Kazuhiro Suganuma

Possible chemoresistance-related genes for gastric cancer detected by cDNA microarray

To identify chemoresistance‐related genes of gastric cancer, we utilized cDNA microarray technology. Thirty‐five gastric cancer specimens surgically resected at our institute between 1998 and 1999 were studied for quantification of expression of 6300 genes by means of oligonucleotide microarray methods, and the results were evaluated in comparison with the chemoresistance of the specimens, which was determined by MTT (tetrazolium‐based 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. Inhibition rates (IR) were determined for cisplatin (DDP), 5‐fluorouracil (5‐FU), mitomycin C or doxorubicin. IR of 60% or more was regarded as sensitive to each agent, and IR of less than 40% was defined as resistant. Clustering was successfully completed for DDP, resulting in selection of 23 candidates as DDP‐resistance‐related genes, including vascular permeability factor, 2 membrane transporting subunits, and retinoblastoma‐binding protein‐1. In addition, further selection of DDP‐resistance‐related genes was performed according to these criteria: 1) Expression of the gene can be detected in more than 70% of resistant tumors. 2) Expression can be detected in less than 30% of sensitive tumors. 3) Expression in tumors is more than twice that of normal mucosa in more than 50% of specimens. Then, metallothionein‐IG and heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) were identified as candidate DDP‐resistance‐related genes. When known DDP‐resistance‐related genes were analyzed according to the MTT assay result, families of glutathione‐S‐transferase and cydooxygenase‐2 genes were also evaluated as resistance‐related genes. For 5‐FU resistance, dihydropyrimidine dehydrogenase and HB‐EGF‐like growth factor genes were also suggested to be resistance‐related genes. The present study demonstrated that oligonucleotide microarrays can provide information regarding chemoresistance factors in cancer. (Cancer Sci 2003; 94: 355–359)

Neutrophil elastase inhibitor improves survival of rats with clinically relevant sepsis.

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1&bgr; (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.ABBREVIATIONS-NE-neutrophil elastase; ALI-acute lung injury; HMGB1-high-mobility group box chromosomal protein 1; CLP-cecal ligation and puncture; SIRS-systemic inflammatory response syndrome; POD-postoperative day; GM-CSF-granulocyte-macrophage colony-stimulating factor; IFN-interferon; POH-postoperative hour; H&E-hematoxylin and eosin; CD-cluster of differentiation; CARS-compensatory anti-inflammatory response syndrome

Mechanistic Probing of Gaseous Signal Transduction in Microcirculation

Nitric oxide (NO) and carbon monoxide (CO) serve as activators of soluble guanylate cyclase (sGC) in vitro, and the latter serves as a microvascular relaxant for the liver, a major organ for heme oxygenase-dependent heme degradation and gas generation. Another important determinant of local sGC activities is superoxide anion, which scavenges NO and/or activates sGC directly. Altered bioavailability of the oxygen-derived species and its functional outcomes remain unknown, because information on amounts and distribution of these molecules has hardly been examined in vivo. Our recent studies provided evidence for such complex actions of multiple gases in vivo. Intravital visualization of NO in microcirculation revealed that two distinct sources, NO synthase-1 and -3, play a major role in the maintenance of NO in arteriolar and venular walls, respectively. Besides its vasorelaxing action in the hepatic microcirculation, CO could induce vasoconstriction in the resistant artery where NO is abundantly available; systemic blood pressure was elevated in transgenic mice overexpressing heme oxygenase-1 site-specifically in vascular smooth muscle cells. Such a relationship between the gases has also been demonstrated by mechanistic bioprobing of sGC function using novel monoclonal antibodies. This article aims to provide an overview of advances in visual assessment of the generation and reception of oxygen-derived gaseous mediators in vivo.

Intraductal growth of a nonfunctioning endocrine tumor of the pancreas.

Intraductal growth of nonfunctioning endocrine tumors of the pancreas may be very rare, and our survey of literature shows only two cases have been described. We report a case of a 43-year-old man with a nonfunctioning endocrine tumor of the pancreas that uniquely grew within the lumen of the main pancreatic duct (MPD) without ductal involvement and completely obstructed the MPD. Endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) were very helpful to delineate the intraductal growth of the tumor and to determine the resection line of the pancreas. A nonfunctioning pancreatic endocrine tumor is important to consider on differential diagnoses when complete obstruction of the MPD is demonstrated on ERCP. It is speculated that the tumor originated from precursor cells of the pancreatic duct or islet cells adjacent to the MPD and slowly proliferated within the lumen of the MPD.

Surgically treated Cronkhite-Canada syndrome associated with gastric cancer

Cronkhite-Canada syndrome is generally accepted to be a benign disorder, with 374 reported cases to the present. Worldwide, there have been 18 previously reported cases of Cronkhite-Canada syndrome associated with gastric cancer. In this report we describe a case of a 52-year-old man with the clinical features of Cronkhite-Canada syndrome combined with gastric cancer. Although the gastric tumor was located at the antrum of the stomach, we performed a total gastrectomy because of the edematous swelling and high risk of malignancy in the remnant stomach. As Cronkhite-Canada syndrome may be a premalignant condition for gastric cancer, as well as for colorectal cancer, we suggest periodic examination of the stomach, colon, and rectum for patients with Cronkhite-Canada syndrome.

