Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma.

BACKGROUND: The majority of advanced gastric carcinoma patients with serosal invasion die of peritoneal recurrence, even when a curative gastrectomy is performed, because peritoneal recurrence occurs due to intraperitoneal free tumor cells that detach from the serosal-invaded focus. In an attempt to prevent peritoneal recurrence, intraperitoneal hyperthermic chemoperfusion (IHCP) treatment was combined with aggressive surgery. METHODS: Between March 1987 and December 1996, 141 gastric carcinoma patients with macroscopic serosal invasion were allocated randomly to 2 groups. Seventy-one patients underwent IHCP combined with surgery (IHCP group) and the remaining 70 patients underwent surgery alone (control group). IHCP was performed just after gastric resection and alimentary tract reconstruction under general anesthesia along with systemic hyperthermia. RESULTS: Postoperative complications were reported in 2 of the 71 patients in the IHCP group and in 2 of the 70 patients in the control group. The peritoneal recurrence rate in the IHCP group was significantly decreased (P = 0.0000847) compared with that in the control group. The 2-year, 4-year, and 8-year survival rates for the IHCP group were 88%, 76%, and 62%, respectively, whereas those for the control group were 77%, 58%, and 49%, respectively. The IHCP group thus reaped a significant survival benefit (P = 0.0362) compared with the control group. CONCLUSIONS: Although this study was conducted randomly for a small number of patients, compared with the control group, the IHCP group had a high survival rate and better prognosis.

[Clinical result of intraperitoneal hyperthermic chemoperfusion for gastric cancer with serosal invasion to prevent peritoneal recurrence].

In order to evaluate clinical effects of intraperitoneal hyperthermic chemoperfusion (IHCP) to prevent peritoneal recurrence in gastric cancer patients with serosal invasion, the clinical outcome was studied in 126 gastric cancer patients with macroscopic serosal invasion. Results of 59 patients who had surgery combined with IHCP (IHCP group) were compared with those of 67 patients who had surgery alone (control group). IHCP was performed for 120 minutes just after surgery under hypothermic general anesthesia with perfusate containing 10 micrograms/ml of mitomycin C. The inflow temperature and the outflow temperature of the perfusate were controlled to be 44.5 approximately 45 degrees C, and 43 approximately 44 degrees C, respectively. The 2-, 4- and 8-year survival rates for the IHCP group were 86%, 74% and 66%, respectively, against 78%, 59% and 50%, respectively, in the control group. The survival rates of the IHCP group were significantly better than those of the control group. Peritoneal recurrences after surgery were encountered in one of 59 patients in the IHCP group and 17 of 67 patients in the control group. The peritoneal recurrence rate of the IHCP group was significantly lower than that of the control group. These results suggest that IHCP treatment is effective in prevention of peritoneal recurrences after surgery for gastric cancer patients with serosal invasion.

Histologic evaluation of preventive measures for scald injury on the peritoneo-serosal surface due to intraoperative hyperthermic chemoperfusion for patients with gastric cancer and peritoneal metastasis.

To histologically assess the preventive efficacy of cimetidine against scald injury on the peritoneo-serosal surface during intraperitoneal hyperthermic chemoperfusion (IHCP) for advanced gastric cancer, a randomized histologic study using cimetidine, a histamine H2-receptor antagonist, was performed for 20 patients with advanced or recurrent gastric cancer and peritoneal metastasis. Cimetidine 50 mg/kg was administered intravenously to 10 patients just prior to the IHCP (cimetidine group), and the remaining 10 patients underwent the IHCP without cimetidine (control group). The background factors and IHCP treatments of these two groups were nearly the same. Although the antitumour efficacy of the IHCP was not histologically different between the two groups, the histological analysis revealed that the peritoneo-serosal surface in the cimetidine group was protected against scald injury, compared with the control group. This finding suggests that pre-IHCP cimetidine is of great benefit for protecting the peritoneo-serosal surface from scald injury due to IHCP.

Improved mortality rate of gastric carcinoma patients with peritoneal carcinomatosis treated with intraperitoneal hyperthermic chemoperfusion combined with surgery.

BACKGROUND: Peritoneal carcinomatosis from gastric carcinoma has a very poor prognosis. The purpose of this study was to evaluate the efficacy of intraperitoneal hyperthermic chemoperfusion (IHCP) in advanced gastric carcinoma patients with peritoneal carcinomatosis. METHODS: IHCP combined with aggressive surgery was performed in 48 gastric carcinoma patients with peritoneal carcinomatosis; 18 gastric carcinoma patients with peritoneal carcinomatosis serving as controls were treated with surgery alone. RESULTS: The survival period was extended for the 48 patients who underwent surgery plus IHCP compared with the control patients (P = 0.00167). Of the 29 patients with peritoneal carcinomatosis in the upper abdominal cavity, the 21 patients treated with IHCP and surgery had survival periods superior to those of the 8 patients treated by surgery alone (P = 0.000817). The 5-year survival rate of the 18 IHCP patients with countable metastases in the entire cavity was 41.6%, whereas the 50% survival duration of the control group was 110 days. Nineteen patients with numerous metastases in the entire cavity died within 673 days, regardless of whether or not IHCP was used. CONCLUSIONS: Peritoneal carcinomatosis is not a disease beyond treatment. IHCP treatment combined with extensive surgery provides an effective and practical method of treating this disease entity.

