The role of angiogenesis in endocrine liver metastases: an experimental study

Liver metastases are a major adverse event during the evolution of digestive endocrine tumors. However, little is known about their natural history and the determinants of their growth. In particular, whereas liver endocrine metastases, like their primary counterparts, are hypervascular, the role of tumor-associated angiogenesis has been little explored. We therefore designed an experimental model to study the intrahepatic growth of tumor endocrine cells; murine enteroendocrine STC-1 cells were injected into the spleen of nude mice to obtain their hepatic dissemination through the portal vein. Three stages of intrahepatic tumor growth were identified. Engraftment stage, until day 4 after intrasplenic injection of STC-1 cells, was avascular. Early growth, until day 17, resulted in small, infralobular nodules. Late growth, after day 17, was characterized by the development of large nodules associated with peritumoral vessels and containing abnormal intratumoral vessels. To test the effects of potentially anti-angiogenic agents on tumor growth, we then used STC-1 cells stably transfected with the endostatin-coding sequence. Intrahepatic tumor volume showed no significant change at days 4 and 8, but a dramatic decrease at day 28 (9.7 +/- 1.7% of liver tissue versus 25.2 +/- 2.4% in controls), because of a markedly lower number of large nodules (11 +/- 1.8% versus 42 +/- 5.8%) likely to result from an increased apoptotic index (39.4 +/- 5.6% versus 18.3 +/- 3.4). Our results suggest that active angiogenesis is not necessary for the engraftment and early growth of endocrine cells metastatic to the liver but is required at a later stage of progression.     

Surgical chemotherapy against lymph node metastases: an experimental study

Accompanying surgical resection of the primary tumor is removal of its drainage lymph nodes. However, all of the minute regional lymph nodes cannot be identified and some may be left behind. If a certain anticancer agent in the form of an emulsion is injected topically into the lymph nodes, it may suppress the lymphatic metastases. Domestic rabbits were used as experimental animals, because transplantable VX2 tumors are available. The vermiform appendix was selected as the transplantation site because of its rich supply of lymph follicles, simulating lymph nodes histologically, and because the path of lymph drainage is very simple. The drainage lymph node, which is located at the root of the appendix, was selected for study. The rate of transfer of bleomycin into lymph nodes and of its sustained release from the nodes was extremely enhanced by the use of a sphere-in-oil-type emulsion--more than two times higher than in the use of a W/O emulsion. Although prolongation of survival time did not take place in animals receiving the bleomycin solution topically or intravenously, five of the seven rabbits receiving the local administration of bleomycin as a sphere-in-oil or a water-in-oil emulsion, between which differences were not found in tumor effects, survived with complete reduction of the lymph node metastases.     

Treatment of experimental liver metastases with a noncontact neodymium: YAG laser.

The extent of tumor and liver damage after treatment with the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was investigated in a rat tumor model. Colon carcinoma CC531 was implanted in the liver and treated with 60 J (14 tumors), 120 J (15 tumors), or 180 J (12 tumors) at a power setting of 20 W. To assess the effects upon the tissues three animals were sacrificed immediately after treatment and 1, 2, 4, and 8 days later. Sections from the tumor sites were evaluated by light microscopy and the maximal depth and width of different zones of tissue damage were measured. Laser effects could be determined most accurately on Days 1 and 2 after treatment. Multiple linear regression analysis of the data indicated a linear relationship between laser energy and depth of tumor damage (P less than 0.01). The results of this study show the potential of the Nd:YAG laser to produce tumor coagulation necrosis with minimal liver necrosis.     

Blood supply of metastatic liver tumors: an experimental study

Based on experiments with 18 female mice with induced secondary liver tumors, the entire liver metastasis blood circulation including characterization of efferent drainage system is described. The center of liver metastases is supplied from capillaries originated from branches of the hepatic artery. From the capillaries, blood is led to the superficial venous network of the metastases and further to intrahepatic veins. The portal vein system is essential for small metastases nutrition. The surface of large metastases is also nourished by the portal vein. Based on these findings, it is suggested that, in human surgery, the catheter for locoregional chemotherapy for liver tumors should be optimally implanted into both the hepatic artery and the portal vein at the same time. Thus, anticancer treatment can reach the whole tumor mass including its periphery, ie, its growth zone.     

