients with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) were enrolled in this study. Diagnosis of ECP was made when imaging findings showed the presence of more than 2 out of 7 endoscopic ultrasound features. Duodenal degranulated eosinophils and glucagon-like peptide 1 producing cells were estimated by immunostaining. There were no significant differences in characteristics and psychogenic factors between ECP and FD-P patients. Interestingly, endoscopic ultrasound score in ECP patients significantly improved, albeit clinical symptoms in ECP patients showed no improvement at one year follow up. The extent of migration of duodenal degranulated eosinophils in FD-P patients was significantly higher compared to that in ECP patients. The levels of elastase-1 and trypsin in ECP patients with improved endoscopic ultrasound features were significantly reduced by the treatment. Further studies will be needed to clarify whether clinical symptoms and endoscopic ultrasound features in ECP patients without alcoholic chronic pancreatitis were improved in longer follow up study.

Influence of hypergastrinemia secondary to long-term proton pump inhibitor treatment on ECL cell tumorigenesis in human gastric mucosa.

Proton pump inhibitor (PPI) therapy causes hypergastrinemia, which could promote the development and progression of neuroendocrine tumors (NETs). Concerns have been raised about the safety of long-term PPI use due to a possible increased risk of NETs. This study aimed to investigate the association between hypergastrinemia and the risk of NETs. Twenty outpatients presenting with serum gastrin levels greater than 400 pg/mL after long-term PPI treatment were registered in this study. Immunohistochemical analyses for chromogranin A (CgA), Ki67, gastrin and CCK/B gastrin receptor (CCKBR) were performed, and positive cell numbers were counted. There were no NET or gastric epithelial neoplasia cases observed among any of the 20 patients examined throughout the PPI treatment period. Histologically, ECL cell hyperplasia were shown in all patients. However, no relationship was found between serum gastrin levels and the number of CgA positive ECL cells. There was also no relationship between serum gastrin levels and the proportion of Ki67 positive cells or the density of CCKBR positive cells. The data indicate no relationship may exist between NETs and hypergastrinemia secondary to PPI treatment in patients having no, or mild, atrophic gastritis.

Acotiamide attenuates central urocortin 2-induced intestinal inflammatory responses, and urocortin 2 treatment reduces TNF-α productions in LPS-stimulated macrophage cell lines.

BACKGROUND: To determine whether central and in vitro administration of urocortin 2 (Ucn 2) affected intestinal inflammatory responses in LPS-stimulated rat models and macrophage cell lines and acotiamide modified mucosal inflammation in this model. METHODS: Rats were divided into four groups. LPS-stimulated group (n = 4); LPS- and urocortin 2-treated group (n = 4); LPS- and acotiamide-treated group (n = 4); and LPS-, urocortin 2-, and acotiamide-treated group (n = 4). CD68-, CCR2-, and corticotropin-releasing hormone receptor type 2 (CRHR2)-positive cells were assessed by immunostaining. Myeloperoxidase (MPO) activity was measured. TNF-α, IL-6, and IL-4 levels were measured by ELISA method. Gastric emptying and small intestinal transit time were determined using Evans blue. KEY RESULTS: Central administration of Ucn 2 significantly aggravated infiltrations of CD68- and CCR2-positive cells in the intestinal mucosa of LPS-stimulated rat models compared to those in LPS treatment alone. Interestingly, acotiamide treatment significantly reduced the migrations of both CD68- and CCR2-positive cells in the jejunum of central Ucn 2-treated LPS-stimulated rat models. Acotiamide significantly reduced the expression levels of IkB-α phosphorylation in LPS- and MCP-1-stimulated NR8383 cells. Central administration of Ucn 2 significantly delayed gastric emptying. In contrast, Ucn 2 stimulation significantly reduced TNF-α and IL-6 productions in LPS-stimulated NR8383 cells and astressin B reversed the inhibition of TNF-α production in stimulated NR8383 cells. Acotiamide (30 µmol/L) significantly reduced TNF-α and IL-6 productions in LPS- and MCP-1-stimulated NR8383 cells. CONCLUSIONS AND INFERENCES: Central and in vitro treatments of Ucn 2 affected intestinal inflammatory responses, respectively, and acotiamide improved them.

