Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma

Background/Aims: Vascular endothelial growth factor‐C (VEGF‐C) is thought to be an important factor in tumor angiogenesis/lymphangiogenesis, but its role in hepatocellular carcinoma (HCC) has not yet been fully investigated. Methods: We immunohistochemically examined VEGF‐C expression in surgically resected tissues of 90 HCC. Results: In the 78 HCC with a single histological grade, VEGF‐C expression was significantly stronger in poorly differentiated HCC than in well‐ (P = 0.003) or moderately differentiated HCC (P = 0.0002). A ‘nodule‐in‐nodule’ case presented VEGF‐A expression in the well‐differentiated component and VEGF‐C expression in the moderately–poorly differentiated component. According to nodular diameter, VEGF‐C expression was significantly higher in nodules of 3.0 cm or larger (P = 0.0263). Extrahepatic metastases seen in seven cases expressed VEGF‐C. In 20 of the 28 cases who were able to be followed up, the frequency of intrahepatic recurrence tended to be higher and extrahepatic metastasis was significantly higher in the cases who had VEGF‐C expression in the tumor casts of the intrahepatic portal/hepatic vein branches than other cases without the expression (P = 0.0139). Disease‐free survival time tended to be shorter in cases with VEGF‐C expression in tumor casts of the portal/hepatic vein than in those without VEGF‐C expression (P = 0.053; log–rank test). Conclusions: VEGF‐C expression is related to the progression of HCC, and VEGF‐C expression in tumor casts of the intrahepatic portal/hepatic vein is considered to be a factor indicating recurrence/metastasis sites.     

Effect of varicella zoster virus antigen-antibody complexes on hydrogen peroxide generation by human polymorphonuclear leukocytes

Hydrogen peroxide (H₂O₂) generation by human polymorphonuclear leukocytes (PMN) incubated with varicella zoster virus (VZV) antigen was studied by cytofluorography. Hydrogen peroxide generation was detected in the presence of VZV-seropositive sera. When seropositive sera were heat-inactivated, H₂O₂ generation was reduced. When PMN were pre-incubated with Leu-1 1b, a monoclonal antibody to the Fc receptor on PMN, H₂O₂ generation was also reduced. These results suggest that VZV antigen-antibody-complement complexes induce H₂O₂ generation by PMN after these complexes attach to Fc receptors on PMN.     

Serum lipoprotein(a) in healthy Japanese children 5 years of age

Serum lipoprotein(a) [Lp(a)] concentrations were investigated in 155 Japanese children aged 5 years. The frequency distribution of Lp(a) concentrations was highly skewed and ranged from 1 to 109 mg/dL. The mean and median values of Lp(a) were 16.5 mg/dL (s.d. 17.3 mg/dL) and 12 mg/dL. The incidence of Lp(a) concentrations ≥30 mg/dL was significantly high in children with total cholesterol ≥3200 mg/dL, not including the case of familial hypercholesterolaemia. Log Lp(a) values showed an inverse correlation with bodyweight and body mass index. No significant differences in Lp(a) levels could be seen between the groups according to the presence or absence of coronary heart disease and cerebral vascular accident in family histories. The results suggest that Lp(a) in Japanese children aged 5 years was essentially the same as that in adults. Further study may be needed to disclose the factors that influence Lp(a) concentration in childhood.     

Update on Cutting Balloon Angioplasty

Cutting balloon (CB) is a unique balloon catheter with 3 or 4 metal blades on its surface making controlled endovascular surgical incisions that show promise of causing less vessel wall injury and less intimai proliferation. Multicenter randomized trials have revealed that CB angioplasty with multiple inflations achieved better lumen enlargement than single inflation and reduced coronary dissection more than plain old balloon angioplasty (POBA). Follow-up results showed CB angioplasty had a smaller late loss and loss index, resulting in lessened restenosis and target lesion revascularization rates. The main indication of CB angioplasty is basically a noncalcified lesion with concentric plaque; however, it could be applied effectively to some lesions unsuitable for POBA including in-stent restenosis, small vessel, long diffuse lesion, or ostial lesion. Additional evaluation would be necessary to determine the role of CB angioplasty in the stent era.     

