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Background and Objective: Photodynamic therapy (PDT) is a recently developed endoscopic method for treating malignant tumors. For obtaining more photodynamic action with less thermal effect, we employed as the excitation light source for PDT an excimer dye laser, which is a pulsed laser with extremely high peak power, instead of an argon dye laser, which is a continuous wave laser and has been used conventionally., Study Design/materials and Methods: The effect of PDT using Photofrin II and the excimer dye laser was evaluated in 27 patients with early gastric cancer., Results: Complete responses (CR) were obtained in 88% of 24 assessable patients and the response rate was 100%. CR was observed in all cases of lesions of superficial depressed type without ulceration and/or with tumor diameter less than 2 cm. Regarding toxicity, mild cutaneous reaction and photosensitivity were seen and lasted several weeks. There were no serious abnormalities in laboratory tests., Conclusion: We conclude that PDT is a promising modality for early gastric cancer.

The effects of oral potassium supplementation on the enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in spontaneously hypertensive rats (SHR), and the norepinephrine concentration in their gastric wall were investigated. The SHR and normotensive Wistar Kyoto rats (WKY) as controls were given a solution of the carcinogen for 25 weeks and then 1% KCl solution or tap water to drink. In Week 52, the incidence of gastric cancers and their number per rat and the norepinephrine concentration in the gastric wall were significantly greater in SHR than in WKY. Prolonged oral treatment of SHR with potassium significantly reduced the incidence of gastric cancers and their number per rat, as well as the blood pressure and the norepinephrine concentration in the antral portion of the gastric wall. These findings indicate that prolonged treatment with KCl attenuated the enhancement of gastric carcinogenesis by MNNG in SHR.

The effect of bromocriptine on inhibition by cysteamine of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. After 25 weeks of p.o. treatment with N-methyl-N'-nitro-N-nitrosoguanidine, rats were given injections every other day: cysteamine (50 mg/kg body weight); cysteamine (50 mg/kg body weight) plus bromocriptine (0.5 or 0.25 mg/kg body weight); or bromocriptine (0.5 or 0.25 mg/kg body weight). In week 52, the group treated with cysteamine showed a significantly decreased incidence of gastric cancers. Concomitant treatment with bromocriptine at 0.5 but not at 0.25 mg/kg body weight significantly attenuated the inhibitory effect of cysteamine on gastric carcinogenesis. Administration of bromocriptine alone at either dosage had no influence on gastric carcinogenesis. The labeling index of the antral mucosa was significantly reduced in rats treated with cysteamine and significantly higher in those treated concomitantly with bromocriptine at 0.5 mg/kg body weight than in those treated with cysteamine alone. These findings indicate that cysteamine suppressed gastric carcinogenesis and that bromocriptine at high dosage attenuated this inhibition. These findings also suggest that dopamine is involved in the mechanism of inhibition of gastric carcinogenesis by cysteamine.

The effect of gamma-amino-n-butyric acid (GABA), the GABA(A) receptor agonist muscimol (5-aminomethyl-3-hydroxyisoxazole), and the GABA(B) receptor agonist baclofen [4-amino-3-(4-chlorophenyl)butanoic acid] on the incidence and number of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Rats received alternate-day i.p. injections of 500 or 1000 mg/kg of body weight GABA, 0.25 or 0.5 mg/kg of body weight muscimol, or 4 or 8 mg/kg of body weight baclofen after 25 wk of p.o. treatment with the carcinogen. Prolonged administration of GABA at 1000 mg/kg of body weight, but not at 500 mg/kg of body weight, and of baclofen at 4 and 8 mg/kg of body weight significantly decreased the incidence and number of gastric cancers of the glandular stomach in Wk 52, but long-term muscimol administration had no influence. Histologically, GABA at the high dosage and baclofen at both dosages significantly decreased the labeling index of the antral mucosa and significantly increased the serum gastrin level. Furthermore, baclofen at both dosages significantly decreased antral pH and significantly increased gastric acid secretion. These findings indicate that GABA inhibits gastric carcinogenesis via the GABAB receptor and that this effect may be related to its effect in decreasing the proliferation of antral mucosa.

The phototoxicity of acridine orange and argon laser irradiation on Walker carcinosarcoma 256 stomach tumors was studied. Wistar strain rats bearing stomach tumors 4-6 mm in diameter 5-10 days after their implantation were injected intraperitoneally with 40 mg/kg of acridine orange 2 hr before irradiation. Then the forestomach was opened and the tumors were exposed to the argon laser at 488 nm at an intensity of 15 mW/cm2 for 20 min. Tumors in rats treated with acridine orange were brightly fluorescent during irradiation. No marked temperature rise was detected during irradiation. Argon irradiation significantly prolonged the survival of rats treated with acridine orange. Histologically, complete or partial tumor necrosis was observed, with sparing of surrounding mucosa, in rats treated by the combination therapy. Phase-contrast and electron microscopy showed that cytotoxicity was mediated by changes in the cell, nuclear and lysosomal membranes. Neither the dye nor laser alone had any effect.

