Takao Yaoita

Increased plasma levels of 8-hydroxydeoxyguanosine are associated with development of colorectal tumors.

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.

Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

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.

Production of Interleukin-10 by Combining a Granulocyte and Monocyte Adsorption Carrier With Ulinastatin

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.

Diagnosis and treatment of eosinophilic esophagitis in clinical practice

Eosinophilic esophagitis (EoE) is a chronic and abnormal Th2 type immunological response characterized by intense eosinophilic inflammation localized within the esophagus. This leads to esophageal dysfunction and remodeling accompanied by subepithelial fibrosis. Recently, EoE has been recognized as one of the major causes of dysphagia or food impaction in adults. The prevalence of EoE has been increasing over the past several decades, particularly in Western countries. EoE should be differentiated from secondary esophageal eosinophilia (EE) in gastroesophageal reflux disease (GERD) and eosinophilic gastroenteritis, involving the entire gastrointestinal tract. EoE is an uncommon condition in Asia compared with Western countries. With the growing interest and awareness of this condition during the past decade, reports of this disease are increasingly emerging in Asian countries including Japan. Typical EoE does not respond to proton pump inhibitor (PPI) therapy according to the current Western diagnostic guidelines. However, some cases of EE exhibit symptomatic relief and histological improvement in response to PPI [i.e., PPI-responsive esophageal eosinophilia (PPI-REE)]. The understanding of the clinical manifestations and unique endoscopic images of EoE, differences and similarities between GERD, PPI-REE, and EoE will all serve as the differential diagnosis. Further knowledge of the indications and efficacy of PPI therapy and topical steroid therapy will also aid in the management of these diseases. In this article, we will review the current diagnosis and treatment of EoE in clinical practice.

Treatment with Anti-Interleukin-6 Receptor Antibody Ameliorates Intestinal Polyposis in Apc Min/+ Mice under High-Fat Diet Conditions

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.

Increased Levels of Serum Glucose-Dependent Insulinotropic Polypeptide as a Novel Risk Factor for Human Colorectal Adenoma

Author contributions: Yu Sasaki: design an writing. Hiroaki Takeda: design and conduct and analysis, and data interpretation. Tomo Shoichi Nishise: data interpretation and man Tanaka: design and conduct of the study, and manuscript writing. ⁎ Corresponding author. Tel.: +81 23 628 5309 E-mail addresses: y-sasaki@med.id.yama stakeshi@med.id.yamagata-u.ac.jp (T. Sato), nagino@med.id.yamagata-u.ac.jp (K. Nagino ytanaka@tohoku-ctr-hsp.com (Y. Tanaka), y-

Impaired Secretion of Glucagon-Like Peptide 1 in Patients with Colorectal Adenoma after an Oral Glucose Load

Background/Aims: Obesity and insulin resistance are associated with an increased risk of colorectal adenoma (CRA). Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis through its amplification of insulin secretion in response to oral nutrients; however, its role in human CRA remains unknown. We investigated oral glucose-mediated GLP-1 secretion in patients with adenoma. Methods: We performed a case-control study of 15 nondiabetic patients with pathologically diagnosed CRA and 10 age-matched healthy controls without adenoma. Plasma concentrations of active GLP-1 were measured during a 75 g oral glucose tolerance test. Results: Mean waist circumference (WC), homeostasis model assessment of insulin resistance (HOMA-IR) values, the total areas under the curve (AUC) of glucose and insulin were significantly higher in patients with CRA than in controls. The total AUC of GLP-1 (p = 0.01) was lower in patients with CRA than in controls. Moreover, the total AUC of GLP-1 showed a negative correlation with WC, total AUC of glucose, and HOMA-IR. Multiple linear regression analyses revealed that the total AUC of GLP-1 was independently correlated with the number and maximum size of CRAs. Conclusion: GLP-1 could actively participate in the development of CRA in humans, particularly in patients with metabolic syndrome.

Tu2130 Anti-Mouse IL-6 Receptor Antibody Suppresses Intestinal Carcinogenesis in APCMIN/+ Mice Receiving a High-Fat Diet

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.