Comparison of Functional Dyspepsia and Early Chronic Pancreatitis.

Functional dyspepsia (FD) is a common disease that can markedly impair quality of life. In the 2016 Rome IV criteria, a diagnosis of FD requires the presence of bothersome FD symptoms. In 2009, a new diagnosis, early chronic pancreatitis (ECP), was proposed as a means to facilitate early treatment of chronic pancreatitis and prevent progression to chronic pancreatitis. Although chronic pancreatitis was reported to be a cause of dyspepsia, data on the relation between ECP and FD patients are limited. We therefore investigated differences between ECP patients and FD patients in the percentages of those with severe epigastric pain, early satiety, and postprandial abdominal fullness. Several studies reported an association between the cause of chronic pancreatitis and endosonographic features. In addition, endosonography was useful for distinguishing ECP patients from FD patients with pancreatic enzyme abnormalities. Thus, we compared endosonographic characteristics in these patient groups. Future studies should attempt to determine why selected FD patients with pancreatic enzyme abnormalities develop ECP.

Camostat Mesilate, Pancrelipase, and Rabeprazole Combination Therapy Improves Epigastric Pain in Early Chronic Pancreatitis and Functional Dyspepsia with Pancreatic Enzyme Abnormalities.

BACKGROUND/AIMS: The aims of the study are to clarify the pathophysiological differences among early chronic pancreatitis (ECP), functional dyspepsia with pancreatic (FD-P) enzyme abnormalities and FD patients and to determine whether camostat mesilate, pancrelipase, and rabeprazole triple therapy improve FD symptoms in the ECP patients and FD-P patients in cross-over way. METHODS: We enrolled 84 consecutive patients presenting with typical symptoms of FD patients (n = 42), ECP patients (n = 15), and FD-P patients (n = 27). Gastric emptying was assessed by the 13C-acetate breath test. ECP was diagnosed based on the criteria recommended by the Japan Pancreatic Association. RESULTS: The proportions of female in ECP patients and FD-P were significantly higher compared to that in FD patients. The early phase of gastric emptying in ECP and FD-P patients was significantly disturbed compared to that in FD patients. The primary outcome of this study is that 4 weeks of camostat mesilate, pancrelipase, and rabeprazole triple therapy significantly ameliorated epigastric pain in ECP patients compared to acotiamide and rabeprazole combination therapy. CONCLUSION: Although there were no significant differences in pathophysiology between ECP patients and FD-P patients, triple therapy can significantly ameliorate epigastric pain in ECP patients. Further studies will be needed to clarify why triple therapy can improve epigastric pain in ECP patients.

Impact of Cyclooxygenase-2 1195 G-Carrier Genotype Associated with Intestinal Metaplasia and Endoscopic Findings Based on Kyoto Classification.

BACKGROUND/AIMS: We aimed to clarify whether cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) genotypes were associated with certain histological findings and endoscopical appearances based on Kyoto classification. METHODS: We enrolled 285 Helicobacter pylori-infected gastritis patients. Genotypes of COX-2 1195, COX-2 1290, mPGES-1, interleukin-1ß (IL-1ß) 511 and tumour necrosis factor-α (TNF-α) 308 were analyzed. Genotyping was performed by polymerase chain reaction. Endoscopic appearances and histological assessment were determined by using Kyoto classification, operative link on gastritic intestinal metaplasia assessment and the updated Sydney system. RESULTS: There was a significant (p = 0.027) relationship between the IL-1ß 511 C-carrier and histological gastric inflammation in H. pylori-infected gastritis patients. There was a significant (p = 0.009) correlation between the COX-2 1195 G-carrier genotype and histological intestinal metaplasia in the gastric antrum of H. pylori-infected gastritis patients and gastric xanthoma (p = 0.027). The COX-2 1195 G-carrier genotype was also significantly (p = 0.038) associated with the score of endoscopic intestinal metaplasia based on Kyoto classification. The mPGES-1 genotype was significantly (p = 0.002) associated with endoscopic swelling of area. CONCLUSION: Our results suggest that in Japan, there exists a significant correlation between the COX-2 1195 G-carrier genotype and intestinal metaplasia in histological and endoscopic findings based on Kyoto classification in H. pylori-infected gastric mucosa.

