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Background: Sorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population., Methods: Patients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected., Results: This interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299-389 days], and the median duration of treatment was 87 days (95 % CI 78-98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection., Conclusions: In general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients., Clinical Trial Registration Number: NCT01411436., Competing Interests: Compliance with ethical standard Conflict of interest Shuichi Kaneko has received research grants from Bayer Yakuhin and Nippon Shinyaku, and grants from Chugai Pharmaceutical, MSD, Kowa, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, Eli Lilly, Boehringer Ingelheim Japan, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Eisai, Daiichi Sankyo, AstraZeneca, Novartis Pharma, Astellas Pharma, Teijin Pharma, Zeria Pharmaceutical, Sanofi, Toray Industries, Shionogi, Novo Nordisk Pharma, and Pfizer Japan. Kenji Ikeda has received lecture fees from Sumitomo Dainippon Pharma and Eisai. Yasushi Matsuzaki has received research grants from Mitsubishi Tanabe Pharma, MSD, Ajinomoto Pharmaceuticals, Eisai, Sumitomo Dainippon Pharma, AbbVie, Daiichi Sankyo, Toray Industries, Minophagen Pharmaceutical, Otsuka Pharmaceutical and Kyowa Hakko Kirin, and lecture fees from Mitsubishi Tanabe Pharma, MSD, Ajinomoto Pharmaceuticals, Bristol-Myers Squibb and Janssen Pharmaceutical. Junji Furuse has received research grants from Taiho Pharma, Ono Pharmaceutical, OncoTherapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, GlaxoSmithKline and Yakult, and lecture fees from Taiho Pharma, Chugai Pharmaceutical, Yakult and Kyowa Hakko Kirin. Hironobu Minami has received research grants from Kyowa Hakko Kirin, Chugai Pharmaceutical, Taiho Pharma and Bristol-Myers Squibb. Yutaka Okayama, Toshiyuki Sunaya, Yuichiro Ito and Lyo Inuyama are employees of Bayer Yakuhin, Ltd. The other authors declare that they have no conflicts of interest.

Purpose: To evaluate the safety and effectiveness of proton beam therapy for hepatocellular carcinoma (HCC) located adjacent to the alimentary tract., Patients and Methods: Forty-seven patients (median age, 69 years; range, 43-82 years) who had HCC located within 2 cm of the alimentary tract underwent proton beam therapy. Liver damage according to the Child-Pugh classification was Class A in 35 patients, Class B in 9, and Class C in 3. Treatment protocols of the early 16 patients and the late 31 patients were 72.6 GyE in 22 fractions and 77 GyE in 35 fractions, respectively., Results: During the median follow-up period of 23 months, 24 patients died; the remaining 23 patients were alive until September 2008. The median overall survival was 33.9 months (95% confidence interval [CI], 10.8-57.0 months). Actuarial overall and local progression-free survival rates at 3 years were 50.0% and 88.1%, respectively. Grade 2 and 3 alimentary tract hemorrhage was observed in 3 (6.4%) and 1 (2.1%) patients, respectively., Conclusions: Our proton beam therapy strategy for HCC located adjacent to the alimentary tract seems to be effective but should be performed with caution., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To investigate the safety and efficacy of proton beam therapy (PBT) in patients with large hepatocellular carcinoma (HCC)., Methods and Materials: Twenty-two patients with HCC larger than 10 cm were treated with proton beam therapy at our institution between 1985 and 2006. Twenty-one of the 22 patients were not surgical candidates because of advanced HCC, intercurrent disease, or old age. Median tumor size was 11 cm (range, 10-14 cm), and median clinical target volume was 567 cm(3) (range, 335-1,398 cm(3)). Hepatocellular carcinoma was solitary in 18 patients and multifocal in 4 patients. Tumor types were nodular and diffuse in 18 and 4 patients, respectively. Portal vein tumor thrombosis was present in 11 patients. Median total dose delivered was 72.6 GyE in 22 fractions (range, 47.3-89.1 GyE in 10-35 fractions)., Results: The median follow-up period was 13.4 months (range, 1.5-85 months). Tumor control rate at 2 years was 87%. One-year overall and progression-free survival rates were 64% and 62%, respectively. Two-year overall and progression-free survival rates were 36% and 24%, respectively. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No late treatment-related toxicity of Grade 3 or higher was observed., Conclusions: The Bragg peak properties of PBT allow for improved conformality of the treatment field. As such, large tumor volumes can be irradiated to high doses without significant dose exposure to surrounding normal tissue. Proton beam therapy therefore represents a promising modality for the treatment of large-volume HCC. Our study shows that PBT is an effective and safe method for the treatment of patients with large HCC., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background and Purpose: The prognosis of patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is extremely poor, as effective treatment options are limited. The authors performed a retrospective review to evaluate the efficacy of proton-beam therapy (PBT) for patients presenting with PVTT in the setting of HCC., Patients and Methods: Between February 1991 and September 2005, 35 patients with HCC and tumor thrombi in the main trunk or major branches of the portal vein presented for consideration of PBT. Their tumor sizes ranged from 25 mm to 130 mm (median, 60 mm). A median total dose of 72.6 GyE in 22 fractions was delivered over 31 days to a target volume that encompassed both the primary hepatic lesion and the PVTT., Results: 32 patients were progression-free during a median follow-up period of 21 months (range, 2-88 months) and three patients experienced disease progression. Local progression-free survival rates were 46% at 2 years and 20% at 5 years, and the median local progression-free survival was 21 months. Acute toxicity > or = grade 3 was observed in three patients, and no patient experienced late toxicity > or = grade 3. None of the patients had to discontinue treatment as a result of toxicity., Conclusion: PBT improved local control and significantly prolonged survival in HCC patients with PVTT.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with a poor prognosis. New therapeutic modalities, such as continuous hepatic arterial infusion chemotherapy (CHAIC), have recently been reported to be promising strategies. The aim of this study was to evaluate the clinical characteristics, prognosis, and survival of patients with PVTT according to treatment regimen. One hundred ninety-three patients with HCC complicated with PVTT at the time of diagnosis were included in this study. All patients were newly diagnosed to have HCC and were observed from January 1992 to December 2003. CHAIC was performed using an implanted drug delivery system with low-dose cisplatin and 5-fluorouracil. Clinical characteristics, prognosis, and patient survival were analyzed by the Kaplan-Meier method and Cox's proportional hazards model. The mean age of the patients complicated with PVTT was 64.3+/-10.3 years (range, 20-88 years). The survival of the 193 patients with PVTT was 37.5%, 24.0%, 18.9%, and 8.3% at 1, 2, 3, and 5 years, respectively. According to treatment, the survival of patients who underwent surgical treatment was the best, followed by CHAIC, transcatheter arterial infusion/embolization, and supportive care. The 3-year survivals for each treatment regimen were 53.0%, 19.3%, 15.0%, and 4.0%, respectively. Although the survival of patients who received surgical treatment was best, such patients were restricted. There was no difference in survival between treated and untreated patients demonstrating Child-Pugh grade C. In Child B patients, treatment for HCC significantly increased survival (P<0.01). Cox's proportional hazards model revealed the Child-Pugh classification to be an independent prognostic factor for patients with HCC and PVTT (P<0.01). We conclude that the prognosis of HCC with PVTT was quite poor. The treatment did not improve the survival of Child C patients. As a result, the prevention, early diagnosis, and development of new treatment strategies are required.

