Origin of neovascular structure in an early stage of hepatocellular carcinoma: Study of alpha-smooth muscle actin immunohistochemistry in serial thin sections of surgically resected cancer

Background: To elucidate the origin of the neovascular structure found in well‐differentiated hepatocellular carcinoma (HCC), an immunohistochemical study was performed on sequential thin section specimens. Method: Eleven surgically resected specimens of well‐differentiated HCC were analyzed for neovascular structure using monoclonal alpha‐smooth muscle actin (α‐SMA) antibody. Each paraffin specimen was serially sliced to a thickness of 3 µm for immunohistochemistry. When a ring‐shaped structure was found unrelated to portal triads on α‐SMA staining, it was regarded as abnormal neovascularity (non‐triadal vessel or unaccompanied vessel). Results: All of the 11 liver cancers had thin‐walled, round‐ or oval‐shaped non‐triadal vessels in their well‐differentiated parts. Immunohistochemistry of serial thin sections of HCC showed that these non‐triadal vessels were connected to portal veins in portal triads in well‐differentiated cancer in a total of nine patients (81.8%). This type of neovascular structure found in a well‐differentiated cancer seemed to be a surviving portal vein among diminishing and disappearing arteries and bile ducts. All 11 tumors showed isovascular staining on ordinary digital subtraction angiography, and four of the tumors showed negative enhancement on intra‐arterial carbon dioxide‐enhanced ultrasonography or computerized tomographic (CT) hepatic arteriography, suggesting a relative arterial blood scarcity in the tumor nodules. Conclusion: At an early stage of HCC, non‐triadal vessels originate from ordinary portal veins in intratumoral portal triads. This fact sufficiently explains the reason why a well‐differentiated liver cancer can sometimes show arterial blood paucity on CT arteriography or enhanced ultrasonography.     

贝伐单抗联合放射方案的实验研究

Objective To evaluate the impact of the hypoxia induced by bevacizumab on the antitumor effect in combining with irradiation in CNI-H441 xenografts in mice. Methods Bevacizumab of 5 mg/kg mouse for groups of control, bevacizumab alone, irradiation alone, earlier combination (EC), and later combination (LC) were initially injected peritoneally. Single irradiation of 14 Gy (122Sc γ-ray) was given at the 4th hour for the group of irradiation alone, 24th hour for EC group, and 72nd hour for LC group after the initial injection. Tumor hypoxia, micro vessels density and permeability of tumor vasculature,pathological responses, apoptosis, and tumor growth delay curve were evaluated after using bevacizumab and/or irradiation. Results Although it was lower than the control at the 24 hr after using bevacizumab (3. 1 × 106: 6.1 × 106 ;t = - 1.73 ,P > 0. 05), the HIF-1α rapidly increased to 3 - 4 times and 2 - 3 times of the control at day 3 (7.4 × 106: 20. 4 × 106; t = 2. 36, P < 0. 05) and lasted until day 10, which was consistent with the changes of tumor function vessels count. The count of residual micro vessel density count in LC group was higher than that in groups of EC and irradiation at day 3 after irradiation (9. 33: 3. 17;t =- 2. 43, P < 0. 05). The apoptotic count of tumor cells was lower in LC group than that in EC group (23.33: 43.83; t= 2.54, P< 0.05, at day 3 after radiation). Tumor growth delay time of LC groupwas shorter than that of EC groups (10. 5 days vs. 23. 0 days , t = 2. 67 , P < 0. 05) . Conclusions Hypoxia level induced by bevacizumab decreases the antitumor effect in later combination of bevacizumab and irradiaion. It shows a time window that determines whether the combination of bevacizumab and irradiation will be benefit or diverse.     

