Toshiro Yoshiyuki

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.

Endoscopic dexamethasone injection following balloon dilatation of anastomotic stricture after esophagogastrostomy

BACKGROUND Anastomotic stricture is common after esophagogastrostomy. Recent advances in nonsurgical treatment include the silicon bougie and balloon dilatation. However, simple dilatation alone with a silicon bougie or endoscopic balloon dilator was repeated a mean of 4.7+/-5.4 times to control anastomotic stricture because of its temporary effect. METHODS For 11 patients, endoscopic injection of dexamethasone (8 mg) around the anastomosis was done immediately after balloon dilatation (40 psi for 5 minutes). RESULTS This method significantly reduced the number of the dilatations to 1.1+/-0.3 (P < 0.05). Ten of the 11 patients did not need any further treatment. There were no side effects or complications of dexamethasone injection. CONCLUSION A combination of endoscopic balloon dilatation and dexamethasone injection provided an easy and safe method for preventing the recurrence of anastomotic stricture.

Role of Helicobacter pylori infection in perforation of peptic ulcer : An age- and gender-matched case-control study

Evidence showed a marked decrease in recurrence rate of peptic ulcer after eradication of Helicobacter pylori infection. However, whether H. pylori infection is etiologically related to perforation of peptic ulcer remains to be clarified. We therefore conducted an age- and gender-matched case-control study between perforated and nonsurgical peptic ulcers in H. pylori infection and examined differences in the cytotoxin genes cagA and vacA. Serum H. pylori IgG antibody (ELISA) was positive in 20/21 (95%) of perforated vs. 37/40 (93%) of nonsurgical duodenal ulcers and in 5/5 (100%) of perforated vs. 24/28 (86%) of nonsurgical gastric ulcer patients. Positivity of H. pylori DNA in gastric juice, which was amplified by PCR and identified by Southern blot hybridization, was 17/23 (74%) of perforated vs. 32/45 (71%) in the nonsurgical duodenal ulcer group. Positivity of the cytotoxin genes cagA and vacA in H. pylori DNA-positive gastric juice was as follows: perforated vs. nonsurgical duodenal ulcer, cagA 11/ 13 (85%) vs. 24/27 (89%); vacA1: 9/13 (69%) vs. 22/27 (82%); vacA2 8/13 (62%) vs. 21/27 (78%). There were no significant differences between the perforated and nonsurgical peptic ulcer groups for these H. pylori serum and gene markers. It is assumed that H. pylori infection is not etiologically related to perforation of peptic ulcer.

Immunohistochemical study of intracellular estradiol in human gastric cancer

Tissues from primary human gastric cancers were examined for intracellular estradiol (E2) by using the avidin‐biotin‐peroxidase complex (ABC) immunohistochemical method on formalin‐fixed paraffinembedded sections. Reaction products of E2 were located only in the cytoplasm of the cancer cells, and not detected in noncancerous gastric epithelium. E2‐positive tissues were found in 23 (44.2%) of 52 male patients, seven (20.6%) of 34 female patients and a total of 30 (34.9%) of 86 patients. In male patients, E2‐positive cases occurred without age distinction. In female patients, however, E2 was not found in patients in older age groups, especially patients in the postmenopausal state. Microscopically, E2 was found frequently in intestinal type of cancers in male patients and in cancer with scirrhous growth pattern, in female patients. This is the first report of the demonstration of E2 in gastric cancer. The findings suggest that hormonal factors are involved in gastric cancer, and that the cancers contain endocrinic characteristics.

Effect of early postoperative feeding on the healing of colonic anastomoses in the presence of intra-abdominal sepsis in rats

PURPOSE: Intra-abdominal infection is generally considered a major risk factor for dehiscence of primary colon anastomosis. To elucidate the indications for nutritional support during intra-abdominal sepsis, we investigated the healing of anastomoses in an animal model. METHODS: Twenty male Sprague-Dawley rats (280–320 g) underwent cecal ligation and single puncture. After 24 hours the perforated cecum was removed, and the left colon was transected and anastomosed in a single-layer inverted fashion. Animals were randomly assigned to receive both chow and water (early-fed group; n=10) or water alone for the first 72 hours and chow thereafter (late-fed group; n=10). Colon-bursting pressure was measured five days after the anastomosis, at which time the anastomosis was excised. RESULTS: The survival rate after cecal ligation and single puncture was 100 percent, and blood cultures were positive in 20 percent of animals five days after surgery. All data are expressed as means ± standard error of the mean. Body weight increased more in the early-fed group than in the late-fed group (15.6±3vs. −6.3±2.8 g;P<0.001). Early feeding resulted in increased anastomotic bursting pressure (200±11vs. 161±12 mmHg;P<0.05) and total collagen concentration at the site of anastomosis (2.36±0.09vs. 2.01±0.07 µg/mg wet tissue;P<0.01) compared with the late-fed group. CONCLUSION: Early feeding has a positive effect on anastomotic healing in the presence of intra-abdominal sepsis. The mechanism by which early feeding enhances the colonic anastomotic healing is unclear, although preservation of colonic collagen seems to play a significant role.