Objective: To evaluate the anti-proliferation effects of dehydroepiandrosterone (DHEAéand DHEA sulfate (DHEAs) on tumor cells., Methods: Human hepatoblastoma cells (HepG2) and colon adenocarcinoma cells (HT-29) were treated with DHEA and DHEAs of various concentrations. The cells were incubated for 8, 24, 48, and 72 hours, and the proliferation, apoptosis, cell cycle and the expression of phosphorylated Akt (Thr308 and Ser473) were analyzed using MTT assay, flow cytometry, and Western blotting at different time points. The influences of an inhibitor (LY294002) and an activator (hepatic growth factor; HGF) of PI3K on the effectiveness of DHEA were determined in HepG2 cells., Results: By increasing the concentrations of DHEA (1, 10, 50, 100, 200 micromol/L), the percentages of HepG2 and HT-29 survival cells treated with DHEA at 24 h were 92.7%+/-0.9%, 84.7%+/-1.2%, 62.4%+/-0.8%, 49.5%+/-0.8%, 50.7%+/-0.3% and 92.5%+/-0.4%, 89.5%+/-0.7%, 80.5%+/-1.1%, 67.5%+/-1.5%, 70.6%+/-0.6%, respectively. Proliferations of HepG2 and HT-29 cells were significantly inhibited after 24 hours of being incubated with 100 micromol/L DHEA treatment; the inhibition effect was stronger on HepG2 cells than on HT-29 cells. The effect of DHEAs on both cell lines on cell proliferation was weaker than that of the DHEA. In the cell cycle assay, DHEA treatment induced cell arrest in G0/G1 phase in both cell lines. Apoptosis of HepG2 cells was significantly triggered (18.6%+/-2.2%) by 100 micromol/L DHEA treatment for 24 hours, but not by DHEAs. In addition, 100 and 200 micromol/L DHEA treatments for 24 hours markedly inhibited phosphorylations of Akt (Thr308 and Ser473) in HepG2 cells, and these effects were enhanced by exposing them to LY294002 and stopped by exposing them to HGF. The anti-proliferative effects of DHEA on tumor cell lines were much stronger than those of DHEAs, and they were even stronger in HepG2 cells than in HT-29 cells., Conclusion: Our results suggest that the induction of apoptosis through the inhibition of Akt signaling pathway is one of the anti-proliferative mechanisms of DHEA in certain tumors, but DHEA also promotes cell-cycle arrest.