Effect of Antithrombotic Therapy and Long Endoscopic Submucosal Dissection Procedure Time on Early and Delayed Postoperative Bleeding.

BACKGROUND: Recent updated guidelines of the Japanese Society of Gastroenterology recommend the use of a single dose of antiplatelet agents in patients undergoing endoscopic submucosal dissection (ESD). However, the postoperative bleeding risk after gastric ESD associated with the continuation or interruption of antithrombotic therapy remains controversial. We aimed to evaluate whether certain factors including interrupted antithrombotic therapy could affect early and delayed post-ESD bleeding risk. METHODS: Three hundred sixty-four patients with gastric neoplasms were treated with ESD at our hospital between October 2005 and December 2012. Seventy-four patients with interrupted antithrombotic therapy were undertaken with ESD. Early and delayed postoperative bleeding patterns were estimated. Various clinical characteristics such as gender, age, tumor location, tumor size, ESD procedure time, platelet count, and comorbidity were evaluated. RESULTS: There was a significant difference (p = 0.042) in the ESD procedure time between the patients with postoperative bleeding and those without it. There was no significant difference in postoperative bleeding between the patients on antithrombotic therapy and not on it. Moreover, interrupted antithrombotic therapy and platelet count were significantly (p = 0.0461 and p = 0.0059, respectively) associated with early postoperative bleeding in multivariate analysis. In addition, in univariate analysis, ESD procedure time was significantly (p = 0.041) associated with delayed postoperative bleeding. CONCLUSIONS: Antithrombotic therapy and prolonged ESD procedure time were significantly associated with early and delayed postoperative bleeding, respectively.

Leu72Met408 Polymorphism of the Ghrelin Gene Is Associated With Early Phase of Gastric Emptying in the Patients With Functional Dyspepsia in Japan.

BACKGROUND/AIMS: There are no available data about the relationship between ghrelin gene genotypes and early phase of gastric emptying in functional dyspepsia (FD) as defined by Rome III classification. METHODS: We enrolled 74 patients presenting with typical symptoms of FD and 64 healthy volunteers. Gastric motility was evaluated using the 13C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and self-rating questionnaires for depression (SRQ-D) scores to determine status of depression. The Arg51Gln (346G->A), preproghrelin (3056T->C), Leu72Met (408C->A), Gln90Leu (3412T->A) and G-protein 3 (825C->T) polymorphisms were analyzed in the DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. RESULTS: There was a significant relationship between the Gln90Leu3412 genotype and SRQ-D score in FD patients (P = 0.009). Area under the curve at 15 minutes (AUC15) value was significantly associated with the Leu72Met408 genotype (P = 0.015) but not with entire gastric emptying. CONCLUSIONS: The Leu72Met (408C->A) single nucleotide polymorphism was significantly associated with early phase of gastric emptying in FD patients. Further studies will be necessary to clarify the association between ghrelin gene single nucleotide polymorphisms and early phase of gastric emptying in FD patients.

Localization of phosphorylated ErbB1-4 and heregulin in colorectal cancer.

