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Interleukin (IL)-23, which is released by activated monocytes and neutrophils, promotes production of high levels of IL-17 by T-helper 17 cells. Cellulose acetate (CA) beads are used as carriers for granulocyte and monocyte (GM) adsorptive apheresis using Adacolumn. Contact between blood and CA beads induces cytokine release; however, their inflammatory effects on IL-23 release are unclear. We aimed to clarify the effect of CA beads on IL-23 release in vitro. We incubated peripheral blood with and without CA beads and measured IL-23. Compared to blood samples incubated without CA beads, blood samples incubated with CA beads had significantly decreased amounts of IL-23. In conclusion, CA beads inhibited IL-23 release from adsorbed GMs. The biological effects of this decrease in IL-23 release during GM adsorption to CA beads need further clarification.

Transforming growth factor-β (TGF-β) is released by activated platelets and induces the differentiation of T-helper 17 from naive T cells. Contact between blood and cellulose acetate (CA) beads induces cytokine release, although their inflammatory effects on TGF-β release are unclear. We aimed to clarify the effect of CA beads on the release of TGF-β in vitro. We incubated peripheral blood with and without CA beads and measured platelets and TGF-β. Compared with blood samples incubated without beads, the platelet count and amount of TGF-β significantly decreased in blood samples incubated with CA beads. In conclusion, CA beads inhibited the release of TGF-β from adsorbed platelets. The biological effects of this reduction of TGF-β release during platelet adsorption to CA beads need further clarification.

Cowden syndrome is an uncommon, autosomal dominant disease characterized by multiple hamartomas and hyperplastic lesions in the skin, mucous membrane, brain, breast, thyroid, and gastrointestinal tract. About 30% of Cowden syndrome cases are reportedly complicated by malignant diseases. Hamartomatous polyps occur throughout the gastrointestinal tract, the most common sites being the stomach, colon, esophagus, and duodenum. Small bowel polyps can occur in Cowden syndrome; however, they are difficult to detect by conventional examination, including double-contrast X-ray study. Here, we report three cases of Cowden syndrome with small bowel polyps, which were detected by capsule endoscopy. The small bowel polyps of Cowden syndrome frequently occur at the oral end of the small bowel, especially in the duodenum and jejunum, and their color is similar to that of the surrounding mucosa; additionally, the polyps are relatively small (2–5 mm). Capsule endoscopy is useful for detecting small bowel polyps in Cowden syndrome.

The prevalence of colorectal malignancies is increasing in the world. The parallel increase of metabolic syndrome gives a speculation between these two conditions, although the precise mechanism is still unclear. Interleukin-6 (IL-6) is a cytokine known to correlate with obesity and serve as a proinflammatory adipokine. In the present study, we investigated the effect of IL-6 signaling blockade on intestinal polyp formation in obesity using a mouse model of adenomatous polyposis coli (Apc). Male C57BL/6J-Apc(Min/+) mice were fed a high-fat diet from 5 weeks of age, and the overweight mice thus obtained were given a weekly intraperitoneal injection of anti-mouse IL-6 receptor antibody (MR16-1) from 6 to 15 weeks of age, while control mice received IgG or phosphate-buffered saline (PBS). The total number of intestinal polyps was significantly decreased in the MR16-1-injected group (53.1 ± 6.8) relative to the control groups (PBS-injected, 81.3 ± 6.1; rat IgG-injected, 74.7 ± 4.8, p = 0.01), and in particular the number of polyps larger than 2 mm in diameter was markedly decreased. In addition, the mean diameter of polyps in the MR16-1-injected group was significantly smaller than that in the control groups. On the other hand, no significant differences in body weight, epididymal fat pad mass, or the plasma levels of glucose, insulin and triglyceride were observed among the three groups. Thus, treatment with anti-IL-6 receptor antibody suppressed polyp growth in obese Apc(Min/+) mice fed the high-fat diet. We suggest that IL-6 signaling may be responsible for the obesity-associated colorectal tumorigenesis.

