Influence of continuous interleukin-2 administration via the portal vein on liver regeneration following partial hepatectomy in rats.

We have reported the efficacy of intraarterial-combined immunochemotherapy including interleukin-2 (IL-2) for unresectable hepatocellular carcinoma (HCC). To further test this therapy for prevention of intrahepatic recurrence after hepatectomy, the influence of IL-2 on liver regeneration was examined using mitotic index (MI) and the bromodeoxyuridine (BrdU) labeling index (LI) in 70% hepatectomized Donryu rats. In addition, gap junction appearance, which may change during liver regeneration, was analyzed using a monoclonal antibody (HAM8). Serum albumin, alanine transaminase, and total bilirubin (TB) levels were also evaluated. IL-2 (45,000 Japanese reference units [JRU]/d) or saline was administered continuously via the portal vein immediately after hepatectomy using an infusion pump. We also examined the influence of IL-2 on liver regeneration after hepatectomy with splenectomy. No difference in the weight of the liver, serum albumin, alanine transaminase, or TB was observed in any groups at 1, 2, or 4 days after hepatectomy. Neither IL-2 nor splenectomy influenced MI and BrdU LI at all three points. Gap junctions began to disappear after hepatectomy and reached a minimum on day 2 in all groups. Four days after hepatectomy, the density of the reappearing gap junctions was markedly lower in groups treated with IL-2 than in those receiving saline with or without splenectomy. However, the density returned to close to preoperative levels 6 days after hepatectomy in all groups. Continuous portal infusion of IL-2 transiently disturbed gap junction reappearance during liver regeneration. However, no other parameters of liver regeneration or liver functions differed. These results suggest that the liver regeneration after partial hepatectomy may be suppressed by the administration of IL-2, even though the suppression may not be harmful for overall recovery of the resected liver. However, it seems that hepatic IL-2 administration can be performed without serious complications after hepatectomy.

In vitro and in vivo analysis of human leukocyte binding by the antitumor polysaccharide, lentinan.

Lentinan (LNT), a (1-->3)-beta-D-glucan with (1--6)-beta-D-glucopyranoside branches, has marked antitumor effects in syngeneic and autochtonous hosts. Clinically, LNT has proved effective with chemotherapeutic agents in patients with recurrent gastric and colorectal cancer. However, the mechanism that triggers subsequent immunologic reactions remains obscure. We hypothesized that LNT must first bind to the host cells. Accordingly, we analyzed LNT binding to host cells in healthy volunteers after incubating their cells under a variety of conditions as well as intravenously injecting LNT then subjecting them to flow cytometry and immunofluorescent staining using monoclonal antibody (anti-LNT mAb). LNT bound to monocytes and neutrophils, but not to lymphocytes in vitro. The most avid LNT binding was to monocytes. The percentage of LNT-bound monocytes after 60 min incubation at 4 degrees C was greater than that at 37 degrees C. The binding of LNT to monocytes was inhibited slightly by anti-iC3b receptor (anti-CR3) mAb, strongly by anti-C3b receptor (anti-CR1) mAb, and completely by anti-CR1 and anti-CR3 mAb together. The percentages of LNT-binding monocytes in the peripheral blood increased significantly 3 and 4 after 2 mg LNT-injection and returned to low levels 5 h later. However, no increase in LNT-binding neutrophils and lymphocytes was observed. We concluded that binding of LNT to human monocytes may initiate the influence of this compound on the immune system and differ between individuals. Its binding site may be similar to the C3b receptor.

[Clinical effects and immunological analysis of intraabdominal and intrapleural injection of lentinan for malignant ascites and pleural effusion of gastric carcinoma].

Twenty-one patients with malignant peritoneal or pleural effusions of gastric carcinomas were treated with intracavitary injection of lentinan (LNT). LNT was injected at a dosage of 4 mg/week for 4 weeks. In total, fifteen (71%) of twenty-one patients demonstrated clinical responses. Toxicity caused a high fever in only one case. LAK and ATK activities induced from peritoneal exudate cells (PEC) after culture with autologous tumor and interleukin-2 were examined before and after LNT injection. ATK activity was augmented, but LAK activity was reduced after LNT injection. These results indicate that intracavitary injection of LNT is a useful treatment for malignant effusions, and that LNT augments the induction of cytotoxic T-lymphocytes.

[A case of multiple liver metastasis from ileac carcinoid effectively treated with continuous intraarterial infusion of somatostatin analog].