BACKGROUND: The ErbB family consists of four proteins including (EGFR)/ErbB1, ErbB2, ErbB3, and ErbB4, and plays a crucial role in the promotion of multiple tumorigenic processes. In addition to the traditional pathways of EGFR signaling, EGFR translocates to the nucleus and acts as a transcription factor in the proliferation of cancer cells. Heregulin is known as both an ErbB3 and an ErbB4 ligand. This study aimed to investigate the expression of heregulin and its relevant EGFR family members as well as their phosphorylated forms in human colorectal cancer (CRC) tissues and to determine the relationship between their expression and clinicopathological factors including patient prognosis. METHODS: We analyzed the effects of exogenous heregulin on ErbB2, ErbB3 and ErbB4 phosphorylation in Caco-2, DLD-1, and HCT 116 colon cancer cell lines by western blot analysis. We examined 155 surgical resections from colorectomy patients. Cellular localization of ErbB1-4, their phosphorylated forms and heregulin protein was analyzed in CRC surgical resections by immunohistochemical analysis. Immunohistochemical results were compared with clinicopathological factors and patient prognosis. RESULTS: Phosphorylated ErbB2 (pErbB2) and phosphorylated ErbB3 (pErbB3) were detected in both nuclear and cytosolic fractions of Caco-2 and DLD-1 cells stimulated by exogenous heregulin. Whereas, phosphorylated ErbB4 (pErbB4) was detected only in cytosolic fractions of HCT 116 cells stimulated by exogenous heregulin. Phosphorylated EGFR (pEGFR) immunoreactivity was observed in the cytoplasm and nuclei of cancer cells, whereas the pattern of EGFR staining was membranous and cytoplasmic. Subcellular localization of pErbB2, cytoplasmic, membranous, or nuclear, varied among cases. pErbB3 immunoreactivity was exclusively observed in the nuclei of cancer cells. pErbB4 immunoreactivity was observed in the cell membrane of cancer cells. Statistically, heregulin immunoreactivity correlated with pErbB2 and pErbB4 expression. In multivariate analysis for disease free survival, lymph node status, pErbB3 and pErbB4 expression retained independent prognostic significance. In multivariate analysis for overall survival, lymph node status, pEGFR and pErbB4 retained independent prognostic significance. CONCLUSIONS: ErbB2 and ErbB3 phosphorylated by heregulin localized in the nucleus of CRC cells. Phosphorylated ErbB1-4 and heregulin contribute to poorer patient prognosis in CRC. This heregulin-ErbB family member autocrine loop may be a candidate for targeted treatment of CRC.

Impact of eating attitude and impairment of physical quality of life between tertiary clinic and primary clinic functional dyspepsia outpatients in Japan.

BACKGROUND/AIMS: There is no available data on factors associated with healthcare-seeking behavior for functional dyspepsia (FD) symptoms at ei-ther tertiary or primary clinics in Japan. Therefore, we aimed to compare clinical symptoms and life styles such as sleep dis-orders and eating attitude in FD patients visiting general practitioners at primary clinics with those consulting gastro-enterologists at tertiary clinics to clarify healthcare-seeking patterns in Japanese patients. METHODS: Fifty-one FD outpatients in a tertiary clinic (college hospital), 50 FD outpatients visiting primary clinics and 50 healthy volunteers were enrolled. Clinical symptoms, quality of life, sleep disorders, eating attitude and anxiety were estimated using the Gastroin-testinal Symptom Rating Scale (GSRS), Social Functioning-8 (SF-8) test, Pittsburg Sleep Quality Index (PSQI) test and State-Trait Anxiety Inventory (STAI) for FD outpatients and healthy volunteers. RESULTS: FD outpatients exhibited higher mean scores of GSRS than healthy volunteers. The SF-8 physical component summary scores in the tertiary clinic group were significantly lower than those in the primary clinic group. GSRS scores were significantly (P < 0.001, P = 0.002) associated with global PSQI scores in FD outpatients as well as with STAI-trait scores (P = 0.006, P = 0.001) compared to healthy volunteers. The frequency of eating between meals in the primary clinic group was significantly (P < 0.05) higher than that in the tertiary clinic group. CONCLUSIONS: It may be important for clarification of healthcare-seeking behavior to determine the difference in both impairment of physical quality of life and eating attitudes between tertiary clinic and primary clinic FD outpatients in Japan.(J Neurogastroenterol Motil 2014;20:506-515).

The preproghrelin 3056 TT genotype is associated with the feeling of hunger and low acylated ghrelin levels in Japanese patients with Helicobacter pylori-negative functional dyspepsia.