Three patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) were treated using proton beam therapy at the University of Tsukuba, Japan. A total dose of 50-70 Gy in 10-35 fractions was given to the primary tumor and IVCTT. All the patients survived for more than 1 year from the beginning of proton beam therapy (13-55 months) and no treatment-related toxicity of grade 3 or higher was observed. These cases suggest that proton beam therapy is safe and effective for patients with HCC associated with IVCTT.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, HCC is rare in young Japanese patients and the clinical features of young patients with HCC have not yet been fully studied. This study was designed to determine the clinical characteristics and prognosis of patients with HCC who are younger than aged 40 years. A retrospective analysis was performed for patients newly diagnosed with HCC and observed from January 1990 to December 2003 at our hospitals. Patients younger than aged 40 years at the diagnosis of HCC were defined as the young group and were reviewed. There were 20 patients (16 males) with HCC who were younger than aged 40 years. The mean age at diagnosis was 33.6 (range, 20-39) years. Fifteen of 20 patients were positive for hepatitis B surface antigen (HBsAg) and 2 patients were positive for hepatitis C virus antibody. According to the Child-Pugh grading, the liver function was relatively good in all patients. Because most of the patients did not receive periodic follow-up, this disease often was discovered at an advanced stage, usually after the appearance of some symptoms. Although intensive treatment was performed for such young patients, the survival was nevertheless poor. Most patients died from this cancer within 1 year. However, one patient who received periodic follow-up and also was in relatively good physical condition had a better prognosis, and he survived for 88 months. Young patients with HCC tended to have a poor prognosis because of advanced stage of HCC, despite a well-preserved liver function and aggressive treatment. Screening for HCC and an early diagnosis is needed for such patients to demonstrate an improved prognosis, especially for HBsAg-positive patients.

Background and Purpose: Hepatocellular carcinoma (HCC) patients with severe cirrhosis are usually treated with supportive care because of their poor prognosis. However, the survival of severe cirrhotic patients has recently improved due to advanced treatments. The aim of this study was to define the role of proton beam therapy for HCC patients with severe cirrhosis., Patients and Methods: 19 HCC patients with Child-Pugh class C cirrhosis received proton beam therapy. The hepatic tumors were solitary in 14 patients and multiple in five, and the tumor size was 25-80 mm (median 40 mm) in maximum diameter. No patient had regional lymph node or distant metastasis. Total doses of 50-84 Gy (median 72 Gy) in ten to 24 fractions (median 16) were delivered to the tumors., Results: Of the 19 patients, six, eight and four died of cancer, liver failure and intercurrent diseases, respectively, during the follow-up period of 3-63 months (median 17 months) after treatment. A remaining patient was alive with no evidence of disease 33 months after treatment. All but one of irradiated tumors were controlled during the follow-up period. Ten patients had new intrahepatic tumors outside the irradiated volume. The overall and progression-free survival rates were 53% and 47% at 1 year, respectively, and 42% each at 2 years. Performance status and Child-Pugh score were significant prognostic factors for survival. Therapy-related toxicity of grade 3 or more was not observed., Conclusion: Proton beam therapy for HCC patients with severe cirrhosis was tolerable. It may improve survival for patients with relatively good general condition and liver function.

Hypercholesterolemia is an important paraneoplastic syndrome in patients with hepatoma, but the nature of this defect has not yet been identified. We investigated the molecular mechanisms of hypercholesterolemia in a hepatoma-bearing rat model. Buffalo rats were implanted in both flanks with Morris hepatoma 7777 (McA-RH7777) cells. After 4 weeks, tumor weight was 5.5+/-1.7 g, and serum cholesterol level increased from 60+/-2 to 90+/-2 mg/dL. Protein and mRNA expression of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) was markedly higher in tumors than in livers. These increases were associated with activation of liver X receptor alpha (LXRalpha) as a result of the increased tissue oxysterol concentrations. The accumulation of oxysterols in the hepatomas appeared to be caused mainly by the upregulation of cholesterol biosynthesis, despite the increased tissue sterol concentrations. Overexpression of the sterol regulatory element-binding protein (SREBP) processing system relative to sterol concentration contributed to the resistance to sterols in this tumor. In addition, bile acid biosynthesis was inhibited despite the reduced expression of the small heterodimer partner (SHP) and activated LXRalpha, which also appeared to contribute to the accumulation of oxysterols followed by the acceleration of cholesterol efflux. In conclusion, hypercholesterolemia in McA-RH7777 hepatoma-bearing rats was caused by increased cholesterol efflux from tumors as a result of activation of LXRalpha. Overexpression of the SREBP processing system contributed to the activation of LXRalpha by maintaining high oxysterol levels in tissue.

Background: The authors conducted a retrospective review to define the usefulness of proton beam therapy for patients who had hepatocellular carcinoma (HCC) with limited treatment options., Methods: Twenty-one patients with HCC for whom other treatment modalities either were contraindicative or were unfeasible because of coexisting diseases and unfavorable conditions received proton beam therapy. Four patients had renal failure, 2 patients had severe heart disease, 9 patients had severe cirrhosis, 1 patient had aplastic anemia, 1 patient had a dissecting abdominal aortic aneurysm before treatment, and 4 patients had bleeding tendency or unresectable tumors. Moreover, 2 of the latter 4 patients were allergic to iodine, and 2 other patients were unable to be catheterized for transcatheter arterial chemoembolization. Hepatic tumors were solitary in 14 patients and multiple in 7 patients, and the tumors ranged in greatest dimension from 25 mm to 100 mm (median, 40 mm). No patient had regional lymph node or distant metastasis. Total doses of 63 grays (Gy) to 84 Gy (median, 73 Gy) in 13 to 27 fractions (median, 18 fractions) were used for tumor treatments., Results: All but 1 of the irradiated tumors were controlled at a median follow-up of 3.3 years. The objective response rate was 81%, and the primary site-control rate was 93% at 5 years. Eleven patients had intrahepatic recurrences, and 2 patients had distant metastases in the lungs. Four of 11 patients with intrahepatic recurrences received a second course of proton beam therapy, and all recurrent tumors were controlled. The overall and cause-specific survival rates were 62% and 82% at 2 years, respectively, and 33% and 67% at 5 years, respectively. Grade > or =3 therapy-related toxicities were not observed., Conclusions: Proton beam therapy was safe and effective for a variety of patients with HCC. The current results suggested that this method was tolerable and effective, even for patients with HCC who had limited treatment options., (Copyright 2006 American Cancer Society.)

