Itsuo Fujita

Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbB-2 in human gastric cancer.

The EGF stimulation system for growth regulation is implicated in normal and neoplastic cell proliferation. The role of EGF, the EGF receptor, and c‐erbB‐2 in human gastric cancer is reviewed on the basis of several reports, which have been mainly oriented toward their clinical significance. EGF has been shown immunohistochemically to be present in 26% of gastric cancers (n = 395). The presence of EGF in gastric cancer is correlated with the degree of gastric wall invasion and lymph node metastasis. The 5‐year survival of patients with EGF‐positive tumors is worse than that of patients with EGF‐negative tumors. The presence of EGF in human gastric cancer may therefore represent a higher malignant potential. Fifteen percent of gastric cancers (n = 352) were also shown to be positive for both EGF and the EGF receptor immunohistochemically, and the simultaneous occurrence of EGF and the EGF receptor suggests that these tumors grow in an autocrine fashion. Tumors exhibiting EGF and the EGF receptor simultaneously show a greater degree of local invasion and lymph node metastasis. Increased expression of EGF receptor protein in gastric cancer appears to be related to biologic aggressiveness, although gene amplification has occurred only to a small extent. Twelve percent of gastric cancers (n = 486) were found to be positive for c‐erbB‐2. This type of tumor has a frequent metastasis, and patients with c‐erbB‐2‐positive cancer have a poorer prognosis than those with c‐erbB‐2‐negative tumors. Selective blockade of the EGF receptor and c‐erbB‐2 from their ligands with monoclonal antibodies (MoAbs) inhibits the growth of human gastric cancer xenografts. These MoAbs may therefore be effective antitumor agents against gastric cancer showing overexpression of EGF receptors or c‐erbB‐2. Cancer 1995;75:1418‐25.

Helicobacter pylori eradication therapy for the remnant stomach after gastrectomy.

Background.The remnant stomach after surgery for gastric cancer is at high risk for the metachronous development of multiple gastric cancers. Here, we report on eradication therapy of Helicobacter pylori in the remnant stomach, comparing the eradication rate with that in unoperated stomachs. We examined gross and histological changes after treatment. Methods. Forty H. pylori-positive patients after distal gastrectomy were treated with proton pump inhibitor (PPI)-based dual and triple therapies. After eradication, histological changes were classified on the basis of the updated Sydney system. Results. The eradication rate in the remnant stomach was 70% (14 of 20) after dual therapy and 90% (18 of 20) after triple therapy, using per-protocol analysis, and these rates were comparable to the rates of 70% (186 of 264) and 88% (58 of 66), respectively, in nonsurgery patients. After eradication, three sites in the remnant stomach showed similar histological changes: significant decreases in inflammation and activity scores (P < 0.001) and no significant changes in glandular atrophy and intestinal metaplasia scores. Conclusion. PPI-based therapy was as effective for H. pylori eradication in the remnant stomach as in the unoperated stomach, and eradication therapy resulted in a significant decrease in inflammatory cell infiltration of the mucosal layer.

Inflammation of the gastric remnant after gastrectomy: mucosal erythema is associated with bile reflux and inflammatory cellular infiltration is associated with Helicobacter pylori infection

BackgroundControversy exists concerning the role of bile reflux and Helicobacter pylori (H. pylori) infection in the development of inflammation of the gastric remnant after gastrectomy. This study was designed to investigate association of bile reflux and H. pylori infection or both with inflammatory changes in the gastric remnant.MethodsA questionnaire on GI symptoms was returned by 200 gastrectomy patients, and 24-h bilirubin monitoring in the gastric remnant was performed on 55 patients with Bilitec 2000. Upper GI endoscopy evaluated reflux gastritis in the gastric remnant, and the presence of H. pylori infection and chronic, active inflammatory cellular infiltration in the biopsy specimens were examined microscopically with the updated Sydney system.ResultsNo difference in the incidence of GI symptoms was observed among individual gastrectomy patients. Bile reflux was lower in patients who had undergone a gastrectomy with jejunal interposition, a pylorus-preserving gastrectomy, and a gastrectomy with Roux–Y anastomosis than those who had undergone a Billroth-II (B-II) anastomosis (P < 0.05). Endoscopy showed positive correlation between mucosal erythema and bile reflux (P < 0.001). No correlation was observed between the mucosal erythema and chronic and active inflammatory cellular infiltration. Infection of H. pylori correlated with chronic and active inflammatory cellular infiltration (P < 0.001). Bile reflux did not correlate with the severity of chronic and active inflammatory cellular infiltration or H. pylori infection.ConclusionsBile reflux into the gastric remnant was observed by Bilitec 2000. Mucosal erythema and chronic, active inflammatory cell infiltration in the gastric remnant after gastrectomy may be caused by bile reflux or H. pylori infection, respectively.