We report a case of multiple liver metastasis from ileac carcinoid treated with continuous intraarterial infusion of somatostatin analog. A 65-year-old man who complained of chest pain was admitted to Yamaguchi University Hospital School of Medicine for further examination of cardiac angina. Liver tumors, which were detected during ECHO cardiogram examination, were diagnosed as metastasis from carcinoid by percutaneous transhepatic liver biopsy. Primary tumor was found at the ileum by colonofiberscopy. We performed ileo-cecal resection and catheterization from the gastroduodenal artery for intraarterial chemotherapy under laparotomy. After the operation, the patient was treated with continuous intraarterial infusion of somatostatin analog (100 micrograms/day, 5 days/week for 16 weeks). The tumor in segment 6 (S6) disappeared, but the tumor in S2 enlarged after the therapy. Hepatic angiography confirming the drug distribution demonstrated the occlusion of the left hepatic artery. This drug was thus distributed to the tumor in S6 but not in S2. These results suggest that somatostatin analog may have a direct anti-tumor effect. Furthermore, no side effect was observed. Thus, intraarterial infusion of somatostatin analog may be a useful therapy for liver metastasis from carcinoid.

Depression of cytotoxicity of nonparenchymal cells in the liver after surgery.

BACKGROUND: The nonparenchymal cells (NPCs) of the liver have a strong cytotoxic activity. Our hypothesis is that their activity, which prevents metastases to the liver, may be impaired after operation. METHODS: First, Sprague-Dawley rats underwent either a sham operation consisting of only a laparotomy (group L, n = 10), a laparotomy and resection of a portion of the small intestine (group R, n = 10) or no operation (group C, n = 10). After 2 days liver NPCs were isolated and divided into two fractions, large and small NPCs. The cytotoxicity of the liver NPCs and of the circulating blood mononuclear cells (BMC) was assessed. Second, we measured the growth of tumor metastases 14 days after the inoculation of a cell line (MRMT-1) into the portal vein of rats undergoing similar surgical stress (group Rm, n = 10 and group Lm, n = 10). RESULTS: The natural killer cell activity (anti-YAC-1) of large NPCs was 38% in group R, which was significantly less (p < 0.002) than that in groups L (72%) and C (83%). Small NPCs showed reduced natural killer activity in groups R and L (26% and 35%, respectively) compared with that in group C (70%) (p < 0.02). The natural killer cell activity of BMCs was similar in each group, and the lymphokine-activated killer cell activity (by anti-EL4) did not change in either the NPCs or BMCs. In the second experiment the area of the tumors occupied in the liver in the group Rm rats was significantly greater compared with that in the group Lm rats (p < 0.01). CONCLUSIONS: Surgical stress depressed the cytotoxic activity of liver NPCs and enhanced the growth of metastatic liver tumors. This suggests the possibility that perioperative immunotherapy might be clinically useful in the future to prevent liver metastases after gastrointestinal surgery.

[Augmentation of cytotoxicity of nonparenchymal cell of the liver after continuous IL-2 administration via the portal vein].

In this study, we discussed the influence of recombinant interleukin-2 (rIL-2) on nonparenchymal cell of the liver. Donryu rats (8-10 weeks, male) were continuously administered rIL-2 (IL-2 group) or saline (control group) for 6 days via the portal vein. On day 0 or 7 after administration, rats were sacrificed to obtain the blood and liver. Blood mononuclear cell (BMC) and nonparenchymal cell (NPC) of the liver were collected, and their cytotoxicity (NK activity and LAK activity) was measured by 51Cr release-assay. NK activity and LAK activity of BMC in IL-2 group were increased on day 0 and day 7 compared to those in the control group. NK activity and LAK activity of NPC in IL-2 group were augmented on day 0, and NK activity in IL-2 group was still high on day 7. These results suggest that preoperative IL-2 administration may be effective for prevention of formation and/or proliferation of liver metastasis, that are provoked by surgical intervention in cancer of the digestive organs.

The surgical management of synchronous hepatocellular carcinoma and thoracic esophageal carcinoma.

A 73-year-old man was hospitalized with pathologically documented hepatocellular carcinoma and cirrhosis, and a 5.0-cm tumor located in the left lobe was resected by a left lateral segmentectomy. At the same time, metastatic squamous cell carcinoma was identified by frozen section in a perigastric lymph node in the lesser omentum. Intraoperative endoscopy revealed a 1.0-cm erosive lesion in the thoracic esophagus that was subsequently found to be primary squamous cell carcinoma. Seven weeks later, a transthoracic subtotal esophagectomy with substernal, cervical esophagogastrostomy was performed. Twenty-two months after these resections there has been no recurrence of either the hepatocellular or esophageal carcinomas.