OBJECTIVE: An impairment of gastric motility is strongly associated with the pathophysiology of functional dyspepsia (FD). Plasma ghrelin is one of the key molecules linked to gastric motility. Therefore, this study aimed to evaluate whether ghrelin (GHRL) gene polymorphisms are associated with clinical symptoms, the plasma ghrelin levels and gastric emptying in patients with FD as defined by the Rome III classification. METHODS: We enrolled 74 Helicobacter pylori-negative patients presenting with typical symptoms of FD (epigastric pain syndrome (EPS), n=23; postprandial distress syndrome (PDS), n=51) and 102 healthy volunteers. Gastric motility was evaluated according to the Tmax value and T1/2 using the (13)C-acetate breath test. We used the Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine the depression status. The Arg51Gln(346G->A), preproghrelin3056T->C, Leu72Met(408C->A) and Gln90Leu(3412T->A) polymorphisms were analyzed in DNA in blood samples obtained from the enrolled subjects. Genotyping was performed using polymerase chain reaction. RESULTS: There was a significant relationship (p=0.048) between the preproghrelin 3056TT genotype and the serum levels of acylated ghrelin in the H. pylori-negative FD patients. The preproghrelin 3056TT genotype was significantly (p=0.047) associated with the feeling of hunger in the H. pylori-negative FD patients. CONCLUSION: The preproghrelin 3056TT genotype is significantly associated with the acylated ghrelin levels and the feeling of hunger in H. pylori-negative FD patients. Further studies are needed to clarify the association between the preproghrelin 3056TT genotype and lower plasma acylated ghrelin levels and the impact of this relationship on the feeling of hunger in H. pylori-negative FD patients.

Impact of sleep disorders in Japanese patients with functional dyspepsia (FD): nizatidine improves clinical symptoms, gastric emptying and sleep disorders in FD patients.

BACKGROUND AND AIMS: The association between functional dyspepsia (FD) and sleep disorders has yet to be studied in detail. The aim of this study is to evaluate the risk factors associated with sleep disorders and the clinical response to nizatidine therapy for sleep disorders in Rome III-based FD patients. METHODS: We enrolled 94 FD patients and 52 healthy volunteers. We used Rome III criteria to evaluate upper abdominal symptoms, and the Self-Rating Questionnaire for Depression scores to determine depression status. Sleep disorder was evaluated using Pittsburgh Sleep Quality Index (PSQI) scores, and degree of anxiety by the State-Trait Anxiety Inventory. Gastric motility was evaluated. Thirty-four FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. The primary end point of this study was to determine whether nizatidine could improve clinical symptoms and sleep disorders in FD patients. RESULTS: The global PSQI score for FD patients was significantly (P < 0.001) higher compared with healthy volunteers. There were significant correlations between global PSQI scores and total Gastrointestinal Symptom Rating Scale and Self-Rating Questionnaire for Depression scores (P < 0.001, P < 0.0001, respectively) in FD patients than in healthy volunteers. We found significant relationships between subjective sleep quality and both Tmax and T1/2 values in FD patients. Nizatidine significantly improved certain clinical symptoms, gastric emptying, and global PSQI score compared with placebo treatment. CONCLUSION: Sleep disorders in FD patients correlated significantly with both clinical symptoms of dyspepsia and depression compared with healthy volunteers. Nizatidine significantly improved gastroesophageal reflux symptoms, gastric emptying, and sleep disorders in FD patients.

Apurinic/apyrimidinic endonuclease-1 (APE-1) is overexpressed via the activation of NF-κB-p65 in MCP-1-positive esophageal squamous cell carcinoma tissue.

Apurinic/apyrimidinic endonuclease-1 (APE-1), a key enzyme responsible for DNA base excision repair (BER), has been linked to cancer chemoradiosensitivity. The phosphorylation of p65 plays a role in the activation of this pathway. In this study, we investigated APE-1 expression and its interaction with p65 in esophageal squamous cell carcinoma (ESCC) tissue. The expression of APE-1, p65, p65 nuclear localization sequence (p65-NLS), and monocyte chemoattractant protein-1 (MCP-1) was assessed by immunohistochemical analysis in 67 human ESCC tissue samples. Real-time PCR and western blotting were also performed. p65 siRNA was evaluated to determine the role of p65 in the regulation of APE-1 expression. We found nuclear localization of APE-1 in 89.6% (60/67) of ESCC tissue samples. We also observed the colocalization of p65-NLS and APE-1 in esophageal cancer tissue. In KYSE220 cells, pretreatment of MG-132 significantly abrogated upregulation of p65 and APE-1 levels induced by MCP-1, and treatment with 10 and 20 nM p65 siRNA significantly inhibited APE-1 mRNA expression. siRNA for p65 treatment significantly increased the apoptotic index in 5-FU-treated KYSE220 cells. We conclude that APE-1 is overexpressed and mainly localized in the nuclear compartment of cancer cells, and partly regulated by p65 in the NF-κB pathway in ESCC tissue.

