[Three long surviving patients with gastric cancer metastasizing to the liver under interdisciplinary therapy].

In 30 patients with gastric cancer metastasizing to the liver over the past 15 years at our hospital the primary foci in the stomach could be resected in a curative manner. The authors report herein three long surviving patients in this series. [Case 1] A 49-year-old male. Distal gastrectomy was performed in November 1984. Metastasis to the liver occurred in June 1986. The right lobe of the liver was resected in November 1987 after transcatheter arterial embolization (TAE). Although hepatic arterial infusion chemotherapy was conducted, the cancer metastasized to the whole body, and the patient died in December 1991. [Case 2] A 65-year-old female. Distal gastrectomy was performed in July 1994. The left hepatic lobe and segment 5 in the right lobe were resected in June 1995. Although TAE was performed six times starting in December 1996, the patient died of hepatic failure in July 1999. [Case 3] A 73-year-old male. This patient simultaneously received distal gastrectomy and extended resection of the posterior hepatic segments in September 1997. Cancer recurred in the remaining liver in July 1998. Although microwave coagulation therapy (MCT) and TAE were performed, the patient died of hepatic failure in January 2000. In these patients who survived for a long period, the primary focus was well-differentiated adenocarcinoma under sufficient local control with metastasis limited to the nearest regional lymph nodes (group 1 lymph nodes). The patients could undergo interdisciplinary therapy, including hepatectomy, MCT, TAE, and hepatic arterial infusion chemotherapy.

Interaction of drugs and Chinese herbs: pharmacokinetic changes of tolbutamide and diazepam caused by extract of Angelica dahurica.

The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2alpha- and 16alpha-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28-5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg(-1) dose. 6beta-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg(-1) dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg(-1). Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg(-1)), but not low dose (0.3 g kg(-1)), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg(-1). It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs.

Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells.

The catalytic properties of CYP3A7 in the metabolism of endogenous and exogenous substrates were compared with those of CYP3A4 and CYP3A5 using COS-7 expressing enzymes. The highest activities of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3-sulfate (DHEA-S) 16alpha-hydroxylase were observed in COS-7 cells expressing CYP3A7. In contrast, the activity of testosterone 6beta-hydroxylase of CYP3A7 expressed in COS-7 cells was much less than that of CYP3A4 expressed in COS-7 cells. The rate of carbamazepine 10, 11-epoxidation was the greatest in COS-7 cells expressing CYP3A4, followed by CYP3A5 and CYP3A7. On the other hand, the formation of reductive metabolite of zonisamide was the highest in COS-7 cells expressing CYP3A4, followed by CYP3A7 and CYP3A5. Furthermore, the addition of triazolam resulted in a decrease in 6beta-hydroxylation catalyzed by CYP3A7, but not by CYP3A4, whereas the pretreatment of microsomes with triacetyloleandomycin (TAO) resulted in a decrease in the reaction catalyzed by CYP3A4, but not by CYP3A7. Together with these results, it was suggested that CYP3A7 exerts differential catalytic properties not only in metabolism of endogenous substrates but also in drug metabolism compared to CYP3A4 and CYP3A5.

[Complication of reservoir hepatic artery infusion chemotherapy and additional treatments].

In 54 patients who underwent hepatic artery infusion chemotherapy for hepatic tumors at our hospital between January 1990 and December 1996, we investigated the complications of this therapy and the therapeutic techniques following its discontinuation. The arterial infusion was discontinued in 36 of the 54 patients; 13 due to death (mean survival period: 15.7 months), and 23 in whom occlusion of the reservoir, etc. made it impossible to use arterial infusion (mean period of use: 13.8 months), and the minimum duration of use was 41 days and maximum duration of use 992 days. The most common complication of the reservoir hepatic artery infusion was reservoir occlusion (14.8%). Another serious complication was reservoir deviation outside the blood vessel in two patients; deviation in to the gastric lumen in one case and intraperitoneal deviation in the other. Four hepatocellular carcinoma patients, in whom it became impossible to use the reservoir due to its occlusion, underwent re-hepatectomy. Three of them survived for more than two years following supplemental local therapy, including subarterial injection, TAE, PEIT, microwave tumor coagulation (MTC). Of four patients with colon cancer metastasizing to the liver, one could undergo re-hepatectomy, one received subarterial injection, and two have survived without relapse. Two of three patients with breast cancer underwent systemic chemotherapy and endocrine therapy successfully, while the third one underwent subarterial injection and TAE, and is still under observation. Hepatic artery infusion should sometimes be discontinued owing to complications caused by various factors. Even if it becomes impossible to use the reservoir, local therapeutic techniques, including re-hepatectomy, TAE, PEIT, MTC, etc., may be performed in some patients. These findings suggest that it is necessary to review the interdisciplinary treatment so as to be appropriate to the primary disease.

[Preoperative synchronized chemoradiation therapy for advanced esophageal cancer].