Significance of serum markers pepsinogen I and II for chronic atrophic gastritis, peptic ulcer, and gastric cancer.

Chronic atrophic gastritis (CAG) is closely correlated with gastric cancer and is predominant in Japan. Epidemiologically, food habits are the primary factor in both CAG and gastric cancer. Two potential serum markers for CAG have recently been investigated, i.e., the concentration of serum pepsinogen (PG) and the presence of serum antibodies against Helicobacter pylori. Serum PG I and II and the PG I:PG II ratio have been reported to be useful as indicators of recurrent peptic ulcer and for screening of patients at risk from gastric cancer. In this study, we examined PG I and II in serum from 483 patients by RIA (DAINABOT), and endoscopic examination performed in the same patients before serological assay revealed CAG in 68, peptic ulcer in 91, and gastric cancer in 48. Analysis of the mean values according to patients age showed that CAG patients in their forties to eighties had low (< 40 ng/ml) levels of PG I, peptic ulcer patients in their teens to eighties had high (> or = 70 ng/ml) levels, except for those in their seventies, and gastric cancer patients in their twenties to sixties had low (< 3.0) PG I:PG II ratios, except for those in their sixties. Thus serum PG assay has potential utility for detection of CAG, peptic ulcer, and gastric cancer.

Sequential changes in the cell mediators of peritoneal and wound fluids after surgery.

The concentrations of cell mediators in the peritoneal and wound fluids of patients who underwent abdominal surgery or mastectomy were determined sequentially and compared with the concomitant changes in blood components. The level of interleukin-6 (IL-6) in the peritoneal and wound fluids was significantly higher than the plasma level after gastrectomy (P<0.001), cholecystectomy (P<0.05), and mastectomy (P<0.05), although the level of plasma IL-6 was also higher postoperatively than before surgery (P<0.001, P<0.05). Significantly higher levels of tumor necrosis factor-α were detected in the peritoneal and wound fluids (P<0.01, P<0.05, respectively) after surgery despite its absence in plasma. A platelet-specific protein and a protein specific for fibroblasts were also measured. Thus, mediators derived from various cells were shown to be present in human peritoneal and wound fluids, indicating that the local production of these mediators plays an important role in the process of tissue repair.

Detection of serum IgG antibody againstHelicobacter pylori from childhood in a Japanese population

Epidemiological evidence has shown that seropositivity forHelicobacter pylori in the stomach is positively correlated with the incidence of gastric cancer. In this study, we investigated serum IgG antibody againstH. pylori in asymptomatic Japanese subjects by an enzyme-linked immunoassay (ELISA) method (Serion, Wuerzburg, Germany). We noted two characteristics: (1) Seropositivity was seen in 41% of individuals aged less than 1 year, and in 9% of those aged 1–2 years, indicating the possibility that IgG antibody in infancy is derived from the mother. (2) Seropositivity was seen in 35% of individuals aged 15–19 years compared to 70% in those aged 20–24 years, indicating the spread ofH. pylori infection with age.

