Expression of matrix metalloproteinases in gastric carcinoma and possibility of clinical application of matrix metalloproteinase inhibitor in vivo.
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Biomedical subjects
Publications and source records attributed to Y Otani.
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Sixty-one patients who were diagnosed with mucosal gastric cancer have been successfully treated with two laparoscopic techniques at our institute from March 1992 to March 1997. One is laparoscopic wedge resection of the stomach using a lesion-lifting method for lesions of the anterior wall, the lesser curvature, and the greater curvature of the stomach. The other is laparoscopic intragastric mucosal resection for lesions of the posterior wall of the stomach and near the cardia or the pylorus. Indications are as follows: (1) preoperatively diagnosed mucosal cancer; (2) <25 mm diameter elevated lesions; and (3) <15 mm diameter depressed lesions without ulcer formation. Patients were discharged in 4 to 8 days uneventfully. There was no major complication or mortality. The resected specimens had sufficient surgical margins horizontally (16 +/- 5 and 8 +/- 4 mm, respectively) and vertically. In one patient histologic examination revealed slight tumor infiltration into the submucosal layer with lymphatic invasion. He underwent gastrectomy with lymph node dissection 1 month after surgery. Otherwise, histologic examination revealed curative surgery. All patients in the series have survived during the 4- to 65-month follow-up period. There have been two recurrences in the series, both of which were found near the staple line 2 years after the initial surgery and were still mucosal lesions. They were successfully treated by open gastrectomy and laser irradiation. A separate early gastric cancer was found 2 years after the initial surgery in one patient, who then underwent curative open gastrectomy. In conclusion, if the patients are selected properly, these laparoscopic procedures are curative, minimally invasive treatment for early gastric cancer.
BACKGROUND: Air leak is a problem commonly occurring in lung and thoracic operations. In this study, a rapidly curable hydrogel glue was prepared as the seal for lung air leak. METHODS: Mixing an aqueous solution of gelatin and poly(L-glutamic acid) with a water-soluble carbodiimide produced a hydrogel. The sealing effect on the air leak wound of rat lung was compared with that of conventional fibrin glue. RESULTS: The gelatin-poly(L-glutamic acid) hydrogel glue was solidified as rapidly as the fibrin glue, and was significantly more effective in sealing the lung air leak than the fibrin glue. Approximately 80% of the lungs treated with the hydrogel glue exhibited no air leak at the lung pressure of 50 cm H2O. Urea addition could prevent spontaneous gelatination of the mixed solution at room temperature and did not affect the hydrogel sealing effect. The bonding strength of the hydrogel glue both with and without urea to the lung tissue was significantly higher than that of the fibrin glue. CONCLUSIONS: We concluded that this strong lung adhesion of the gelatin-poly(L-glutamic acid) hydrogel glue resulted in its superior sealing effect.
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R-94138, a matrix metalloproteinase inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. When the supernatant of a co-culture of TMK-1 cells and human normal fibroblast cells was subjected to gelatin zymography, it was clear that the protein expression of MMP-2 had been inhibited by R-94138. When TMK-1 was injected intraperitoneally (i.p.) into nude mice at 5 x 10(5) cells/body, the resulting peritoneal dissemination mimicked clinical carcinomatous peritonitis. When the maximum tolerated dose of mitomycin C (MMC) or cisplatin (DDP) was given 12 h after the tumor inoculation, peritoneal dissemination was completely inhibited, while the effect of R-94138 was limited when it was given i.p. at a dose of 20 mg/kg in a schedule of q.d. x 5 starting 12 h after tumor injection. MMC and DDP also suppressed peritoneal dissemination when they were administered 1 week after the tumor inoculation at a single dose of 2 and 3 mg/kg i.p., respectively. R-94138 inhibited peritoneal dissemination when it was administered i.p. at a dose of 30 mg/kg in a schedule of q.d. x 5 starting from 1 week after tumor injection. The combination of MMC and R-94138 increased the preventive effect on peritoneal dissemination. R-94138 seems to be a promising candidate to prevent peritoneal dissemination of gastric cancer.