Ubenimex (bestatin) inhibits invasion and matrilysin activation of human uterine cervical adenocarcinoma OMC-4 cells

The purpose of the study was to investigate the effect of the aminopeptidase inhibitor ubenimex (bestatin) on the invasive activity of cultured human uterine cervical adenocarcinoma cells. The enzymatic degradation of the extracellular matrix by tumor cells during the invasive process was also examined. The invasion of cervical adenocarcinoma OMC-4 cells into reconstituted basement membrane (Matrigel) was inhi-bited by the presence of bestatin in a concentration-dependent manner. However, bestatin did not have any effect on tumor cell proliferation and migration. The casein zymography of tumor conditioned medium showed that the treatment of tumor cells with bestatin resulted in the drastic reduction of the 19 kDa-enzyme level (matrilysin, active form) and the slight reduction of the 28 kDa-enzyme level (matrilysin, latent form) in OMC-4 cells. The effect of bestatin on matrilysin secreted by OMC-4 cells were also confirmed by immunoblot analysis, and the disappearance of matrilysin in the active form was found. Bestatin inhibited hydrolysing activities towards substrates of aminopeptidases in tumor cells, but did not directly inhibit matrilysin. These results suggest that bestatin may inhibit the invasion of uterine cervical adenocarcinoma OMC-4 cells possibly through the inhibitory mechanisms for production and activation of matrilysin modulated by tumor aminopeptidases.     

Mechanism for Drug Absorption from Rat-liver Surface Membrane: Effect of Dose and Transport Inhibitors on the Pharmacokinetics of Phenol Red

We examined the effect of dose and transport inhibitors on the pharmacokinetics of phenol red as a model drug after application to rat liver surface in-vivo, employing a cylindrical glass cell (i.d. 9 mm, area 0·64 cm²), to elucidate the mechanism for drug absorption from liver surface membrane. Absorption ratios of phenol red in 6 h were determined to be 91·1, 91·8 and 89·9% at a dose of 0·3, 1 and 3 mg, respectively. The AUC value for plasma concentration profile of phenol red was proportional to the dose. It is thus suggested that the absorption process of phenol red from rat liver surface does not approach saturability. The time course of the remaining amount of phenol red in the glass cell obeyed first-order kinetics at a dose of 0·3 mg, and its rate constant K_a was calculated to be 0·0069 min^?1. Moreover, no significant difference was seen in the K_a value within the dose range of 0·3-3 mg, which was estimated by curve fitting of the plasma concentration profile of phenol red after application to rat liver surface in the two-compartment model with first-order absorption. 2,4-Dinitrophenol (0·3 mg) and probenecid (0·5 and 1 mg), inhibitors of metabolic energy and anion transport, respectively, had no significant effect on the pharmacokinetics of phenol red after application to rat liver surface. These data demonstrate that a specific transport mechanism such as active transport is not involved in phenol red absorption from rat liver surface membrane.     

Herbal medicine 'Sho-saiko-to' induces tumour necrosis factor-α and granulocyte colony-stimulating factor in vitro in peripheral blood mononuclear cells of patients with hepatocellular carcinoma

‘Sho-saiko-to’ (TJ-9) is a Japanese herbal medicine that is commonly administered to patients with chronic viral liver disease in order to improve their overall physical condition and to prevent the development of liver cancer. The present in vitro study demonstrated that, by adding TJ-9 to cell cultures, there were dose-dependent increases in production levels of tumour necrosis factor-α (TNF-α) and granulocyte colony-stimulating factor (G-CSF) in peripheral mononuclear cells of patients with hepatocellular carcinoma accompanied by liver cirrhosis. Increases in the production of TNF-α and G-CSF in control cell cultures exposed to different herbal medicines were low, and this indicates the specificity of the responce increases in production of these cytokines to TJ-9. TNF-α and G-CSF are known to play important roles in the biological defence mechanism. Administration of TJ-9 may, therefore, be beneficial for patients afflicted with intractable liver diseases because it could mildly induce these cytokines.     

Myocardium Extending from the Left Atrium onto the Pulmonary Veins: A Comparison Between Subjects with and Without Atrial Fibrillation

