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ABSTRACT: Serum tumor markers, including alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), are currently used in the diagnosis of hepatocellular carcinoma (HCC). There is an aberrant increase in serum DCP, however, in patients with obstructive jaundice, vitamin K deficiency or who are taking warfarin, resulting from a problem with the current methodology for measurement of this marker. This study aimed to elucidate the utility of a new biomarker, NX-PVKA, for early diagnosis of HCC. A total of 96 patients were included in the HCC group. The control group included 138 liver cirrhosis (LC) patients without HCC. Serum concentrations of conventional DCP, AFP, AFP-L3 and NX-PVKA were measured. The NX-PVKA ratio was calculated by dividing DCP by NX-PVKA. In patients not taking warfarin, the area under the curve values of DCP, NX-PVKA ratio, AFP and AFP-L3 were 0.715, 0.690, 0.737 and 0.654, respectively, confirming the clinical utility of these markers in detecting HCC. In cases with DCP > 35 mAU/ml in particular, a significant increase in the NX-PVKA ratio was observed in patients with HCC. In those cases, the cut-off value for the NX-PVKA ratio that was optimized by the ROC curve was 1.15. In addition, the sensitivity and specificity for diagnosing HCC were 69.2% and 75.9%, respectively. Patients with HCC had higher NX-PVKA ratios compared to patients with LC taking warfarin (p = 0.063). These results suggest that, when used in combination with DCP, the NX-PVKA ratio is a promising novel marker for the detection of HCC.
Cancer Science 03/2013; · 3.33 Impact Factor
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Keiichiro Nojiri,
Kazushi Sugimoto, Katsuya Shiraki,
Masahiko Tameda,
Yuuji Inagaki,
Satoko Kusagawa,
Suguru Ogura,
Junichiro Tanaka,
Misao Yoneda,
Norihiko Yamamoto,
Hiroshi Okano,
Yoshiyuki Takei,
Masaaki Ito,
Chika Kasai,
Hidekazu Inoue,
Koujiro Takase
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ABSTRACT: Toll-like receptors (TLRs) are pattern-recognition receptors that are important in immune signaling. TLR recognition of various viral components including double-stranded RNA (TLR3) and unmethylated CpG-DNA (TLR9) plays a crucial role in cell survival. However, TLR expression and function in colon carcinoma cells are not well clarified. We investigated the expression of TLR3 and TLR9 in colon carcinoma cells using immunohistochemical methods. The function of TLR3 and TLR9 signaling in carcinoma cell lines was studied by direct cell stimulation with, or by cell transfection of, polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA, and by cell stimulation with CpG-oligodeoxynucleotides (ODNs), respectively. Positive TLR3 and TLR9 immunohistochemical staining was observed in 91 and 86% of human hepatocellular carcinoma (HCC) tissues, respectively. Cell surface stimulation of TLR3 with Poly I:C did not affect cell viability but it did activate NF-κB activity. By contrast, stimulation of intracellular TLRs with transfected Poly I:C significantly induced apoptosis. Cell surface stimulation of TLR9 with CpG-ODNs promoted cell proliferation, and, furthermore, these CpG-ODN TLR9 agonists reduced the cytotoxicity of the anticancer drug adriamycin. Cell surface expression of TLR3 and TLR9 in colon carcinoma cells plays an important role in cell survival. In addition, the proapoptotic activity of intracellularly expressed TLR3 may provide the possibility of using TLR3 agonists as novel clinical cytotoxic agents against colon carcinoma cells.
Oncology Reports 03/2013; · 1.84 Impact Factor
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ABSTRACT: The purpose of this article is to retrospectively evaluate the frequency of and risk factors for complications after liver radiofrequency ablation (RFA).
This was a retrospective study of 656 patients (with 1755 liver tumors) who underwent 1500 CT fluoroscopy-guided liver RFA sessions. Of those patients, 501 had primary liver tumor and 155 had liver metastases. Mortality and treatment-related complications were documented. Complications were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0). Major complications were defined as grade 3 or higher adverse events. Factors affecting frequent complications with a frequency of 1% or more were detected using multivariate analysis.
