Therapeutic efficacy of sustained drug release from chitosan gel on local inflammation.

The model anti-inflammatory drug prednisolone (PS) was retained in chitosan (CS) gel beads, which were prepared in a 10% aqueous amino acid solution (pH 9.0). Sustained release of PS from the CS gel beads was observed. Carrageenan solution was injected into air pouches (AP), which were prepared subcutaneously on the dorsal surface of mice, in order to induce local inflammation. CS gel beads retaining PS were then implanted into the AP to investigate the therapeutic efficacy of sustained PS release against local inflammation. In vivo PS release from CS gel beads was governed by both diffusion of the drug and degradation of the gel matrix. Sustained drug release by CS gel beads allowed the supply of the minimum effective dose and facilitated prolonged periods of local drug presence. Inflammation indexes were significantly reduced after implantation of CS gel beads when compared with injection of PS suspension. Thus, extension of the duration of drug activity by CS gel beads resulted in improved therapeutic efficacy. These observations indicate that CS gel beads are a promising biocompatible and biodegradable vehicle for treatment of local inflammation.

Biodegradation and drug release of chitosan gel beads in subcutaneous air pouches of mice.

Chitosan (CS) gel beads were prepared in 10% amino acid solution (pH 9) and implanted into air pouches (AP) prepared subcutaneously on the dorsal surface of mice. No inflammatory response was observed, and degradation of the beads in the AP increased as their degree of deacetylation decreased. Degradation could be altered by changing the nature of the CS or by increasing the CS concentration. The release of prednisolone (PS) in vivo from CS gel beads was similar to the release in vitro. When a suspension of PS was injected into the AP, the PS had almost completely disappeared 24 h after injection. Retention of PS in the AP was not increased by using a viscous CS solution. Alginate (Alg) gel beads, which were not degraded, released PS slowly into the AP over 3d. The in vitro release profile of PS using 1% CS (deacetylation: 70% (7B) and 80% (8B)) and 1.5% CS (deacetylation: 90% (9B)) gel beads was similar to that with Alg gel beads. However, the in vivo release of PS was affected by the degradability of the gel beads. CS7B and 8B (1%) gel beads had released PS into the AP earlier than 3 d according to their rate of degradation. CS9B (1.5%) gel beads were not degraded after 3 d and went on to release PS into the AP for 3 d similar to the release profile of Alg gel beads. CS9B (2%) gel beads were also not degraded after 3 d and the release of PS from these beads into the AP was sustained; 76% and 27% of administered PS remained in the gel beads after 1 and 3 d, respectively. Therefore, degradation and drug release of CS gel beads can be controlled by changing the structure of the gel matrix, which appears to make these beads a promising biodegradable vehicle for sustained drug delivery.

The significance of MMP-1 and MMP-2 in peritoneal disseminated metastasis of gastric cancer.

The purpose of this study was to clarify the role of the matrix metalloproteinases (MMPs), collagenase (MMP-1), and gelatinase A (MMP-2), both of which are known to be involved in the development of gastric cancer, in peritoneal dissemination. The concentrations of MMP-1 and MMP-2 in the supernatant of mixed culture simulated peritoneal dissemination were measured in vitro with mesothelial cells and cancer cells using an enzyme-linked immunosorbent assay. The concentration of MMP-1 increased significantly after the contact culture was mixed with these two cells, in comparison with the non-contact mixed culture or the mesothelial cell culture alone. These results demonstrate that the production of MMP-1 derived from mesothelial cells was increased by contact with cancer cells. To clarify the effect of MMP-1 and MMP-2 on gastric cancer invasion, an invasion assay using matrigel was performed. After treatment with anti-MMP-1 monoclonal antibody (mAb) or anti-MMP-2 mAb, the number of matrigel-penetrating cancer cells was significantly reduced, indicating that MMP-1 and MMP-2 derived from mesothelial cells had a strong reaction to gastric cancer invasion. In conclusion, as MMP-1 showed a paracrine-like action responding to stimulus from cancer cells, it seemed to play an important role in the progression of peritoneal dissemination.