Classification of patients who experience a higher distress level to transoral esophagogastroduodenoscopy than to transnasal esophagogastroduodenoscopy.

BACKGROUND: In Japanese routine clinical practice, endoscopy is generally carried out without sedation. The present study aimed to identify the factors essential for appropriate selection of transnasal esophagogastroduodenoscopy (TN-EGD) as an alternative to unsedated transoral esophagogastroduodenoscopy (TO-EGD). PATIENTS AND METHODS: Subjects in this prospective cohort study comprised consecutive outpatients who underwent EGD at a single center. Factors predicting TO-EGD-induced distress were evaluated on a visual analog scale (VAS) and analyzed. Patients were classified into a two-layered system on the basis of these predictive factors, and the severity of distress between the TN-EGD and TO-EGD groups was compared using VAS and the change in the rate-pressure product as subjective and objective indices, respectively. RESULTS: In total, 728 outpatients (390 male, 338 female; mean age, 63.1 ± 0.5 years; TO-EGD group, 630; TN-EGD group, 98)met the inclusion criteria. Multivariate logistic regression analysis confirmed that age <65 years (P < 0.01; odds ratio [OR], 1.69; 95% confidence interval [CI], 1.14-2.52), gender (female; P < 0.01; OR,1.97; 95% CI, 1.34-2.91), marital status (single; P < 0.01; OR, 1.96; 95% CI, 1.18-3.27), and anxiety towards TO-EGD (P < 0.001; OR, 3.62; 95% CI, 2.44-5.37) were independently associated with intolerance. Both indices were significantly higher in the TO-EGD subgroup than in the TN-EGD subgroup in the high predictive class, but not in the low predictive class. CONCLUSION: Predictive factors for detecting intolerance to unsedated TO-EGD may be useful to appropriately select patients who transpose unsedated TO-EGD to TN-EGD.

Implication of antithrombotic agents on potential bleeding from endoscopically determined peptic ulcers, incidentally detected as surrogate markers for nsaids-associated ulcers complication.

BACKGROUND AND AIM: Little is known about the clinical significance of treatment for endoscopically determined peptic ulcers (EPU), incidentally detected as surrogate endpoints for non-steroidal anti-inflammatory drugs (NSAIDs)-associated ulcers complication, such as overt bleeding and perforation. Even uncomplicated-EPU without overt bleeding signs when antithrombotic agents (AT) were cotherapied may be of potential bleeding sites. The aim of the present study was to evaluate whether microcytic anemia, implying potential bleeding, is associated with NSAIDs-associated EPU or cotherapies with AT. METHODS: Two hundred and thirty-eight outpatients with rheumatoid arthritis under long-term NSAIDs therapies underwent upper endoscopy and were divided into the following four groups according to the pattern (presence: + or absence: -) of AT cotherapy/EPU, respectively: A, -/- (n = 165); B, -/+ (n = 44); C, +/- (n = 25); and D, +/+ (n = 4). RESULTS: EPU were found in 48 of the 238 studied patients (20.2%). After significant interactions among four groups hadstatistically been identified, hemoglobin (Hb) and mean corpuscular volume (MCV) as biomarkers for potential bleeding were compared between the groups.Hb and MCV were significantly lower in the D group than in the A,B, or C groups (Hb: P < 0.01, respectively; P < 0.05, MCV; P < 0.01 or P < 0.05, respectively). CONCLUSIONS: Patients with NSAIDs-associated EPU and AT cotherapy indicated significantly more severe microcytic anemia pattern than those without EPU or AT cotherapy, despite no evidence of overt bleeding. Even uncomplicated-EPU without overt bleeding when ATs were cotherapied may be of potential bleeding sites.