Katsunori Iijima

Pathogenesis and risk factors for gastric cancer after Helicobacter pylori eradication

Helicobacter pylori (H. pylori) infection was thought to be the main cause of gastric cancer, and its eradication showed improvement in gastric inflammation and decreased the risk of gastric cancer. Recently, a number of studies reported the occurrence of gastric cancer after successful eradication. Patients infected with H. pylori, even after eradication, have a higher risk for the occurrence of gastric cancer when compared with uninfected patients. Metachronous gastric cancer occurs frequently following the endoscopic removal of early gastric cancer. These data indicate that metachronous cancer leads to the occurrence of gastric cancer even after successful eradication of H. pylori. The pathogenesis of this metachronous cancer remains unclear. Further research is needed to identify biomarkers to predict the development of metachronous gastric cancer and methods for gastric cancer screening. In this article, we review the role of the H. pylori in carcinogenesis and the histological and endoscopic characteristics and risk factors for metachronous gastric cancer after eradication. Additionally, we discuss recent risk predictions and possible approaches for reducing the risk of metachronous gastric cancer after eradication.

The Roles of the Gut Microbiota and Toll-like Receptors in Obesity and Nonalcoholic Fatty Liver Disease

Obesity is characterized by low-grade chronic inflammation and is closely associated with the cardiovascular diseases, diabetes, and nonalcoholic fatty liver disease. Emerging data demonstrate that the gut microbiota contributes to the development of obesity by regulating the innate immune system, including the Toll-like receptors (TLRs): an altered gut microbiota composition and elevated TLR ligands are observed in obese mice and humans. The changes in the gut microbiota include an increased abundance of Firmicutes phylum and a decreased abundance of Bacteroidetes phylum. The population of beneficial bacteria that function as probiotics is decreased whereas harmful bacteria that can produce lipopolysaccharide, a TLR4 ligand, are increased in the obese state. In addition, the gut permeability is increased in obesity, which allows the delivery of larger amounts of bacterial components to the liver through the portal vein. Immune cells recognize these bacterial components through TLRs and produce diverse cytokines that kill invading pathogens. However, the sustained activation of TLR signaling induces host damage due to chronic exposure to harmful cytokines, which are produced from TLR expressing cells, including monocytes/macrophages. In the obese state, the expression of TLR is increased in several organs, including the adipose tissue and the liver. At the cell level, negative regulators of TLR signaling are suppressed, leading to activation of TLR signaling. These alterations promote inflammation in many organs. Thus, the gut microbiota and TLR signaling are therapeutic targets in patients with obesity and its related diseases.

Feasibility of colorectal endoscopic submucosal dissection (ESD) carried out by endoscopists with no or little experience in gastric ESD

Colorectal endoscopic submucosal dissection (ESD) is recommended to be carried out only by endoscopists with sufficient experience in gastric ESD. However, early gastric carcinoma is less common in Western countries than in Japan, and endoscopic maneuverability differs between the stomach and colorectum. We assessed the feasibility of colorectal ESD carried out by endoscopists with no or little experience in gastric ESD.

Phlegmonous Gastritis: A Report of Three Cases with Clinical and Imaging Features

Phlegmonous gastritis is a rare but often fatal acute pyogenic infection of the stomach. We herein report three cases of phlegmonous gastritis with different causes: the long-term placement of a nasogastric feeding tube, bacteremia associated with cellulitis in a diabetic patient, and an adverse reaction to paclitaxel/carboplatin chemotherapy for cancer of unknown primary cause, which were classified as primary, secondary, and idiopathic types, respectively. Coping with the increasing morbidity rate associated with the diverse background of such patients requires a thorough understanding of the clinical features and image findings associated with this entity.

Chronological Changes in the Gastric Cancer Subsite in Akita, Japan: The Trends from the Data of a Hospital-Based Registration System

With the decreasing global trend in the Helicobacter pylori infection rate, compositional changes in the gastric cancer subsites have occurred worldwide. However, the compositional changes in Asian countries, including Japan, remain to be clarified. The aim of this study is to investigate the latest chronological changes in the gastric cancer subsite using a hospital-based registration system in Akita prefecture in Japan. From 2007-2015, subsites of gastric cancers were coded according to the International Classification of Diseases for Oncology (ICD-03). The nine-year registration period was divided into the three 3-year periods: 2007-2009, 2010-2012, and 2013-2015. A total of 10,804 cases of gastric cancer were registered. The proportion of cardiac cancer among total gastric cancer slightly but significantly declined from 12.1% in 2007-2009 to 9.2% in 2013-2015 (P < 0.01). Among non-cardia cancer, the proportion of corpus cancer significantly increased from 41.3% to 50.2% during the study period (P < 0.01), while that of antropylorus cancer significantly decreased from 37.6% to 34.3% (P < 0.05). Such compositional changes in the gastric cancer subsite were observed largely in men, regardless of the histologic subtype of cancer. With the decreasing H. pylori infection rate, compositional changes in the gastric cancer subsite are occurring in Japan. While the proportion of cardia and antropylorus cancer is declining, that of corpus cancer is increasing, indicating diverse etiology of gastric carcinogenesis depending on the subsites. Identifying the most common sites of occurrence, may help to improve the efficiency of screening for gastric cancer.

Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats

Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1β and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.

