Clinicopathological Characteristics of Everolimus-Associated Interstitial Lung Disease: A Single-Center Consecutive Analysis.

BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

A Proposed New Clinical Classification of Metastatic Gastric Cancer: Pyloric and Antral Gastric Cancer.

BACKGROUND: We aimed to classify metastatic pyloric/antral gastric cancer in terms of macroscopic morphology and metastatic form. METHODS: Thirty-eight patients with pyloric/antral gastric cancer were included in the study. Patients were classified according to a combination of Borrmann classification type and metastatic type, and the clinicopathological characteristics of each group were compared. RESULT: Of the 38 patients, 33 (type II: 9 and type III: 24) (87%) had ulcerative gastric cancer. Ulcerative gastric cancer was classified into four groups: lymphatic only group (L+H-P-), lymphatic + hematogenous group (L+H+P-), disseminated ± lymphatic group (L±H-P+), and lymphatic + hematogenous + disseminated group (L+H+P+). In the L+H-P- group, all patients had bulky lymph nodes and serum levels of both carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were high; the condition of patients was good, and the therapeutic response was good. In the L+H+P- group, metastases other than liver metastases were rare, and serum CEA levels were high. In the L±H-P+ group, the predominant histological type was signet ring cell carcinoma; both serum CEA and CA19-9 levels were low. Patients in the L+H+P+ group had higher serum CA19-9 levels and were more prone to hematogenous metastasis to various organs; these patients had worse patient status and lower treatment response. Gastric cancer other than ulcerative type was only detected in five patients (type V: 3, type IV: 1, type I: 1). CONCLUSION: Classification by a combination of macroscopic and metastatic form in pyloric/antral metastatic gastric cancer might be useful for diagnosis and treatment.

Readministration of Cancer Drugs in a Patient with Chemorefractory Metastatic Colorectal Cancer.

A 63-year-old woman was admitted to our institution for severe pain in her right lower abdomen caused by the perforation of cecal cancer. She underwent emergency surgery, from which she was diagnosed with cecal carcinoma with liver, lung, and lymph node metastases. As she was taking aspirin to prevent cerebral infarction, anti-vascular endothelial growth factor (receptor) antibody and regorafenib therapy were not used. Thus, we started a modified FOLFOX 6+cetuximab regimen. This first-line treatment initially achieved a partial response (PR), but she then developed progressive disease (PD) after 14 months. We changed the regimen to FOLFIRI, followed by trifluridine/tipiracil, but her progression-free survival periods were 2.7 months and 1 month, respectively. Although we cycled through the available array of standard cancer drugs, the patient showed a good performance status, and some benefit from treatment still seemed plausible. We readministered the 5-fluorouracil oral preparation S-1, which maintained stable disease (SD) for 7 months. After PD emerged, we readministered the anti-epidermal growth factor receptor (EGFR) antibody panitumumab for 7.5 months of SD. Finally, 39 months after her diagnosis, she died from rapidly progressing disease. However, her relatively long survival implies that readministering drugs similar to those used in previous regimens might benefit patients with metastatic colorectal cancer.

Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy.

PURPOSE: Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ. METHODS: Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ. RESULTS: The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032). CONCLUSIONS: The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.

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.

Clinical Complete Response from Chemotherapy in an Elderly Patient with Metastatic Gastric Cancer: A Case Report.

An 81-year-old man was admitted with upper abdominal pain and weight loss. Esophagogastroduodenoscopy revealed a large tumor located from the gastric angle to the body. Histological analysis of a biopsy revealed a moderately differentiated adenocarcinoma. Computed tomography revealed metastases in the liver and lung and the patient was subsequently diagnosed with metastatic advanced gastric cancer. He was treated with chemotherapy using S-1 (80 mg/m2) and cisplatin (CDDP) (60 mg/m2). Twenty-two months after chemotherapy, the gastric tumor, and the nodules in the liver and lung, had disappeared. We subsequently diagnosed a clinical complete response. The patient was treated with further S-1 monotherapy for 7 months after complete response assessment. He has lived for more than 7 years since the initial diagnosis without recurrence. Chemotherapy using S-1 and CDDP may be a potent strategy for improving survival in elderly patients with advanced gastric cancer.

