Biomedical subjects

Ken Shirabe

Publications and source records attributed to Ken Shirabe.

34 records · Page 2Linked to original sources

PubMed2002

Oncogenic signal transduction and therapeutic strategy for hepatocellular carcinoma.

Discoveries of oncogenic signaling molecules lead to the comprehension of molecular mechanisms of tumor progression, as well as to the development of novel therapeutic tools for hepatocellular carcinoma. We have identified critical functions of intracellular signals transmitted from insulin-like growth factor and Wnt oncoprotein in carcinogenesis. The insulin-like growth factor system activates a number of signaling cascades resulting not only in hepatic mitogenesis, but also in cell survival. The secreted oncoprotein Wnt transforms beta-catenin potentials as a component of cell adhesion complexes with cadherins, into a transcription factor in the nucleus. Here, the important role of such signal transduction is reviewed, and we emphasize its control as a promising approach for the treatment of hepatocellular carcinoma.

Carcinoma, Hepatocellular↗

PubMed2002

A 16-year experience in performing hepatic resection in 303 patients with hepatocellular carcinoma: 1985-2000.

BACKGROUND: Hepatic resection is an accepted therapeutic modality for hepatocellular carcinoma (HCC). Over the past 2 decades, liver surgery has evolved to a refined and deliberate operation. In the present study surgical results are analyzed with an aim toward further improving the treatment of HCC. METHODS: We studied 303 patients with HCC who underwent a hepatic resection at 2 university hospitals from 1985 through 2000. Living-related liver transplantation was a procedure of choice in 1 patient with early staged HCC. Fifty-five percent of the patients had associated cirrhosis. Before the operation, the liver function was mainly evaluated with the indocyanine green retention test. RESULTS: The mortality rate within 30 days after the operation was 1.6%. One-, 3-, 5-, 10-, and 15-year cumulative survival rates were 84%, 67%, 51%, 20%, and 11%, respectively. The tumor stage I and II groups showed superior survival rates to those of the tumor stage III and IV groups, respectively, and the difference was statistically significant. The disease-free survival curves, however, showed the rate to be 27% at 5 years and 11% at 10 years. CONCLUSIONS: Although the surgical results have greatly improved in the treatment of HCC, the recurrence rate is still high. In carefully screened patients with poor liver function and small HCC, liver transplantation enhances the possibility of cure.

Aged↗

PubMed2002

Intrahepatic cholangiocarcinoma: its mode of spreading and therapeutic modalities.

Intrahepatic cholangiocarcinoma (IHCC) is a primary adenocarcinoma of the liver, arising from the intrahepatic bile ducts. The prognosis is generally poor because locoregional extension is usually advanced at the time of diagnosis. Even after a resection, the outcome for patients with advanced IHCC is extremely poor, and the presence of lymph node metastasis has been reported in most previous studies to be the worst prognostic factor after a resection. There are no clear guidelines on lymph node dissection with IHCC. In this article, we review the mode of invasion and the therapeutic modalities: hepatic resection, lymph node dissection, liver transplantation, radiation, and chemotherapy for IHCC.

Adenocarcinoma↗

PubMed2002

Minimally invasive hepatectomy: modulation of systemic reactions to operation or laparoscopic approach?

BACKGROUND: A new concept of surgical stress has been proposed that consists of both aggressiveness of operation and systemic reactions to an operation. METHODS AND RESULTS: We have investigated a possible modulation of such systemic reactions to operation and have demonstrated the following 3 points: (1) coagulation and fibrinolytic systems are independently activated during hepatectomy and such activation can be modulated by protease inhibitors such as nafamostat mesilate and antithrombin III; (2) elevated thromboxane A2 during hepatectomy is characterized in the prostanoid system, the elevation of thromboxane A2 is inhibited by thromboxane A2 synthetase inhibitor, and postoperative liver injury is reduced; (3) cytokine response induced by hepatectomy is modulated by preoperative administration of methylprednisolone, leading to possible prevention of bacterial translocation. Therefore, modulating systemic reactions to hepatectomy may be important for successful minimally invasive hepatectomy. Another important option for minimally invasive hepatectomy is the use of operative procedures such as laparoscope or thoracoscope. We have investigated the usefulness of a laparoscopic hepatectomy from the standpoints of early and long-term outcome after hepatectomy. Laparoscopic hepatectomy, which is a difficult and dangerous procedure, can be a feasible option and can result in better short-term outcome and a similar long-term outcome after hepatectomy when compared with conventional open hepatectomy. Therefore, the laparoscopic approach is also a viable option for minimally invasive hepatectomy. CONCLUSIONS: Modulation of systemic reactions to the operation itself and laparoscopic hepatectomy may be new strategies for performing minimally invasive hepatectomy.