Clinicopathologic characteristics of gastric cancer patients with cancer infiltration at surgical margin at gastrectomy.

Although curative surgery is desirable in patients with gastric cancer, tumors adjacent to the esophagogastric and/or gastroduodenal junctions present surgeons with some difficulty in estimating whether or not the lesion has infiltrated beyond the surgical margin. We report herein a retrospective analysis with respect to the clinicopathologic features of the primary lesion and margin positivity for tumor cells. Between 1982 and 1993, 861 gastric cancer patients underwent gastrectomy in our clinics. Of these, 340 had early cancer and the remaining 521 advanced cancer. Cancer infiltration at the surgical margin was determined macroscopically in the fresh resected specimen; re-resection was carried out immediately for positive cases and, subsequently, a rapid histologic examination at the newly-incised edge was carried out intraoperatively. Of the 340 patients with early cancer. 15 (4.4%) had a positive surgical margin which was directly resected successfully. Of the 521 patients with advanced cancer, 73 (14%) had a positive surgical margin and 28 of them had a microscopically negative surgical edge after re-resection; however, 8 others had a positive result at the newly-excised edge after re-resection, and the remaining 37 could not undergo re-resection because of their poor general condition and/or because the tumor had spread to other sites. The positive rate for the final surgical margin was 5.2% (45/861 patients). All of the patients with a positive margin and early cancer had a superficial or excavative type lesion, and 76.7% (56/73 patients) of those with advanced cancer had Borrmann's III or IV type lesion. These findings suggest that in such patients with a tumor adjacent to the esophagogastric and/or gastroduodenal junctions, particular attention should be paid to Borrmann's III or IV lesions in advanced cancer and to superficial or excavated type lesions in early cancer in order to reduce the frequency of positive surgical margin. Additionally, an immediate histologic examination after re-resection is extremely important.

In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.

Efficacy of ER-30346, a novel oral triazole antifungal agent, in experimental models of aspergillosis, candidiasis, and cryptococcosis.

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. In the present study, we investigated the therapeutic effects of oral ER-30346 on experimental local infections caused by Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans and compared them with those of itraconazole and fluconazole. In experimental murine models of pulmonary aspergillosis, candidiasis, and cryptococcosis, ER-30346 reduced the numbers of CFU in the lungs significantly compared with the numbers of CFU in the lungs of the controls (P < 0.05). ER-30346 was as effective as or more effective than itraconazole against pulmonary aspergillosis. Against pulmonary candidiasis and cryptococcosis, ER-30346 was more effective than itraconazole and was as effective as fluconazole. ER-30346 was also effective against pulmonary candidiasis caused by fluconazole-resistant C. albicans. In mice with intracranial cryptococcosis, ER-30346 reduced the numbers of CFU in the brains significantly compared with the numbers of CFU in the brains of the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. In an experimental model of oral candidiasis in rats, ER-30346 reduced the numbers of CFU in oral swabs significantly compared with the numbers of CFU in oral swabs from the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. Thus, ER-30346 shows efficacy in murine aspergillosis, candidiasis, and cryptococcosis models. Further studies are needed to determine the potential of ER-30346 for use in the treatment of these infections.

Survival time and prevention of side effects of intraperitoneal hyperthermic perfusion with mitomycin C combined with surgery for patients with advanced gastric cancer.

In an attempt to prevent postoperative intraperitoneal recurrence in patients with advanced gastric cancer and consequently to improve survival time, we treated patients with intraperitoneal hyperthermic perfusion (IPHP) using mitomycin C (MMC) combined with surgery. There were 60 patients with advanced gastric cancer who were treated with IPHP (long-term study) group, and the survival of this group was compared with the outcome in 52 patients with advanced gastric cancer treated with surgery alone (control group). To avoid or diminish side effects derived from scald injury of the peritoneal surface due to IPHP, 50 mg/kg of cimetidine was given intravenously just before administration of IPHP. For prophylaxis of anastomotic leakage, duodenostomy using a Foley catheter was performed. The 60 patients who were treated with IPHP lived longer than the 52 patients in the control group (p = 0.000610). The 3 year survival rate was 45 percent for the former compared with 16 percent for the latter. The intravenous administration of cimetidine just prior to IPHP protected the peritoneoserosal surface from scald injury, even though the heated perfusate exposure was at 44.3-46.3 degrees C for 2 hours. Because the intraabdominal pressure within the duodenum and jejunum was decompressed postoperatively through catheter duodenostomy and the peritoneoserosal surface was protected from scald injury caused by IPHP, anastomotic leakage in the study group was nil. Therefore, IPHP treatment plus aggressive surgery combined with pre-IPHP cimetidine administration are indicated for patients with advanced gastric cancer. The side effects of IPHP and postoperative morbidity can thus be reduced and a favorable outcome obtained.

