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Tsutomu Masaki

Publications and source records attributed to Tsutomu Masaki.

At least 19 recordsLinked to original sources
PubMed2007

Identification of c-Yes expression in the nuclei of hepatocellular carcinoma cells: involvement in the early stages of hepatocarcinogenesis.

It is thought that the subcellular distribution of Src-family tyrosine kinases, including c-Yes binding to the cellular membrane, is membranous and/or cytoplasmic. c-Yes protein tyrosine kinase is known to be related to malignant transformation. However, the expression patterns of c-Yes in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that c-Yes is expressed not only in the membrane and cytoplasm, but also in the nuclei of cancer cells in some human HCC tissues and in a human HCC cell line. We examined the expression and localization of c-Yes in human HCC cell lines (HLE, HLF, PLC/PRF/5 and Hep 3B) by Western blotting and immunohistochemical analyses; we also examined the expression of c-Yes by immunohistochemistry and Western blotting in the tissues of various liver diseases, including 39 samples from HCC patients. We used an antibody array to detect proteins that bind to nuclear c-Yes in PLC/PRF/5 cell line. c-Yes was found to be expressed in the membranes and cytoplasm of HLE, HLF and Hep 3B HCC cells; it was also detected in the nuclei in addition to the membranes and cytoplasm of PLC/PRF/5 HCC cells. HCC with nuclear c-Yes was detected in 5 of 39 cases (13.0%), and nuclear c-Yes expression was not detected in normal, chronic hepatitis or cirrhotic livers. All HCCs with nuclear c-Yes expression were well-differentiated, small tumors at the early stages. In the PLC/PRF/5 cell line, the nuclear localization of c-Yes with cyclin-dependent kinase 1 was confirmed by a protein antibody array. In conclusion, nuclear c-Yes expression was found in cancer cells at the early stages of hepatocarcinogenesis, suggesting that nucleus-located c-Yes may be a useful marker to detect early-stage HCC.

Adult↗
PubMed2007

Sequential assessment of the intrahepatic expression of epidermal growth factor and transforming growth factor-beta1 in hepatofibrogenesis of a rat cirrhosis model.

Responses of the liver to chronic injury include inflammation, regeneration and fibrosis, which finally lead to cirrhosis. The cause of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage, and subsequent accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). Epidermal growth factor (EGF) and transforming growth factor-beta1 (TGF-beta1) play a crucial role in hepatocyte proliferation and hepatofibrogenesis, respectively. However, sequential analyses of the intrahepatic expression of EGF and TGF-beta1 in the course of cirrhosis development have not been examined fully. In the present study, liver cirrhosis was produced in rats by intraperitoneal administration of dimethylnitrosamine (DMN), and intrahepatic mRNA expression levels of proliferating cell nuclear antigen (PCNA), EGF and TGF-beta1 were quantitatively estimated by a real-time reverse transcription-polymerase chain reaction method. Histological and semiquantitative densitometric examination of liver sections revealed that the accumulation of extracellular matrix components was increased according to the period of DMN treatment. Histological examination of liver sections of rats treated with DMN for 4 and 6 weeks revealed pre-cirrhosis and cirrhosis, respectively. Intrahepatic mRNA expression levels of PCNA and EGF correlated well. Expression levels of both molecules were increased significantly during the course of cirrhosis development, but decreased significantly at the time of complete cirrhosis manifestation. In contrast, intrahepatic TGF-beta1 expression was increased significantly according to the period of DMN treatment, and reached a peak at the time of cirrhosis manifestation. These results suggest that proliferative capability of hepatocytes was impaired by continuous liver damage due, in part, to the decrease of a hepatocyte mitogen EGF, and that increased intrahepatic TGF-beta1 activated HSCs to retrieve space lost by hepatocyte destruction, resulting in complete cirrhosis manifestation.

Animals↗
PubMed2006

Analysis of CD28 and bcl-2 expression on peripheral blood and liver-infiltrating mononuclear cells in patients with autoimmune hepatitis.