Blood Coagulation↗

PubMed2002

The utility of keratin 903 as a new prognostic marker in mass-forming-type intrahepatic cholangiocarcinoma.

The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development. We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80% of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10%), 6 (20%), and 1 (3%) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74%), 66 (90%), and 61 (84%) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P <.0001), in those with medullary-type stromal reaction (P =.0327), in those without perineural invasion (P =.0001), and in those without lymph node metastasis (P =.0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively). Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor. In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.

Aged↗

PubMed2002

High metabolic function of primary human and porcine hepatocytes in a polyurethane foam/spheroid culture system in plasma from patients with fulminant hepatic failure.

It has been demonstrated that plasma from patients with fulminant hepatic failure (FHF) interferes extensively with cellular function. We placed primary human and primary porcine hepatocytes in a polyurethane foam (PUF)/spheroid culture system and compared the metabolic functions in the plasma of patients with FHF in a 24-h stationary culture to those in a monolayer culture. The PUF/spheroid culture system using primary human and primary porcine hepatocytes significantly decreased ammonia content during 28-day culture. Fisher's ratio significantly increased at culture days 3 and 7. Tauroursodeoxycholic acid significantly increased and glycochenodeoxycholic acid and taurochenodeoxycholic acid decreased in the FHF patients' plasma at culture day 3. During at least a 24-h culture in the FHF patients' plasma, metabolic functions of primary human and primary porcine hepatocytes were almost identical. The present results indicate that the PUF/spheroid culture system using primary human or primary porcine hepatocytes demonstrated more advantageous metabolic functions in the plasma from patients with FHF than the monolayer culture.

Ammonia↗

PubMed2002

[Current therapeutic strategy of hepatocellular carcinoma with extensive portal thrombus].

Prognosis of the patients with hepatocellular carcinoma with tumor thrombi in the portal vein is known to be extremely poor. The current results of various therapies, such as surgery, chemotherapy, immuno-therapy, radiation and combination therapy were reviewed, herein. Our recent therapeutic strategy for hepatocellular carcinoma with tumor thrombi in portal vein is also shown.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

The Sialyl Lewis X expression in hepatocarcinogenesis: potential predictor for the emergence of hepatocellular carcinoma.

BACKGROUND/AIMS: Sialyl Lewis X (sLeX), one of the cancer-associated glycoproteins, has been reported to be expressed in both liver tissue from various types of liver disease and hepatocellular carcinoma. In order to clarify sLeX expression during the early stage of hepatocarcinogenesis, we examined sLeX expressions in either liver tissue specimens without any nodular lesions, dysplastic nodules or hepatocellular carcinomas. METHODOLOGY: Immunohistochemical observations were performed using a monoclonal antibody for sLeX. As for the liver tissue specimens, 8 livers without any chronic liver disease and 42 diseased livers were examined, while for the nodular lesions, 5 dysplastic nodules (borderline lesions) and 47 hepatocellular carcinomas were examined in this study. RESULTS: sLeX was not expressed in all 8 normal livers. sLeX was expressed membraneously in 8 of 15 (53%) chronic hepatitic liver tissue specimens, in 8 of 9 (89%) precirrhotic liver tissue specimens and in 16 of 18 (89%) cirrhotic liver tissue specimens. The incidence of sLeX expression on hepatocytes in both pre-cirrhotic and cirrhotic liver tissue was higher than that in chronic hepatitic liver tissue (P < 0.05). The sLeX expression in liver tissue was positive in all 14 liver tissue specimens containing multiple hepatocellular carcinomas, in which at least one of the nodules was a well-differentiated hepatocellular carcinoma regarded as multicentric hepatocellular carcinomas. In 18 of 28 (64%) liver tissue specimens without multicentric hepatocellular carcinomas, sLeX was positive and the difference was statistically significant (P < 0.05). In nodular lesions, sLeX was negative in 5 dysplastic nodules (borderline lesions). In hepatocellular carcinoma, 14 of 47 (30%) hepatocellular carcinoma nodules showed a positive expression. Six of 14 (43%) well-differentiated hepatocellular carcinomas were positive on the cell membrane. Four of 23 (17%) moderately differentiated hepatocellular carcinomas were positive on the cell membrane, while one of 23 (4%) moderately differentiated hepatocellular carcinoma was positive in the cytoplasm. In addition, 3 of 10 (30%) poorly differentiated hepatocellular carcinomas were positive in the cytoplasm. CONCLUSIONS: These results suggested that the sLeX-positive liver tissue specimens possessed a high degree of carcinogenicity and therefore sLeX expression in the diseased liver might be a good predictor for hepatocellular carcinoma emergence. At the same time, the suppression of sLeX occurred at a very early stage of hepatocarcinogenesis. In addition, the phenotype of sLeX was also considered to change during the progression of hepatocarcinogenesis.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

