[Show abstract][Hide abstract] ABSTRACT: Preoperative autologous blood donation has been suggested for patients with liver disease who are to undergo liver resection. The aim of this retrospective study was to clarify the risk factors for increased blood loss and the need for blood transfusion during hepatectomy for hepatocellular carcinoma (HCC).
From January 1996 to December 2000, 206 consecutive patients, 98.5 per cent of whom had underlying liver disease, underwent elective hepatectomy for HCC.
Major hepatectomy was performed in 34 patients (16.5 per cent) and minor hepatectomy in 172 patients (83.5 per cent). The mean blood loss was 410 (median 260) ml. Eleven (5.3 per cent) of the 206 patients received blood transfusion during or after the operation. Operation time (P = 0.004) and central venous pressure (CVP) (P = 0.041) were independently correlated with blood loss of more than 1000 ml. Only preoperative haemoglobin level (P = 0.001) was independently correlated with the need for blood transfusion.
In patients with underlying liver disease, maintaining CVP at a level below 5 cm H2O during parenchymal transection to reduce blood loss is more important than reserving autologous blood before the operation.
British Journal of Surgery 02/2003; 90(1):23-8. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The age-related changes in the electrical and physiological properties of the skin were examined in rats at the ages of 5, 10, 21, 90, and 180 d. The resistance of the stratum corneum, the resistance of the viable skin (epidermis and dermis), and the capacitance of the stratum corneum were analyzed from skin impedance data using an equivalent circuit. With development and aging, the resistance of the stratum corneum and the viable skin increased, whereas the capacitance of the stratum corneum decreased. Physiological characteristics such as the thickness of skin strata and the content of lipid and water in the stratum corneum were also measured. The lipid content in the stratum corneum was constant at all ages. The water content in the stratum corneum decreased, and the thickness of skin strata increased with age. Comparison between electrical data and physiological properties suggested that the increase in the resistance of the stratum corneum with aging is primarily caused by the decrease in the water content and that the capacitance of the stratum corneum and the resistance of the viable skin depend on age-related increases in the thickness of skin strata. In conclusion, the age dependency of cutaneous electrical properties may affect the permeation profile of drugs through the skin, and impedance analysis can be used to estimate age-related changes in transdermal drug delivery.
[Show abstract][Hide abstract] ABSTRACT: The effect of pH on the skin permeation enhancement of three acidic drugs by the l-menthol-ethanol system was investigated. The total flux of acidic drugs from the system remarkably varied over the pH range 3.0-8.0, and the permeation enhancement factor depended on the system pH and drug. A skin permeation model, which consists of two permeant (unionized and ionized) species, two system (oily and aqueous) phases, and two permeation (lipid and pore) pathways, was developed. The assumptions were made that only the unionized species can distribute to the oily phase and transport via the lipid pathway. The model explained the relationship between the concentration of drug in the aqueous phase and system pH. The skin permeability data were also described by the model and permeability coefficients corresponding to the physicochemical properties of permeant were calculated for the lipid and pore pathways. The model simulation showed that the permeation of acidic drugs occurred from the aqueous phase and the oily phase acted as a reservoir. Whether the total flux increased with increase of pH was dependent on the lipophilicity of drug. These results suggest that the pH of l-menthol-ethanol system should be given attention to elicit the maximum permeation enhancement.
International Journal of Pharmaceutics 10/2001; 226(1-2):69-80. · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Plasma concentration and vasodilating effect after i.v. bolus injection of stereoisomeric organic nitrates were evaluated. Pharmacokinetics of mononitrates was analyzed with a linear one-compartment model. The apparent volumes of distribution were almost identical, but systemic clearances were different among stereoisomers. The concentration data after dinitrate administration could be described based on a two-compartment model with elimination only from the central compartment via metabolism to mononitrate, and then mononitrate-dependent metabolic clearance was estimated. In the vasodilation by mononitrate administered intravenously, the maximum effect was not observed. The reduction of mean arterial pressure from baseline level was related to plasma concentration with a log-linear model. The pharmacological effect following dinitrate dosing was analyzed by a sigmoidal Emax model assuming a simple additive effect of dinitrate and mononitrate. Although almost the same Hill's constant and maximum effect (Emax) values were estimated, the concentrations required to produce 50% of Emax (EC50) differed among stereoisomers. The clearance and EC50 values of stereoisomers with nitrate group at the exo position were generally higher than those with the same group at the endo position. This suggests that the stereostructure of organic nitrates controls the vasodilator potency and duration of action.
