Celiac vagotomy attenuates the ingestive responses to epinephrine and hypertonic saline but not insulin, 2-deoxy-D-glucose, or polyethylene glycol

The ingestive responses of rats given celiac vagotomy (C), combined celiac and hepatic vagotomy (CH), or low total vagotomy (removal of all tissue from around the esophagus, stomach and duodenum; LT) were compared with sham operated controls (S) in a series of regulatory challenges. The vagotomized groups responded normally to 2-deoxy-D-glucose (2DG; 125, 250, 500 mg/kg, IP), insulin (4, 8, 12 U/kg, IP), and polyethylene glycol (10 ml/kg: 30% w/v, SC), but displayed attenuated responses to epinephrine (40, 80, 120 micrograms/kg, IP) and hypertonic saline (10 ml/kg: 0.25, 0.5, 1.0 M, IP). These results can be interpreted as evidence that the celiac vagus carries a major component of hepatic afferent innervation. Additionally, when considered with other findings they suggest that whereas the anorectic activity of epinephrine is mostly confined to the liver, 2DG hyperphagia involves stimulation of a wider population of peripheral metabolic receptors.     

Synergistic effect of interleukin-2 and a vaccine of irradiated melanoma cells transfected to secrete staphylococcal enterotoxin A

We have previously reported that immunization of mice with melanoma cells transfected to secrete the superantigen, Staphylococcal enterotoxin A (SEA), increased the production of antibodies to the B700 melanoma antigen, stimulated the production of endogenous interleukin 2 (IL-2), activated the expression of CD4, CD8 and CD25 T cell markers and enhanced NK cell activity. Now we show that immunization of mice with a vaccine of irradiated sea-transfected melanoma cells coupled with IL-2 therapy was even more effective in inhibiting the growth of primary melanoma tumors and the development of lung metastases than was the irradiated melanoma cell vaccine alone or IL-2 alone. The morphological and immunological effectiveness of the therapy was dose-dependent on IL-2.     

Cyclooxygenase-2 expression in colorectal cancer liver metastases

Cyclooxygenase-2 (COX-2) is up-regulated in 85-90% of primary human colorectal cancers and is a putative target for the chemopreventative activity of non-steroidal anti-inflammatory drugs. However, COX-2 expression by human colorectal cancer liver metastases has been poorly characterized. We studied a consecutive series of 38 patients who underwent liver resection for metastatic disease, for whom long-term (up to 57 months), prospective follow-up data were available. Semi-quantitative immunohistochemistry for COX-2 was performed on 54 metastases from 35 patients, for whom adequate histological material was available. Diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastases (COX-2 score 1, n=25; score 2, n=29). There was no relationship between metastasis size or differentiation grade and the level of COX-2 protein expression. There was no difference in colorectal cancer-free or overall survival between patients with high (score 2) and low (score 1) COX-2 scores (Kaplan–Meier survival analysis and log rank test, both P=0.97). Multivariate Cox regression analysis identified age, incomplete resection and presence of extra-hepatic disease as independent predictors of disease-free and overall survival following surgery. COX-2 protein was also localized to a subset of stromal fibroblasts and mononuclear cells within metastases as well as hepatocytes from resection specimens. COX-2 protein was expressed by cancer cells in all human colorectal cancer liver metastases which were studied. Investigation of the effect of selective COX-2 inhibition on metastasis growth and metastasis cancer cell proliferation/apoptosis in vivo are warranted.     

Mouse Colon Carcinoma Cells Established for High Incidence of Experimental Hepatic Metastasis Exhibit Accelerated and Anchorage-Independent Growth

Highly metastatic variants of mouse colon 38 colon carcinoma cells were established by repeated selection in vivo for liver metastasis and designated as SL4 cells. The SL4 cells formed colonies in the liver of 100% of syngenic mice when injected intrasplenically, while the incidence of liver metastasis was 27% of mice injected with parental cells. The weight of livers, which is an indicator of experimental hepatic metastasis formation, was significantly higher after intrasplenic injection and subsequent splenoctomy with SL4 cells than colon 38 cells. The incidence of hepatic metastasis after intracecal injection of SL4 cells was significantly higher than that of colon 38 cells. The SL4 cells were tested in vitro for their properties. Differences were not detected in the motility and invasive behavior between colon 38 cells and SL4 cells. SL4 cells showed a higher proliferation rate than colon 38 cells under adherent conditions. SL4 cells maintained a capacity to proliferate under non-adherent conditions whereas parental cells did not. SL4 cells should be a useful tool to study the mechanism of hepatic metastasis of colon carcinoma cells and to develop methods to prevent hepatic metastasis.     