Because the underlying mechanism of hepatocellular damages in autoimmune hepatitis (AIH) still remains unclear, analysis of CD28 and bcl-2 molecules, which are critical for T cell activation and survival, was performed in patients with AIH. The number of CD28(+)CD4(+) peripheral blood mononuclear cells (PBMC) in corticosteroid (CS)-treated patients was comparable to normal control individuals but decreased in untreated AIH patients. In contrast, the number of CD28(+)CD8(+) PBMC was decreased in both CS-treated and untreated AIH patients. Analysis of liver-infiltrating mononuclear cells (LIMC) showed that the number of CD28(+)CD4(+) and CD28(-)CD8(+) LIMC were positively correlated with the histology activity index score. Bcl-2(+)CD4(+) LIMC were observed in the portal area of the liver and the numbers fluctuated with disease activity during the time course after CS administration. By contrast, CD8(+) LIMC were shown not to express bcl-2. Taken collectively, these results suggest that bcl-2(+)CD28(+)CD4(+) and bcl-2(-)CD28(-)CD8(+) cells may play critical and distinct roles in hepatocellular damage in AIH.

Adrenal Cortex Hormones↗
PubMed2006

Usefulness of liver infiltrating CD86-positive mononuclear cells for diagnosis of autoimmune hepatitis.

AIM: Although the pathogenic mechanism underlying autoimmune hepatitis (AIH) remains unclear, the immune system is thought to be critical for the progression of the disease. Cellular immune responses may be linked to the hepatocellular damage in AIH. Recently, much attention has been focused on the critical functions of costimulatory molecules expressed on mononuclear cells in the generation of effective T cell-mediated immune responses. Analysis of costimulatory molecule expressed on mononuclear cells from the patients with AIH may give us insight into the pathogenic mechanism of hepatocellular damage in AIH. METHODS: Peripheral blood mononuclear cells (PBMC) were taken from the patients with AIH (34 cases) and healthy controls (25 cases). Liver infiltrating mononuclear cells (LIMCs) were taken from the patients with AIH (18 cases), the patient with chronic hepatitis C (CH-C) (13 cases) and the patients with fatty liver (2 cases). Using flow cytometry, the cells were analyzed for the expression of costimulatory molecules, such as CD80, CD86, and CD152 (CTLA-4). The results were compared with clinical data such as the level of gammaglobulin, histological grade, presence or absence of corticosteroids administration and the response to corticosteroids. RESULTS: The levels of CD80+, CD86+ and CD152+ PBMC were significantly reduced in the patients with AIH as compared with healthy controls. By contrast, those cells were significantly higher in LIMC than in PBMC of the patients with AIH. Especially, the level of CD86+ LIMC showed a marked increase irrespective of the degree of disease activity in the patients with AIH, although CD86+ cells were rarely present in PBMC. The levels of CD86+ cells were present in significantly higher frequency in patients with AIH than in the patients with CH-C. Furthermore, the patients with AIH with high levels of CD86+ LIMC showed good responses to corticosteroids, whereas 2 cases of AIH with low levels of CD86+ LIMC did not respond well. CONCLUSION: These results suggest that LIMC over-expressing costimulatory molecules such as CD80 and CD86 appears to play a role in the pathogenesis of AIH. Especially, CD86 molecule expressed on the LIMC may be useful for the diagnosis of AIH and for the prediction of the therapeutic effects of corticosteroids on AIH.

Adrenal Cortex Hormones↗
PubMed2006

Further resolution of alpha-fetoprotein glycoforms by two-dimensional isoelectric focusing and lectin affinity electrophoresis.