Purpose: To retrospectively evaluate the safety and effectiveness of repeated proton beam therapy for newly developed or recurrent hepatocellular carcinoma (HCC)., Methods and Materials: From June 1989 through July 2000, 225 patients with HCC underwent their first course of proton beam therapy at the University of Tsukuba. Of them, 27 with 68 lesions who had undergone two or more courses were retrospectively reviewed in this study. Median interval between the first and second course was 24.5 months (range 3.3-79.8 months). Median total dose of 72 Gy in 16 fractions and 66 Gy in 16 fractions were given for the first course and the rest of the courses, respectively., Results: The 5-year survival rate and median survival period from the beginning of the first course for the 27 patients were 55.6% and 62.2 months, respectively. Five-year local control rate for the 68 lesions was 87.8%. Of the patients, 1 with Child-Pugh class B and another with class C before the last course suffered from acute hepatic failure., Conclusions: Repeated proton beam therapy for HCC is safe when the patient has a target in the peripheral region of the liver and liver function is Child-Pugh class A.

Aim: To identify the clinical and prognostic features of patients with hepatocellular carcinoma (HCC) aged 80 years or more., Methods: A total of 1310 patients with HCC were included in this study. Ninety-one patients aged 80 years or more at the time of diagnosis of HCC were defined as the extremely elderly group. Two hundred and thirty-four patients aged > or = 50 years but less than 60 years were regarded as the non-elderly group., Results: The sex ratio (male to female) was significantly lower in the extremely elderly group (0.90:1) than in the non-elderly group (3.9:1, P < 0.001). The positive rate for HBsAg was significantly lower in the extremely elderly group and the proportion of patients negative for HBsAg and HCVAb obviously increased in the extremely elderly group (P < 0.001). There were no significant differences in the following parameters: diameter and number of tumors, Child-Pugh grading, tumor staging, presence of portal thrombosis or ascites, and positive rate for HCVAb. Extremely elderly patients did not often receive surgical treatment (P < 0.001) and they were more likely to receive conservative treatment (P < 0.01). There were no significant differences in survival curves based on the Kaplan-Meier methods in comparison with the overall patients between the two groups. However, the survival curves were significantly worse in the extremely elderly patients with stage I/II, stage I/II and Child-Pugh grade A cirrhosis in comparison with the non-elderly group. The causes of death did not differ among the patients, and most cases died of liver-related diseases even in the extremely elderly patients., Conclusion: In the patients with good liver functions and good performance status, aggressive treatment for HCC might improve the survival rate, even in the extremely elderly patients.

The potential anti-proliferation effect of interferon-alpha (IFN-alpha) against hepatocellular carcinoma (HCC) and its growth inhibitory mechanisms remain unclear. We examined four human HCC cell lines and every cell line had the anti-proliferative effect of IFN-alpha. The PLC/PRF/5 cell line, which expressed the IFN receptor most abundantly, responded most effectively to IFN-alpha stimulation. Here, we delineate the anti-proliferative effect of IFN-alpha via the MAPK pathway in human HCC cell lines. IFN-alpha retarded G1/S transition with no evidence of apoptosis and inhibited cell proliferation. IFN-alpha diminished the phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK), but not Raf, within 5 min. Knockdown of signal transducers of activation and transcription1 (STAT1) or Janus kinase1 (JAK1) suppressed the reduction of phosphorylation both of ERK and MEK and diminished the growth inhibition by IFN-alpha. These results suggest that IFN-alpha induces anti-proliferative signaling via the JAK/STAT pathway downstream of IFN-alpha receptors and may reduce the growth stimulation signaling by cross-talk with the MEK/ERK pathway without IFN-alpha-induced transcription.

Background: Treatment modalities for patients with hepatocellular carcinoma (HCC) who have portal vein tumor thrombus (PVTT) are limited and controversial; furthermore, the prognosis for these patients is extremely poor. The authors conducted a retrospective review to determine the role of proton beam therapy in the treatment of patients who had HCC with PVTT., Methods: Twelve patients with HCC who had tumor thrombus in the main trunk or major branches of the portal vein (clinical T3-T4N0M0) were treated with proton beam therapy. At the time they received proton beam irradiation, patients ranged in age from 42 years to 80 years (median, 62 years), and their tumors ranged in size from 40 mm to 110 mm (median, 60 mm) in greatest dimension. A total dose of 50-72 gray (Gy) (median, 55 Gy) in 10-22 fractions was delivered to the tumors, including PVTT., Results: All tumors that were treated with proton beam therapy remained controlled at a median follow-up of 2.3 years (range, 0.3-7.3 years). Among 12 patients, 10 patients had new liver tumors outside the irradiated volume 0.1-2.4 years after proton beam therapy, and 3 patients also had distant metastases; consequently, 8 patients died of disease, and 2 patients were salvaged by further therapies. The remaining two patients were alive with no evidence of disease 4.3 years and 6.4 years after proton beam therapy. The progression-free survival rates were 67% at 2 years and 24% at 5 years. The median progression-free survival was 2.3 years. According to the Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group), therapy-related toxicity > or = Grade 3 was not observed., Conclusions: Proton beam therapy for patients with HCC who had PVTT was feasible and effective. It appeared to improve survival and local control significantly for these patients.