Hepatic reinnervation following orthotopic liver transplantation in man.

We have studied changes in the pattern of intrinsic hepatic innervation in sequential liver biopsies from 16 patients who underwent orthotopic liver transplantation. Seventy-one needle biopsies were used, including specimens obtained at the time of transplantation (time zero) and up to 4 years post-transplantation; five transplant hepatectomy tissue blocks removed 3-32 months after transplantation were also assessed. Paraffin sections were immunostained with anti-PGP 9.5 and anti-S-100 to identify nerve fibres. All 'time zero' biopsies contained portal nerves and all but two showed staining of parenchymal fibres. After 1 week, no subsequent biopsies contained parenchymal fibres. The disappearance of portal fibres was less rapid and showed greater variability between patients, but they had all disappeared by 6 weeks and there was no positive staining between 6 and 60 weeks. Thereafter, a minority of biopsies showed innervation of a few small portal tracts. Samples from the porta hepatis, hepatectomy specimens, and needle biopsies containing large tracts showed persistence of major nerve trunks at all stages. Abnormally large nerve bundles were seen in some of these areas. The pattern of nerve staining showed no obvious relationship to the intensity of rejection changes. Our results suggest that there is a limited, delayed capacity for regeneration of portal, but not parenchymal, fibres in the transplanted human liver. The physiological significance of this long-term parenchymal denervation in transplanted livers remains to be determined.     

Two Autopsy Cases of Primary Leiomyosarcoma of the Liver Superiority of Muscle-specific Actin Immunoreactivity in Diagnosis

Two autopsy cases of leiomyosarcoma of the liver in a 49-year old female and 63-year-old male are reported. Both of the liver tumors showed electron microscopically dense patches in the cytoplasm and intermediate junctions between the tumor cells, suggesting a smooth muscle cell origin, irrespective of their different histological features. The nature of both tumors was confirmed by positive immunoreactivity for muscle-specific actin in the tumor cells, whereas desmin immunoreactivity was labile in both cases, showing a higher diagnostic value of the former compared with the latter in these leiomyosarcomas. Both cases, showed extensive distant metastases in spite of an evident difference in their mitotic indices, indicating that this index is not reliable for judging the metastatic potential of these tumors. Acta Pathol Jpn 41: 461–465, 1991.     

大鼠再生肝对二乙基亚硝胺启动作用的敏感性

目的比较再生肝和正常肝对二乙基亚硝胺（ＤＥＮ）启动作用的敏感性。方法以２／３肝叶切除后８周末的大鼠为实验组,正常大鼠为对照组,作如下比较：肝重、常规组织学检查及３Ｈ－ＴｄＲ掺入试验;用修改的Ｓｏｌｔ－Ｆａｒｂｅｒ模型,通过对ＧＧＴ阳性癌前病灶的体视学测量,观察肝脏对ＤＥＮ的启动效应;在体内和体外（无血清原代培养肝细胞）经ＤＥＮ攻击后,以核酸原位缺口标记方法观察肝细胞ＤＮＡ的损伤程度。结果２／３肝叶切除后８周末的实验组肝脏的修复过程已完成,未见肝细胞继续增生的表现;经ＤＥＮ攻击后,实验组肝癌前病灶在数密度和体积密度上都显著高于对照组;无论在体内或体外接受ＤＥＮ攻击后,实验组肝细胞ＤＮＡ的损伤程度都显著大于对照组。结论即使再生过程已经完成,再生肝仍比正常肝具有较高的致癌敏感性,这与再生肝肝细胞在ＤＥＮ攻击后其ＤＮＡ损伤较重相关。     