Journal of Pharmacology and Experimental Therapeutics 08/2001; 298(1):346-53. · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Translational initiation of hepatitis C virus (HCV) genome RNA occurs via its highly structured 5' noncoding region called the internal ribosome entry site (IRES). Recent studies indicate that HCV IRES and 40 S ribosomal subunit form a stable binary complex that is believed to be important for the subsequent assembly of the 48 S initiation complex. Ribosomal protein (rp) S9 has been suggested as the prime candidate protein for binding of the HCV IRES to the 40 S subunit. RpS9 has a molecular mass of approximately 25 kDa in UV cross-linking experiments. In the present study, we examined the approximately 25-kDa proteins of the 40 S ribosome that form complexes with the HCV IRES upon UV cross-linking. Immunoprecipitation with specific antibodies against two 25-kDa 40 S proteins, rpS5 and rpS9, clearly identified rpS5 as the protein bound to the IRES. Thus, our results support rpS5 as the critical element in positioning the HCV RNA on the 40 S ribosomal subunit during translation initiation.
Journal of Biological Chemistry 07/2001; 276(24):20824-6. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TT virus (TTV) has been reported to occur in association with elevated alanine aminotransferase (ALT) levels in patients with posttransfusion hepatitis of unknown etiology. We examined whether the presence, change of DNA titer, or variation in sequence of this virus is associated with acute or chronic liver dysfunction in Japanese. We detected TTV by polymerase chain reaction (PCR) using primers generated from the conserved region of the TTV genome. Direct DNA sequencing of the original N22 region was used to characterize TTV isolates. We detected TTV DNA in 15 (25%) of 60 patients with liver dysfunction. Variants recovered from infected patients formed four genotypes/subtypes, corresponding to G1a, G1b, G2, and G4. Although TTV DNA titers in patients with G2 and G4 were lower than those with G1, TTV was consistently detected regardless of genotype/subtype. TTV infection continued for at least 1 year after normalization of ALT level in patients with acute liver dysfunction. Changes in DNA titer, substitutions of deduced amino acids, and variety of quasispecies of TTV were detected during the observation period, but no significant fluctuation in ALT level was found. We conclude that persistent infection, changes in DNA titer, and variation in sequence of this novel virus are not significantly related to hepatic disorders.
Hepatology Research 04/2001; 19(3):212-224. · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 5' noncoding region (NCR) of hepatitis C virus (HCV) contains an internal ribosome entry site for translation initiation. Cellular proteins (e.g. La, polypyrimidine tract-binding protein, and p25) that interact with HCV 5' NCR have been implicated in facilitating efficient internal initiation. The 5' NCR may also contain RNA structures and specific RNA sequences that interact with cellular proteins to promote RNA replication. UV crosslinking experiments revealed a 43-kDa cellular protein (p43) also interacts with the HCV 5' NCR. Further UV crosslinking experiments with deletion mutants of HCV 5' NCR demonstrated that p43 bound specifically to the 5'-terminal stem-loop of the HCV 5' NCR. Achromobactor proteinase I digests, competition experiments, and immunoprecipitation confirmed that p43 was identical to human poly(rC)-binding protein 2 (PCBP2). We prepared a PCBP2-immunodepleted rabbit reticulocyte lysate with an anti-PCBP2 antibody. Translation activity promoted by the HCV internal ribosome-entry site was the same in PCBP2-depleted lysates as in mock-depleted lysates. In conclusion, PCBP2 specifically interacted with the 5' terminus of HCV genome but had no effect on HCV translation. We speculate that PCBP2's interaction with HCV 5' NCR may be involved in the replication-initiation complex of HCV.