[A case of multiple primary small intestinal adenocarcinomas].

A 62-year-old woman, with a past history of long-term non-steroidal anti-inflammatory drug use and gastric ulcer, was hospitalized for intestinal obstruction in April 2012. Two stenoses were identified in the ileum in association with small intestinal ulcers, and she underwent partial resection of the small intestine. Histologically, the two lesions were poorly differentiated adenocarcinomas; metastatic small intestinal cancer was suspected, but whole body examination revealed no other lesions. The final diagnosis was multiple primary small intestinal malignancies, necessitating additional resection of the small intestine in July. We report this case to raise awareness among physicians of the possibility of primary small intestinal cancer in patients with multiple small intestinal stenoses.

Apurinic/apyrimidinic endonuclease-1 is associated with angiogenesis and VEGF production via upregulation of COX-2 expression in esophageal cancer tissues.

Apurinic/apyrimidinic endonuclease-1 (APE-1) is a key enzyme responsible for DNA base excision repair and is also a multifunctional protein such as redox effector for several transcriptional factors. Our study was designed to investigate APE-1 expression and to study its interaction with cyclooxygenase (COX)-2 expression and VEGF production in the esophageal cancer. The expression of APE-1, COX-2, monocyte chemoattractant protein (MCP)-1, CC-chemokine receptor (CCR)2, and VEGF were evaluated by immunohistochemistry in 65 human esophageal squamous cell carcinoma (ESCC) tissues. Real-time PCR and Western blotting were performed to detect mRNA and protein expression of APE-1 and p-signal transducer and activator of transcription 3 (STAT3) expression in MCP-1-stimulated ESCC cell lines (KYSE 220 and EC-GI-10). siRNA for APE-1 was treated to determine the role of APE-1 in the regulation of COX-2 expression, VEGF production, and antiapoptotic effect against cisplatin. In human ESCC tissues, nuclear localization of APE-1 was observed in 92.3% (60/65) of all tissues. There was a significant relationship (P = 0.029, R = 0.49) between nuclear APE-1 and cytoplasmic COX-2 expression levels in the esophageal cancer tissues. In KYSE 220 and EC-GI-10 cells, MCP-1 stimulation significantly increased mRNA and protein expression of APE-1. Treatment with siRNA for APE-1 significantly inhibited p-STAT3 expression levels in MCP-1-stimulated cells. Furthermore, treatment of siRNA for APE-1 significantly reduced COX-2 expression and VEGF production in MCP-1-stimulated esophageal cancer cell lines. Treatment with APE-1 siRNA significantly increased apoptotic levels in cisplatin-incubated KYSE 220 and EC-GI-10 cells. We concluded that APE-1 is overexpressed and associated with COX-2 expression and VEGF production in esophageal cancer tissues.

Impact of coexisting irritable bowel syndrome and non-erosive reflux disease on postprandial abdominal fullness and sleep disorders in functional dyspepsia.

BACKGROUND/AIMS: The association between clinical symptoms and sleep disorders in functional dyspepsia (FD)-overlap syndrome has not been studied in detail. METHODS: The subjects were 139 patients with FD, 14 with irritable bowel syndrome (IBS), 12 with nonerosive reflux disease (NERD), and 41 healthy volunteers. Gastric motility was evaluated with the (13)C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms, and Self-Rating Questionnaire for Depression (SRQ-D) scores to determine depression status. Sleep disorders were evaluated with Pittsburgh Sleep Quality Index (PSQI) scores. RESULTS: There were no significant differences in age, body-mass index, alcohol intake, and smoking rate between patients with FD alone and those with FD-overlap syndrome. The postprandial abdominal fullness score in patients with FD-NERD-IBS was significantly greater than that in patients with FD-NERD overlap syndrome (p<0.001) or FD alone (p<0.001). The score for the feeling of hunger in patients with FD-NERD-IBS was significantly greater than that in patients with FD alone (p=0.0025), FD-NERD overlap syndrome (p=0.0088), or FD-IBS overlap syndrome (p=0.0057). The heartburn score in subjects with FD-NERD-IBS overlap syndrome was significantly greater than that in subjects with FD alone (p=0.0035) or FD-IBS overlap syndrome (p=0.0026). The Tmax in patients with FD-overlap syndrome or FD alone was significantly higher than that in healthy volunteers. The Pittsburgh Sleep Quality Index score in subjects with FD-NERD-IBS overlap syndrome was significantly greater than that in subjects with FD alone. CONCLUSION: Symptom scores, such as those for postprandial abdominal fullness, heartburn, and the feeling of hunger, in patients with FD-overlap syndromes are significantly greater than those in patients with FD alone. Further studies are necessary to clarify whether various symptoms are related to sleep disorders in patients with FD-NERD-IBS overlap syndrome.