The present report describes a rare case of esophageal carcinoid tumor that was treated by endoscopic resection. A 43-year-old woman underwent esophagogastroduodenoscopy at her family clinic for screening of the upper digestive tract and a small lesion resembling a submucosal tumor was detected in the lower esophagus. A biopsy sample from the lesion was diagnosed as esophageal carcinoid tumor and the patient visited our hospital for detailed examination. The tumor was approximately 3 mm in diameter and its surface appeared to be covered with normal squamous epithelium. The tumor had a shiny reddish surface without ulceration or erosion. Magnifying endoscopy with narrow-band imaging showed structures resembling reticular vessels under the epithelium. Endoscopic ultrasonography depicted the tumor as a low-echoic mass within the lamina propria. Computed tomography did not detect the tumor and no metastatic lesions were evident in other organs. With the patient's informed consent, the tumor was resected using endoscopic submucosal dissection, with a sufficient free margin in both the vertical and horizontal directions. Magnifying endoscopic examination showed the resected tumor to have abundant reticular vessels. Finally, the tumor was diagnosed immunopathologically as an esophageal carcinoid tumor (neuroendocrine cell tumor, grade 1), without lymphatic or vascular invasion.

Tumor necrosis factor-α, (TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide (LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified.

Interleukin (IL)-23, which is released by activated monocytes and neutrophils, promotes production of high levels of IL-17 by T-helper 17 cells. Cellulose acetate (CA) beads are used as carriers for granulocyte and monocyte (GM) adsorptive apheresis using Adacolumn. Contact between blood and CA beads induces cytokine release; however, their inflammatory effects on IL-23 release are unclear. We aimed to clarify the effect of CA beads on IL-23 release in vitro. We incubated peripheral blood with and without CA beads and measured IL-23. Compared to blood samples incubated without CA beads, blood samples incubated with CA beads had significantly decreased amounts of IL-23. In conclusion, CA beads inhibited IL-23 release from adsorbed GMs. The biological effects of this decrease in IL-23 release during GM adsorption to CA beads need further clarification.

Interleukin (IL)-10 is an anti-inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti-inflammatory intestinal macrophages with macrophage colony-stimulating factor (M-CSF). Thus, IL-10- and M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M-CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL-10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL-10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL-10 in the plasma was measured. Compared with the level in the Control group, plasma IL-10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL-10 production with monocyte adsorption stimuli. By increasing not only M-CSF but also IL-10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti-inflammatory intestinal macrophages.

Purpose: It is widely acknowledged that chronic low-grade inflammation plays a key role in the development of obesity-related insulin resistance and type 2 diabetes. The level of circulating interleukin-6 (IL-6), one of the major proinflammatory adipokines, is correlated with obesity and insulin resistance, which are known to be risk factors for colorectal adenoma. We examined the association between the circulating level of IL-6 and the presence of colorectal adenoma. Experimental Design: In a total colonoscopy-based cross-sectional study conducted between January and December 2008, serum levels of IL-6 were measured in samples of venous blood obtained from 336 male participants attending health checkups (118 individuals with colorectal adenoma and 218 age-matched controls) after an overnight fast. Results: In the colorectal adenoma group, the median levels of serum IL-6 (1.24 vs. 1.04 pg/mL; P = 0.01), triglyceride, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were to be significantly higher than those in the control group. When restricted to individuals with adenoma, levels of IL-6 were positively correlated with body mass index, insulin, and HOMA-IR. Multiple logistic analyses adjusted to include insulin or HOMA-IR showed that high levels of IL-6 were associated with the presence of colorectal adenoma. There was no significant interaction of IL-6 with HOMA-IR to modify this association. Conclusions: Our findings suggest that increased serum levels of IL-6 are positively associated with the presence of colorectal adenoma in men, independently of insulin and HOMA-IR. Clin Cancer Res; 18(2); 392–9. ©2011 AACR.