The controlled release of a drug from biodegradable chitosan gel beads.

Chitosan (CS) forms a gel in solutions with a pH above 12, and the gelation occurs at pH of about 9 in 10% amino acid solutions. In this paper, we investigated the enzymatic degradation and the drug release profile of this novel CS gel beads. The degradability of the CS gel beads was affected by the CS properties, e.g. the degree of deacetylation. The release of prednisolone (PS), as a model drug, from the CS gel beads was sustained significantly compared with the gel prepared with NaOH only. However, the release was not able to be sustained by the increment of NaOH concentration in the solution employed for the preparation of CS gel beads. We also investigated the control of drug release from CS gel beads by application of a complex formed between chondroitin sulfate (Cho) and CS. The release of PS from the CS gel beads treated with Cho was prolonged, and the release pattern was not affected by the treatment time. The time to 50% drug release was about 5 min with PS powder, about 200 min in CS gel beads with 10% glycine (Gly) (pH 9.0), and about 330 min in the CS gel beads with 10% Gly (pH 9.0) treated with Cho. Thus CS gel beads appear promising as a vehicle for sustained drug delivery, and the degradation of CS gel beads may be controlled by the degree of deacetylation of CS.

Preparation and drug retention of biodegradable chitosan gel beads.

Chitosan (CS) gel beads containing drug could be prepared in amino acid solutions of pH about 9, despite the requirement for a pH above 12 for gelation in water. This phenomenon was observed not only in amino acid solutions but also in solutions of compounds having amino groups. A solute concentration of more than 10% was required for preparation of gel beads at pH 9. Gelation of the CS beads required about 25 to 40 min, depending on the species of amino acid. Lidocaine hydrochloride (LC) as a model drug was retained in the beads to about 20 to 35% of the theoretical total amount, despite being a water-soluble drug. The release of LC from the CS gel beads was prolonged. The release pattern was not affected by the species of amino acid or CS, or the preparation time.

Lymph node metastasis and lymphadenectomy for carcinoma in the gastric cardia: clinical experience.

METHOD AND MATERIALS: To suggest improved guidelines for treating lymphatic spread and to understand the results of extended lymphadenectomy. A total of 141 cases of cardia carcinoma admitted to our hospital during 1980 to 1993 were analyzed. RESULTS: 123 of 141 cases underwent resection. The incidence of mediastinal lymph node involvement rose from 8.7% in cases with 1-2 cm invasion to 52.9% in cases with more than 4 cm invasion into the esophagus. The incidence of abdominal lymph node involvement also rose with increasing esophageal invasion. Paraaortic lymph node metastasis was frequently observed in cases of more than 1 cm esophageal invasion. D4 lymphadenectomy (extended lymphadenectomy) revealed better results for the cases with lymph node involvement (P<0.05). There was no difference in the incidence of postoperative complication or in operative death, between the abdominal approach and the thoracoabdominal approach, or between the D4 lymphadenectomy and D2 lymphadenectomy. CONCLUSION: Sufficient mediastinal and abdominal lymphadenectomy under a clear wide surgical field achieved through the thoracoabdominal approach appeared to bring better results.

Gastrectomy with combined resection of other organs for carcinoma of the stomach with invasion to adjacent organs: clinical efficacy in a retrospective study.