Sleep disorders in functional dyspepsia and future therapy.

Sleep disorder is a common medical problem. Sleep disorder has been associated with several diseases, including pulmonary disease, gastroesophageal reflux disease (GERD) and fibromyalgia. Interest in sleep phenomenology and gastrointestinal functioning has recently increased, because sleep disorder causes significant morbidity, as evidenced by the increased need for general medical and mental health treatment for emotional problems. A number of studies have found an association between sleep disorders and functional gastrointestinal (GI) disorders. Although arousal from sleep serves several protective roles, such as increase in the speed of esophageal clearance and in airway refluxes to prevent aspiration, awakening from sleep unfortunately induces impairment of sleep quality. Some investigations about the relationship between psychogenic factors and gut motility are controversial. In addition, reports of alterations in gut motility during sleep have also been contradictory. We have evaluated sleep disorder in functional dyspepsia (FD) patients using Pittsburgh Sleep Quality Index (PSQI) score. In our recent data, PSQI score of FD patients was significantly higher compared to that in healthy volunteers. Another study has reported that the distribution of subjects who thought that they got enough sleep was significantly lower for the FD/irritable bowel syndrome (IBS) subjects than for control subjects. Several studies have reported that anti-acid therapy and prokinetic agents are effective for certain FD patients. In addition, previous study has reported tricyclic antidepressants (TCA) drugs are effective for some FD patients. Finally, new drug, actiamide, a muscarinic antagonist and cholinesterase inhibitor, significantly improves Postprandial Distress Syndrome (PDS) symptoms. It might be critical issues for determination of precise mechanism for functional gastrointestinal disorders to clarify the relationship between gut motility and sleep disorders.

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.

The incidence of deep vein thrombosis in Japanese patients undergoing endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) is more invasive than other common endoscopic procedures and may increase the risk for deep vein thrombosis (DVT)/pulmonary embolism. The incidence of DVT/pulmonary embolism after ESD has not been adequately studied. OBJECTIVE: To evaluate DVT incidence and disease-specific features of D-dimer levels in ESD patients. DESIGN: Prospective cohort study. SETTING: Single academic center. PATIENTS: This study involved 60 patients with superficial gastric neoplasms indicated for ESD. INTERVENTION: For all patients who underwent ESD, ultrasonography of the lower limbs was performed to detect DVT the day after ESD. D-dimer levels were measured 3 times: before ESD, immediately after ESD, and the day after ESD. MAIN OUTCOME MEASUREMENTS: DVT incidence after ESD. RESULTS: The DVT incidence was 10.0% (6/60). At all 3 time points, D-dimer measurements were higher in patients with DVT than in patients without DVT. According to receiver operating characteristic curve analysis, the resulting cut-off value of the D-dimer level the day after ESD was 1.9 µg/mL (sensitivity 83.3%; specificity 79.6%) for ESD patients, with superior association to pre-ESD or immediately after ESD. In univariate analyses, high D-dimer levels the day after ESD and the presence of comorbidities were significantly associated with DVT development. LIMITATIONS: Single center and small number of patients. CONCLUSION: ESD procedures have a moderate risk for venous thromboembolism. In patients undergoing ESD, D-dimer levels, especially on the day after ESD, may have specific features associated with DVT development.

Migration of eosinophils and CCR2-/CD68-double positive cells into the duodenal mucosa of patients with postinfectious functional dyspepsia.