NOVEL TECHNIQUE OF ENDOSCOPIC SUBMUCOSAL DISSECTION USING AN EXTERNAL GRASPING FORCEPS FOR SUPERFICIAL GASTRIC NEOPLASIA

Endoscopic submucosal dissection (ESD) for early stage gastric cancer (EGC) has improved the success rate of en bloc resection but results in perforation more often than does endoscopic mucosal resection. We report a novel technique of ESD using an external grasping forceps. A total of 265 lesions with EGC or gastric adenoma were enrolled in this study. Sixteen lesions were located in the upper third portion of the stomach, 114 in the middle third portion, and 135 in the lower third portion. After submucosal injection followed by circumcision of the lesions with a flex knife, the external grasping forceps was introduced with the help of a second grasping forceps and anchored at the margin of the lesion. Oral traction applied with this forceps could elevate the lesion and make the submucosal layer wider and more visible, thereby facilitating dissection of the submucosal layer under direct vision. The mean lesion size was 15.0 mm (range: 5–50 mm). All but 11 lesions (95.8%) could be resected en bloc with free margins. Mean procedure time was 45 min (range: 20–180 min). It was difficult to carry out this procedure when the lesions were located in the cardia, lesser curvature, or posterior wall of the upper third of the gastric body. Bleeding after ESD occurred in 10 patients (3.8%) and perforation occurred in one patient (0.4%). The endoscopic submucosal dissection using an external grasping forceps for superficial gastric neoplasia is efficacious and safe.

Morphologic analysis of gastroesophageal reflux diseases in patients after distal gastrectomy

The precise mechanisms that cause gastroesophageal reflux after distal gastrectomy remain unclear. We analyzed the endoscopic findings of the cardia and the position of the remnant stomach, which are related to gastroesophageal reflux. We retrospectively examined the records of 45 patients with Billroth I (B-I) and 39 patients with Roux-en-Y (R-Y) procedure for gastric cancer. Esophagitis was evaluated by the Los Angeles (LA) classification. The endoscopic findings of hiatus hernia were classified according to the criteria of the Keio Cancer Detection Center form (K-form). The valvular appearance of the cardia was classified according to V-grades. The height of the remnant stomach was measured on computed tomography scans. The postoperative findings of esophagitis in the B-I group were significantly worse than the preoperative findings, but no significant change was observed in the R-Y group. The postoperative V-grades and K-forrn findings in the B-I group were worse than their preoperative findings. In the R-Y group, however, there was no significant change in the V-grades or K-form findings. In addition, the height of the remnant stomach was significantly higher in the B-I group than in the R-Y group. This study suggested that an aggravated cardia is associated with the B-I procedure and that the position of the remnant stomach may therefore play an important role in the occurrence of postoperative reflux esophagitis. In contrast, the R-Y operation was shown to preserve the cardia and the position of the remnant stomach better. As a result, R-Y might help prevent not only duodenogastric reflux but also gastroesophageal reflux.

Surgery for Advanced Gastric Cancer After Coronary Artery Bypass Grafting Using the Right Gastroepiploic Artery: Report of a Case

Ischemic heart disorders are often treated by coronary artery bypass grafting (CABG) using the right gastroepiploic artery (RGEA). We report the case of a 57-year-old man with a history of CABG using the RGEA, who underwent D2 radical total gastrectomy followed by Roux-en-Y anastomosis, with successful dissection of the #6 lymph nodes, while preserving the RGEA. The patient had a 9-month history of gastric cancer, during which time the Maruyama Vaccine (Specific Substance Maruyama, or SSM) was given as alternative therapy. This case report serves to demonstrate that radical gastrectomy can be safely performed after CABG using the RGEA, and that gastric cancer will progress in spite of SSM therapy.

Minimally invasive surgery for gastric carcinoid tumor

Minimally invasive laparoscopic wedge resection for gastric mucosal carcinoma and submucosal tumor was first performed in Keio University hospital in 1992. Since then, 172 gastric tumor patients, including four cases of carcinoid tumor, have been successfully treated at the Keio University hospital using this procedure. No local disease recurrence or distant metastases have been observed in follow-ups over as long as 10 years. Chronic atrophic gastritis patients with carcinoid tumors occurring secondary to hypergastrinemia are candidates for the minimally invasive surgery. With careful patient selection according to tumor size, depth of invasion, and histopathological findings of malignancy grade, endoscopic and laparoscopic therapy for these patients can be a safe, curative, and minimally invasive procedure.

Gastric carcinoid tumors with aggressive lymphovascular invasion and lymph node metastasis.

We report a patient with multiple gastric carcinoid tumors without hypergastrinemia. An abdominal computed tomography (CT) scan was performed in a 66-year-old Japanese man who had abdominal discomfort. An abnormal, round, 2.5 cm mass close to the lesser curvature of the stomach was detected. Multiple small gastric carcinoid tumors were also detected by endoscopy. A total gastrectomy with lymph node dissection was performed after it was determined that the round mass was a lymph node metastasis of carcinoid tumor. Further pathological investigation of the surgical specimen revealed multiple gastric carcinoid tumors with severe lymphovascular invasion. The carcinoid tumors in the present patient were not related to hypergastrinemia. These lesions could not be grouped as any of the three types of gastric carcinoid tumors in the recent classification. Furthermore, as a simple distal gastrectomy is the standard treatment for multiple carcinoid tumors of the stomach, we recommend that a precise histopathological evaluation should be performed before an appropriate curative surgical treatment is selected.