Laparoscopy-Assisted Distal Gastrectomy for Gastric Cancer

ObjectiveThe purpose of this study was to evaluate the safety and value of laparoscopy-assisted distal gastrectomy (LADG) for early stage gastric cancer (stages IA, IB, and II).Materials and MethodsWe retrospectively assessed 101 cases treated by LADG and compared to 49 contemporaneous cases treated by open distal gastrectomy (DG) between 2001 and 2006. Clinical variables, such as tumor diameter, operation time, blood loss, number of lymph nodes dissected, and length of stay were investigated.ResultsTumor size (mm) was significantly smaller in the LADG group (p < 0.0001). Although operation time (min) in the two groups was similar (278 ± 57 vs. 268 ± 55), mean blood loss was significantly higher in the DG group (139 ± 181 vs. 460 ± 301, p < 0.0001). Fewer lymph nodes were harvested in the LADG group (27 ± 14 vs. 34 ± 19, p = 0.012). Hospital stay was longer in the DG group (13.3 ± 8.5 vs. 16.7 ± 10.5, p = 0.034). There was no mortality in either group. Postoperative surgical complications occurred in six (6%) of the LADG and four (8%) of the DG.ConclusionsThe authors conclude that laparoscopy-assisted distal gastrectomy is a safe and useful operation for early-stage gastric cancers. If patients are selected properly, laparoscopy-assisted distal gastrectomy can be a curative and minimally invasive treatment for gastric cancer.

Laparoscopic Surgery Improves Blood Glucose Homeostasis and Insulin Resistance Following Distal Gastrectomy for Cancer

BACKGROUND Prevention of blood glucose elevation and insulin resistance could be more pronounced in patients undergoing laparoscopic rather than open gastrectomy. METHODS Fifty-seven patients underwent distal gastrectomy by either laparoscopy (n = 36) or an open approach (n = 21). Blood glucose, serum insulin, and the daily insulin secretion rate (urinary C-peptide) were measured. Insulin resistance was evaluated using an adapted homeostasis model assessment of insulin resistance (HOMA-R). RESULTS Blood glucose levels were lower in the laparoscopy group than in the open group on the operative day and on postoperative days (POD) 1 and 3 (P < .001, P = .001, and P = .024, respectively). Serum insulin levels were lower in the laparoscopy group than in the open group on POD 1 and 3 (P = .045 and P = .027, respectively). HOMA-R was lower in the laparoscopy group than in the open group on POD 1 and 3 (P = .024 and P = .009, respectively). Daily insulin secretion rates were lower in the laparoscopy group than in the open group on POD 1 (P = .023). CONCLUSIONS Laparoscopic surgery prevents blood glucose elevation and improves insulin resistance compared with open surgery.

The presence of tumor necrosis factor-α and its antibody in the sera of cachexic patients with gastrointestinal cancer

Although cancer cachexia has been shown to involve several cytokines, the tumor necrosis factor-α (TNF) has rarely been detected in such patients. In this study, sera from 21 patients with cancer cachexia were examined for the presence of TNF and the anti-TNF antibody using an enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively. All of the patients had recurrent cancer and manifested the characteristics of progressive body weight loss. TNF was found in the sera of four patients (20%) at levels ranging from 10.4 to 53.1 pg/ml, while a positive reaction for the anti-TNF antibody was detected in the sera from six patients (30%), two of whom showed both TNF and its antibody. Thus, either TNF or the anti-TNF antibody was present in the sera from 8 of 21 patients (40%). The results of this study indicate that TNF may be present in the circulation of at least 40% of cachexic patients, and suggest that it may be one of the main mediators of cancer-associated cachexia.

Supportive techniques and devices for endoscopic submucosal dissection of gastric cancer

The indications for endoscopic treatment have expanded in recent years, and relatively intestinal-type mucosal stomach carcinomas with a low potential for metastasis are now often resected en bloc by endoscopic submucosal dissection (ESD), even if they measure over 20 mm in size. However, ESD requires complex maneuvers, which entails a long operation time, and is often accompanied by complications such as bleeding and perforation. Many technical developments have been implemented to overcome these complications. The scope, cutting device, hemostasis device, and other supportive devices have been improved. However, even with these innovations, ESD remains a potentially complex procedure. One of the major difficulties is poor visualization of the submucosal layer resulting from the poor countertraction afforded during submucosal dissection. Recently, countertraction devices have been developed. In this paper, we introduce countertraction techniques and devices mainly for gastric cancer.