Human alpha-fetoprotein (AFP) from serum of patients with cirrhosis and hepatocellular carcinoma (HCC) was separated into several bands by IEF and by erythroagglutinating phytohemagglutinin (E-PHA) affinity electrophoresis. These AFP bands were directly compared in 2-D IEF and E-PHA affinity electrophoresis. IEF of serum AFP was run in 1% agarose IEF gel with 3% Pharmalyte 4.5-5.4. After IEF, a part of the gel was stained for AFP and another part of the gel corresponding to the area of separated AFP bands was cut in 1 mm x 39 mm along the focused direction and transferred to a trough in 1% agarose gel with 0.3 mg/mL E(4)-PHA for second-dimensional affinity electrophoresis. Separated 2-D AFP spots were visualized by antibody-affinity blotting and identified by combining the systems of Johnson et al.. (Johnson, P. J., Ho, S., Cheng, P., Chan, A. et al.., Cancer 1995, 75, 1663-1668) for AFP-I-+IV and of Taketa et al.. (Taketa, K., Ichikawa, E., Taga, H., Hirai, H., Electrophoresis 1985, 6, 492-497) for AFP-P1-5. AFP-P2, the major AFP glycoform, was composed of AFP-I, AFP+I, and AFP+II; AFP-P3, a nonspecific monosialo-AFP, was composed of AFP+II; AFP-P4, HCC-specific monosialo-AFP, was composed of AFP+II, AFP+III, and AFP+IV; and malignancy-related AFP-P5 was composed of AFP+I and AFP+II. Monosialo-AFP (AFP+II) was recovered in all the glycoforms of AFP-P2, -P3, -P4, and -P5; thus, AFP-P4 is more specific to HCC than monosialylated AFP+II.

Carbohydrate Sequence↗
PubMed2006

Ischemic preconditioning of the murine liver protects through the Akt kinase pathway.

Hepatic ischemia-reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt-signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20-minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase beta, and caspase-3. In addition, IPC also inhibited the activities of c-Jun N-terminal kinase and nuclear factor kappaB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage.

Animals↗
PubMed2006

Multidisciplinary treatment of patients with hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common malignancies in the world. When it is diagnosed, patients can choose from among several potentially curative treatments, such as surgical resection, transplantation, ablation therapy and transcatheter arterial chemoembolization. This review will give an overview of the present management of hepatocellular carcinoma. Liver transplantation is considered the best curative option, achieving a high rate of complete response, especially in patients with small hepatocellular carcinoma and good residual liver function. However, a shortage of donor livers restricts the availability of transplantation. In addition, only a minority of patients with hepatocellular carcinoma can be treated surgically, owing to impaired hepatic reserve, multiple intrahepatic lesions, extrahepatic lesions and the inability to obtain an optimal tumor-free margin. Therefore, for most patients, other types of interventions (transcatheter arterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation) have been developed. Among them, two local ablative modalities, percutaneous ethanol injection and percutaneous radiofrequency ablation, have been accepted as the only potentially curative nonsurgical treatments for hepatocellular carcinoma. Radiofrequency ablation may become a standard nonsurgical treatment option for patients with early hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed2006

Time-lag performance of radiofrequency ablation after percutaneous ethanol injection for the treatment of hepatocellular carcinoma.

We have previously reported that the combination therapy of percutaneous ethanol injection and radiofrequency ablation (PEI-RFA) was more effective than RFA alone to induce wider coagulated necrosis for the treatment of hepatocellular carcinoma (HCC). In the present study, the effect of time-lag performance of RFA after PEI was evaluated under the same ablation condition as PEI-RFA by analyzing the volume of coagulated necrosis, the energy requirement for ablation and the amount of ethanol injected into HCC. The comparative study between time-lag PEI-RFA and no time-lag PEI-RFA showed that the total energy requirement and the energy requirement per unit volume for whole and marginal coagulated necrosis were significantly smaller in the time-lag group than in the no time-lag PEI-RFA group. In time-lag PEI-RFA, the volume of coagulated necrosis induced positively correlated with the amount of ethanol injected into HCC as previously observed in PEI-RFA treatment. These results suggest that time-lag PEI-RFA can induce comparable coagulated necrosis with a smaller energy requirement than no time-lag PEI-RFA, and that time-lag PEI-RFA is likely to be less invasive than no time-lag PEI-RFA for inducing comparable coagulated necrosis. Thus, time-lag performance of RFA after PEI may make RFA treatment more effective and less invasive for the treatment of patients with HCC.