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.

Tacrolimus enhances colon anastomotic healing in rats

Tacrolimus inhibits T‐cell function and neutrophil chemotaxis during inflammation. We hypothesized that tacrolimus would enhance healing of a rat colon anastomosis by reducing the inflammatory response. Fifty‐five male Sprague Dawley rats, 230–260 g body weight, underwent identical surgical manipulation consisting of a single‐layer, inverted colon anastomosis and the implantation of osmotic pumps subcutaneously in the left flank area. The animals were randomly assigned to receive tacrolimus, at a dose of 0.01, 0.1, or 1.0 mg/kg/day, or only the control solvent solution. The animals were euthanized 4 days after surgery. Colon‐bursting pressure (mmHg), anastomotic collagen content (µg hydroxyproline/mg wet tissue), and anastomotic type IV collagenase activity (mU/mg protein) were measured. Tacrolimus significantly increased colon‐bursting pressure at all doses used (146 ± 9, 158 ± 10, 151 ± 6 mmHg; 0.01, 0.1, and 1.0 mg/kg/day, respectively) vs. control (119 ± 7 mmHg, p < 0.01). There was no effect on collagen accumulation except at a dose of 0.01 mg/kg/day, which significantly decreased anastomotic collagen content (p < 0.05). Tacrolimus at a dose of 0.01 mg/kg/day increased anastomotic collagenase activity, which was not changed by treatment with the higher doses. Microscopic examination revealed the preservation of the multilayered structure, including the mucosal muscle, a thickened submucosa, and the proper muscle of the anastomotic site in the tacrolimus‐treated groups. These data suggest that tacrolimus enhances wound strength during acute anastomotic healing despite a reduction in collagen content.(WOUND REP REG 2002;10:308–313)

Immunohistochemical demonstration of epidermal growth factor in human gastric cancer xenografts of nude mice

Thirty‐two surgical specimens and three cell lines of human gastric cancers were used for subcutaneous transplantation into nude mice, resulting in the establishment of eight (25%) xenografts from the surgical specimens and two (67%) from the cell lines. The localization of epidermal growth factor (EGF) in the surgical specimens and cell lines of the gastric cancers and their xenografts in nude mice was then investigated immunohistochemically. Epidermal growth factor was stained in the cytoplasm of the cancer cells, being detected in 16 (50%) of the 32 surgical specimens and in all of the cell lines. Seven (44%) of the sixteen EGF‐positive surgical specimens and one (6%) of the 16 EGF‐negative ones were tumorigenic in nude mice. All of the xenografts in nude mice were positive for EGF. The tumorigenicity of human gastric cancer xenografts in nude mice may, therefore, be correlated with the presence of EGF in cancer cells.

Contrasting Actions of Estradiol on the Growth of Human Gastric Cancer Xenografts in Nude Mice

The effects of estradiol on the growth of six human gastric xenografts in nude mice were studied and diverse effects were found, including one case of stimulation, two of inhibition and three of unchanged condition. Neither the histological features of the original tumor nor the estrogen‐binding capacity seemed to be related to the response to estradiol. It is concluded that the growth of human gastric cancer can be modulated by estradiol.

Simultaneous gastric cancer in monozygotic twins

Monozygotic twins developed gastric cancers that were found almost simultaneously. A 47‐year‐old man complained of nausea and vomiting; an upper gastrointestinal series and endoscopy revealed advanced gastric cancer invading the serosa. Palliative subtotal gastrectomy was performed. In his asymptomatic twin a gastric polyp was detected during a screening examination, and this was observed for 2 years. After the former twin had undergone surgery, the latter twin was given a detailed endoscopic examination, and biopsy revealed gastric cancer limited to within the mucosa. Curative subtotal gastrectomy was performed. The noncancerous gastric mucosa of the former twin showed severe intestinal metaplasia, but that in the latter showed only spotty metaplasia. They had lived together for 40 years, but the former was a heavy smoker and drank alcohol, while the latter did not. These differences in taste might have contributed to the observed difference in intestinal metaplasia, which indicates chronic mucosal damage.