Obesity and insulin resistance are thought to be risk factors for colorectal adenoma. Glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion from the pancreas and promotes fat accumulation in adipocytes. The association between serum GIP and the risk of colorectal adenoma has not been examined previously. We investigated this association in 370 subjects who underwent total colonoscopy during thorough physical checkups between January and December 2008. We used a cross-sectional design and classified the subjects into a colorectal adenoma group and a control group without adenoma according to their endoscopic findings. Serum GIP concentrations in samples of venous blood obtained after an overnight fast were measured using a sandwich enzyme-linked immunosorbent assay kit. The mean levels of fasting GIP (34.9 ± 49.5 vs 25.0 ± 20.1 pg/mL, P = .04), triglyceride, glucose, and insulin and the values of the homeostasis model assessment of insulin resistance in the colorectal adenoma group were significantly higher than those in the control group. Multiple logistic regression analysis showed that the highest quartile of fasting GIP levels was associated with a significantly high risk of colorectal adenoma (odds ratio, 2.1; 95% confidence interval, 1.08-3.96; P = .01) in comparison with the lowest quartile. Quartile analysis demonstrated that increased levels of GIP were related to increased levels of fasting insulin and values of homeostasis model assessment β-cell. These results suggest that an increased level of fasting GIP is associated with an increased risk of colorectal adenoma.

Increased oxidative stress is generally thought to be associated with tumorigenesis. In this cross-sectional study, we evaluated plasma 8-hydroxydeoxyguanosine (8-OHdG) levels in patients with colorectal adenoma and cancer, as a surrogate marker of oxidative damage to deoxyribonucleic acid (DNA). We collected blood samples from 58 patients with adenoma, 32 with early cancer, 25 with advanced cancer, and 36 without polyps or cancer (as controls), and measured plasma levels of 8-OHdG by enzyme-linked immunosorbent assay. Univariate analysis by logistic regression showed that an increased level of 8-OHdG was a significant risk for adenoma [odds ratio (OR) 1.393, 95% confidence interval (CI) 1.008-1.926, p = 0.045]. In patients with early cancer, univariate analysis revealed significant differences for age, body mass index (BMI), systolic blood pressure, and 8-OHdG level. Subsequent multivariate analysis revealed that 8-OHdG [OR 1.627, 95% CI 1.079-2.453, p = 0.020] and BMI [OR 1.283, 95% CI 1.038-1.585, p = 0.021] were significant risk factors for early cancer. However, 8-OHdG was not a significant risk factor for advanced cancer. Our results suggest that an increased plasma level of 8-OHdG is associated with development of colorectal adenoma and cancer.

Transforming growth factor-β (TGF-β) is released by activated platelets and induces the differentiation of T-helper 17 from naïve T cells. Contact between blood and cellulose acetate (CA) beads induces cytokine release, although their inflammatory effects on TGF-β release are unclear. We aimed to clarify the effect of CA beads on the release of TGF-β in vitro. We incubated peripheral blood with and without CA beads and measured platelets and TGF-β. Compared with blood samples incubated without beads, the platelet count and amount of TGF-β significantly decreased in blood samples incubated with CA beads. In conclusion, CA beads inhibited the release of TGF-β from adsorbed platelets. The biological effects of this reduction of TGF-β release during platelet adsorption to CA beads need further clarification.

In the ABC classification for gastric cancer risk screening, group A (Helicobacter pylori infection-negative, pepsinogen [PG]-negative) patients are assumed to be at low risk, but some patients do have atrophic gastritis and H. pylori infection. This study aimed to identify the characteristics of group A patients. Healthy adults in Yamagata City who underwent barium radiography and ABC classification participated in the survey. Patient radiographs were randomly interspersed and reviewed by two gastroenterologists who were blinded to the H. pylori and PG statuses. Group A patients (n=1462) was subclassified as follows: atrophic gastritis group, 21.5%; intermediate group, 15.7%; and no atrophic gastritis group, 62.8%. Elderly subjects and those with H. pylori antibody titers of 3.0-9.9U/ml should be carefully evaluated while interpreting the results of the ABC classification for gastric cancer risk screening.

Tumor necrosis factor-α, (TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide (LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified.

