Factors relating to coagulation, fibrinolysis and hepatic damage after liver resection.

A survey of the blood of twenty-two patients who had undergone hepatic resection was performed. Serum levels of alpha-2 plasmin inhibitor-plasmin complex initially decreased from 1.58 +/- 0.31 microgram/ml on the preoperative day (PREOP), to 0.92 +/- 0.14 mu/ml on the first postoperative day (POD 1), and then increased to 3.13 +/- 0.92 micrograms/ml on the seventh postoperative day (POD 7) (mean +/- SE)). Thrombin-anti-thrombin III complex (14.2 +/- 4.3 ng/ml on PREOP and 26.0 +/- 4.1 ng/ml on POD 7 (mean +/- SE)) and D-dimer (335 +/- 96 ng/ml on PREOP and 1859 +/- 258 ng/ml on POD 7 (mean +/- SE)) increased in the early postoperative stage. The level of 6-keto-prostaglandin F1 alpha increased after the operations (from 13.2 +/- 1.8 pg/ml on PREOP to 37.8 +/- 12.8 pg/ml on POD 7 (mean +/- SE)). The level of thromboxane B-2 decreased at first, and then gradually increased and returned to its preoperative level on POD 7 (144.7 +/- 43.8 pg/ml on PREOP, 57.6 +/- 27.5 pg/ml on POD 1 and 152.5 +/- 58.4 pg/ml on POD 7 (mean +/- SE)). Superoxide dismutase activity increased at first, and then gradually decreased, postoperatively (2.8 +/- 0.5 NU/ml on PREOP, 4.8 +/- 0.8 NU/ml on POD 1 and 2.6 +/- 0.3 NU/ml on POD 7 (mean +/- SE)). That is, biodefensive reactions which protect patients against the shift to disseminated intravascular coagulation (DIC) were inferred with by the increase in antiplatelet aggregation, despite the activation of coagulation and fibrinolytic mechanisms after hepatic resection.

Blood supply and drug delivery to primary and secondary human liver cancers studied with in vivo bromodeoxyuridine labeling.

BACKGROUND: Because bromodeoxyuridine (BrdU) is incorporated into DNA synthesizing (S-phase) cells, the blood supply of liver tumors can be traced by injecting BrdU into either the hepatic artery or portal vein. It also is possible to study the delivery of anti-cancer drugs acting during S-phase when they are injected by these routes. The blood supply of and drug delivery to liver tumors were examined using BrdU in patients with 19 metastatic liver cancers and 8 hepatocellular carcinomas. METHODS: At the time of hepatic resection, 200 mg of BrdU was injected by the various routes or 200 mg of BrdU suspended in 2 ml of a lipid contrast medium was injected into the hepatic artery by a reported method 2 weeks before hepatectomy. The liver tumors resected were stained immunohistochemically with an avidin-biotin-peroxidase complex method using anti-BrdU monoclonal antibody. RESULTS: BrdU injected into the hepatic artery or portal vein was incorporated into the metastatic liver tumor. After intraarterial infusion BrdU suspension, the delivery of BrdU was enhanced. The nuclei of hepatocellular carcinomas that received BrdU from the hepatic artery or portal vein incorporated BrdU. CONCLUSIONS: Metastatic liver cancers had both arterial and portal blood supplies. Hepatocellular carcinomas also had, not only an arterial, but also a portal blood supply. In both primary and secondary hepatic cancers, the delivery of anti-cancer agents acting during S-phase using the lipid contrast medium administration method was excellent.

[Clinical study of drug accumulation in gastric cancer after preoperative intra-arterial EA'P injection therapy].

In order to deliver a high concentration of anti-cancer drugs in tumor tissue, preoperative intra-arterial injection therapy using Etoposide (VP-16), Pirarubicin (THP-ADM) and Cisplatin (CDDP), was used for 22 patients with resectable advanced gastric cancer. The concentration of VP-16, Adriamycin (ADM) and platinum (Pt) were measured in cancer tissue, normal mucosa and lymphnodes without metastasis at the greater curvature, which were gathered operatively and in serum just before operation. Student's t test was performed with their data. The mean concentration of VP-16 was less than the detectable limit in all tissues and in serum. The mean concentration of ADM in cancer tissue was significantly higher than in normal gastric mucosa, in lymphnodes without metastasis, and in serum. The mean concentration of platinum in cancer tissue was higher than those in lymphnodes, normal mucosa, and serum, but no significant differences were noted among them. It was concluded that the intra-arterial injection of THP-ADM and CDDP was an effective method to maintain a high concentration of ADM and Pt in gastric cancer tissue. However, intra-arterial injection of VP-16 was not useful.