Aged↗
PubMed2006

Relationship between the proliferative capability of hepatocytes and the intrahepatic expression of hepatocyte growth factor and c-Met in the course of cirrhosis development in rats.

Liver cirrhosis is the fatal end stage of various chronic liver diseases. One of the most important causes of liver cirrhosis appears to be an impaired proliferative capability of hepatocytes caused by continuous hepatic damage. Hepatocyte growth factor (HGF) and its specific receptor, c-Met, play a pivotal role in hepatocyte proliferation. However, the relationship between the proliferative capability of hepatocytes and the intrahepatic expression of HGF and c-Met during the course of cirrhosis development has not been studied fully. In the present study, liver cirrhosis was produced in rats by intraperitoneally administering dimethylnitrosamine (DMN) and intrahepatic expression levels of HGF and c-Met were quantitatively estimated using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Histological examination of liver sections and biochemical estimation of serum levels of transaminase revealed that the degree of hepatocyte destruction was elevated gradually during cirrhosis development in the DMN-induced rat cirrhosis model. The proliferative capability of hepatocytes estimated immunohistochemically by proliferating cell nuclear antigen staining was markedly increased at an early stage of cirrhosis development. However, it was gradually decreased thereafter and suppressed substantially at the time of cirrhosis manifestation. Intrahepatic HGF expression was also increased significantly during the course of cirrhosis development but decreased significantly at the time of cirrhosis manifestation. Conversely, there was a tendency for the intrahepatic expression of c-Met to decrease from an early stage of cirrhosis development and intrahepatic c-Met expression was decreased significantly at the time of cirrhosis manifestation. These results suggest that the highly proliferative capability of hepatocytes at an early stage of cirrhosis development is induced by increased intrahepatic HGF expression. However, both HGF and c-Met expression levels in the liver are decreased significantly there-after. Accordingly, the proliferative capability of hepatocytes is severely impaired and extracellular matrix components are deposited to retrieve space lost by the destruction of hepatic parenchyma, resulting in the establishment of liver cirrhosis.

Alanine Transaminase↗
PubMed2006

Thoracoscopic ethanol injection and radiofrequency ablation for the treatment of hepatocellular carcinoma located immediately under the diaphragm.

We previously reported that the combination therapy of percutaneous ethanol injection and radiofrequency ablation (PEI-RFA) was more effective than RFA alone in inducing wider coagulated necrosis for the treatment of hepatocellular carcinoma (HCC). In the present study, we thoracoscopically applied the combination therapy to the treatment of HCC located immediately under the diaphragm. RFA electrode and ethanol injection needle were inserted into the tumor through the right side of the diaphragm in 6 patients with HCC close to the diaphragm. In all cases, the tumor was completely ablated with enough safety margin around the tumor. No local tumor recurrence has been observed in a relatively short-time follow-up period. The volume of coagulated necrosis and the energy requirement for coagulation in thoracoscopic ethanol injection and RFA (T-EI-RFA) were comparable to those of PEI-RFA. Although HCC located immediately under the diaphragm is difficult to treat with a percutaneous approach due to the poor visualization by ultrasonography, T-EI-RFA is considered to be an effective treatment modality.

Carcinoma, Hepatocellular↗
PubMed2006

Successful treatment of large-size advanced hepatocellular carcinoma by transarterial chemoembolization followed by the combination therapy of percutaneous ethanol-lipiodol injection and radiofrequency ablation.