Radio-frequency tissue ablation in liver trauma: an experimental study

The liver is the most frequently injured intra-abdominal organ. Radio-frequency tissue ablation (RFA) with cooled tip electrodes is here experimentally used for the treatment of liver trauma. A grade III and a grade III to IV trauma each were produced in the livers of 10 domestic pigs. RFA was applied around the sites of injury until hemostasis was achieved. The animals were sacrificed at 0, 3, 7, 14, and 21 days and examined. The livers were subjected to histologic and radiologic examination. Two similar traumas were created in the livers of two more animals and were left surgically untreated as a control group. The two untreated animals died immediately postoperatively, proving the severity of the injuries. Hemostasis was achieved in all treated animals. Mortality and morbidity were zero. No blood, pus, bile, or other fluid was found in the abdomen at sacrifice. A three-zone pattern of lesion was recognized around the electrode placement at histology. RFA is an efficient and safe hemostatic method for grade III and grade III to IV hepatic trauma. Further studies are required for its use in humans.     

One liver for two: an experimental study in primates

Abstract. The need for liver grafts is critical in countries where brain death is not accepted as a legal criterion for organ retrieval. This experimental study was conducted with nonhuman primates in order to evaluate the feasibility of liver transplantation using a living donor. An original technique was employed to remove the left part of the liver from the donor: transection of the parenchyma was done while the blood flow was kept to the left part of the liver. In the recipients, the graft was placed heterotopically. No blood transfusions were administered to donors or recipients. In spite of a few failures, due to consequences of intraoperative bleeding, several donor operations using this original technique were successful, in the immediate postoperative period as well as several months later. Among the recipients, the large number of early failures suggests that the heterotopic position is probably not the appropriate one and that orthotopic transplantation should be preferred.     

One liver for two: an experimental study in primates

The need for liver grafts is critical in countries where brain death is not accepted as a legal criterion for organ retrieval. This experimental study was conducted with nonhuman primates in order to evaluate the feasibility of liver transplantation using a living donor. An original technique was employed to remove the left part of the liver from the donor: transection of the parenchyma was done while the blood flow was kept to the left part of the liver. In the recipients, the graft was placed heterotopically. No blood transfusions were administered to donors or recipients. In spite of a few failures, due to consequences of intraoperative bleeding, several donor operations using this original technique were successful, in the immediate postoperative period as well as several months later. Among the recipients, the large number of early failures suggests that the heterotopic position is probably not the appropriate one and that orthotopic transplantation should be preferred.     

Internal bioartificial liver with xenogeneic hepatocytes prevents death from acute liver failure: an experimental study.

OBJECTIVE: To demonstrate that a bioartificial liver, using allogeneic or xenogeneic hepatocytes protected from rejection by a semipermeable membrane, could prevent death from acute liver failure. SUMMARY BACKGROUND DATA: An implantable bioartificial liver using isolated hepatocytes could be an alternative to orthotopic liver transplantation to treat patients with acute liver failure. It could serve either as a bridge until liver transplantation or as the main treatment until recovery of the native liver. However, allogeneic or xenogeneic hepatocytes that could be used in clinical applications are spontaneously rejected. METHODS: Acute liver failure was induced in rats by 95% liver resection. Twenty-five million hepatocytes harvested in rats (allogeneic) or guinea pigs (xenogeneic) were encapsulated in a semipermeable membrane to protect them from rejection. The hollow fibers containing hepatocytes were transplanted into the peritoneum of recipient rats. Survival rates were compared between rats transplanted or not with hepatocytes. RESULTS: In groups not transplanted with viable hepatocytes, 73% to 93% of rats died after 95% liver resection. The mortality rate was reduced to 39% in rats transplanted with allogeneic hepatocytes and 36% in rats transplanted with xenogeneic hepatocytes. The bioartificial liver could be removed 1 month after transplantation, when regeneration of the native liver was complete. Allogeneic and xenogeneic hepatocytes remained viable. CONCLUSIONS: The implantable bioartificial liver was able to prevent death in this model of acute liver failure. This could be an important step toward clinical application of the method.     