贝伐单抗联合放射方案的实验研究

Objective To evaluate the impact of the hypoxia induced by bevacizumab on the antitumor effect in combining with irradiation in CNI-H441 xenografts in mice. Methods Bevacizumab of 5 mg/kg mouse for groups of control, bevacizumab alone, irradiation alone, earlier combination (EC), and later combination (LC) were initially injected peritoneally. Single irradiation of 14 Gy (122Sc γ-ray) was given at the 4th hour for the group of irradiation alone, 24th hour for EC group, and 72nd hour for LC group after the initial injection. Tumor hypoxia, micro vessels density and permeability of tumor vasculature,pathological responses, apoptosis, and tumor growth delay curve were evaluated after using bevacizumab and/or irradiation. Results Although it was lower than the control at the 24 hr after using bevacizumab (3. 1 × 106: 6.1 × 106 ;t = - 1.73 ,P > 0. 05), the HIF-1α rapidly increased to 3 - 4 times and 2 - 3 times of the control at day 3 (7.4 × 106: 20. 4 × 106; t = 2. 36, P < 0. 05) and lasted until day 10, which was consistent with the changes of tumor function vessels count. The count of residual micro vessel density count in LC group was higher than that in groups of EC and irradiation at day 3 after irradiation (9. 33: 3. 17;t =- 2. 43, P < 0. 05). The apoptotic count of tumor cells was lower in LC group than that in EC group (23.33: 43.83; t= 2.54, P< 0.05, at day 3 after radiation). Tumor growth delay time of LC groupwas shorter than that of EC groups (10. 5 days vs. 23. 0 days , t = 2. 67 , P < 0. 05) . Conclusions Hypoxia level induced by bevacizumab decreases the antitumor effect in later combination of bevacizumab and irradiaion. It shows a time window that determines whether the combination of bevacizumab and irradiation will be benefit or diverse.     

Macroglobulinemia and Chronic B-Cell Type Lymphocytic Leukemia in Japan -- Study of Autopsy Cases --

Autopsy cases of Waldenstroöm's macroglobulinemia (WM)and chronic lymphocytic leukemia of B-cell type (B-CLL) wereexamined to determine the geographical distribution and histologicalcharacteristics of these diseases in Japan. Both diseases occurred primarily at 50 to 60 years of age witha predominance of males and were distributed throughout Japanwith a population slightly lower than that of T-CLL in southwesternJapan. Histologically WM (31 cases) consisted mainly of smallcell type malignant lymphoma with plasmacytic differentiation(27 cases) according to the Japanese Classification (LSG) andcytoplasmic immunoglobulins with a monoclonal pattern of immunoglobulinM (IgM) (lambda 12; kappa seven). The bone marrow involvement(27 cases) was follicular, mixed (follicular and diffuse) ordiffuse. B-CLL (58 cases) also showed principally a small celltype histology (48 cases) and 16 of the cases showed plasmacyticdifferentiation as in WM. Cytoplasmic immunoglobulins with amonoclonal pattern were found in 10 (six of IgG, two of IgM,one of IgG and M, and one of IgA). Bone marrow involvement (56cases) revealed the same histological pattern as WM. According to the growth pattern of the tumor cells in the bonemarrow and lymph nodes, both diseases may be categorized asbone marrow-based lymphoma.     

Pharmacokinetics:Pharmacokinetic Differences Between Lansoprazole Enantiomers in Rats

Because limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats. There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg^?1) to rats. C_max (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5–6 times greater than those for (—)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (—) enantiomer. CL_tot/F values (where CL_tot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (—) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (—) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (—)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 μM lansoprazole. These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.     

Comparative Study on Inclusion Complexation of Maltosyl-β-cyclodextrin,Heptakis(2,6-di-O-methyl)-β-cyclodextrin and β-Cyclodextrin with Fucosterol in Aqueous and Solid State

Abstract— The complexation of fucosterol with three kinds of β-cyclodextrin (β-CyD) was investigated in aqueous solution and in the solid state. The solubility of fucosterol increased significantly on its complexation with maltosyl-β-CyD and heptakis(2,6-di-O-methyl)-β-CyD (DM-β-CyD), while no appreciable increase was observed when complexed with β-CyD. The stability constant of complexation with β-CyD estimated from solubility determinations was greater for a 1:2 complex than for a 1:1 complex. On the other hand, 1:1 complexation of fucosterol with maltosyl-β-CyD or DM-β-CyD was greater than 1:2 complexation. The solid complexes were obtained in molar ratios of 1:2 and 1:3 for β-CyD and maltosyl-β-CyD complexes, respectively. The inclusion behaviour of fucosterol with maltosyl-β-CyD was compared with β-CyD in the solid state using DSC, powder X-ray diffractometry and CP/MAS ¹³C NMR. Maltosyl-β-CyD showed different inclusion behaviour compared with β-CyD, and produced an amorphous structure of fucosterol on complex formation. The dissolution rate of fucosterol-maltosyl-β-CyD complex was significantly faster than other complexes due to its high aqueous solubility and amorphous structure.     