The role of MTA1 gene expression in human hepatocellular carcinoma.

The MTA1 gene has been identified as metastasis-associated gene and has been seen to correlate with the degree of invasion and lymphatic metastasis in gastric, colorectal, and esophageal carcinomas. We investigated the possible role of MTA1 gene expression in hepatocellular carcinoma (HCC). The mRNA expression level of the MTA1 gene was examined using reverse transcription polymerase chain reaction (RT-PCR) in HCC and paired non-tumor liver tissues which were obtained from 33 patients who underwent curative hepatectomy. The expression level of each case was calculated as tumor/non-tumor (T/N) ratios. To clarify the clinical significance of MTA1 gene expression in HCC, patient disease-free survival rate after hepatectomy were univariately analyzed using 25 clinicopathological variables, including MTA1 expression level. High expression (T/N > or =1) of the MTA1 gene in HCC as compared to the paired non-tumor tissues was recognized in 14 of 33 (42%) samples. With regard to the differentiation of HCC, the high expression of MTA1 gene in well or moderately differentiated HCC and poorly differentiated HCC were observed in 9 of 27 (33%) and 5 of 6 (83%) samples, respectively. There was no relation between expression levels of the MTA1 gene and cancer invasion to the portal vein or intrahepatic metastasis. However, the disease-free survival rate of the MTA1-high expression group (T/N > or =1) was significantly lower than that of the MTA1-low expression group (T/N <1) (p<0.05). High expression of the MTA1 gene is suggested to be a new prognostic indicator after curative hepatectomy for HCC.

Aged↗

PubMedDate not supplied

Analysis of the prognostic factors for liver metastasis of gastric cancer after hepatic resection: a multi-institutional study of the indications for resection.

BACKGROUND/AIMS: The number of reports of hepatic resection for metastatic gastric cancer is very small. The outcome and indications of hepatic resection for metastatic gastric cancer remains unknown. METHODOLOGY: A multi-institutional study was made. Thirty-six patients who underwent a hepatic resection for liver metastasis of gastric cancer with no residual tumor were included in this study. The clinicopathological factors were examined as prognostic factors by multivariate analyses. Thirty patients had recurrence and the recurrence pattern and risk factors for extrahepatic recurrence was examined. RESULTS: The overall survival rate was 64% at 1 year, 43% at 2 years, 26% at 3 years 26% at 5 years, and 26% at 10 years after hepatectomy. Multivariate analysis showed that lymphatic invasion, venous invasion of cancer cells of primary gastric cancer and the number of the liver metastasis (> 3) were independent poor prognostic factors after hepatic resection. The most common recurrence pattern was intrahepatic recurrence in 22 patients (73%). The risk factors for extrahepatic recurrence was serosal invasion, lymph node metastasis of primary gastric cancer, stage, and curability of operation. CONCLUSIONS: Hepatic resection for liver metastasis should be attempted in case primary gastric cancer has neither lymphatic invasion nor venous invasion. The most common recurrent site was the liver. In patients with advanced gastric cancer, having neither serosal invasion nor lymph node metastasis, who underwent a less curative operation, the intra-hepatic recurrence would be expected. Thus, aggressive adjuvant chemotherapy through the hepatic artery may improve the survival after hepatectomy in these patients.

Aged↗

PubMedDate not supplied

Change in alpha glutathione s-transferase levels during liver resection.