Virus Research 02/2001; 73(1):67-79. · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We analyzed cagA genes from Helicobacter pylori strains isolated from Japanese and non-Japanese individuals for differences that could be associated with variations in virulence. The cagA genes from Japanese isolates (n = 12) and non-Japanese American Type Culture Collection (ATCC) strains (n = 4) were sequenced and compared with three published sequences. Phylogenetic analysis resolved two distinct clusters with a genetic distance of 0.1602. Similarity plot analysis of the amino acid sequences identified two highly variable regions of which each was unique to the Japanese and non-Japanese isolates, respectively. Furthermore, nucleic acid sequence analysis revealed that the multiple repeated sequences present in cagA may have been generated by homologous recombination and/or misaligned replication to promote variation in the cagA gene products. Our data indicate that alleic variations in the H. pylori genome exist between isolates from Japanese and non-Japanese subjects and that distinct H. pylori populations may be circulating in different geographical regions. Phylogenetic analysis did not reveal any association of a specific CagA type with a particular disease. Although extensive alterations were found in the cagA gene, none of the isolates contained a prematurely terminated CagA protein. The cagA gene may be advantageous to H. pylori, possibly by aiding its escape from host immune recognition by antigen modulation. Thus, this ability to elude the host immune system may contribute to an increased risk for gastric disease.
Journal of Gastroenterology 01/2001; 35(12):890-7. · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the clinicopathologic features and biological behaviors related to the gross appearance of intrahepatic cholangiocarcinoma.
Fourteen patients with intrahepatic cholangiocarcinoma who underwent hepatic resection between 1986 and 1998 were divided into four groups according to the gross appearance of the tumor: ID (intraductal growth) type (n = 1), PD (periductal-infiltrating) type (n = 4), MF (mass-forming) type (n = 5), MF-with-PD type (n = 4).
Overall survival at 1, 5, and 10 years was 50.0%, 35.7%, and 35.7%, respectively. All three long-term survivors without recurrence had tumors unassociated with vascular invasion, intrahepatic metastasis, or lymph node metastasis. The MF and MF-with-PD tumors were more frequently associated with vascular invasion and/or lymph node metastasis than the ID or PD type. The Ki-67-positive grade of the cancer cells was clearly higher in the MF and MF-with-PD tumors than in the ID or PD type. All of the cases of MF-with-PD tumors were stage IV-A and had a poor outcome.
Extended hepatic resection with a sufficient surgical margin yielded good results in intrahepatic cholangiocarcinoma patients without vascular invasion, intrahepatic metastasis, or lymph node metastasis. However, it is necessary to develop a new effective strategy for advanced intrahepatic cholangiocarcinomas, such as the MF-with-PD type.
[Show abstract][Hide abstract] ABSTRACT: To clarify the indication of percutaneous microwave coagulation therapy for hepatocellular carcinoma.
Thirty-three hepatocellular carcinoma patients who underwent percutaneous microwave coagulation therapy were enrolled in this study, including 18 primary and 15 recurrent hepatocellular carcinoma patients. We examined the local recurrence rates and the long-term results after the treatment.
The overall survival rates of the primary group at 1, 2, 3, 4 and 5 years were 94.4%, 77.8%, 77.8%, 77.8% and 48.6%, respectively, whereas those of the recurrent group were 100%, 85.7%, 66.7% and 50.0% at 1, 2, 3 and 4 years, respectively. Local recurrence after percutaneous microwave coagulation therapy was found in about 50% of patients in both groups. Seventeen of the 27 patients (63.0%) with a moderately or poorly differentiated hepatocellular carcinoma tumor had local recurrence, while none of the 6 patients with a well-differentiated hepatocellular carcinoma tumor did (P = 0.005).
Irrespective of primary or recurrent hepatocellular carcinoma, the indication of percutaneous microwave coagulation therapy as an alternative to hepatic resection should be limited to cases of a well-differentiated hepatocellular carcinoma tumor smaller than 2 cm in diameter.