Purpose: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy., Experimental Design: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days., Results: The overall survival rate for all of the 162 patients was 23.5% at 5 years. The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients. The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%. The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments., Conclusions: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases.

Phospholipase A(2) IIA (PLA(2)IIA), which plays a crucial role in arachidonic acid metabolism and in inflammation, is upregulated under various pathological conditions, including in the gallbladder and gallbladder bile from patients with multiple cholesterol gallstones, in the liver and kidney of rats with cirrhosis, as well as in the colonic tissue of animals treated with a chemical carcinogen. The administration of ursodeoxycholic acid (UDCA) partially attenuated the PLA(2)IIA expression level in these different models. The aim of this study was to investigate the modulatory effect of UDCA on the PLA(2)IIA expression level at the cellular level. The HepG2 cells were selected to investigate the direct inhibitory effect of UDCA on PLA(2)IIA expression level. The proinflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) -induced PLA(2)IIA expression in HepG2 cells was partially inhibited by the presence of UDCA in a dose-dependent fashion. The effect of UDCA on proinflammatory cytokines-induced PLA(2)IIA expression occurred at the transcriptional level. In addition, among the bile acids tested, this inhibitory effect was UDCA-specific. In conclusion, this study supports the possible alteration of arachidonic acid metabolism and PLA(2)IIA expression level, in particular, as the protective action of UDCA in patients with chronic liver disease.

Background: We have reported that proton radiotherapy for hepatocellular carcinoma (HCC) is a safe and effective therapeutic option. However, it is difficult to evaluate its effect in certain cases. Recently, it has been reported that the usage of contrast-enhanced color Doppler ultrasonography (CECDU) can improve diagnostic accuracy, both in terms of the presence of hepatic tumor and in the evaluation of treatment. The aim of this study was to determine the usefulness of CECDU in assessing the therapeutic response of HCC treated with proton radiotherapy., Methods: Twenty-two patients treated with the proton radiotherapy were studied. We inspected HCC lesions by CECDU, before and after the irradiation, over time. The magnitude of blood flow in the HCC was quantified on still images by CECDU. The ratio of the number of color pixels against that of the total number of pixels in the tumor area was defined as the tumor blood flow ratio (TBFR)., Results: Immediately after the proton treatment, a transient increase of blood flow in the tumor was recognized in more than half of the patients, while the TBFR was unchanged or decreased in the remaining patients. At longer periods after irradiation, the TBFR in all HCCs gradually decreased, and this reduction of TBFR was statistically significant from 9 months after irradiation. These findings are consistent with those obtained previously by computed tomography (CT) as well as magnetic resonance imaging (MRI)., Conclusions: We propose CECDU as a useful diagnostic option for the evaluation of HCC treated with proton radiotherapy.

The aim of this study is to elucidate the important role of the previous infection of HBV, and the relations among HBV genome integration and p53 gene mutation, telomerase activity and genetic instability in liver tissue with HBsAg-negative (NB) and anti-HCV negative (NC) hepatocellular carcinoma (HCC). We examined the backgrounds of 34 NB and NC (NBNC) Japanese patients with chronic liver disease (CLD) patients not associated with HCC and 26 NBNC CLD patients with HCC. HBV genome integration into host cell genome, p53 gene mutation telomerase activity and genetic instability were examined in 6 with NBNC HCC (NBNC-HCC) tumorous tissue (T) and non-tumorous tissues (NT). In the NBNC group, HBV-related antibody positive patients with HCC are significantly more than the patients without HCC. Moreover, concerning the stage of the coexisted liver diseases, in NBNC CLD, LC patients with HCC is 19 of 26 (73.1%) , on the other hand, LC patients without HCC is 16 of 34 (47.1%). LC patients with HCC group is significantly more than that without HCC. Three (50%) of 6 in T and 3 cases (50% ) in NT were found to integrated genome of HBV. p53 gene mutation was observed in 3 (50%) of T. Concerning the telomerase activity, 3 of 6 cases (50%) in T and 1 case in NT was recognized. There was no genetic instability (LOH or RER) of D2S123, D3S1067 and TP 53 in T and NT. Finally in T of NBNC HCC cases, TTVDNA was detected in 3 of 5. Even in the HBsAg-negative and anti-HCV negative HCC cases, CLD coexisting with LC, previous HBV infection and HBVDNA integration were observed. There were a few cases with HBVDNA integration, p53 gene mutation, telomerase activity and genetic instability, simultaneously in HCC tissue, and in some cases, the coexistence with TTVDNA were concurrently confirmed. It is speculated that the important role of the previous infection of HBV may have also been proposed for HCC oncogentic progression in NBNC CLD [corrected].