BACKGROUND: Carcinoma of the stomach invading one or more adjacent organs raises serious concerns over en bloc dissection because en bloc resection has an associated high risk and such advanced carcinoma is frequently associated with incurable factors. Thus, it is important to understand the efficacy of gastrectomy combined with other organ resection and to refine the indications for en bloc dissection. STUDY DESIGN: Seventy-seven patients with carcinoma of the stomach directly invading adjacent organs or structures were analyzed retrospectively to investigate the efficacy of en bloc resection. Forty-one patients underwent gastrectomy combined with resection of one or more invaded organs (combined resection group), while the other 36 patients underwent gastrectomy with palliative abrasion between the primary tumor and the invasion site (noncombined resection group). RESULTS: The five-year survival rate was 23 percent in the combined resection group and 0 percent in the noncombined resection group (p < .05). The 23 curative cases and 18 noncurative cases in the combined resection group had a survival rate of 41 percent and 0 percent, respectively (p < .05). The survival rate after a single organ resection was 29 percent, and after a multiple organ resection, 0 percent (p < .05). Cases of carcinoma invading either the pancreas or mesocolon had a slightly but not significantly better prognosis. In Borrmann type IV carcinoma there was no difference in survival between the curative and noncurative operation. Cases with P1 dissemination had a better prognosis than those of P2 and P3 dissemination. CONCLUSIONS: The best indication for an en bloc combined organ resection was an invasion limited to only one other organ, not more than N2, no incurable factor, and any type except Borrmann type IV. Additionally, an en bloc combined resection would be worth trying for any type of gastric carcinoma with not more than P1 dissemination and with no other incurable factor.

Gallstones and gallbladder disorder after gastrectomy for gastric cancer.

The incidence of gallbladder diseases, in particular of gallstones, was investigated in 268 cases during follow-up after resection of a gastric cancer. Factors investigated for correlation with any incidence included the extent of gastrectomy, reconstruction, and the degree of lymph node dissection. Moreover, in 20 of these, the contractile function test using a cerulein injection was performed, while in a further 6 cases, a sequential contractile function test with fatty meal was performed. The incidence of gallstones was 10.5% after total gastrectomy, 12.4% after distal gastrectomy. Debris was found in a further 6.7% after total gastrectomy and in 1.2% after distal gastrectomy. There was no difference in the incidence of gallstones among the reconstruction methods. With respect to lymph node dissection, the incidence of gallstone formation was 16.3% after D3 and 8.5% after D2-1. In the contractile function test, although the basal area was significantly larger after D3 than after D2-1, there was no difference in the contractile rate. The sequential contractile function test showed a peak contraction at 15 minutes after feeding with gradual refilling in both those after D3 and those after D2-1.

[Expression of the growth factors (EGF, EGFR, and TGF alpha) and PCNA in superspreading and penetrating types of gastric carcinomas].

Expression of EGF, EGFR, TGF alpha, and PCNA in resected gastric carcinomas (15 cases of superspreading type and 25 cases of penetrating type) was immunohistochemically studied to understand biological features of these two types of gastric carcinomas. EGF, EGFR, and TGF alpha positive cases were preferentially found in the penetrating type rather than in the superspreading type (p < 0.05). Incidence of PCNA high expression cases in the penetrating type was significantly higher than that in superspreading type. Nineteen cases (76%) of the penetrating type and 1 case of the superspreading type (6.7%) were diffusely PCNA (+), and the incidence of in the former type was significantly higher than that of the latter type (p < 0.001). One case of the superspreading type and 13 cases of the penetrating type were either EGF (+) or TGF alpha (+), and EGFR (+), and the incidence in the latter type was significantly higher than that in the former type (p < 0.05), suggesting that growth and invasion of carcinoma cells, especially in the penetrating type, may depend on "autocrine mechanism". Incidence of the growth factors (+) and PCNA (+) cells in classical type of signet ring cells was lower than that in other types of singnet ring cells.

[A case of advanced gastric cancer with liver and lung metastasis effectively treated by combined chemo-immunotherapy of MMC, 5'-DFUR, OK-432].

A sixty-eight-year-old male patient was diagnosed as having inoperable advanced gastric cancer with liver and lung metastasis. The patient was treated by combined chemo-immunotherapy of MMC 10 mg/M, 5'-DFUR 800 mg/day and OK-432 5 KE/2 W. Six months after commencing chemotherapy, CT-scan and upper GI series revealed that metasized liver tumors and stomach lesion were remarkably decreased in size and no cancer cell was confirmed by endoscopic biopsy. Further, the metastatic lung tumor has disappeared on chest X-ray. The patient had been well without any evidence of tumor re-progression for over one year, but from July the liver tumor began to metastasize again and the patient eventually died of liver metastasis on Jan. 1, 1993.