OBJECTIVES: Recent studies have shown that postinfectious functional dyspepsia (FD) symptoms may persist after elimination of gastrointestinal (GI) infection as well as postinfectious irritable bowel syndrome accompanying colonic inflammation. However, it is unclear whether intestinal chronic inflammation can contribute to clinical symptoms of certain FD patients such as postinfectious FD. To determine the relationship between local inflammation of the duodenum and clinical symptoms, we evaluated the infiltration of several phenotypes of duodenal inflammatory cells as well as gastric motility using (13)C urea breath test in postinfectious FD patients. METHODS: We enrolled 136 consecutive patients diagnosed with FD according to Rome III criteria, and 20 healthy controls, after upper GI endoscopy. Gastric motility was evaluated by gastric emptying time (T-max) using the (13)C-acetate breath test. Upper abdominal symptoms including epigastric pain, epigastric burning, postprandial fullness, abdominal distension, and early satiety were assessed by questionnaire scores. We obtained biopsy specimens from the stomach and duodenum during upper GI endoscopy. Histological gastritis and duodenitis were assessed as mild, moderate, or severe according to previously described criteria. Characteristics of inflammatory cells and neuroendocrine cells were determined immunohistochemically with antibodies to CD3, CD68, CCR2, Vdelta1 TCR, and serotonin. RESULTS: Endoscopic duodenitis was observed in only 5.7% of postinfectious FD patients. However, the rates of histological duodenitis in duodenal biopsies of postinfectious FD patients were 17% for mild, 26% for moderate, and 57% for severe grades of duodenitis. The degree of histological duodenitis of postinfectious FD patients was significantly greater than that of healthy volunteers. There was a significant correlation between epigastric burning and the degree of duodenitis in postinfectious FD patients. There was no significant difference in histological duodenitis and T-max value in the postinfectious FD patients with or without Helicobacter pylori infection. In addition, CD68-positive cell number in postinfectious FD patients was significantly increased compared with the numbers in subjects with epigastric pain syndrome or postprandial distress syndrome and in healthy volunteers. CCR2-/CD68-double positive cell number in postinfectious FD patients was significantly (P=0.009) increased compared with those in healthy volunteers. CONCLUSIONS: Migration of inflammatory cells, in particular, duodenal CCR2-positive macrophages, may have an important function in the pathophysiology of postinfectious FD patients.

Celecoxib inhibits CD133-positive cell migration via reduction of CCR2 in Helicobacter pylori-infected Mongolian gerbils.

BACKGROUND/AIMS: To see whether celecoxib prevents gastric cancer occurrence by disrupting the progression of chronic gastritis into gastric carcinoma through its inhibition of the migration of CD133-positive cells, one of the surface markers of bone marrow-derived cells, in Helicobacter pylori-infected gerbils. METHODS: 70 gerbils were divided into six groups. Group 1 gerbils served as control (n = 6). 10 gerbils were given N-methyl-N-nitrosourea (MNU), 30 ppm (group 2). 6 short-term Helicobacter pylori-infected gerbils (group 3) were sacrificed after 8 weeks of H. pylori infection and 6 long-term H. pylori-infected gerbils were sacrificed after 42 weeks of H. pylori infection (group 4). 20 gerbils were given MNU pretreatment and long-term H. pylori infection (group 5). In addition, after H. pylori inoculation, 22 gerbils also received a celecoxib in their diet (group 6). CD133 and CCR2 expression in gastric tissues was evaluated by Western blot analysis and immunostaining. RESULTS: CD133-positive cells were mainly localized in the bottom of the gastric epithelial cells. CD133-positive cells also migrated into gastric cancer tissues in this model. CD133-positive cells in MNU-pretreated H. pylori-infected gerbils were significantly increased compared to those in H. pylori short-term infected gerbils. Celecoxib treatment significantly reduced CD133-positive cell migration and CCR2 expression levels. CD133- and CCR2-positive cells were colocalized in H. pylori-infected gastritis and gastric cancer tissues. Celecoxib treatment significantly reduced the number of CD133- and CCR2-positive cells. CONCLUSIONS: Celecoxib inhibits CD133-positive cell migration via the reduction of CCR2 in this model. Further studies are needed to clarify the precise mechanisms driving H. pylori infection-induced CD133-positive cell migration and its link to the progression of chronic gastritis into gastric cancer.