Mixing associated with "stretch-and-fold" convective flow patterns has recently been demonstrated to play a potentially important role in aerosol transport and deposition deep in the lung (J. P. Butler and A. Tsuda. J. Appl. Physiol. 83: 800-809, 1997), but the origin of this potent mechanism is not well characterized. In this study we hypothesized that even a small degree of asynchrony in otherwise reversible alveolar wall motion is sufficient to cause flow irreversibility and stretch-and-fold convective mixing. We tested this hypothesis using a large-scale acinar model consisting of a T-shaped junction of three short, straight, square ducts. The model was filled with silicone oil, and alveolar wall motion was simulated by pistons in two of the ducts. The pistons were driven to generate a low-Reynolds-number cyclic flow with a small amount of asynchrony in boundary motion adjusted to match the degree of geometric (as distinguished from pressure-volume) hysteresis found in rabbit lungs (H. Miki, J. P. Butler, R. A. Rogers, and J. Lehr. J. Appl. Physiol. 75: 1630-1636, 1993). Tracer dye was introduced into the system, and its motion was monitored. The results showed that even a slight asynchrony in boundary motion leads to flow irreversibility with complicated swirling tracer patterns. Importantly, the kinematic irreversibility resulted in stretching of the tracer with narrowing of the separation between adjacent tracer lines, and when the cycle-by-cycle narrowing of lateral distance reached the slowly growing diffusion distance of the tracer, mixing abruptly took place. This coupling of evolving convective flow patterns with diffusion is the essence of the stretch-and-fold mechanism. We conclude that even a small degree of boundary asynchrony can give rise to stretch-and-fold convective mixing, thereby leading to transport and deposition of fine and ultrafine aerosol particles deep in the lung.
We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and the enzymatic activity and mRNA levels of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) using human tumor xenografts in nude mice. Three gastric carcinoma xenografts (SC-1-NU, St-4, and H-111), two colon carcinoma xenografts (Co-4 and Col-3-JCK), one pancreatic carcinoma xenograft (PAN-3-JCK), and one breast carcinoma xenograft (MX-1) were inoculated into nude mice. When the resultant tumors reached 100-300 mg, 5-FU was administered i.p. at a dose of 60 mg/kg in a schedule of three times every 4 days, and the antitumor activity of 5-FU was evaluated as the relative mean tumor weight in treated mice compared to control mice. Xenografts were also inoculated into untreated nude mice. When tumors weighed 200-300 mg, tumor tissues were resected for measurement of tumoral TS and DPD. TS and DPD activities were detected by the TS-binding assay and a radioenzymatic assay, respectively. mRNA levels were measured by semiquantitative reverse transcription-PCR, with glyceraldehyde-3-phosphate dehydrogenase coamplified as an internal standard. TS and DPD activities ranged from 84.7 to 775.5 fmol/mg protein and from not detectable to 79.7 pmol/min/mg protein, respectively. TS and DPD mRNA levels ranged from 0.51 to 9.90 and from not detectable to 0.93, respectively. The enzymatic activities of TS and DPD were correlated with observed mRNA levels. DPD levels were significantly correlated with 5-FU sensitivity, with high DPD activity and high DPD mRNA level resulting in low sensitivity to 5-FU. In contrast, no correlation between TS level and 5-FU sensitivity was observed. Tumoral DPD activity and DPD mRNA level may be useful indicators in predicting the antitumor activity of 5-FU.
The patient was an 83-year-old Japanese male with the chief complaint of difficulty in swallowing. On Feb. 24, 1997, he was referred to our hospital under suspicion of esophageal cancer. X-P revealed an image of a protrusion at Im-Iu having a long diameter of 6 cm. Endoscopy revealed that the esophageal lumen was nearly completely obstructed due to the presence of an irregularly-shaped tumor. The pathological finding of biopsized specimen was a squamous cell carcinoma. Thus, this case was diagnosed as esophageal cancer, but surgery was deemed inappropriate due to the patient's advanced age. Accordingly, on March 12, treatment was started with oral administration of UFT-E granules (Tegafur, 450 mg/day). Initially, the patient was unable to ingest even liquids, but beginning around May the blockage of the esophagus disappeared. Endoscopic examination performed in June revealed that the tumor had shrunk to a about 1 cm in diameter. Although tumor tissue remained, the tumor was observed to have undergone further reduction in size at 6 months after the start of chemotherapy. Moreover, the patient gained weight. This is considered to be a very rare case of an excellent response of esophageal cancer to oral administration of only UFT agents.