Predictive factors in eradicating hepatitis C virus using a relatively small dose of interferon

Interferon (IFN) can reduce hepatitis C virus load and even eliminate the virus in 30-40% of patients. Several predictive factors for eradication of the virus have been reported and a higher dose of IFN tends to result in elimination of the virus. However, a small dose of IFN sometimes is as effective as a large dose in eradicating the virus. The predictive factors for such a response are not well established. We retrospectively analysed 50 patients with chronic hepatitis C who were treated with relatively small amounts of IFN (equal or less than 252 million units). Eleven patients were responders (elimination of hepatitis C virus (HCV) and normalization of alanine amino transferase (ALT) for at least 6 months), but the remaining 39 were non-responders. Multivariate analysis showed that the pretreatment viral load and total dose of IFN per kilogram of bodyweight were significant predictive factors of response to therapy. We also assessed the amino acid substitutions in the IFN sensitivity determining region (ISDR), NS5A codon 2209-2248, of HCV in serum samples obtained from 31 patients with HCV genotype 1 b. The presence of more than one amino acid substitution in the ISDR tended to correlate with HCV genotype lb elimination. As IFN is expensive and has a number of serious side effects, our study suggests that the optimal dose of IFN may vary from one patient to another and that more stringent criteria should be used to select the optimal dose for therapy.     

Drug Metabolism: Renal Excretion of Rhodamine 123, a P-Glycoprotein Substrate,in Rats with Glycerol-induced Acute Renal Failure

To clarify renal handling of rhodamine 123, a substrate for P-glycoprotein, in normal and diseased states, in-vivo clearance studies were performed with normal rats and rats with glycerol-induced acute renal failure. For normal rats the excretion ratio of unbound rhodamine 123-to-inulin was 3.25, indicating the presence of the renal tubular secretion of rhodamine 123. Co-administration of cyclosporin, a P-glycoprotein inhibitor, significantly reduced tubular secretion of rhodamine 123. Administration of glycerol induced both an increase in blood urea nitrogen and a reduction in the glomerular filtration rate, confirming the induction of acute renal failure. Total plasma, renal, and tubular secretory clearances of rhodamine 123 were significantly lower for rats with acute renal failure than for control rats. There was no difference between the ATP content of the renal cortex in control rats and those with acute renal failure. In addition to the decrease in renal clearance, a decrease in the biliary clearance of rhodamine 123 was also observed in rats with acute renal failure. These results imply that rhodamine 123 is secreted via P-glycoprotein in renal tubules and that the renal secretory clearance of rhodamine 123 was reduced after acute renal failure, probably because of impairment of P-glycoprotein.     

Overdrive Suppression of Antegrade Conduction Over A Kent Bundle Induced by Disopyramide

Overdrive Suppression of Kent Conduction. A patient with Wolff-Parkinson-White syndrome was described in whom antegrade conduction over the Kent hundle was suppressed after termination of orthodromic tachycardia. A phenomenon indicative of overdrive suppression of conduction occurred after intravenous disopyramide, and tended to be rate and lime dependent. (J Cardiovasc Electrophysiol, Vol. 1, No. 6, pp. 512–516 December 1990)     

Computed tomographic study of aged schizophrenic patients

Abstract  The width of interhemispheric fissure, lateral ventricles and third ventricle were measured using cranial computed tomography (CT; linear method) in 45 elderly inpatients with chronic schizophrenia and in 28 age-matched control subjects. Twenty-three patients were men and 22 were women. In addition, Mini-Mental State Examination, Brief Psychiatric Rating Scale (BPRS) and a subclass of BPRS were undertaken in all patients. There is a significant enlargement of the maximum width of the interhemispheric fissure (in both male and female) and a significant enlargement of ventricular system (more severe in men than in women) in aged schizophrenics, as seen with CT, compared with normal controls. These findings are consistent with previous studies of non-aged schizophrenic patients. Based upon the relation between psychiatric symptoms and CT findings, the most striking is a significant negative correlation between the third ventricle enlargement and the positive and depressive symptoms in all patients. This result suggests that the advanced third ventricle enlargement may decrease these symptoms in aged schizophrenics.