Bisphosphonate increases risk of gastroduodenal ulcer in rheumatoid arthritis patients on long-term nonsteroidal antiinflammatory drug therapy.

BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of peptic ulcers (PU) induced by nonsteroidal antiinflammatory drugs (NSAIDs). However, the impact of potential drug interactions on the development of PU has yet to be determined in a daily clinical setting. The aim was to estimate the clinical important interactions for PU presented by comedication in Japanese RA outpatients on long-term NSAID treatment. METHODS: This retrospective cohort study enrolled 196 consecutive RA outpatients on NSAID medication for at least 3 months. Potential risk factors for endoscopic PU were analyzed in RA outpatients on longterm NSAID treatment. RESULTS: PU incidence was 31% with bisphosphonate co-therapy and 17% without the co-therapy. PU incidence was only 5% in subjects with proton pump inhibitors (PPI) or prostaglandin E1 analogues (PG) co-therapy, 14% with histamine-H(2) receptor antagonists(H2RA) co-therapy, and 27% without anti-ulcer agents. In multivariate logistic regression analysis, bisphosphonate co-therapy remained a significant risk factor for PU (OR, 2.29; 95% CI, 1.09-4.81). Other risk factors for ulcer development were advanced age (greater than 60 years) and smoking (OR, 2.58; 95% CI, 1.03-6.49 and OR, 2.71; 95% CI, 1.13-5.53, respectively.) Factors that significantly reduced the incidence of PU were H2RA or PPI/PG cotherapies (OR, 0.29; 95% CI, 0.12-0.68.). CONCLUSIONS: Bisphosphonate co-therapy as well as advanced age and smoking was found to be a significant risk factor in PU, while co-therapies of standard-dose H2RA or PPI/PG proved effective in preventing PU in Japanese RA patients on long-term NSAID treatment.

Celecoxib inhibits apurinic/apyrimidinic endonuclease-1 expression and prevents gastric cancer in Helicobacter pylori-infected mongolian gerbils.

BACKGROUND AND AIMS: The aim of this study was to see whether administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, could prevent the development of gastric cancer via inhibition of apurinic/apyrimidinic endonuclease-1 (APE-1) expression induced by Helicobacter pylori infection. METHODS: 70 Mongolian gerbils were divided into 6 groups. Group 1 gerbils served as controls (n = 6). Ten gerbils were given N-methyl-N-nitrosourea (MNU), 30 ppm, 5 times biweekly (group 2). Short-term H. pylori infection was induced in 6 gerbils which were sacrificed 8 weeks after H. pylori infection (group 3). Long-term H. pylori infection was induced in 6 other gerbils which were sacrificed 44 weeks after H. pylori infection (group 4). Twenty gerbils were given MNU pretreatment 5 times biweekly and long-term H. pylori infection (group 5). In addition, after H. pylori inoculation, group 6 gerbils also received celecoxib with their diet for 26 weeks. APE-1 expression alone or with COX-2 in gastric tissues was evaluated by Western blot and immunohistological analysis. Myeloperoxidase (MPO) activity and thiobarbituric-acid-reactive substance (TBARS) levels were also evaluated. RESULTS: APE-1 was localized in gastric epithelial cells and mesenchymal cells including macrophages in H. pylori-infected gerbils. The numbers of APE-1-positive cells in group 4 and 5 were significantly increased compared to those of group 3. Celecoxib treatment significantly reduced MPO activity, TBARS levels and the incidence of gastric cancer. APE-1 and IkappaBalpha phosphorylation levels were significantly increased in MNU-pretreated H. pylori-infected gerbils compared to those in MNU-only gerbils. Celecoxib significantly reduced APE-1 and IkappaBalpha phosphorylation levels in MNU-pretreated H. pylori-infected gerbils. COX-2 and APE-1 were coexpressed in the macrophages of H. pylori-infected gerbils. CONCLUSION: Celecoxib prevented gastric cancer in MNU-pretreated H. pylori-infected gerbils with a reduction in APE-1 expression thereby suggesting the implication of APE-1 in gastric carcinogenesis in this model.