BACKGROUND: In the early phase after the onset of acute aortic dissection, oxygenation impairment often occurs. However, the etiology and clinical course of this phenomenon have not been established. We examined the serial changes of oxygenation, inflammatory reaction and laboratory data in patients with acute aortic dissection. METHODS: Nine patients (DeBakey type I; 4, type II; 3 and type IIIb; 2), aged 46 to 82 years were included in this study. All patients were managed in the intensive care unit, and systolic arterial pressure was maintained at around 110 to 120 mm Hg. Oxygenation was impaired in all patients, three (33%) of whom required mechanical ventilatory support. RESULTS: Pleural effusion was observed in eight (89%) of nine patients. Respiratory index was 0.98+/-0.19 (mean +/-SEM) at the time of admission, and elevated to 1.59+/-0.35, 1.58+/-0.21, 1.60+/-0.28 respectively, at day 1, 2 and 3. Oxygenation index was 318+/-34 at the time of admission, and decreased to 271+/-34, 255+/-19, 263+/-26, respectively, at day 1, 2 and 3. These values recovered to normal after day 4. The increase of white blood cells and high fever (>38 degrees C) continued until day 3. Platelet counts recovered after day 4. The serum bilirubin level was highest (2.0+/-0.5 mg/dl) at day 3, and decreased gradually after day 4. In two recent patients whose serum interleukin-8 (IL-8) was measured, IL-8 levels increased according to the impaired oxygenation or aneurysmal enlargement. Impaired oxygenation, inflammatory changes, platelet consumption and bilirubin elevation continued until day 3 and resumed normal levels after day 4. CONCLUSIONS: These changes may be due to hemolysis, consumption coagulopathy or inflammation associated with acute aortic dissection. IL-8 elevation may be associated with aneurysmal enlargement and these phenomena.
We succeeded in establishing a rectal cancer cell line RKK-YK from the primary lesion in a patient with rectal cancer. It took 36.2 hours for duplication. We were able to transplant the RKK-YK cell line to nude mice at a transplantation rate of 50%. The transplanted tumor exhibited histological features similar to those of the primary lesion. Cancer cells with two different degrees of differentiation, in which features of moderately differentiated adenocarcinoma and well-differentiated adenocarcinoma were observed together, were established. The levels of the tumor markers (CEA, CA19-9 and AFP) were elevated in the supernatant of the culture solution and the serum of the nude mice over time course. In the immunohistological examination of the transplanted tumor, anti-CEA, anti-CA19-9 and anti-AFP antibodies were positively stained. Molecular biological analysis revealed nor point mutation or deletion in K-ras gene exon 1 and 2, p53 gene exon 5 to 11 or MCC.
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BACKGROUND AND OBJECTIVES: 1-Ethyl-2-¿[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-+ ++oxothiazolidin-2-ylidenemethyl¿pyridium chloride (MKT-077, formerly known as FJ776), a delocalized lipophilic cation, is known to accumulate in the mitochondria, according to the negative potential inside the mitochondria, and exert its cytotoxicity. METHODS: The single-cell suspensions of human cancer cell lines, human spleen cells, and fresh cancer specimens obtained from patients with gastric carcinoma were used for the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. RESULTS: The antitumor activity of MKT-077 was dose and concentration related, and 50% inhibitory concentrations (IC50) ranged from 1.7 to 14.3 microg/ml, with a mean +/- standard deviation (SD) of 8.4 +/- 4.6 microg/ml. The IC50 of fresh surgical spleen-cell specimens ranged from 0.34 microg/ml to >100 microg/ml in a 48 h incubation, with a mean +/- SD of 66.5 +/- 37.7 microg/ml. When the antitumor activity of MKT-077 was compared between gastric cancer cells and spleen cells obtained from the same patient, the concentration-dependent antitumor activity of this agent was obvious in the cancer cells, while no significant cytotoxicity was observed in the spleen cells. The fresh surgical specimens of gastric cancer showed higher sensitivity to MKT-077 than did spleen cells at a concentration of 30 microg/ml, with a statistically significant difference at P < 0.05. CONCLUSIONS: The selective antitumor activity of MKT-077 was confirmed using fresh surgical specimens and warrants further investigation.