Synchronized chemoradiation, where 5-FU and CDDP were synchronously administered in the same schedule with radiation therapy, was applied for advanced esophageal cancer in neoadjuvant fashion. Ten patients with advanced esophageal cancer were enrolled for this regimen consisting of 5-FU; 500 mg/day x 5/w x 4, CDDP; 10 mg/day x 5/w x 4 and radiation; 2 Gy x 5/w x 4. Tumor regression was achieved in all cases. In terms of toxicity, bone marrow suppression of more than grade 3 was observed in 60% of the cases, though it was safely controlled. Radical operation was performed on 8 cases. Histological responses in the resected specimen were as following: grade 3, 3 cases; grade 2b, 4 cases; grade 2a, 1 case; and 6 node-negative cases were found. As a postoperative complication, minor leakage occurred in 62.5%, while no major complications such as pneumonia were encountered. This neoadjuvant synchronized chemoradiation improved curability of the salvage operation and permitted reduction surgery for high-risk patients.

[Preoperative chemoradiation therapy for lower rectal cancer].

To identify appropriate candidates with rectal cancer for preoperative chemoradiation therapy, the local recurrence rate and clinicopathological characteristics of 232 patients with rectal cancer undergoing curative resection in our department were investigated. The local recurrence rates were 3.8%, 10.8% and 16.5% in the Rs, Ra and Rb lesions, respectively. Regarding lower (Rb) rectal cancer, depth of lesion (> a1) and nodal metastasis consisted of high factors for local recurrence. Basing on these results, entry criteria for preoperative chemoradiation therapy were established, and concurrent chemoradiation therapy with fluorouracil and cisplatin was delivered preoperatively in 9 primary cases of locally advanced rectal cancer and 3 cases with local recurrence. A partial response was obtained in 7 of 12 cases with a response rate of 58%, size-reduction of the distant metastatic lesions was found in 2 cases, and clinical symptoms were improved in all cases. The histological responses of the 6 resected cases were Grade 2 in 2 cases and Grade 1b in 4 cases. The toxicities of this chemoradiation regimen were well tolerable. As a postoperative complication, infection of the perineal wound was most frequent. Preoperative chemoradiation therapy with the present regimen would be a useful adjuvant treatment for advanced lower rectal cancer.

[Long-term survival in two cases of multiple liver metastasis successfully treated with intraoperative ultrasound-guided microwave tumor coagulation (MTC)].

Since April 1990, multiple metastatic liver tumors have been treated with intraoperative ultrasound-guided microwave tumor coagulation (MTC) in combination with postoperative intraarterial chemotherapy. Twenty-four patients have been enrolled in this therapeutic modality and two of five patients treated in 1990 achieved long-term survival. In case 1, a 67-year-old woman was diagnosed as bearing gastric leiomyosarcoma with multiple liver metastasis. Total gastrectomy was performed, and six hepatic lesions were treated by MTC along with implantation of an intraarterial reservoir. Postoperative intraarterial chemotherapy was administered in a selective or subselective manner. Her survival time was 4 years and 6 months. In case 2, a 47-year-old man was diagnosed as having liver metastasis from descending colon cancer 1 year and 5 months after left hemicolectomy. When he was laparotomized for the treatment of adhesive ileus, three metastatic liver tumors were treated with MTC. Afterward, he underwent hepatic resection, intraarterial and intraportal chemotherapy. He survived for 5 years and 5 months after being diagnosed with liver metastasis. MTC is one of the useful modalities for the treatment of multiple liver metastasis.

[Cytochrome P-450 in human fetal liver. Properties of P-450 HFLa,a form of cytochrome P-450 in human fetal livers].

One of the major forms of cytochrome P-450, named P-450 HFLa, of human fetal livers was purified and characterized. The cytochrome P-450 preparation had an apparent molecular weight of 51,500 as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. N-Terminal amino acid sequence of P-450 HFLa was similar but not identical to that of P-450NF involved in nifedipine oxidation in adult human livers. P-450 HFLa catalyzed 16 alpha-hydroxylation of dehydroepiandrosterone 3-sulfate (DHEA-sulfate) in a reconstituted system. The concentration of P-450 HFLa in liver homogenates from human fetuses highly correlated with the activity of DHEA-sulfate 16 alpha-hydroxylase. Furthermore, anti-P-450 HFLa antibodies inhibited the 16 alpha-hydroxylation. P-450 HFLa was also found to catalyze the mutagenic activation of aflatoxin B1 (AFB1) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The antibodies to P-450 HFLa inhibited efficiently the mutagen-producing activities from AFB1 and IQ in human fetal livers. The nucleotide and the deduced amino acid sequences of lambda HFL33 containing the entire coding region for a form of cytochrome P-450 related to P-450 HFLa, were highly similar to but clearly distinct from those of NF25 and HLp complementary deoxyribonucleic acids. The oligonucleotide probes specific to the coding and 3'-noncoding region of lambda HFL 33 (oli-HFL and oli-HFL3', respectively) gave hybridizable bands with ribonucleic acid (RNA) from fetal but not adult livers. In contrast, an oligonucleotide probe specific to the coding region of NF 25 and HLp (oli-NF) gave hybridizable bands with RNA from only adult but not fetal livers.