We report the case of a 61-year-old female with advanced gastric cancer and mediastinal lymph node metastasis who developed chylothorax. The patient presented with cough, dyspnea and pain in the left lower limb, back, and hips. Her lower limb symptoms were attributed to cellulitis. Computed tomography revealed right-sided pleural effusion, multiple lymph node swelling, and thickening of the gastric wall. Following pleural aspiration, the effusion was identified to be chyle. Cytopathologically, numerous adenocarcinoma cells were detected in clumps, and subsequent esophagogastroduodenoscopy revealed type 3 gastric cancer. We diagnosed multiple lymph node metastases with pleural dissemination. Chemotherapy was administered; however, she eventually succumbed to disease progression. We suspected that the chylothorax resulted from the mediastinal lymph node metastasis that caused thoracic duct obstruction.

Interleukin (IL)-10 is an anti-inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti-inflammatory intestinal macrophages with macrophage colony-stimulating factor (M-CSF). Thus, IL-10- and M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M-CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL-10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL-10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL-10 in the plasma was measured. Compared with the level in the Control group, plasma IL-10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL-10 production with monocyte adsorption stimuli. By increasing not only M-CSF but also IL-10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti-inflammatory intestinal macrophages.

Su1487 Impact of Diabetes Mellitus on Postoperative Bleeding After Endoscopic Submucosal Dissection for Esophago-Gastric Tumor Yu Sasaki*, Yasuhiko Abe, Kazuya Yoshizawa, Takeshi Sato, Eiki Nomura, Daisuke Iwano, Makoto Yagi, Kazuhiro Sakuta, Rika Shibuya, Naoko Mizumoto, Nana Kanno, Shoichi Nishise, Yoshiyuki Ueno Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan Metabolic syndrome has been more widespread due to a rise in obesity rates among adults. We have thus increased opportunities to perform endoscopic submucosal dissection (ESD) for patients with esophago-gastric tumors complicated with type 2 diabetes (DM), hypertension (HT) and hyperlipidemia (HL). These patients are at risk for atherosclerosis and often taking antithrombotic agents, which are likely to be risk for bleeding in ESD. However, the potential risk of post-ESD bleeding in these patients was still unclear. Therefore, we investigated whether DM, HT and HL were associated with increased risk of bleeding post-ESD. Methods: 185 consecutive patients, who underwent ESD for 28 esophageal tumors and 159 gastric tumors at Yamagata University Hospital, between January 2009 and December 2011, were enrolled and reviewed retrospectively. ESD was performed by using standard techniques. Antithrombotic agents were interrupted preoperatively with/without using heparin as a bridge therapy, and were restarted when hemostasis was confirmed by second-look endoscopy. All patients were treated with proton pump inhibitors after ESD. Post-ESD bleeding was defined as an episode of any of the following: overt hematemesis/hematochezia; a drop of hemoglobin O2 g/dL; or requirement of endoscopic hemostasis and/or transfusion. The risk of post-ESD bleeding was evaluated by logistic regression analysis. Results: Post-ESD bleeding occurred in 8 patients (4.3%). In comparison with the nonbleeding group, individuals in the postESD bleeding group have had a significantly higher proportion of DM (62.5% vs. 14.8%, p!0.01) and antithrombotic agents usage (50% vs. 15.3%, p Z 0.03). There were no significant differences between the groups in the proportion of male, HT (p Z 0.07) and HL (p Z 0.06). Similarly, no differences were observed in median age, BMI, blood pressure, PT-INR, APTT, counts of platelets and specimen diameter. Univariate analysis indicated that DM (OR, 9.6; 95%CI, 2.16-42.6) had a greater odds ratio (OR) for post-ESD bleeding than antithrombotic agents usage (OR, 5.5; 95%CI, 1.31-23.5). Multivariate-adjusted ORs of post-ESD bleeding for the bleeding group compared with the nonbleeding group were 7.7 (95%CI, 1.68-35.8), 4.1 (95%CI, 0.91-19.2) and 29.5 (95%CI, 5.00-174) for DM, antithrombotic agents usage and DM with antithrombotic agents usage, respectively. Furthermore, none of the patients had thromboembolism. In conclusion, this study suggests that DM is associated with the risk of postoperative bleeding after esophago-gastric ESD. Given that patients with DM carry more comorbidities, ESD should be done more carefully for these patients. To prevent post-ESD bleeding, further studies will be needed to confirm our findings and to elucidate the underlying the mechanisms.