Two deaths (0.1% [2/1500]) occurred. One patient died of liver failure subsequent to hemorrhage, and the other died of liver failure. The major complication rate was 2.8% (42/1500). The most frequent major complication was hemorrhage (1.1% [16/1500]). The absence of arterial embolization before RFA (p < 0.01), low hemoglobin level (p < 0.04), and elevated serum creatinine level (p < 0.04) were identified as significant risk factors for major hemorrhage. The minor complication rate was 17.1% (257/1500). Pneumothorax (7.7% [116/1500]) was the most frequent minor complication, followed by hemorrhage (7.0% [105/1500]). A transthoracic approach (p < 0.01) and subphrenic tumor location (p < 0.01) were significant risk factors for pneumothorax, and the use of a cluster needle (p < 0.02) and multiple tumors (p < 0.01) were significant risk factors for minor hemorrhage.
CT fluoroscopy-guided RFA is a safe procedure with an acceptably low rate of major complications for liver tumor treatment. Factors identified in this study will help to stratify high-risk patients.
American Journal of Roentgenology 03/2013; 200(3):658-64. · 2.78 Impact Factor
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ABSTRACT: PURPOSE: To report 10-year outcomes of treating hepatocellular carcinomas (HCCs) by combination therapy of chemoembolization and radiofrequency (RF) ablation. MATERIALS AND METHODS: Combination therapy was administered in 277 patients with 382 treatment-naïve HCCs. Therapeutic effects, safety, survival rate, and prognostic factors were evaluated. RESULTS: Tumor enhancement disappeared after 466 RF sessions in all tumors, resulting in a complete response rate of 100% (277 of 277) based on modified Response Evaluation Criteria In Solid Tumors. Local tumor progression developed in 15 patients (5.4%; 15 of 277) during the mean follow-up of 44.9 months±29.1 (range, 6.0-134.4 mo). Overall and recurrence-free survival rates were 56.3% (95% confidence interval [CI], 52.5%-60.2%) and 22.5% (95% CI, 19.3%-25.6%) at 5 years and 23.5% (95% CI, 17.7%-29.2%) and 9.3% (95% CI, 6.3%-12.4%) at 10 years. The Child-Pugh class was the only significant prognostic factor detected in both the univariate (P<.001) and the multivariate analyses (hazard ratio, 3.8; 95% CI, 2.5-5.6; P<.001). The 5-year and 10-year overall survival rates were 66.4% (95% CI, 62.0%-70.8%) and 30.6% (95% CI, 23.3%-37.9%) in 210 Child-Pugh class A patients. In addition to the Child-Pugh class, the maximum tumor diameter (≤3 cm vs>3 cm) and the tumor number (single vs multiple) were significant independent factors affecting recurrence-free survival. No death was related to the combination therapy. The major complication rate was 3.2% (15 of 466). CONCLUSIONS: RF ablation combined with chemoembolization is a safe and useful therapeutic option for treating HCCs. Prognostic factors detected in this study help to stratify patients who benefit from this combination therapy.
Journal of vascular and interventional radiology: JVIR 02/2013; · 1.81 Impact Factor
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ABSTRACT: Biomarkers that enable an accurate diagnosis of hepatitis C virus (HCV)-induced liver diseases are necessary to prevent subsequent patient morbidity and suffering from the onset of hepatocellular carcinoma (HCC). In particular, the identification of novel biomarkers for liver cirrhosis (LC) will be an important new diagnostic tool since more than 70% of HCV-induced LCs are destined to develop into HCC. In our current study, we performed a search for new serological protein biomarkers of HCV-induced chronic hepatitis (CH), LC and HCC, using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The disease-affected spots were subsequently identified as isoforms of protein components of haptoglobin, transthyretin, the haptoglobin α-chain and apolipoprotein A-IV (apo A-IV), and in specific instances were significantly reduced in LC (p<0.001) and HCC (p<0.01), compared with CH patients. We further examined these isoforms by receiver operating characteristics (ROC) curve analysis and found that they showed high area under ROC curve (AUC) values of more than 0.8 between CH and LC, suggesting that they are appropriate markers that could be utilized to discriminate LC from CH. In conclusion, protein variants in serum that arise as a result of post-translational modifications prove to be useful biomarkers for the accurate diagnosis of specific liver diseases.
