Effect of a selective neutrophil elastase inhibitor on early recovery from body water imbalance after transthoracic esophagectomy.

The objective of the study was to evaluate the efficacy of sivelestat, a selective neutrophil elastase inhibitor, on body fluid balance after transthoracic esophagectomy. Esophagectomy with elective lymphadenectomy may induce excessive release of neutrophil elastase, which then promotes vascular permeability and an excessive water shift from the intravascular space to the peripheral compartment. Body fluid imbalance after esophagectomy often leads to circular instability, a decrease of urine output, and a delay in the shift to a diuretic state. The study was designed as a case-control study with a historical control group. A retrospective analysis was performed to examine our hypothesis that sivelestat improves abnormal body fluid retention and prevents subsequent pulmonary complications. To reveal the direct influence of sivelestat on the postoperative course, we avoided using steroids or other diuretic agents. Eighty-eight patients who underwent thoracic esophagectomy with extended lymphadenectomy from 2000 to 2008 were divided into two groups: those treated from 2003 to 2008, who all received postoperative administration of sivelestat (n=60); and those treated from 2000 to 2002, who did not receive sivelestat and were used as the control group (n=28). Both groups received fluid management using the same protocol. The time to reach a diuretic state, time until extubation of the tracheal tube, and development of delayed respiratory dysfunction were compared between the groups using univariate and multivariate analysis. The time until a shift to a diuretic state was significantly shorter after treatment with sivelestat (p<0.0001) and with a shorter operation time (p<0.0001). The tracheal tube was extubated significantly earlier in the sivelestat group (p<0.0001) and the incidence of delayed respiratory dysfunction was also significantly lower (p=0.0028) in this group. Multivariate logistic regression analysis showed that a delay in a shift to a diuretic state was a strong independent risk factor for the time to tracheal extubation (odds ratio 2.539, p=0.0056) and occurrence of delayed respiratory dysfunction (odds ratio 1.989, p=0.0104). Sivelestat treatment was not independently associated with reduced pulmonary complications, but the diuretic state was strongly regulated by sivelestat treatment (odds ratio 0.044, p=0.0003). Thus, administration of sivelestat has a beneficial influence on recovery from body water imbalance through a more rapid return to a diuretic state after esophagectomy, which contributes to prevention of subsequent pulmonary complications.

A new technique using free ileocaecal patch transplantation for secondary voice restoration after total laryngectomy.

SUMMARY: We introduce our newly designed voice restoration technique, which uses free ileocaecal patch transplantation for patients who have undergone prior total laryngectomy. Two women received ileocaecal patch transplantation for secondary voice restoration after total laryngectomy. In order to make the tracheoesophageal shunt for speech, a new orifice on the anterior wall of the hypopharynx had to be opened, which was closed at the time of laryngectomy. The hypopharyngeal orifice was covered by a free caecal patch harvested from an ileocaecal segment. Then, a tracheoesophageal shunt was created by anastomosing the terminal ileum of the patch and the remnant of the cervical trachea. Expiratory air was diverted into the pharynx through the ileum of the transplanted graft when the tracheostoma was closed by digital occlusion. Aspiration through an oesophagotracheal shunt in swallowing was prevented by the ileocaecal valve on the patch. Both patients began to speak up to 4 weeks after surgery without requiring training or difficult practice to achieve initial phonation and to be able to swallow without aspiration. The advantages of our procedure are (1) it can be carried out at the time of laryngectomy and also at secondary voice restoration after earlier laryngectomy; (2) the graft contains an ileocaecal valve that prevents aspiration through the shunt and also functions as a vibrating device to produce voice; (3) our procedure can be adapted to individuals whose tracheostoma is detached from the oesophagus and becomes contraindicated for a voice prosthesis. We believe that our newly designed procedure is a unique and useful alternative, especially for secondary voice restoration after prior total laryngectomy.

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity.

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.

Role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients.

This study was designed to investigate the role of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) on tumour progression and sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). Tumour tissue was obtained from surgically resected samples from 93 patients with primary gastric cancer. Tumour TP and DPD expression levels were determined by the enzyme-linked immunosorbent assay (ELISA) system and compared with several clinicopathological factors and in vitro sensitivity to 5'-DFUR. DPD showed no correlation with any clinicopathological factors. However, the TP level was significantly correlated with the depth of tumour, lymphatic invasion and venous invasion. In comparison with 5'-DFUR sensitivity, there was a weak inverse correlation between the DPD level and the sensitivity to 5'-DFUR (r(s)=-0.361). Furthermore, the TP/DPD ratio showed a significant correlation with 5'-DFUR sensitivity (r(s)=0.634). In a subgroup of patients with postoperative 5'-DFUR administration, the survival rate was significantly better in patients with a high TP/DPD ratio (n=8) than in those with low TP/DPD ratio (n=14) (P=0.0140). These results suggest that sensitivity to 5'-DFUR is predictable by measurement of both TP and DPD levels.