Rapid discharges from the myocardium extendingfrom the left atrium onto the pulmonary vein (PV) have been shown to initiate AF, and AF may be eradicated by the catheter ablation within the PV. However, if there is any difference in the distribution patterns of the myocardial sleeve onto the PV between the subjects with and without AF is to be determined. Twenty-one autopsied hearts were examined. Eleven patients previously had AF before death and another 10 patients had normal sinus rhythm as confirmed from the medical records including ECGs before death. After exposing the heart, the distance to the peripheral end of the myocardium was measured from the PV-atrial junction in each PV. Then, the PVs were sectioned and stained and the distal end of myocardium and the distribution pattern were studied. The anteroposterior diameter of the left atrium was also measured. In 74 of 84 PVs, the myocardium extended beyond the PV-atrial junction. The myocardium was localized surrounding the vascular smooth muscle layerforming a myocardial sleeve. The peripheral end of the myocardial sleeve was irregular and the maximal and minimal distances were measured in each PV. The myocardium extended most distally in the superior PVs compared to the inferior ones and the maximal distance to the peripheral end was similar between the AF and non-AF subjects (8.4 +/- 2.8 vs 8.7 +/- 4.4 mm for the left superior and 6.5 +/- 3.5 vs 5.1 +/- 3.9 mm for the right superior PV, respectively). A significant difference was found in the maximal distance in the inferior PVs: 7.3 +/- 4.6 vs 3.3 +/- 2.8 mm for the left (P < 0.05) and 5.7 +/- 2.4 vs 1.7 +/- 1.9 mm for the right inferior PV (P < 0.001) in the subjects with and without AF, respectively. The diameter of left atrium was slightly dilated in AF patients but insignificantly (4.1 +/- 0.1 vs 3.6 +/- 0.1 cm, P > 0.07). The myocytes on the PV were less uniform and surrounded by more fibrosis in patients with AF compared to those without AF. In conclusion, the myocardium extended beyond the atrium-vein junction onto the PVs. The distribution patterns of the myocardium was almost similar between subjects with and without AF, but the histology suggested variable myocytes in size and fibrosis in patients with AF.     

Biological and Clinical Implication of Neuron-Specific Enolase and Creatine Kinase BB in Small Cell Lung Cancer

The specificity of neuron-specific enolase (NSE) and creatinekinase BB (CK-BB) for small cell lung cancer (SCLC) was determinedby biological and immunohistochemical procedures in lung cancertissues and cultured cell lines. Average values of extractableNSE and CK-BB of SCLC tissues were significantly higher thanthose of non-SCLC and normal lung tissues. A large amount ofNSE and CK-BB was demonstrated in SCLC cell lines. Immunohistochemical examination showed positive staining forNSE and CK-BB in most cases of SCLC and in a few cases of non-SCLC.From these data NSE and CK-BB should be considered to be highlyspecific for SCLC. In a clinical study serum values exceeding 10 ng/ml for NSEand 1.5 ng/ml for CK-BB were set as positive for the enzymes.Positive rates in SCLC were 71.4% for NSE and 65.3% for CK-BB,which were significantly higher than those in non-SCLC. Allpositive cases were in an advanced stage. Consecutive dailyNSE determinations during induction chemotherapy showed transientelevation immediately after the initiation of drug administration(tumor lysis syndrome), followed by a decline to the normalrange in responders. This phe nomenon seems to indicate tumorsensitivity to cytotoxic drugs. NSE positive non-SCLC was assensitive to cytotoxic drugs as SCLC. These findings indicatethat lung cancer with elevated serum NSE and CK-BB levels atdiagnosis should be strongly suspected of being SCLC in theadvanced stage.     

Difference in Prognosis between T- and B-Cell Lymphomas: Clinical Study at Shikoku Cancer Center Hospital

In order to determine whether the surface marker phenotypesof non-Hodgkin's lymphomas affect the prognosis, we have studiedthe differences in response rate and duration of survival betweenT- and B-cell lymphomas. Sixty-four patients who underwent first-linetherapy, including combination chemotherapy and/or radiotherapy,from February 1979 to August 1985 were evaluated. With the aidof standard immunological methods and monoclonal antibodiesrelated to T-cells and B-cells. 21 T-cell lymphomas and 21 B-celllyrnphomas were identified. In the other 22 cases phenotypeswere not determined mainly because of the inability to obtainfresh samples. The complete remission rate was 100% for B-celllymphomas and 52.3% for T-cell lymphomas. The median survivaltime for patients with lymphomas of Stage III and IV. excludingthose with low-grade histology, was nine months for T-cell lymphomasand 17 months for B-cell lymphomas. T-cell lymphomas were foundto have significantly poorer prognosis than B-cell lymphomas.One patient with B-cell lymphoma and six patients in an undeterminedphenotype group, who were treated with combination chemotherapy,have been alive more than three years without relapse and thesepatients are considered potentially cured. Our results suggestthat the surface marker phenotype study of lymphoma cells aswell as histological subtying is important in prognosis andthat more effective therapy is needed to improve the prognosisof T-cell lymphomas.