[Show abstract][Hide abstract] ABSTRACT: The absorption, distribution and excretion of butylidenephthalide after dermal application to hairless mouse have been examined with [8-14C]butylidenephthalide. By the investigation of the whole body autoradiogram and liquid scintillation analysis, it was indicated that the transdermally applied butylidenephthalide quickly permeate into peripheral circulation system without accumulation in the skin and then distribute into lung, liver, bile and kidney. The total radioactivity, however, was decreased due to excretion into urine, and in the case of i.v.-administration, 80% of the administered butylidenephthalide was excreted into urine within 24 h, while only 5% was excreted into feces within 24 h. Then, the metabolite in urine was determined to be a cysteine conjugate by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method. Thus, it has been concluded that after dermal application butylidenephthalide quickly permeates through skin into peripheral circulation system; distributes to lung, liver, bile and kidney; and then excreted into urine as a cysteine adduct.
Journal of Ethnopharmacology 09/2000; 71(3):401-9. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A physiological pharmacokinetic model describing the absorption and disposition of topically applied drugs was proposed, and the effect of various pharmacokinetic and physiological parameters on the drug delivery into the targeted muscle was simulated. The proposed model consists of vehicle, and stratum corneum, viable epidermis and muscle below the application and reference sites, and plasma, each joined with transfer clearance and plasma flow. Indomethacin concentrations in tissues and plasma after topical application to rats could be explained by the model. Most indomethacin delivered into the underlying muscle was via direct penetration. The model simulation showed that the increase in plasma clearance and clearance between viable skin and muscle, and the decrease in application area and plasma flow rate into viable skin and muscle would promote the targeting efficacy of topically applied drugs to the underlying muscle.
[Show abstract][Hide abstract] ABSTRACT: The high incidence of cancer after renal transplantation is now a critical concern since the graft survival rate has been improved extensively. We experienced 9 malignancies in 8 patients out of 168 recipients up to December 31, 1999 in our hospital, consisting of a case of gastric plasmacytoma and cases of cancer in the liver (2), thyroid (2), prostate (1), breast (1), sigmoid colon (1) and gall-bladder (1). Two patients were diagnosed as having tumors within 3 months after transplantation, suggesting post-transplant acceleration of growth of the latent tumors. The other patients were diagnosed at an average of 128 months, ranging from 84 to 263 months after transplant. Two patients died of gastro-intestinal bleeding and acute heart failure. Four patients died directly of progressive neoplasm within 3 months after diagnosis. These results suggest that the course of malignancies developing in post-transplant recipients is more aggressive than that expected in non-transplant patients, and it is very important to intensively follow long-term surviving cases to detect the malignant tumors as early as possible.
Hiroshima journal of medical sciences 07/2000; 49(2):117-20.
[Show abstract][Hide abstract] ABSTRACT: The ion pair skin transport of cephalexin was investigated using various counter ions and solvents. The permeability of cephalexin was enhanced by 1-alkylsulfonates (ASs) at pH 3.0 and by tetraalkylammoniums (AAs) at pH 7.0; the enhancing ratio increased with the number of carbon atoms in their alkyl chains. The corresponding effects of these additives were observed on the partitioning of cephalexin. Most of the additives did not affect the skin transport of D-mannitol and cortisone. These results suggest that the enhanced transport of cephalexin results from the ion pair formation with additives. Although ASs increased the partitioning of cephalexin above that of AAs, the transport enhancement effect of ASs was lower than AAs having the same number of carbon atoms in their alkyl chains, indicating higher diffusivity of the ion pairs with AAs in skin. Moreover, the transport enhancement by AAs increased even more when ethanol-buffer solutions were used as solvents. The conductivity measurement of dissolving solutes in donor solvents showed that the further enhancement might be caused by the increasing ion pair formation in solvents with low dielectric constants. To obtain the maximum enhancement of skin transport of zwitterionic drugs via ion pair concept, one should select a counter ion having high lipophilicity and small volume, and a solvent with suitable pH and low dielectric constant.