Vesnarinone, a quinolinone derivative, induces apoptosis and differentiation in some tumor cell lines. We examined the antitumor effect of vesnarinone on three human hepatocellular carcinoma (HCC) cell lines. Vesnarinone suppressed the proliferation of all three HCC cell lines, but did not induce apoptosis and differentiation. Vesnarinone has also been reported to inhibit both nucleoside and nucleobase transport. Concomitant administration of vesnarinone and a de novo nucleotide synthesis inhibitor potentiated the growth-inhibitory effect of vesnarinone on HCC cells. Vesnarinone may be useful as a new biochemical modulator of anticancer agents.

The aim of this study was to clarify whether histological parameters reflected tumor aggressiveness in patients with hepatocellular carcinoma (HCC). The tumor volume doubling times (TVDTs) of 21 HCCs, less than 3 cm in diameter at the start of the observation period, were calculated in 21 patients in whom the natural progression of the lesion was observed by ultrasonography. Paraffin-embedded sections were prepared from samples obtained by ultrasound-guided fine-needle liver biopsy at the end of the observation period. The histological parameters examined were the MIB-1 labeling index (LI), for which we performed immunohistochemical staining with the MIB-1 monoclonal antibody, using an antigen retrieval method; the nucleo-cytoplasmic (N/C ratio), cellularity, and the nuclear form factor (NFF), were calculated with an imaging analyzer. We performed multiple regression analysis for estimating the growth of small HCCs. With the N/C ratio (0.154 +/- 0.068; mean +/- SD), cellularity (453 +/- 21.8 cells/10(4) microm2), NFF (1.150 +/- 0.096), and degree of HCC differentiation as independent variables, only the MIB-1 LI (11.8 +/- 6.1%) showed a significant correlation with TVDT (207.5 +/- 162.6 days) (r = -0.658; P < 0.05). Compared to the conventional indices of histological atypism tested, i.e., N/C ratio, cellularity NFF, and degree of HCC differentiation, only MIB-1 LI was significantly correlated with small HCC growth rate. The MIB-1 LI may therefore be a simple and useful index of tumor aggressiveness.

We investigated the role of apoptosis in relation to proliferative activity in hepatocellular carcinoma (HCC) using in situ DNA nick end labeling (ISNEL) and immunostaining for the Ki-67 antigen in 35 patients with HCC. We also performed immunostaining for Fas and Fas ligand (Fas L) to determine the relationship between the Fas system and apoptosis. The ratio of the ISNEL labeling index (LI) to the Ki-67 LI was significantly lower in HCC than in surrounding nontumorous liver tissue (p<0.0001), suggesting that a decrease in apoptosis relative to cell proliferation is important in the pathogenesis of HCC. Fas and Fas L were expressed in both HCC and nontumorous tissue, but Fas and Fas L LIs were significantly lower in HCC (p<0.0001). Fas expression by cells near ISNEL-positive cells tended to be increased in nontumorous tissue in mirror-image sections, suggesting that apoptosis is related to Fas expression. However, this pattern was rarely observed in HCC. These findings indicate that the Fas system may not play a major role in apoptosis in HCC.

The aim of this study is to clarify the existence and the form of HCV RNA and HBV DNA genome integration and genetic instability in liver tissue with HBsAg-negative and anti-HCV-positive HCC. We investigated 16 Japanese patients with HBsAg-negative and anti-HCV-positive HCC. HBV genome integration into host cell genome by Southern hybridization and PCR was examined. Moreover, we analyzed loss of heterozygosity (LOH) and replication errors (RER) of chromosomes 2p, 3p and 17p using the PCR and an autosequencer to determine the three microsatellite regions D2S123, D3S1067, TP53. Eight (50.0%) of 16 were found to have integrated genome of HBV in tumor tissue (T) by PCR. In even the non-tumor regions (NT), seven patients (43.8%) were found to have HBV genome integration. The coincidence between T and NT was found in 4 (25%). Integration of HBV-X gene in T was revealed in three (18.7%), and HBV-integration was confirmed in all NT. No integration of the X gene alone was found in the liver tissue. Five (37.5%) of eight HBV DNA integrated cases simultaneously had HCV RNA minus strand. Concerning the genetic instability, RER were detected in two of 16 (12.5%). RER at 2p; D2S123 was observed in one of 16 (6.2%) and at 3p; D3S1067 was observed in one (6.2%). LOH at the D2S123 locus was observed in one of 12 tumors with heterozygosity (8.3%). There was no genetic instability (LOH or RER) of TP53 which was p53 locus on 17p in T. There was only one case of eight HBV DNA integrated cases (6.2%) with genetic instability of RER of 3p simultaneously in T. In conclusion, the majority of HBsAg-negative and anti-HCV-positive HCC liver tissue was found to have HCV-RNA and HBV DNA integration, and in some samples, HBV DNA integration and genetic instability were concurrently confirmed. It is speculated that multistep carcinogenesis may have been proposed for HCC oncogenetic progression.

Prolonged infection of hepatitis B virus (HBV) is reported to cause hepatocellular carcinoma (HCC) via liver cirrhosis. However, it is still unknown whether the HCC is induced by the HBV DNA integration or by inflammatory stimulation during the phase of liver cirrhosis. The aim of this study is to determine the intracellular or intranuclear distribution of HBV DNA with a highly sensitive assay. Here we directly detected the integration of HBV DNA by fluorescence in situ polymerase chain reaction (FISPCR). Since FISPCR products directly incorporate rhodamine-4-dUTP, the nucleus of Alexander cells integrated with HBV gene reacted with the HBV primers emits obvious fluorescence. The fluorescence values which were measured with an imaging analyzer show a significant difference between Alexander cells as compared to the controls. In conclusion, the target sequences of HBV were specifically amplified as fluorescent DNA after the present FISPCR procedure. This method could provide a novel and simple strategy for determining the quantitative role of viral DNA integration in oncogenesis.

