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1.  Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance 
Oncology Reports  2013;30(2):545-552.
Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI) >15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS) >110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions.
doi:10.3892/or.2013.2497
PMCID: PMC3816550  PMID: 23708326
angiogenesis; BCAA; glucose; insulin; IR; HCC; VEGF
2.  A case of severe acalculous cholecystitis associated with sorafenib treatment for advanced hepatocellular carcinoma 
Sorafenib, a multikinase inhibitor, is the first and only drug, which improves significantly the overall survival in patients with advanced hepatocellular carcinoma (HCC). However, many patients experience diverse side effects, some of them severe and unexpected. To date, acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib. Here, we report the case of a 43-year-old woman with hepatitis C virus-related advanced HCC. She received sorafenib, and later complained of a sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense. Laboratory examination showed mild elevation of transaminases, biliary enzymes, bilirubin, inflammation markers, and a marked peripheral eosinophilia. Abdominal computed tomography (CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris. Consequently, sorafenib treatment was stopped immediately, and steroid-pulse therapy was performed. Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings, eosinophilia, and liver functions. In summary, we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.
doi:10.4251/wjgo.v4.i5.115
PMCID: PMC3360105  PMID: 22645635
Hepatocelluar carcinoma; Sorafenib; Acalculous cholecystitis
3.  Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents 
Oncology Letters  2010;2(1):69-73.
The identification of biomarkers of anti-angiogenic therapy that predict clinical benefit is of vital importance. We previously reported that a combination treatment with clinically available safe agents, specifically angiotensin-converting enzyme inhibitor (ACE-I) and vitamin K (VK), inhibited the cumulative recurrence of hepatocellular carcinoma (HCC) via suppression of the vascular endothelial growth factor (VEGF). The present study aimed to identify non-invasive biological markers that predict the clinically beneficial effect of this combination regimen. A combination of ACE-I (perindopril; 4 mg/day) and VK (menatetrenone; 45 mg/day) was administered for 54 months following curative therapy for HCC. The cumulative recurrence and several indices, which are reportedly considered as biological markers of anti-angiogenic therapies, were analyzed. The combined treatment of ACE-I and VK markedly inhibited the cumulative recurrence of HCC during the 54-month follow-up. The serum VEGF and soluble VEGF receptor (sVEGFR)-2 were significantly suppressed with this combination regimen, whereas sVEGFR-1 was not. In HCC patients without recurrence, a significant suppression of VEGF and sVEGFR-2 was achieved within 6 and 3 months after treatment, respectively. In conclusion, the combination treatment of ACE-I and VK is a potentially novel anti-angiogenic strategy for secondary chemoprevention against HCC since the two agents are widely used in clinical practice without serious side effects. Furthermore, sVEGFR-2 may become a useful clinical predictive marker of this combination treatment.
doi:10.3892/ol.2010.196
PMCID: PMC3412527  PMID: 22870131
vascular endothelial growth factor; soluble vascular endothelial growth factor receptor-2; angiogenesis; hepatocellular carcinoma
4.  Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138 
AIM: To investigate the possible use of the multiple cytokine production modulator, Y-40138, as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model.
METHODS: We allocated 6-wk-old male F344 rats to choline-supplemented, L-amino acid-defined (CSAA) diet (control group), CSAA diet + Y-40138 (control + Y-40138 group), choline-deficient, L-amino acid-defined (CDAA) diet (NASH group), or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group, we measured the plasma alanine aminotransferase (ALT) levels, and the plasma and liver levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining, Azan staining, Sirius red staining, and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method, and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay kit.
RESULTS: In comparison to the NASH group, serum ALT elevation was mild, production of serum and liver TNF-α and IFN-γ was inhibited, and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups, whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH group.
CONCLUSION: Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator, Y-40138, is promising as a novel treatment for NASH.
doi:10.3748/wjg.15.5533
PMCID: PMC2785055  PMID: 19938191
Nonalcoholic steatohepatitis; Y-40138; Tumor necrosis factor α; Interferon γ; Interleukin-10; Kupffer cell; Innate immunity
5.  Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis 
AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).
METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18-immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.
RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18 expression and HOMA-R were significantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization.
CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.
doi:10.3748/wjg.15.5193
PMCID: PMC2773899  PMID: 19891019
Angiogenesis; Cytokeratin-18; Fatty liver; Insulin resistance; Non-alcoholic steatohepatitis; Liver fibrosis
6.  Development of hepatocellular carcinoma in a patient 13 years after sustained virological response to interferon against chronic hepatitis C: a case report 
Cases Journal  2009;2:18.
Background
Although several recent reports have shown that hepatocellular carcinoma (HCC) developed in patients with chronic hepatitis C (CH-C) even after having a sustained virological response (SVR) to interferon (IFN) therapy, it is not common for HCC to develop more than 10 years after SVR.
Case presentation
A 73-year-old Japanese man with CH-C who achieved SVR to IFN therapy 13 years ago was admitted into our hospital because of huge multiple liver tumors along with marked elevation of the tumor markers. Several diagnostic modalities strongly suggested HCC, and we performed histopathological examination. After confirming the diagnosis as well-differentiated HCC, we successfully treated these tumors with intensive combination therapies.
Conclusion
Our report highlights the need for careful follow-up for more than 10 years even if the patients with CH-C achieve SVR to IFN therapy.
doi:10.1186/1757-1626-2-18
PMCID: PMC2634763  PMID: 19128460
7.  Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet 
AIM: To investigate the innate immune reactivity of tumor necrosis factor-alpha (TNF-α), Toll-like receptor 4 (TLR4), and CD14 in the liver of non-alcoholic steatohepatitis (NASH) model rats.
METHODS: Male F344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet. The rats were killed after 4 or 8 wk of the diet, and their livers were removed for immunohistochemical investigation and RNA extraction. The liver specimens were immunostained for TNF-α, TLR4, and CD14. The gene expressions of TNF-α, TLR4, and CD14 were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Kupffer cells were isolated from the liver by Percoll gradient centrifugation, and were then cultured to measure TNF-α production.
RESULTS: The serum and liver levels of TNF-α in the CDAA-fed rats increased significantly as compared with the control group, as did the immunohistochemical values and gene expressions of TNF-α, TLR4, and CD14 with the progression of steatohepatitis. TNF-α production from the isolated Kupffer cells of the CDAA-fed rats was elevated by lipopolysaccharide stimulation.
CONCLUSION: The expressions of TNF-α, TLR4, and CD14 increased in the NASH model, suggesting that TLR4 and CD14-mediated endotoxin liver damage may also occur in NASH.
doi:10.3748/wjg.14.6655
PMCID: PMC2773307  PMID: 19034968
Nonalcoholic steatohepatitis; Kupffer cells; Toll-like receptor 4; CD14; Endotoxins; Tumor necrosis factor-alpha
8.  Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model 
AIM: To investigate Kupffer cell dynamics and phagocytic activity, using a rat nonalcoholic steatohepatitis (NASH) model.
METHODS: Male F344 rats were fed either a control diet or a choline-deficient L-amino acid-defined (CDAA) diet, followed by contrast enhanced ultrasonography (CEUS) using Levovist®. The uptake of latex beads by the Kupffer cells was determined by fluorescent microscopy. The status of the Kupffer cells was compared between the two groups, using the immunohistochemical staining technique.
RESULTS: After 4 or more wk of the CDAA diet, CEUS examination revealed a decrease in the signal intensity, 20 min after intravenous Levovist®. Fluorescent microscopic examination showed that the uptake of latex beads by the Kupffer cells was reduced at week 1 and 2 in the study group, compared with the controls, with no further reduction after 3 wk. Immunohistochemical staining revealed no significant difference in the Kupffer cell counts between the control group and the CDAA group.
CONCLUSION: CEUS examination using Levovist® demonstrated reduced contrast effect and phagocytic activity in the liver parenchymal phase, although the Kupffer cell numbers were unchanged, indicating reduced phagocytic function of the Kupffer cells in the rat NASH model. We believe that CEUS examination using Levovist® is a useful screening modality, which can detect NASH in fatty liver patients.
doi:10.3748/wjg.14.6036
PMCID: PMC2760201  PMID: 18932283
Nonalcoholic steatohepatitis; Kupffer cells; Contrast enhanced ultrasonography; Levovist; Ultrasound contrast agent; Phagocytic activity

Results 1-8 (8)