[Clinical study of the drug delivery in metastatic liver cancer using bromodeoxyuridine].

As the model of an anti-cancer agent acting at DNA synthesizing phase, BrdU was infused for metastatic liver cancers into the portal vein and/or the hepatic artery. After administration, the liver tumors were resected, and immunohistochemical staining was performed using anti-BrdU monoclonal antibody. Two of 6 portal group tumors were stained. All 4 arterial and 3 arterio-portal group tumors were stained. Therefore, it was proved that metastatic liver tumors had both arterial and portal blood supply. But areas to which BrdU was delivered were only peripheral, and the inmost area was 2 mm from the tumor surface. After the intra-arterial infusion of BrdU suspended in lipiodol, the delivery of BrdU was highly enhanced and 4 of 6 tumors were stained even to the deepest areas. However, one tumor of which the major part was necrotic and one tumor which produced mutin were not stained at all. It was interesting that after intra-arterial administration of BrdU suspended in lipiodol, BrdU was also found in the cytoplasm of normal liver cells.

[Clinical study of platinum accumulation in gastric cancer after preoperative intra-arterial injection of cisplatin].

In order to deliver a high concentration of CDDP in tumor tissue, we attempted to infuse CDDP intra-arterially for preoperative patients with resectable gastric cancer. Thirty-two patients (21 males and 11 females) were treated. The concentration of platinum was measured in cancer tissue, normal mucosa, lymph nodes without metastasis at the greater curvature. These were gathered operatively and in serum just before operation. The serum concentration of free-CDDP was also measured. Student's-t test was performed with the data. After intra-arterial injection of 60 mg CDDP, the mean concentration of platinum in cancer tissue was 1.11 +/- 0.45 microgram/g and after intravenous injection of 40 mg CDDP that was 0.30 +/- 0.11 microgram/g. After intra-arterial injection of 40 mg CDDP, the mean concentration of platinum in cancer tissue was 0.64 +/- 0.12 microgram/g, which was significantly higher than in normal gastric mucosa (0.27 +/- 0.06 micrograms/g) or serum (0.37 +/- 0.10 micrograms/ml) (p less than 0.025). The mean concentration of platinum in cancer tissue was higher than in the lymph nodes (0.45 +/- 0.10 micrograms/g), but there was no significant difference. In sera the concentrations of free-CDDP were all under the detectable limit. It was concluded that intra-arterial injection therapy of CDDP was an effective method to maintain a high concentration of CDDP in gastric cancer tissue.

[Experimental studies on drug uptake by metastatic liver tumor after intra-arterial, intraportal and intravenous administration of BrdU].

To compare the pharmacological advantage of intra-arterial, intraportal and intravenous administration of anticancer drug for metastatic liver tumor, BrdU was administered to rabbits with metastatic liver tumor of VX2 from various routes and taken up into the nuclei of tumor cells. Both one-shot injection and continuous infusion (30 min) of BrdU was performed from celiac artery, portal vein or peripheral vein. In some rabbits, the portal vein or the celiac artery was ligated to form one blood supply to the liver. After the administration of BrdU, the liver was removed. The samples were stained by the immunohistochemical procedure using monoclonal antibody to BrdU. The result was that the drug uptake of small metastatic liver tumor by both arterial and portal one-shot injection was good, and the uptake following intra-arterial injection of BrdU was superior to its intraportal injection in large metastatic tumor. However, only peripheral cells of large tumor took up BrdU after intra-arterial injection and inner cells of large tumor did not take up BrdU after any continuous infusions. The intraportal and intravenous administration of BrdU without ligation of celiac artery had the same effect as its intra-arterial administration.