**6. Acknowledgements**

This study was supported by an unconditional scientific grant from AstraZeneca.

### **7. References**

88 Gastrointestinal Endoscopy

in the squamous epithelium from ERD-patients, however no correlation was found between

The expression of NADPH oxidase was not increased in the ERD-patients compared to the healthy individuals. This could be compared with studies made on gastritis caused by Helicobacter Pylori where NADPH oxidase was significant higher in infected patients compared to healthy volunteers (18). Our finding may perhaps suggest the possibility that the reflux of acid is not strong enough as triggering, compared to pathogens. A recent study made by Feagins LA et al. have found that different components of gastric juice, acidic media or acidic bile acid media, induce ROS production through different mechanisms (19). Moreover, no signs of active inflammation were detected in the esophageal mucosa, defined as presence of lymphocytes, amount of eosinophiles granulocyts or plasmacells. The present study is also made on patients with mild esophagitis, classified to LA-A by the endoscopist (1). Several studies have looked at pro-inflammatory cytokines expression along the inflammation- metaplasia- dysplasia- adenocarcinoma sequence in the esophagus and have also found a stepwise-elevated expression correlate to grade of severity of the disease (20- 21). Such association was not made in the present study for IL-1β and IL-6 at protein level, whereas gene transcript for IL-6 was increased in ERD-patients indicating somewhat small

We have previously shown that two sources of NO formation exist in esophagus, both dependent on the presence of acid in the esophageal lumen; enzymatic degradation of Larginine by NO synthase and non-enzymatic NO-production their nitrite from the salvia is reduced when it meets the extremely low pH in refluxate, a mechanism related to dietary intake of nitrate (6). The sources of body nitrate are intake through drinking water and vegetables, and endogenous synthesis (22). Vegetables vary greatly in their nitrate content, and water nitrate content also varies with geographical location (22). It follows that luminal NO formations differ between individual dependent on nitrate intake during acidic reflux. Enzymatic NO formation is constantly expressed but may be activated upon presence of acid in esophageal lumen (6). Several studies have described the expression of iNOS in esophageal squamous epithelium which have been associated with pathological condition such as cell transformation but also suggested a function related to epithelial integrity (6, 23- 24). Thus, our results confirm the expression of iNOS in the surface epithelium. However, neither the biopsies taken from ERD-patients nor the red streak areas in ERD-patients were

The topographical organisation of the iNOS in the epithelium in combination with luminal non-enzymatic NO, may create particular conditions for NO gradients through the mucosa. Immunoreactivily to MPO and NADPH oxidase was also found in the surface epithelium. Therefore we could assume that during gastric acidic reflux huge level of NO is formed simultaneous with production of epithelial mucosal ROS leading to increased formation of

MPO, NADPH oxidase and iNOS are usually found in phagocytes including neutrophils, eosinophils, monocytes and macrophages with the primary function of phagocytosis and destruction of microorganisms (26). However, except MPO that was localized in both lymphocytes and epithelial cells, immunostaining for NADPH oxidase and iNOS was *only* found in the esophageal epithelial cells. Thus, the presently increased radical forming capacity

In the morphological investigation of reflux signs we found that all parametric used, dilatation of intracellular spaces, papillary length, basal cell layer thickness, and total epithelium thickness were significantly increased in the distal esophagus in ERD-patients

MPO and the morphological changes.

alteration may exist beyond the detections level for protein.

significant different in iNOS expression compared to controls.

in the epithelium is independent of inflammatory cells.

ONOO-, which may contribute to cellular injury and DNA damage (7, 25).


**8** 

*Japan* 

**Combination Therapy After** 

Ota M., Nakamura T. and Yamamoto M. *Department of Surgery, Institute of Gastroenterology,* 

 *Tokyo Women's Medical University, Tokyo,* 

**EMR/ESD for Esophageal Squamous** 

**Cell Carcinoma with Submucosal Invasion** 

Recently, nonoperative treatment such as chemotherapy or radiotherapy has commonly been performed for submucosal carcinoma of the esophagus. Although endoscopic mucosal resection1)2) (EMR) or endoscopic submucosal dissection3) (ESD) is usually done as curative treatment for mucosal cancer of the esophagus, the efficacy of multimodal therapy combined with EMR/ESD for esophageal squamous cell carcinoma (SCC) with submucosal

At our hospital, several patients who had SCC with submucosal invasion received multimodal

From 1996 to 2005, 36 patients who had esophageal SCC with submucosal invasion underwent multimodal treatment. Esophagectomy was not performed because of associated

In all patients, EMR/ESD was performed before any other treatment. Then chemotherapy, radiotherapy, or chemoradiotherapy was added, depending on the histopathological findings, which were classified according to the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus4). Submucosal invasion was classified into the following three grades: sm1: ≤200 μm, sm2: >200 μm, and sm2 EM (+): residual cancer cells

In principle, radiotherapy or chemoradiotherapy was added if the resected margin was suspected to contain residual cancer cells, while chemotherapy was performed if lymphatic invasion was found in the resected specimen (Fig 1). Argon plasma coagulation was added

EMR was performed by the EEMR or EMRC method1)2). EMRC was done by using a singlechannel endoscope (GIF Q260; Olympus) with a cap (Olympus, Tokyo, Japan). After chromoendoscopy with iodine solution, saline was injected into the submucosal layer.

therapy combined with EMR or ESD, and the results are reported here.

complications in 19 cases and due to patient refusal in 17 cases.

without radiation if the residual tumor was limited to a small area.

**1. Introduction** 

invasion is controversial.

**2. Patients and methods** 

at the resected margin.

**2.1 Method of EMR** 

associated esophagitis induces endogeneous cytokine production leading to motor abnormalities. Gastroenterology 2007; 132:154-165