To elucidate the risk factors for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-related liver cirrhosis (LC), we examined 204 cirrhotic patients negative for hepatitis B surface antigen and positive for HCV antibodies. The independent influence of various clinical characteristics in these patients was analyzed by multiple logistic regression, and the risk factors for HCC were identified. Multiple logistic regression analysis identified and ranked the following four risk factors: male sex (P < 0.001), habitual heavy drinking (P < 0.005), hepatitis B virus antibody positivity (anti-HBs and/or anti-HBc, P < 0.05), and age greater than 60 years (P < 0.05). The odds ratio of HCC was 4.20 (95% confidence interval; CI, 1.80-9.78) in male patients, 3.27 (95% CI, 1.46-7.30) in habitual heavy drinkers, 2.01 (95% CI, 1.01-3.99) in patients positive for hepatitis B virus antibodies, and 2.06 (95% CI, 1.00-4.23) in patients older than 60 years. The cumulative occurrence rates of HCC after blood transfusion were significantly higher in habitual heavy drinkers (4.8%, 49.4%, and 74.7% at 10, 20, and 30 years, respectively) than in non-drinkers (0%, 21.0%, and 23.3% at 10, 20, and 30 years, respectively, P < 0.0003). The mean interval for progression to LC after blood transfusion was significantly shorter in the habitual heavy drinkers than in the non-drinkers (22.4 +/- 4.4 years vs 28.4 +/- 3.9 years; P < 0.0003). This multivariate analysis revealed that habitual heavy drinking and hepatitis B virus antibody positivity are significant risk factors for HCC in HCV-related liver cirrhosis.

Background/aims: This study attempts to clarify the clinicopathologic definition of early hepatocellular carcinomas (HCCs)., Materials and Methods: We evaluated 57 patients, with HCCs less than 3 cm in diameter, in terms of prognosis, incidence of extrahepatic metastasis, and tumor recurrence rate following treatment., Results: Survival was related to both tumor number and histologic differentiation, but was not related to tumor size. Furthermore, prognosis appeared to depend on the functional reserve of the liver. The incidence of extrahepatic metastasis was related to histologic differentiation. There was no significant difference in the recurrence rates of patients with uninodular tumors in terms of tumor size., Conclusions: Our findings indicate that early HCCs measure 15 mm or less in diameter, are uninodular, and are histologically well-differentiated. Finally, the functional reserve of the liver will likely be an additional parameter that will further characterize early HCCs.

Objective: Worldwide epidemiological studies have demonstrated that hepatitis C virus (HCV) probably is a causative agent of hepatocellular carcinoma (HCC). However, there are no available reports that clearly identify the risk factors for the development of HCC in HCV-related chronic liver disease (CLD). The aim of the present study is to explore the risk factors for hepatocarcinogenesis in HCV-related CLD., Methods: We prospectively observed 412 patients with anti-HCV-positive CLD but without co-infection of hepatitis B virus (232 patients with chronic hepatitis and 180 with liver cirrhosis) for between 0.5 and 15.8 yr (median: 4.9 yr). Risk factors for hepatocarcinogenesis were identified with a Cox proportional-hazard model., Results: Sixty-three patients (15.3%) developed HCC during the observation period; the cumulative occurrence rates at the end of the 5th, 10th, and 15th yr was 3.7%, 12.1%, and 12.1%, respectively, for chronic hepatitis patients and 23.3%, 49.4%, and 90.7%, respectively, for 180 cirrhotic patients. The Cox proportional-hazard model showed that the risk of hepatocarcinogenesis increased almost 5-fold in cirrhotic patients (risk ratio, 5.14; 95% confidence interval, 2.52-10.46, p = 0.0001), 2-fold in patients with positive antibodies against hepatitis B surface antigen and/or antibodies against hepatitis B core antigen (risk ratio, 2.14; 95% confidence interval, 1.13-4.07, p = 0.0201), and 2.5-fold in heavy smokers (risk ratio, 2.46; 95% confidence interval, 1.11-5.49, p = 0.0276)., Conclusion: These epidemiological results indicate that previous infection with hepatitis B virus and heavy smoking (in addition to liver cirrhosis, a known risk factor) play important roles as risk factors for carcinogenesis in HCV-related CLD.

We examined the action of baicalein, a flavonoid contained in the herbal medicine sho-saiko-to (TJ-9), on three cell lines of human hepatocellular carcinoma (HCC). Treatment with baicalein strongly inhibited the activity of topoisomerase II and suppressed the proliferation of all three HCC cell lines. But the mode of cell death induced by baicalein differed according to the cell line. Baicalein induced apoptosis in a concentration-dependent manner in only one cell line, and an increased concentration of baicalein produced cell death via necrosis in the other two lines. These results suggest that the inhibition of topoisomerase II is not by itself sufficient for induction of apoptosis, and that there is a more important mechanism which can account for the difference in susceptibility of cells to apoptosis induced by baicalein.