The effects of bombesin on the incidence, number, histological type, and depth of involvement of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in male Wistar rats. Rats received alternate-day s.c. administration of 20 or 40 micrograms/kg body weight of bombesin in depot form after p.o. treatment with the carcinogen for 25 weeks. Prolonged administration of bombesin at 40 micrograms/kg led to a significant increase in the incidence and number per rat of gastric cancers of the glandular stomach at Week 52. In rats that had received alternate-day injections of 20 micrograms/kg of bombesin, the number of gastric cancers per rat, but not the incidence of cancer, was significantly more than in untreated rats. However, bombesin at both dosages did not affect the histological appearance of the lesions or their depth of involvement. At Weeks 30 and 52, norepinephrine concentrations in the fundic and antral portion of the gastric walls and labeling indices in the antral and fundic mucosae were significantly higher in rats treated with bombesin at both dosages than in untreated rats. These findings indicate that bombesin enhances gastric carcinogenesis after administration of N-methyl-N'-nitro-N-nitrosoguanidine is stopped and that this effect may be related to its effects in increasing tissue norepinephrine concentrations in the stomach wall and increasing cell proliferation in the gastric mucosa.

The effect of histamine on induction of tumors in the forestomach and the glandular stomach after N-nitroso-N-methylnitroguanidine (MNNG) administration was studied in male inbred W rats. Animals were given 50 micrograms MNNG solution/ml orally for 25 weeks and then 4 mg histamine dihydrochloride sc per day in depot form. Administration of histamine in depot form after MNNG significantly increased the incidence of tumors in the forestomach, but it significantly decreased the incidence of adenocarcinomas in the glandular stomach. All of the tumors induced in the forestomach were of the squamous cell type, and 50% of them were squamous cell carcinomas. Histamine alone had no apparent carcinogenicity in rats.

HpD photodynamic therapy (PDT) was performed on 4 patients with superficial esophageal cancer, 20 patients with 22 early gastric cancer lesions and one patient with advanced gastric cancer. About 50 h before irradiation, 3 mg/kg of HpD or 1.3-2.5 mg/kg of Photofrin II was injected intravenously. The entire lesion including a 5-mm border of normal surrounding mucosa, was irradiated with an argon dye laser at 630nm wavelength with an output of 100-400mW at the tip of the fiber. Complete response (CR) to HpD-PDT was obtained in 2 of 2 mucosal esophageal cancers, and one of 2 submucosal lesions, totalling 3 of 4, and in 13 of 13 mucosal gastric cancers and 7 of 9 submucosal lesions totalling 20 of 22. The depths of cancer involvement were determined endoscopically. In Borrmann 1 lesion with muscularis externa involvement, in spite of two trials with HpD-PDT, only partial response (PR) was obtained. Tumor laser dose had to be more than 90 J/cm2, and in several cases combined hot biopsy with electrodiathermy and/or repeated HpD-PDT was needed to obtain CR. HpD-PDT is indicated for superficial esophageal cancer and depressed and/or assembled protuberant-type of early gastric cancer with poor risk.

The effects of truncal vagotomy after administration of N-methyl-N'-nitro-N-nitrosoguanidine on the incidence and number of gastric carcinomas and gastric acid secretion, gastrin secretion, antral pH, and duodenal reflux were investigated in inbred Wistar rats. Rats were subjected to truncal vagotomy after N-methyl-N'-nitro-N-nitrosoguanidine treatment. Vagotomy significantly increased the incidence and number of adenocarcinomas of the glandular stomach. It also resulted in significantly more atypical glandular hyperplasias, which are precursors of gastric cancer. Furthermore, it caused a decrease in gastric secretion and an increase in mucosal pH in the antrum but did not increase duodenal reflux. These findings indicate that vagotomy has a promoting effect on the development of gastric cancers. The reduced gastric acid secretion, but not duodenal reflux, may be related to this increased incidence of gastric cancer.

The phototoxicity of hematoporphyrin derivatives (HPD) and dye-laser radiation on adenocarcinoma cells of the human stomach was examined by light and electron microscopy. Adenocarcinoma cells were obtained from human stomach tissue by endoscopic biopsy. The cells were incubated for 5 minutes in the patient's own serum that contained 0.6 mg HPD/ml and then were exposed to dye-laser radiation at 630 nm at an irradiance of 15 mW/cm2. Electron microscopy showed that cytotoxicity was mediated by mitochondrial damage, dilatation of the rough endoplasmic reticulum, and alterations of the nuclear membrane. The degenerative changes were greater and more frequent in poorly differentiated adenocarcinoma cells than in well-differentiated ones. No marked temperature rise was detected during irradiation. Neither the dye alone nor light alone had any effect. A singlet oxygen-trapping agent, 1,3-diphenylisobenzofuran, prevented adenocarcinoma cell degeneration that otherwise would result from exposure to HPD and dye-laser radiation. Thus singlet oxygen may be the cytotoxic agent in this system.

Forty gastric adenocarcinomas in 30 resected stomachs were examined by an endoscopic immunofluorescent technique using fluorescein isothiocyanate (FITC)-labeled antibodies to carcinoembryonic antigen (CEA). Fluorescence images of the tumors were obtained with a newly developed endoscopic television system for detecting faint fluorescence. Computer-assisted processing was used to enhance the detection and localization of the tumors visualized by the immunofluorescent technique. Twenty seven (90%) of 30 tumors showed positive fluorescence after treatment with FITC-labeled antibodies for 60 minutes, whereas only two (40%) of five cancers could be detected by the immunofluorescent technique after treatment with antibodies for less than 60 minutes. There was no significant relationship between positive fluorescence and the gross and histological types or the stages of the tumors. In contrast, no positive fluorescence could be demonstrated in cases of benign gastric lesions or after pretreatment with FITC-labeled alpha-fetoprotein. This study therefore suggests that the immunofluorescent technique using FITC-labeled anti-CEA antibodies can be useful in detecting the early stages of gastric cancer.