Stromal reaction in cancer tissue: Pathophysiologic significance of the expression of matrix-degrading enzymes in relation to matrix turnover and immune/inflammatory reactions

Cancers are characterized by invasive growth and distant metastasis. Cancer cells not only destroy the pre-existing extracellular matrix, but cancer invasion per se usually induces new matrix formation by activation of stromal cells; that is, desmoplastic reaction. This process includes both matrix production and degradation; that Is, the remodeling process. The similarity between desmoplastic reactions in cancer stroma and the wound healing process has already been pointed out, and it has been well documented that matrix-degrading processes are actively involved In the wound healing process. A recent study revealed that most matrix-degrading enzymes, generally considered to be one of the main mechanisms of cancer invasion and metastasis, are originated from stromal cells. Based on these preconditions, the present review postulates that the abundant expression of matrix-degrading enzymes by fibroblasts, coupled with the abundant expression of type I procollagen, is involved in the matrix remodeling processes occurring in cancer stroma; that is, the mechanism similar to the wound healing process. Next, macrophages distributed along the invasive margin are known to express matrix-degrading enzymes/factors. Data from past studies of colon carcinoma indicate that the tissue expression of matrix metalloproteinase-9 and urokinase-type plas-mlnogen activator receptor Is inversely associated with simultaneous liver metastasis and infiltrating growth pattern. Previous clinicopathologic data have indicated that immune/Inflammatory cells are one of the factors for a favorable prognosis. This suggests that the expression of matrix-degrading enzymes/factors by these host cells may be involved in host immune/inflammatory reactions, and that the net function of these cells can be defensive towards the host. Data from past studies of colon carcinoma on the expression of the intercellular adhesion molecule-1 suggest that the interaction between macrophages, lymphocytes, and the phenotypes of venules distributed along the Invasive margin, further support the pro-inflammatory milieu there. Therefore, the matrix degradation process in cancer tissue is multifunctional: besides the Involvement in cancer invasion and metastasis, the matrix degradation process is also involved in the tissue remodeling process and in the immune/inflammatory reaction occurring in the stroma.     

Niemann-Pick disease

Summary The results of a complex analysis of liver tissue are presented (four biopsy and two autopsy samples) obtained from six patients with Niemann-Pick disease (NPD) with a gross deficiency of sphingomyelinase (SMase) accompanied by a typical increase in sphingomyelin (SM). There were five cases of NPD type A (four of them with an atypical, prolonged course) and one case of type B. By means of lipid histochemistry it was possible to demonstrate SM storage both in hepatocytes and in the reticuloendothelial system (RES) of the liver (Kupffer cells and portal macrophages) and to show in two siblings with NPD type A a so-far undescribed centrilobular storage pattern. Enzyme histochemistry revealed a secondary deficit of nonspecific esterase activity and acid -galactosidase in liver storage macrophages and varying degrees of suppression of hepatocytic enzyme activities as a reaction to lipid storage of sudden onset. Ultrastructurally, it was possible to demonstrate cholesterol in lysosomes by using digitonin fixation, the involvement of Ito cells in lipid storage, the aggregation of storage lysosomes with certain other organelles and their occasional connections with the endoplasmic reticulum. The problems of possible lipid extraction during processing were considered as a cause of pronounced lysosomal electron-lucidity and of the ultrastructural identification of the participating lipopigment. The significance of the findings is discussed in relation to the existing classification and, particularly, to the stored lipid dilemma of cases of NPD type C.     

The distribution of metastases in the liver

Summary Seventy-five livers with metastases were cut sagitally into 1 cm thick slices. A total number of 11,581 metastases sections was exactly mapped. There was an average of 154 metastases sections per liver. The average diameter of the metastases was 1 cm. 40% of the metastases reached to the hepatic surface, and 60% were invisible due to their deposition in the internal parenchyma. In 8% of the livers there were only superficial metastases (average 3.2 metastases), and in 12% were only deep metastases detected (average 2.6). The total number of superficial metastases increased with increasing diameter of the secondary tumors.An approximately homogeneous distribution of hepatic metastases within the liver parenchyma has been demonstrated.