We report a case of large-size hepatocellular carcinoma (HCC) successfully treated with transarterial chemoembolization (TACE) followed by the combination therapy of percutaneous ethanol-lipiodol injection and radiofrequency ablation (PELI-RFA) and percutaneous ethanol-lipiodol injection (PELI) therapy. In the present case, the patient had a large-size advanced HCC, 7 cm in diameter, located in the S8 region of the liver. In addition, the hepatic reserve of the patient was severely poor. In order not to impair the poor hepatic reserve, we chose PELI-RFA and PELI, originally developed in our department and reported as milder treatment modalities than others. After TACE , PELI-RFA and PELI were performed several times, the HCC was totally destroyed and early enhancement shown by helical dynamic computed tomography disappeared completely after treatment. The hepatic reserve of the patient was not impaired by the series of treatments. Serum levels of tumor markers, alpha-fetoprotein and Des-gamma-carboxy prothrombin, were rapidly decreased to almost normal levels. PELI-RFA and PELI may be effective for the treatment of large-size HCC of patients with poor hepatic reserve.

Aged↗
PubMed2005

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-alpha.

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-alpha (PEG-IFN-alpha). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-alpha was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-alpha and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-alpha with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.

Aged↗
PubMed2005

Comparison between combination therapy of percutaneous ethanol injection and radiofrequency ablation and radiofrequency ablation alone for patients with hepatocellular carcinoma.

AIM: In the present study, the characteristics of PEI-RFA treatment were further elucidated by analyzing the relationship between the volume of coagulated necrosis and the energy requirement for ablation or the amount of ethanol injected into HCC. METHODS: The volume of coagulated necrosis, total energy requirement and energy requirement for coagulation of per unit volume were examined in the groups of PEI-RFA and RFA alone using the Cool-tip RF system. RESULTS: The results showed that the volume of coagulated necrosis induced was significantly larger in PEI-RFA group than in routine RFA group, when the total energy administered was comparable in both groups. In PEI-RFA, enlargement of coagulated necrosis was admitted in 3 dimensions and the amount of energy requirement per unit volume of coagulated necrosis was negatively correlated with the amount of ethanol injected into HCC. CONCLUSION: These results suggest that, compared to RFA alone, PEI-RFA enables to induce comparable coagulated necrosis with smaller energy requirement, and that PEI-RFA is likely to be less invasive than RFA alone irrespective of inducing enhanced coagulated necrosis. Thus, simple prior injection of ethanol may make RFA treatment more effective and less invasive for the treatment of patients with HCC.

Administration, Cutaneous↗
PubMed2005

Estimation of the stent placement above the intact sphincter of Oddi against malignant bile duct obstruction.

BACKGROUND: In endoscopic biliary stenting against malignant biliary obstruction, stent blockage remains as an important problem. Stent blockage occurs as a result of bacterial adherence to the inner wall of the stent. We evaluated the stent placement above the intact sphincter of Oddi to retain the function of the sphincter of Oddi as a bacteriological barrier. METHODS: Sixteen patients with malignant biliary obstruction were assessed as the patients with the stent above the intact sphincter of Oddi. Sixteen patients with malignant biliary obstruction were assessed as the patients with the conventional stent placement across the sphincter of Oddi. Tannenbaum 10-Fr. stents were used in both the groups. RESULTS: The median patency periods of the stent were 255 days (25th to 75th percentiles, 212-454 days; range, 39-454 days) for the group of the stents placed above the sphincter of Oddi and 82 days (25th to 75th percentiles, 48-131 days; range, 22-196 days) for the group of the stents placed across the sphincter of Oddi, respectively, with significant difference (P = 0.0001). The occlusion rates of stents placed above and across the sphincter of Oddi were 37.5% and 93.8%, respectively, with significant difference (P = 0.0008). The dislocation rates of the stent were 0% and 6.3%, respectively (not significant). CONCLUSIONS: Placement of the stent above the intact sphincter of Oddi was associated with longer stent patency and lower occlusion rate.

Aged↗