Journal of Controlled Release 06/2000; 66(1):63-71. · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We performed percutaneous microwave coagulation therapy (PMCT) for 34 hepatocellular carcinoma (HCC) patients, including 18 primary and 16 recurrent HCC ones. Cumulative 1, 2-, 3- and 4-year survival rates of primary HCC patients were 94, 78, 78% and 62%, respectively, while those of recurrent HCC patients were 100, 79, 62% and 41%, respectively. There were no differences between groups. In both groups, local recurrence was found in about 50% of patients. The mean tumor size (diameter 2.6 +/- 0.6 cm) of patients with local recurrence was relatively larger than that (2.2 +/- 0.6 cm) of patients without local recurrence (p = 0.081). Seventeen of 27 patients with moderately or poorly differentiated HCC had local recurrence, while none of patients with well-differentiated HCC did (p = 0.005). Subsequently, local control failure led some patients to have progressive diseases such as multiple intrahepatic metastasis, tumor thrombi in the portal vein, and distant metastasis. From these findings, PMCT should be performed only for well-differentiated HCC less than 2 cm in diameter. If the patients with moderately or poorly differentiated HCC larger than 2 cm in diameter cannot tolerate hepatic resection because of their poor hepatic functional reserve, PMCT should be performed in combination with other non-surgical treatment modalities.
Gan to kagaku ryoho. Cancer & chemotherapy 11/1999; 26(12):1841-4.
[Show abstract][Hide abstract] ABSTRACT: Hepatic arterial infusion of low-dose CDDP (10 mg/day), 5-FU (250 mg/day) was performed in 5 unresectable hepatocellular carcinoma (HCC) patients with tumor thrombi in the trunk and/or the first branch of the portal vein. Infusion chemotherapy was continued for five days, then discontinued for the subsequent two days. This procedure was performed repeatedly for at least three weeks. Decrease in the serum levels of the alpha-fetoprotein after the treatment was found in 3 of 4 patients. In one patient, the size of the primary tumor decreased 92%. In two of five patients, the tumor thrombi in the portal vein disappeared, or decreased in size. Side effects of the chemotherapy included liver functional disorder (Grade 3; 1 case), thrombocytopenia (Grade 3; 1 case, Grade 2; 1 case), and leukopenia (Grade 2; 1 case). The present protocol proved to be effective and applicable for patients with advanced HCC associated with severe cirrhosis.
Gan to kagaku ryoho. Cancer & chemotherapy 11/1999; 26(12):1832-5.
[Show abstract][Hide abstract] ABSTRACT: Brain metastasis from hepatocellular carcinoma (HCC) is a rare, yet perplexing problem in patients with cancer. We report on 5 patients with metastasis of HCC to the brain after radical hepatectomy. Intrahepatic recurrence occurred in 3 patients, and distant metastasis to sites other than the brain was observed in 3 patients (lung, 2; bone, 1). The symptoms for brain metastasis included headache, hemiparesis, and vomiting. Hemorrhage was found in 4 of 5 patients. All patients had a single nodular lesion in the brain. The alpha-fetoprotein levels were more than 10,000 ng/ml in 4 patients. Two patients underwent surgical resection, 1 received cranial irradiation, and 2 were administered corticosteroids. The interval between diagnosis of the primary cancer and detection of brain metastasis ranged from 2 to 54 months. The mean survival period was only 3 months after diagnosis of brain metastasis. All 5 patients died of neurologic causes. Because no effective treatment for brain metastasis from HCC is available, further study is needed.
Hiroshima journal of medical sciences 10/1999; 48(3):91-4.
[Show abstract][Hide abstract] ABSTRACT: We studied the relation of perioperative blood transfusion and the outcomes in 175 patients with hepatocellular carcinoma (HCC) who underwent hepatic resection from 1986 to 1994 in our hospital. Hepatectomy was performed in 23 (13.1%) patients with and 152 (86. 9%) without blood transfusions. The cumulative cancer-free survival rates for patients who had received blood transfusion was significantly lower than that for patients who had not received blood transfusions (p = 0.003). Further examinations revealed a significant difference in cancer-free survival rates for stage I-II patients (n = 75) of HCC (p = 0.02) but not for stage III-IV patients (n = 56) (p = 0.06). Cox regression analysis for recurrence revealed that blood transfusion was the most significant prognostic indicator (p = 0.001) for recurrence in stage I-II patients but not in stage III-IV patients (p = 0.99). These results suggest that a perioperative blood transfusion may be a significant prognostic indicator for patients with HCC who had underwent hepatectomy, especially in stage I-II patients of HCC.
World Journal of Surgery 08/1999; 23(7):676-80. · 2.35 Impact Factor