Fulminant liver failure: clinical and experimental study.

Clinical experience of some newer methods of hepatic support is described. The results are unpredictable and far from satisfactory. The need for an animal model in which potential therapeutic methods can be studied is emphasized. Such a model based on carefully imposed ischaemic insult to the liver in the absence of portacaval shunting is described. It is suggested that bacterial presence in the bowel together with a depression of the liver reticuloendothelial function plays an important part in the early and rapid mortality of acute liver failure. Temporary auxiliary liver transplantation using an allograft or a closely related primate heterograft seem to be the 2 best available methods of hepatic support for potentially reversible acute liver failure.     

Norepinephrine in small-for-size liver grafts: an experimental study in pigs

BACKGROUND: Norepinephrine plasma levels may play a role in small-for-size grafts dysfunction at the early posttransplant period. MATERIALS AND METHODS: The 18 pigs used as recipients were assigned to group 1 (n = 6), group 2 (n = 6), and group 3 (n = 6) and given grafts with graft-to-recipient volume ratios of 1:1, 2:3, and 1:3, respectively. Blood serum norepinephrine was measured by high-performance liquid chromatography with electrochemical detection at the following time points: pre-anhepatic period (baseline); anhepatic period; and 30, 60, 180, and 360 min after reperfusion. Graft arterial and portal vein flows were obtained 30, 60, 180, and 360 min after reperfusion by the aid of an ultrasonic flowmeter. Aspartate transferase (AST) and international normalized ratio (INR) were measured before the procedure (baseline), and at 180 and 360 min after reperfusion. RESULTS: Anhepatic phase was characterized by a significant increase (6- to 8-fold) of norepinephrine in all groups (P < 0.05). In groups 1 and 2 plasma norepinephrine returned to normal values 30 min after reperfusion. In group 3, plasma norepinephrine remained significantly increased at every time point of the study compared to groups 1 and 2 (P < 0.001). Hepatic artery and portal vein flows in group 3 were significantly (P < 0.05) reduced and increased, respectively, compared to groups 1 and 2 at all times measured. Liver function tests (AST and INR) 360 min after reperfusion were significantly higher in group 3 compared to groups 1 and 2. CONCLUSIONS: Norepinephrine levels are increased in very small-for-size grafts and this increase may be associated with early graft dysfunction.     

The blood supply of experimental liver metastases: V. Increased tumor perfusion with epinephrine

The effects of epinephrine on the vascular perfusion of solitary Walker tumors implanted in the liver were studied in Sprague-Dawley rats. Colored silicone rubber (Microfil) solutions were injected into the arterial and portal circulations in each animal, and specimens were studied under a stereomicroscope. Internal vascular volume was calculated on the basis of the interference of light passing through the central portions of the tumors by Microfil-filled vessels. Intraarterial epinephrine, in doses of 100 or 10 μg, markedly increased vascular perfusion in the encircling plexus and the internal tumor circulation compared with control animals. Internal vascular volume was significantly increased from 9.4 percent in controls to 22.5 percent in epinephrine-treated animals. Increased perfusion was also seen when epinephrine was administered through the portal system, and in larger tumors after intraarterial administration. Internal tumor vessels were capillary-like in appearance.     

Intravitreous silicone balloon: an experimental study.

A specially designed silicone balloon, expanded in vivo with normal saline, was tested for possible use as a retinal tamponade in desperate cases of rhegmatogenous retinal detachment. In six pigmented rabbits there were extensive postoperative complications, but in eight owl monkeys results were noticeably better. When the seam of the balloon was in contact with the retina there were adverse effects; seamless areas of the balloon did not appear to disturb the retina. Histopathologic studies indicated that excessive expansion of the balloon can cause significant damage, but that carefully controlled expansion can probably minimize complications. The presence of the balloon appears to alter electroretinographic response, but without necessarily causing histopathologic changes. Balloons of this type have been used in treatment of a small number of otherwise inoperable cases of retinal detachment with promising results.