International Journal of Molecular Medicine 02/2013; · 1.98 Impact Factor
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ABSTRACT: To evaluate the clinical utility of radiofrequency (RF) ablation combined with chemoembolization in treatment of hepatocellular carcinoma (HCC) located in the caudate lobe.
Between September 2000 and October 2011, 20 consecutive patients with single HCC measuring≤5 cm were treated with combination therapy of chemoembolization and RF ablation. Technical success was defined as completion of a planned electrode placement and ablation protocol. The effectiveness of the technique was defined as disappearance of tumor enhancement with an ablative margin of≥5 mm. Technical success, technique effectiveness, local tumor progression, overall and recurrence-free survival, and complications were evaluated.
RF electrodes were placed in planned sites of each tumor, and ablation was complete in all patients (technical success rate 100%). Tumor enhancement disappeared with sufficient ablative margins after 20 RF sessions in all patients (technique effectiveness rate 100%). Major and minor complication rates were 10.0% and 15.0%. Local tumor progression was found in 2 of 20 patients (10.0%) with local tumor progression rates of 6.3% at 1 year and 13.5% at 3 years and 5 years. Six patients died during the follow-up period (mean, 40.0 months; range, 2.0-110.5 months). Overall and recurrence-free survival rates were 94.4% and 70.8% at 1 year, 86.6% and 36.9% at 3 years, and 67.5% and 45.5% at 5 years.
RF ablation combined with chemoembolization is a safe and useful therapeutic option to treat HCCs located in the caudate lobe.
Journal of vascular and interventional radiology: JVIR 12/2012; 23(12):1622-8. · 1.81 Impact Factor
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Tetsuya Beppu,
Kazushi Sugimoto, Katsuya Shiraki,
Masahiko Tameda,
Yuji Inagaki,
Suguru Ogura,
Chika Kasai,
Satoko Kusagawa,
Keiichiro Nojiri,
Misao Yoneda, [......],
Yoshiyuki Takei,
Masashi Fujimori,
Takaaki Hasegawa,
Takashi Yamanaka,
Junichi Uraki,
Masataka Kashima,
Haruyuki Takaki,
Atsuhiro Nakatsuka,
Koichiro Yamakado,
Kan Takeda
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ABSTRACT: We evaluated the clinical efficacy of transarterial infusion chemotherapy using a cisplatin-lipiodol emulsion for unresectable hepatocellular carcinoma (HCC).
Fifty-seven patients with advanced HCC, with no indications for surgical resection or local ablative therapy, such as percutaneous ethanol injection and radiofrequency ablation, were enrolled in this retrospective study.
Twelve patients were treated with cisplatin-alone at a dose of 65 mg/m(2) by infusion into the artery. Forty-two patients were treated with the same dose of cisplatin suspended in 1-10 ml of lipiodol (C/LPD). Cumulative survival rates in the cisplatin-treated group were 46.2% at one year, and 18.5% at two years, whereas these in the C/LPD group were 81.6% and 44.4%, respectively, with a significant difference between the two groups (p<0.01). In the cisplatin-treated group (n=13), no (0%) patients had a complete response (CR), two (15%) a partial response (PR), three (23%) no change (NC), and eight (62%) progressive disease (PD). In the C/LPD group (n=44), four (9%) patients had CR, 16 (35%) PR, 12 (26%) NC, and 12 (26%) PD. CR and PR were seen in 15% of the cisplatin-treated group and in 44% of the C/LPD group. C/LPD was significantly more effective than cisplatin-alone (p=0.039). Some patients showed tumor response to C/LPD after intra-arterial infusion of low-dose 5-fluorouracil.
C/LPD produced superior effects compared to cisplatin-alone for unresectable HCC, causing no major side-effects, and increasing the survival rate.