BACKGROUND/AIMS: Alpha-glutathione s-transferase (GST) is a 50,000-kDa cytosol protein of the hepatocytes. It comprises 5% of the soluble protein of hepatocytes and is readily released in response to injury. Its half-life time is 60 minutes (AST: 47 hrs, ALT: 22 hrs). The aim of this study is to clarify the usefulness of GST measurement during liver resection. We obtained data from 26 patients undergoing liver resection and compared GST levels with AST and ALT levels. METHODOLOGY: Patients included 15 hepatocellular carcinoma, 5 cholangiocellular carcinoma and 6 metastatic cancers (4: colon, 2: stomach). We performed lobectomy for 11, segmentectomy for 5 and partial resection for 10 patients. From these patients, blood samples were collected before surgery, beginning of resection, end of resection, 15, 30, 60 min after resection, end of surgery, 1, 3, 6, 12, 24 hr after operation and 2, 3, 4, 5, 6, 7, 10, 14 postoperative days (POD). GST (Biotrin, Ireland) levels in the serum samples were determined by an ELISA. We also measured AST, ALT levels from the same set of samples. RESULTS: At the end of resection, GST showed highest level and quickly decreased at 1 hr after operation. On the other hand, AST and ALT showed peak levels at 12 hr after operation. CONCLUSIONS: Our findings suggest that perioperative GST measurement may be a sensitive and useful marker to evaluate liver function after liver resection.

Adult↗

PubMedDate not supplied

Preoperative hyaluronic acid measurement to assess the hepatic functional reserve.

BACKGROUND/AIMS: With liver surgery, preoperative assessment of the hepatic functional reserve is important for estimating the extent of hepatectomy. Hyaluronic acid (HA) is specifically cleared and metabolized by endothelial cells in the liver. Its half-life time is 2-5 min and HA might be a sensitive liver function marker. We obtained data from 44 patients with liver tumor undergoing liver resection. METHODOLOGY: We studied 44 liver resected patients. Blood samples were obtained before surgery and HA levels and other liver function markers [type IV collagen (IV), procollagen-III-peptide (PIIIP), lecithin-cholesterol acyltransferase (LCAT), cholinesterase (ChE), albumin (Alb), platelets (Plt), prothrombin time (PT%)] levels in the samples were measured. We also performed indocyanine green retention test and calculate R15% (ICG). RESULTS: HA showed strong positive correlation with ICG, IV and PIIIP, negative correlation with LCAT, ChE, Alb, Plt and PT%. ICG was not correlated with ChE, Plt and PT%. The HA levels and ICG of the patients who had more than 2 segments of the liver resected were below 100 ng/mL and 20%, respectively. In the patients with obstructive jaundice HA levels of the 3 patients with obstructive jaundice who underwent bisegmentectomy were below 100 ng/mL. CONCLUSIONS: Our findings suggest that HA is a useful preoperative liver function test as well as ICGR15%. Preoperative HA levels <100 ng/mL and ICGR15% <20% might be helpful indicators for major liver resection. We also recommend that HA measurement for evaluating liver function in the patients with obstructive jaundice ICG is not helpful.

Adult↗

PubMedDate not supplied

Role of tissue trace elements in liver cancers and non-cancerous liver parenchyma.

BACKGROUND/AIMS: The role of trace elements in liver fibrosis, carcinogenesis and progression of hepatocellular carcinoma (HCC) has not yet been clarified. The aim of this study is to analyze the characteristics of trace elements in liver cancers and non-cancerous liver and to discuss their role in hepatic fibrosis, hepatocarcinogenesis and progression of HCC. METHODOLOGY: The amount of zinc (Zn), iron (Fe), and copper (Cu) in 20 HCCs, 2 cholangiocellular carcinomas (CCC), 7 metastatic liver cancers (Meta) and their non-tumorous liver parenchyma were measured using an atomic absorption spectrophotometer. RESULTS: The amounts of Zn and Fe in non-tumorous liver parenchyma were reduced by liver fibrosis, and the amounts were lower in HCC tissue compared to non-tumorous liver parenchyma. The amounts of Zn and Cu were higher in HCC than the amounts found in CCC and Meta. The amount of Zn in HCC tissue decreased, but the amount of Fe increased in tumors more than 4cm in diameter. CONCLUSIONS: These results suggest that the decrease in the amount of Zn and Fe found in non-tumorous liver parenchyma correlates with liver fibrosis leading to cirrhosis and hepatocarcinogenesis. Also that decreases in Zn and increases of Fe in HCC tissue correlates with HCC tumor progression.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

A novel intrahepatic arterial chemotherapy after radical resection for advanced hepatocellular carcinoma.