Detection of Acetaldehyde in the Esophageal Tissue among Healthy Male Subjects after Ethanol Drinking and Subsequent L-Cysteine Intake

Ethanol is oxidized by alcohol dehydrogenase to acetaldehyde, a recognized carcinogen for the esophagus. However, no previous study has measured the acetaldehyde levels in the esophageal tissue. L-cysteine has been shown to reduce the acetaldehyde levels in the saliva; however, it is unknown whether L-cysteine intake affects the acetaldehyde concentration in the esophageal tissue. The aim of this study was to measure the acetaldehyde concentration in the esophageal tissue after ethanol drinking and evaluate the effect of L-cysteine intake on the acetaldehyde levels in the esophagus. We enrolled 10 male subjects with active acetaldehyde dehydrogenase-2*1/*1 (ALDH2*1/*1) genotype and 10 male subjects with the inactive acetaldehyde dehydrogenase-2*1/*2 (ALDH2*1/*2) genotype, the mean ages of whom were 25.6 and 27.9 years, respectively. In this prospective, single-blind, placebo-controlled study using L-cysteine and placebo lozenges (first and second examination), saliva and blood were collected before and after ethanol drinking. Esophageal tissue was obtained by endoscopic biopsy at 60 minutes after drinking, and the acetaldehyde and ethanol concentrations were measured. The acetaldehyde concentration of the saliva was significantly lower in those taking L-cysteine than in those taking the placebo. Acetaldehyde in the esophageal tissue was detected only in those taking L-cysteine lozenges. There were no correlations between the acetaldehyde concentrations in the esophageal tissue and saliva or blood. In conclusion, we detected acetaldehyde in the human esophageal tissue after ethanol drinking. Unexpectedly, intake of L-cysteine lozenges appears to contribute to detection of acetaldehyde in the esophageal tissue.

Homocysteine supplementation ameliorates steatohepatitis induced by a choline-deficient diet in mice: Homocysteine and choline in experimental NASH

High concentrations of homocysteine are believed to induce lipid synthesis and cell injury through endoplasmic reticulum (ER) stress in metabolic syndrome. However, homocysteine could be used to improve steatohepatitis induced by choline deficiency, in which methyl donors are decreased. The aim of the present study was to clarify the role of the physiological concentration of homocysteine in the development of steatohepatitis induced by choline deficiency.

Does Estrogen Contribute to the Esophageal Barrier Function in Women

Esophageal adenocarcinoma (EAC) develops as a series on the gastroesophageal reflux disease (GERD) spectrum, progressing from reflux esophagitis to Barrett’s esophagus and finally EAC. EAC has received intense focus for decades, especially in Western countries, where the incidence of EAC been increasing since the 1970s. However, in Asian countries, there has been no definite increasing trend with regard to EAC studies, with the proportion of EAC accounting for only a small percentage of total esophageal cancer cases. However, a very recent study from Japan indicated that the incidence of EAC has started to increase in Japan, due at least in part to a decreasing trend in the Helicobacter pylori infection rate in the general Japanese population, which is lagging 50 years behind Western countries. One prominent characteristic of EAC is its overwhelming male predominance, as described in a recent review. Furthermore, such male predominance is already initiated at the initial stage of the GERD spectrum, e.g., reflux esophagitis, although the tendency is amplified as the disease spectrum progresses. Hence, understanding the mechanism underlying the male predominance of reflux esophagitis may be important not only for the treatment of reflux esophagitis, but also for the prevention of the most advanced stage of GERD, EAC. A recent animal model study showed that the female hormone estrogen plays an important role in protecting the esophageal tissue from refluxed liminal noxious agents. In addition, another study indicated that estrogen enhances the epithelial barrier function of the esophagus by potentiating a tight-junction protein, occludin, consequently preventing luminal noxious agents from entering the esophageal epithelium. Consistent with these animal model studies, many epidemiological studies support the potentially pivotal role of estrogen in the esophageal barrier function. For example, the prevalence of reflux esophagitis is suppressed in premenopausal women compared with that in men; however, the prevalence steadily increases in postmenopausal women to a level similar to that in men. Furthermore, the prevalence of reflux esophagitis is relatively stable in all age groups in men. These epidemiological studies also indicate that esophageal mucosal injury is suppressed in premenopausal women by the protective action of estrogen. However, direct evidence that estrogen enhances the esophageal barrier function in human remains elusive. In the present issue of Gut and Liver, Kim et al. investigated the expression of tight-junction-related protein mRNA in male and female GERD patients and found several key differences in the mRNA expression according to the severity of the disease (e.g., erosive reflux esophagitis vs nonerosive reflux esophagitis vs controls). However, they failed to find any significant difference in the mRNA levels between genders. Unfortunately, the patients enrolled in their study appear to have been unsuitable for an investigation into the effects of estrogen on the esophageal barrier function, as the authors acknowledged in the article, as only three premenopausal women with controls and no premenopausal women with GERD were included in that study. Thus, studies enrolling premenopausal patients with GERD will be required to investigate the potential effects of estrogen on the esophageal barrier function. In addition, several methodological issues remain to be resolved. As the authors described in the article, not only the amount of the protein mRNA but also the localization of the proteins may be important for the maintenance of the esophageal barrier function. Furthermore, given that the mRNA level can be upor down-regulated, depending on the degree of concomitant inflammation of the esophageal epithelium, the interpretation of such results may be complicated. In this

A case of esophageal actinomycosis with a unique morphology presenting as a refractory ulcer

A 60-year-old man presented with odynophagia after bronchial artery infusion chemotherapy for pulmonary metastasis of hepatocellular carcinoma. Esophagogastroduodenoscopy (EGD) revealed an esophageal ulcer in the middle thoracic esophagus. An esophageal biopsy demonstrated no malignancy. However, the symptoms had not improved after a month. EGD was performed again and showed a white cord lump at the bottom of the same esophageal ulcer identified before, showing no improving tendency. A repeated biopsy of the lump revealed actinomycosis, and the symptoms were improved by the oral administration of ampicillin. We herein report a case in which esophageal actinomycosis with a unique morphology of refractory esophageal ulcer was rapidly improved by the administration of antibiotics.