Roles of thymidylate synthase and dihydropyrimidine dehydrogenase in tumor progression and sensitivity to 5-fluorouracil in human gastric cancer.

BACKGROUND: The role of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) enzyme activities in tumor progression and sensitivity to 5-fluorouracil (5-FU) were evaluated. MATERIALS AND METHODS: TS and DPD activities were measured in 81 clinical samples of gastric cancer. TS and DPD activities were determined by 5-fluorodeoxyuridine monophosphate binding assay and by radioenzymatic assay, respectively. Sensitivity to 5-FU was determined by in vitro ATP assay. RESULTS: There was no correlation between TS activity and sensitivity to 5-FU. However, a weak correlation was found between DPD activity and sensitivity to 5-FU. In a subgroup of patients who did not receive adjuvant chemotherapy, overall survival was poorer in patients with high TS activity (p=0.0265). Conversely, in a subgroup of patients who received 5-FU-based adjuvant chemotherapy, overall survival was poorer in patients with high DPD activity (p=0.0465). CONCLUSION: These results suggest that TS has an important role in tumor progression and DPD may be the dominant predictor of 5-FU sensitivity in gastric cancer.

Telomerase assay as a possible predictor of the response to anticancer chemotherapy.

BACKGROUND: The correlation between telomerase activity and antitumor effects was investigated in cell lines of human gastric (MKN-28, MKN-45, and MKN-74) and breast (T-47D, MCF-7, ZR75-1) cancers to evaluate the possibility of utilizing this enzyme to predict tumor response to chemotherapy. MATERIALS AND METHODS: After culture with various concentrations of 5-fluorouracil (5-FU) or doxorubicin (DOX) for 3 days, cell viability (trypan blue exclusion), cell cycle distribution (flow cytometry), and telomerase (TRAP-EZE) were measured. RESULTS: Telomerase activity correlated significantly with the number of viable cells. After drug exposure, this activity decreased rapidly in a dose-dependent fashion in most cell lines. There was no correlation between telomerase activity and the distribution of cells in the cell cycle. CONCLUSIONS: As the assay for telomerase activity is extremely sensitive and is virtually specific to cancer cells, this method may prove useful for the sensitivity testing of small specimens of human tumors.

[Therapeutic efficacy of intra-peritoneal infusion of cisplatin and continuous intravenous infusion of 5-fluorouracil in gastric cancer patients with peritoneal metastasis].

A combination chemotherapy with intra-peritoneal infusion of CDDP and continuous intravenous infusion of 5-FU was used with a total of 16 gastric cancer patients with peritoneal metastasis (P 2 or P 3). Infuse A-port was inserted at the time of operation, CDDP 70 mg/m2 was administered intra-peritoneally at day 1, and 5-FU 700 mg/m2 was continuously administered intravenously at day 1-5. This treatment was repeated twice. Toxicity was evaluated according to the criteria from JCOG. Major toxicities of this regimen were anemia, leukocytopenia and nausea/vomiting. Except for one patient with Grade 3 venous thrombosis, all toxicities were less than Grade 2 and well tolerable. Median survival time was 343 days, but, one patient has survived more than 6 years. According to the multivariate analyses, depth of invasion was selected as an independent prognostic factor for this treatment. This therapy is considered to be a safe and effective treatment modality for gastric cancer patients with peritoneal metastasis.

[Pharmacokinetic analysis of low-dose intra-peritoneal cis-platinum administration].

Pharmacokinetic parameters after intra-peritoneal administration of low-dose cis-platinum (CDDP) were analysed in order to evaluate the possibility of applying low-dose 5-FU/CDDP therapy (1-FP) for outpatients. Four patients with advanced gastric cancer were the subjects of this study. CDDP at a dose of 20 mg/body was administered intra-peritoneally, and peripheral venous blood was collected at 30 min, 4, 8, 24, 48, 72, 96 and 120 hr after drug administration. The plasma platinum (Pt) concentration was determined by atomic absorption spectrometry. Pharmacokinetic parameters were calculated using a two-compartment open model. C max, AUC, t1/2 alpha and t1/2 beta of total-Pt were 1. 27 +/- 0.21 micrograms/ml, 95.28 +/- 16.93 micrograms.hr/ml, 1.91 +/- 0.76 hr and 190.2 +/- 125.6 hr, respectively. Total-Pt concentration at 120 hr, after administration was 0.54 +/- 0.14 microgram/ml. This result suggests that intraperitoneal low-dose CDDP administration is a promising method for 1-FP therapy for outpatients, because the plasma total-Pt level is maintained at a sufficiently high level for a long period.