Growing evidence suggests that metabolic syndrome is not only a cluster of risk factors for cardiovascular disease and type 2 diabetes, but also for some cancer including a colorectal cancer. We have previously shown that insulin resistance, an increased visceral fat, hypoadiponectinemia and low-grade systemic inflammation assessed by serum IL-6 levels are linked to the risk of colorectal adenoma. Recently, it has been reported that chemerin, as a novel adipokine, can act as a chemoattractant for immune cells. And obesity, insulin resistance and inflammation have shown to have elevated serum levels of chemerin. However, the role of chemerin in human colorectal adenoma is still unknown. Therefore, we investigated the relationship between serum chemerin levels and the incidence of colorectal adenoma. Methods: We conducted a total colonoscopy-based cross-sectional case-control study. 76 male individuals with an endoscopically diagnosed colorectal adenoma were enrolled along with 72 age-matched male for our control group. Both cohort groups underwent health checkups, between 2007 and 2009, at Tohoku Central Hospital. Serum levels of chemerin were measured in samples of venous blood obtained from the participants after an overnight fast. The risk for colorectal adenoma was evaluated by logistic regression analysis. Results: In the colorectal adenoma group, the mean levels of serum insulin, fasting, plasma glucose, value of HOMA-IR and HbA1c were higher than those in the control group. There were no differences between the groups in the proportions of current smokers, alcohol consumers, mean BMI, bold pressure and serum triglyceride. The mean concentration of serum chemerin was significantly higher in the colorectal adenoma group than in the control group (791±354 ng/ml vs. 538±401 ng/ml, p

9, respectively) were cultured on the rat or human subcutaneous adipose tissue-embedded or -nonembedded gel. Adipose tissue promoted the expression of the growth markers, Ki67 antigen and 24 h-labeling bromodeoxyuridine (BrdU) in the cancer cell types, whereas it inhibited that of the apoptosis marker, cleaved caspase 3. Adipose tissue promoted the basal and superficial expression of the differentiation markers, p63 and involucrin, respectively, within the epithelial layer formed by cancer cell types. Adipose tissue accelerated the invasion of cancer cell types into the gel, together with increased expression of filamin A, laminin-5 and membrane type 1-matrix metalloproteinase (MT1-MMP), and with decreased display of E-cadherin. Adipose tissue promoted the expression of mitogen-activated protein kinase (MAPK: Raf-1, MEK-1 and pERK-1/2) and phosphoinositide 3-kinase-Akt (PI3K-Akt: PTEN, p-4E-BP1 and S6) pathways, and insulin-like growth factor-I receptor (IGF-IR) in the cell types, while it decreased that of the molecularly targeted protein, human epidermal growth factor receptor 2 (HER2). Adipose tissue did not affect the expression of the prostaglandin biosynthetic enzyme cyclooxgenase-2 (COX-2) in the cell types. The COX-2 inhibitor celecoxib did not affect the morphology and invasion of the cell types. Cancer cell types in turn decreased adiponection, leptin and registin production in adipose tissue. The data suggest, first, that adipose tissue may influence the progression of esophageal cancer with the increased growth/invasion and the decreased apoptosis through MAPK, PI3K-Akt and IGF-IR up-regulation in a COX-2-independent way, although adipose tissue seems to induce the differentiation of cancer cells; second, that adipose tissue may adversely affect the HER2targeted therapy; and third, that the cancer cells may affect adipokine production of adipose tissue. Collectively, we conclude that adipose tissue may be involved in the progression of esophageal cancer under adipose tissue-cancer cell interaction.