Objective: The aim of this study was to prove whether lipo-prostaglandin E1 (PGE1)/glucagon insulin therapy combination could prevent the acute liver dysfunction induced by Lipiodol (iodized oil)-targeted chemotherapy for hepatocellular carcinoma., Methods: This study was a randomized control trial. Patients in two groups (groups A and B: n = 29) were each given an intravenous injection of 10 units of insulin and 1 mg glucagon every 12 hours for 1 week after Lipiodol-targeted chemotherapy. Patients in group B (n = 11) were each given an intravenous injection of 20 micrograms lipo-PGE1 every 12 hours over 1 week. Several items, including conventional liver function tests, were evaluated at the start of the study and on the days 1, 2, 4, 7, and 14 after Lipiodol-targeted chemotherapy., Results: Combined lipo-PGE1/glucagon-insulin therapy can prevent the elevation of serum ALT level and total bilirubin level after Lipiodol-targeted chemotherapy. In the group A (glucagon-insulin therapy only), the maximum level in the follow-up interval was statistically higher than that in the pretreatment level (p < 0.05), whereas there was no significant difference in group B (treated with combined glucagon-insulin therapy and lipo-PGE1). Changes of ALT level in group B tend to be lower than in group A; however, there was no significant statistical difference. There were few episodes of side effects in both groups., Conclusion: Combined lipo-PGE1/glucagon-insulin therapy may be a safe and effective treatment for the prevention of acute hepatic failure.

Seventy-five patients with hepatocellular carcinoma were treated with proton beams from 1983-1993 at the Proton Medical Research Center, University of Tsukuba. For the purpose of confirming the feasibility of proton therapy for hepatocellular carcinoma, we investigated the influence of proton therapy on liver function and also tried to evaluate the possibility of optimization using dose-volume histogram (DVH) analysis. The results indicated that proton therapy did not cause clinically symptomatic damage in liver function and the only notable change after proton therapy was the transient increase of transminase. DVH analysis showed that this transient increase of transaminase was well correlated to the normal tissue complication probability (NTCP). These results indicate that localized high dose radiation using proton beams is feasible for the treatment of liver cancers and optimization of this treatment may be possible using DVH analysis.

Radiation hepatitis is clearly demonstrated by noncontrast and contrast enhanced CT following radiotherapy for liver diseases. Radiation hepatitis is dependent on dose distribution and is usually demonstrated as a non-segmental bandlike lesion after photon therapy. We report a case of focused, oval-shaped radiation hepatitis that was induced by photon therapy. The attenuation difference was localized in a high-dose area caused by Bragg-peak proton therapy.

Background/aims: Conventional radiation is almost useless for hepatocellular carcinoma (HCC) because of the severe adverse effects of the irradiation to the accompanying liver cirrhosis. In contrast, the proton beam has Bragg peak, which limits distribution of the beam. The aim of this study was to prove the usefulness of proton irradiation for HCC., Methods: The proton irradiation was performed in 32 nodular lesions in 24 patients with HCC who had unresectable tumors or serious complications; the proton irradiation was performed either as monotherapy (15 lesions) or as combination therapy to insufficient Lipiodol-targeted chemotherapy (Kodama Co. Ltd., Tokyo, Japan) (17 lesions). The energy was 250 MeV, and 50-87 Gy (76.5 +/- 9.5, mean +/- SD) in total was irradiated for a time period of 17-69 days., Results: After 1 year, size reduction was seen in 12 out of 13 lesions (92%) in the monotherapy group and 9 out of 9 lesions (100%) in the combination therapy group; after 2 years, size reduction was seen 4 out of 5 lesions (80%) in the monotherapy group and 5 out of 5 lesions (100%) in the combination therapy group. Local tumor control has being assured for 2 years of the observation, which is continuing for another 2 years. None of the patients have experienced any serious adverse effects., Conclusions: These results show that proton irradiation is a new, safe, and effective therapeutic option in cases of HCC, even in patients with unresectable tumors or those with serious complications.

In order to assess the etiologic role of hepatitis C virus (HCV) as well as hepatitis B virus (HBV) in the etiology of HCC, we compared the prevalence of HCV-related antibodies (anti-C100-3, anti-CP9, anti-CP10) and HBV-related markers (HBsAg, anti-HBs, anti-HBc) in sera of patients with liver cirrhosis (LC) with (n = 62) and without (n = 54) hepatocellular carcinoma (HCC). In HBsAg-negative cases, at least one HCV-related marker (including HCV RNA) was detected in 92.3% (48/52) of HCC cases and in all of the 44 LC cases without HCC, with no significant difference between these two groups. In HBsAg-positive cases, the prevalence of either one of these HCV-related markers was 40.0% (4/10) both in patients with and without HCC, and there was no significant difference between these two groups. Moreover, in HBsAg-negative cases and 11 cases of positive HCV-related markers, the prevalence of anti-HBs and/or anti-HBc was significantly higher in LC patients with HCC (85.4%) than those without HCC (43.2%, P < 0.001). These results show a high prevalence of hepatitis B and C viral markers in Japanese patients with HCC and further indicate that previous HBV infection is a risk factor in the occurrence of HCC in HBsAg-negative LC and LC with positive HCV-related markers.