Carcinoembryonic antigen level in peritoneal washing is a prognostic factor in patients with gastric cancer.

This study was designed to evaluate the usefulness of carcinoembryonic antigen (CEA) and sialyl-Tn antigen (STN) levels in peritoneal washings in gastric cancer patients. At the time of laparotomy, peritoneal washings were collected from 96 gastric cancer patients and CEA and STN levels were determined. Patients with elevated CEA (100 ng/g protein) had a high incidence for peritoneal metastasis, lymph node metastasis and serosal invasion. In addition, prognosis in patients with high CEA level was significantly poorer than in those without it. The peritoneal CEA is a prognostic factor in patients with gastric cancer.

[Pharmacokinetic analysis of intra-peritoneal administration of cisplatin].

Pharmacokinetic parameters after intra-peritoneal administration of cis-platinum (CDDP) were evaluated and compared with those after intravenous administration. CDDP at a dose of 70 mg/m2 were administered intra-peritoneally in 5 patients with advanced gastric cancer (IP group). Pharmacokinetic parameters and toxicities were evaluated in these patients and compared with those in 4 esophageal cancer patients administered the same dose of CDDP intravenously (IV group). In IP group, Cmax of total- and free-Pt were 3.41 +/- 0.89 micrograms/ml and 1.10 +/- 0.30 micrograms/ml, and AUC of total- and free-Pt were 59.6 +/- 14.3 micrograms.hr/ml, 3.12 +/- 0.89 micrograms.hr/ml, respectively. On the other hand, Cmax and AUC of total- and free-Pt in IV group were 3.31 +/- 0.59 micrograms/ml. 1.13 +/- 0.21 micrograms/ml and 45.89 +/- 9.24 micrograms.hr/ml, 1.22 +/- 0.8 micrograms.hr/ml, respectively. AUC of free-Pt in IP group was significantly higher than in IV group. This result suggests that a more promising antitumor effect will be obtained systemically by intraperitoneal administration of CDDP. The incidence and grade of toxicities were similar in these two groups.

Microvessel count predicts metastasis and prognosis in patients with gastric cancer.

BACKGROUND AND OBJECTIVES: In order to evaluate the clinical relevance of angiogenesis in patients with gastric cancer, we investigated the microvessel count in gastric cancer tissues and compared the results with several clinicopathologic factors and prognosis. METHODS: A total of 55 patients with gastric cancer were included in this study. Microvessel count was determined by immunohistochemical staining using antifactor VIII-related antigen antibody. Histologically recognizable blood vessels within tissue sections served as internal control for immunostaining. Normal mouse IgG diluted to an equivalent protein concentration was used as a negative control in place of the primary antibody in each experiment. RESULT: The microvessel count ranged from 4.4 to 39.8 and the median count was 15.6. Microvessel count was significantly higher in patients with hepatic metastasis, lymph node metastasis, adjacent organ invasion, and lymphatic invasion. In patients who had undergone a curative operation, survival time in the hypervascular group was significantly shorter than that in the hypovascular group. CONCLUSIONS: Microvessel count correlated well with tumor progression and may serve as a useful prognostic factor in patients with gastric cancer.

[Pharmacokinetic analyses of intra-arterial and intra-portal chemotherapeutic agent infusion].

In order to determine the optimal drug administration route in patients with metastatic liver tumor, we studied the pharmacokinetic parameters after intra-arterial or intra-portal adriamycin (ADM) administration. Four patients with metastatic liver tumors were included in this investigation. One catheter was inserted into the gastroduodenal artery for arterial infusion and the other catheter was inserted into the portal vein via mesenteric vein for portal infusion under laparotomy. ADM 30 mg was infused and blood samples were collected from peripheral and hepatic veins. The concentration of ADM was determined with HPLC technique and the pharmacokinetic parameters were analyzed with a three-compartment open model. The parameters analyzed were blood concentration at t0, half-life, rate of elimination, total body clearance, volume of distribution and area under the blood concentration versus time curve. There were no significant differences of the pharmacokinetic parameters between intra-arterial infusion and intra-portal infusion. Also, no differences were observed between the data from peripheral venous blood and those from hepatic venous blood. These data suggest that the drug distributions were almost similar between intra-arterial and intra-portal drug administration in patients with metastatic liver tumor.