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The hemostatic capability of rapidly curable glues composed of gelatin and poly(L-glutamic acid) (PLGA) was compared with that of the conventional fibrin glue. The hydrogels produced from mixed gelatin and PLGA aqueous solution within several seconds by addition of water-soluble carbodiimide (WSC) was applied to the dog spleen injured by needle pricking. The WSC-catalyzed gelatin-PLGA glues exhibited higher hemostatic capability than the fibrin glue. The total amount of bleeding from the injured spleen until hemostasis when the gelatin-PLGA hydrogel glues were applied was significantly smaller than that of the fibrin glue application. The gelatin-PLGA glue application enhanced the success rate of complete hemostasis to a significantly greater extent than the fibrin glue, while the frequency of glue applications until achieving complete hemostasis decreased. The gelatin PLGA hydrogels strongly adhered to the surface of dog spleen, whereas the fibrin hydrogel was easily detached from the spleen surface. It was concluded that this strong adhesion mechanically suppressed the bleeding, leading to enhanced hemostasis by the rapidly curable gelatin-PLGA glues.
Gelation and tissue adhesion of mixtures of gelatin and poly (L-glutamic acid) (PLGA) aqueous solution were investigated in the presence of additives following the addition of a water-soluble carbodiimide (WSC) that induced chemical cross linking between gelatin and PLGA. To prevent spontaneous gelation of the mixed solution through physical cross linking between gelatin molecules at room temperature, additives were added to the mixed solution. Among the additives studied, starch and urea were effective in preventing the spontaneous physical gelation. The mixed gelatin and PLGA solution set to a cross-linked hydrogel within scores of second by WSC addition, irrespective of the presence of urea, whereas the viscosity of the solution with added starch was too high to measure the gelation time. The cross-linked gelatin-PLGA hydrogels with and without urea showed higher bonding strength to soft tissues than fibrin glue. This was in marked contrast to gelatin-PLGA hydrogels with soluble starch. Irrespective of the presence of urea, the gelatin-PLGA hydrogels gradually biodegraded in the back subcutis of mice over 3 months and no severe inflammatory response to the hydrogels was observed. These findings indicate that urea is promising as an additive to prevent spontaneous physical gelation of the mixed gelatin and PLGA aqueous solution without changing the characteristics of WSC-induced cross linking and tissue adhesion of the formed hydrogel.
BACKGROUND: A clinicopathological study of early gastric cancer with submucosal invasion was carried out in relation to lymph node metastasis. METHODS: A retrospective study was conducted of 245 patients with submucosal gastric cancer treated by gastrectomy combined with D2 lymph node resection between 1985 and 1994 in a university hospital. RESULTS: Lymph node metastasis was observed in 34 patients (14 per cent). The mortality rate due to recurrence in patients with lymph node metastasis (three of 34) was significantly higher than in those without lymph node metastasis (five (2 per cent) of 211) (chi2 = 3.95, 1 d.f., P < 0.05). Tumour size, depth of invasion, lymphatic involvement of cancer cells and preoperative diagnosis of advanced cancer correlated significantly with the presence of lymph node metastasis. When the submucosal carcinomas were classified into three categories according to depth of invasion by dividing the submucosal (sm) layer into three equal parts, sm1, sm2 and sm3, the incidence of lymph node metastasis increased from 2 per cent to 12 and 20 per cent respectively. CONCLUSION: When the pathological report reveals sm1 invasion after laparoscopic or endoscopic surgery, reoperation should not be necessary because sm1-carcinomas with diameters of less than 2 cm do not usually metastasize to the lymph nodes.