In vitro and in vivo antibacterial activities of E1077, a novel parenteral cephalosporin.

E1077, a new injectable cephalosporin with a broad antibacterial spectrum and potent antibacterial activity, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of cefpirome, cefuzonam, ceftazidime, and cefotaxime. E1077 showed broad in vitro antibacterial activity against gram-positive and gram-negative bacteria. Against methicillin-susceptible Staphylococcus aureus, E1077 was as active as cefpirome; the MIC for 90% of strains tested (MIC90) was 1.0 microgram/ml. Against methicillin-resistant S. aureus, E1077 was less active (MIC90, 64 micrograms/ml). For Enterobacter cloacae and Pseudomonas aeruginosa, E1077 was fourfold more active than cefpirome, with MIC90s of 1.0 and 16 micrograms/ml, respectively. For Proteus vulgaris, the MIC90 of E1077 was 32 micrograms/ml, which was fourfold greater than that of cefpirome. Against other gram-negative strains tested, the in vitro activity of E1077 was comparable to that of cefpirome. The broad antibacterial spectrum of E1077 was reflected by its in vivo efficacy against experimental septicemia caused by gram-positive and gram-negative bacteria. Against S. aureus 90 and P. aeruginosa E7, E1077 had activity superior to those of the reference compounds; against most other bacterial strains, the efficacy of E1077 was similar to that of cefpirome. Levels of E1077 in plasma and tissue of mice were studied. At 15 min after a single subcutaneous administration, E1077 displayed high peak levels (mean, 31.8 +/- 3.1 micrograms/ml). These results indicate that the in vitro and in vivo efficacies of E1077 are similar to those of cefpirome except against P. aeruginosa and P. vulgaris.

[Effect of cefclidin and E1077, new cephalosporins, on the alcohol-metabolizing system in rats].

Administration of latamoxef and cefoperazone, reported to act like disulfiram in humans, caused a depression of mitochondrial low Km aldehyde dehydrogenase (low Km ALDH) activity in rats. In addition, a marked increase of blood acetaldehyde concentration was observed when rats were given alcohol orally at 18 hours after administration of these cephalosporins. However, mitochondrial low Km ALDH activity and blood acetaldehyde level were not altered by repeated administration of 300 mg and 1,000 mg of cefclidin (CFCL, E1040) or E1077 per kg. From these results, it was concluded that neither CFCLn or E1077 affected the alcohol metabolizing-system.

Prophylactic activity of dihydroheptaprenol, a synthetic polyprenol derivative, against Sendai virus infection in mice.

The effect of a chemically synthesized polyprenol derivative, dihydroheptaprenol (DHP), on the non-specific resistance of mice to Sendai virus infection was investigated. The mice that received 200 micrograms of DHP intranasally twice, at 3 days and 1 day before the infection, showed a significant protection against Sendai virus infection. Treatment of mice twice even with as much as 2000 micrograms of DHP through the subcutaneous route, however, had no protective effect against infection. Excess interferon and tumour necrosis factor production in intranasally DHP-treated mice was seen 1 day after the infection when compared with Sendai virus alone controls or with DHP alone controls. Variance analysis of these findings indicates a prophylactic activity of DHP in pulmonary viral infections.

[Ulcerative colitis complicated by early carcinoma of the rectum and cholecystolithiasis].

Reported is a case of a 73-year-old male with a history of ulcerative colitis that had started at the age of 57. In 1985, on receiving a barium enema, a polypoid lesion was found in his rectum. In 1986, the results of a colonoscopy showed that the polypoid lesion had reached an IIa-aggregated elevation, and biopsies of this lesion were diagnosed as an adenoma or a hyperplastic polyp. A year later, in 1987, another biopsy specimen was taken and was histologically diagnosed as being an adenomatous cancer. Thus, a pull-through operation and a cholecystectomy were performed. The lesion was 4.5 x 3.0 cm in diameter, and the histological findings showed it to be a well-differentiated adenocarcinoma with a submucosal invasion. Accordingly, physicians should be advised that patients with a longstanding ulcerative colitis ought to undergo periodic examination that includes a colonoscopy and a biopsy of any suspicious growth.