BACKGROUND/AIMS: Advanced hepatocellular carcinoma (HCC) with portal vein invasion and/or intrahepatic metastasis has an unfavorable prognosis even after radical hepatic resection. The aim of this study was to evaluate the effectiveness of a novel postoperative adjuvant chemotherapy given through the hepatic artery and based on biochemical modulation using cisplatin (CDDP) and 5-fluorouracil (5-FU). METHODOLOGY: Fifteen patients with advanced HCC with portal vein invasion into the main trunk and/or intrahepatic metastases of more than 3 segments were included in this study. After radical hepatic resection, the patients were divided to two groups: the adjuvant chemotherapy group (n=7) given the novel arterial infusion regimen with CDDP and 5-FU, and the control group (n=8) given no adjuvant chemotherapy. RESULTS: Three-year survival rate of the adjuvant chemotherapy group tended to be significantly longer compared to that for the control group (p < 0.05). Most of the tumor recurrence was in the remnant liver, 5 cases in both of the groups. Significant difference of the recurrence patterns was recognized, rather than difference of the disease-free survival rate between the two groups. All of the intrahepatic recurrences are multiple in the control group, but in the adjuvant chemotherapy group, 2 cases of the recurrences showed a localized tumor surgically resected. It is noteworthy that the occurrence of multiple recurrence was significantly later in the adjuvant chemotherapy group compared to the control group (18.9 months vs. 6.5 months; p<0.05). CONCLUSIONS: Our data suggest that this novel adjuvant chemotherapy can improve the postoperative prognosis of patients with the advanced HCC.

Aged↗

PubMedDate not supplied

Preoperatively undiagnosable intrahepatic bile duct dilatation contains early-stage intrahepatic cholangiocarcinoma.

Intrahepatic bile duct dilatation is a clue to indicating the presence of IHCC. Moreover it is still often difficult to find IHCC at an early stage in spite of recent progress in the area of molecular biological markers and imaging modalities. We had three interesting cases in which we were suspicious of the presence of IHCC. Preoperative imaging studies of these three cases showed the dilatation and stenosis of the intrahepatic bile duct without any apparent mass. As IHCC could not be ruled out, a hepatectomy was done for the purpose of both diagnosis and treatment of the patients. Postoperative diagnoses were IHCC in one, hepatolithiasis in another and chronic cholangitis in the third patient. A histological analysis revealed that the tumor of IHCC was not infiltrating the parenchyma of the liver with neither vascular nor lymphatic invasion, which suggested that it was an initial nature of the IHCC. In the case of intrahepatic bile duct dilatation and stenosis, which makes it hard to identify IHCC, surgical resection is crucial to make a definite diagnosis and prescribe the most effective course of treatment.

Abdominal Pain↗

PubMedDate not supplied

Gemcitabine combined with 5-fluorouracil and cisplatin (GFP) in patients with advanced biliary tree cancers: a pilot study.

BACKGROUND: Advanced biliary tree cancers have poor prognosis and chemotherapy has been shown to have little impact. To date, no standard chemotherapy regimens have been established. A pilot study to evaluate gemcitabine/5-Fluorouracil(5-FU)/cisplatin(CDDP) (GFP) chemotherapy in patients with advanced biliary tree cancers was performed. PATIENTS AND METHODS: Eight patients with advanced intrahepatic cholangiocarcinoma and gallbladder carcinoma with no prior chemotherapy were treated with a 4-week cycle GFP chemotherapy consisting of gemcitabine at 1000 mg/m2 on days 1, 8, and 15, and of 5-FU at 250 mg/patient and CDDP at 5 mg/patient on days 1 to 5, 8 to 12 and 22 to 26. RESULTS: Of these 8 patients, no complete responses (CR) were observed, but 3 patients (37.5%) demonstrated partial responses (PR) with an additional 3 patients (37.5%) having stable diseases (SD), as assessed by RECIST. Two patients with PR and 1 patient with SD were treated by curative operation after GFP chemotherapy and all of them survived with no recurrence. The median overall survival time was 23.5 months, and median time to progression was 14.5 months. Grade 3/4 side-effects, such as leukopenia, thrombocytepenia and anemia were found in 4 patients (50%), but no patients dropped out because of toxicity. CONCLUSION: This GFP chemotherapy has promising antitumor activity and is well tolerated in patients with advanced biliary tree cancers. This regimen warrants further evaluation in a phase II study including larger numbers of patients.

Adenocarcinoma↗