Anticancer research 11/2012; 32(11):4923-30. · 1.73 Impact Factor
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Keiichiro Nojiri,
Kazushi Sugimoto, Katsuya Shiraki,
Masahiko Tameda,
Yuuji Inagaki,
Suguru Ogura,
Chika Kasai,
Satoko Kusagawa,
Misao Yoneda,
Norihiko Yamamoto,
Yoshiyuki Takei,
Tsutomu Nobori,
Masaaki Ito
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ABSTRACT: A multi-kinase inhibitor, sorafenib, was recently approved and is currently recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, HCC treatment outcomes are still poor and necessitate improvement. Therefore, we investigated the influence of sorafenib in combination with each of cytotoxic chemotherapy agents, hypoxia or tumor necrosis factor (TNF)-related apoptosis‑inducing ligand (TRAIL), on cytotoxicity to determine which is the better adjuvant. Additive cytotoxicity of sorafenib to chemotherapy agents, hypoxia and TRAIL, to HCC cells was assessed using cell viability assay. Intracellular levels of anti-apoptotic proteins were determined using western blot analysis. Activation of Wnt/β-catenin signaling was assessed using a luciferase reporter gene assay. Sorafenib significantly and synergistically enhanced the cytotoxicity of TRAIL to HCC cells and 4',6-diamidino-2-phenylindole (DAPI) staining showed increased apoptosis among cells treated with sorafenib and TRAIL. This augmentation in cytotoxicity was derived from sorafenib-mediated downregulation of anti-apoptotic proteins. However, sorafenib did not enhance the cytotoxicity of chemotherapy agents (cisplatin, 5-FU or doxorubicin) or hypoxic treatment to HCC. Moreover, hypoxic treatment induced Wnt/β-catenin signaling activation. Our data showed that in combination TRAIL and sorafenib had a synergistic cytokilling effect on HCC cells and that this effect derived from sorafenib-mediated downregulation of anti-apoptotic proteins.
International Journal of Oncology 10/2012; · 2.40 Impact Factor
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Tatsunori Nakano,
Hiroshi Okano,
Makoto Kobayashi,
Keiichi Ito,
Shigeru Ohmori,
Tomoyuki Nomura,
Hideaki Kato,
Minoru Ayada,
Yoko Nakano,
Shigehiro Akachi,
Kazushi Sugimoto,
Naoki Fujita, Katsuya Shiraki,
Yoshiyuki Takei,
Masaharu Takahashi,
Hiroaki Okamoto
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ABSTRACT: In Mie prefecture in Japan, 12 cases of sporadic hepatitis E occurred from 2004 to 2011. Mie prefecture is located in the central region of Japan, far from the most prevalent regions of hepatitis E virus (HEV) infection in Japan, the north and northeastern part. These 12 cases did not have any common risk factors of HEV infection. We analyzed the molecular epidemiology of the cases in Mie prefecture. We obtained the nucleotide sequences of the HEV strains and analyzed them with the sequences of other HEV strains by phylogenetic and coalescent analyses. Japan-indigenous genotype 3 HEV strains were divided into two major subtypes, namely, 3a and 3b; one minor subtype, 3e; and a few other unassigned lineages. The Japan-indigenous subtype 3e strains were closely related to European subtype 3e HEV strains and were comparatively rare in Japan; however, eight strains of the 12 cases we examined belonged to subtype 3e, indicating a close phylogenetic relationship, despite the lack of common risk factors. Coalescent analyses indicated that the Mie 3e strains seemed to have intruded into Mie prefecture about 10 years ago. Sporadic acute hepatitis E cases caused by the 3e strains occurred consistently from 2004 to 2011 in Mie prefecture. This is the first report of unexpected persistent occurrence of hepatitis by the European-type genotype 3 HEV, subtype 3e, in a country outside of Europe. Phylogenetic and coalescent analyses traced the history of the indigenization of the Mie 3e strains from Europe. Because hepatitis E cases caused by 3e strains are relatively rare in Japan, molecular evolutionary analyses of HEV infection in Mie prefecture is important for preventing a future hepatitis endemic or epidemic by 3e strains in Japan.
Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 06/2012; 12(7):1524-34. · 3.22 Impact Factor
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ABSTRACT: We retrospectively evaluated whether combined use of chemoembolization expands ablative zone sizes created by radiofrequency (RF) ablation in patients with small hepatocellular carcinomas (HCCs).
Fifty-seven patients treated with single RF ablation for solitary HCC measuring ≤2 cm were assessed. RF ablation alone was done in nine patients and in 48 patients following chemoembolization, with an interval of 0 days in 6, 1-14 days in 27, 15-28 days in 6, and ≥4 weeks in 9. Ablative zone sizes, disappearance of tumor enhancement, and creation of sufficient ablative margins (>5 mm) were evaluated on contrast-enhanced computed tomography (CT) images.
Both mean long-axis (4.2-4.7 vs. 3.6 ± 0.4 cm, p < 0.04) and short-axis (3.3-3.8 vs. 2.3 ± 0.5 cm, p < 0.03) diameters were expanded significantly when RF ablation was done until 4 weeks after chemoembolization than with RF ablation alone. Tumor enhancement disappeared in all patients. Frequency of achieving sufficient ablative margins was significantly higher when RF ablation was done until 4 weeks after chemoembolization than with RF ablation alone (74.0-83.3 vs. 22.2 %, p < 0.05).
Ablative zones created by RF ablation with chemoembolization become larger than RF ablation alone, leading to secure ablative margins.
Japanese journal of radiology 05/2012; 30(7):553-9. · 0.65 Impact Factor
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Yuji Inagaki,
Kazushi Sugimoto, Katsuya Shiraki,
Naohiko Yoshizawa,
Masahiko Tameda,
Suguru Ogura,
Misao Yoneda,
Yoshiyuki Takei,
Hiroyuki Fuke,
Akira Hashimoto,
Norihiko Yamamoto,
Atsuya Shimizu
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ABSTRACT: We herein report a rare case of hepatocellular carcinoma (HCC) with sarcomatous changes. A 66-year-old man was admitted to our hospital with a high fever and upper abdominal pain. Initially, he was diagnosed as having a liver abscess; however, antibiotic treatment and drainage were ineffective. Further imaging studies revealed the typical appearance of HCC: the tumor had invaded the hepatic and portal veins. Surgical resection of the tumor was performed. A pathological examination demonstrated the presence of a sarcomatous hepatocellular carcinoma. Sarcomatous hepatocellular carcinoma with remittent fever is a rare disease entity.
Internal Medicine 01/2012; 51(21):3025-9. · 0.94 Impact Factor
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Tatsunori Nakano,
Kazuaki Takahashi,
Oliver G Pybus,
Naoaki Hashimoto,
Hideaki Kato,
Hiroshi Okano,
Makoto Kobayashi,
Naoki Fujita, Katsuya Shiraki,
Yoshiyuki Takei,
Minoru Ayada,
Masahiro Arai,
Hiroaki Okamoto,
Shunji Mishiro
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ABSTRACT: Since previous studies have investigated the population dynamics of Japan-indigenous genotype 3 hepatitis E virus (HEV) using virus sequences, more nucleotide sequences have been determined, and new techniques have been developed for such analysis.
To prevent future hepatitis E epidemic in Japan, this study aimed to elucidate the cause of past HEV expansion.
The epidemic history of Japan-indigenous genotype 3 HEV was determined using the coalescent analysis framework. Bayesian skyline plot (BSP) and Bayesian estimate of phylogeny with relaxed molecular clock models were calculated using Markov chain Monte Carlo sampling.
Japan-indigenous strains consist of New World strains (subtype 3a), Japanese strains (3b) and European strains (3e). The oldest lineage, 3b, appeared around 1929. Lineages 3a and 3e appeared around 1960. BSPs indicated similar radical population growth of the 3a and 3b lineages from 1960 to 1980.
Population dynamics of the three lineages shared some common characteristics, but had distinguishing features. The appearance of 3a and 3e lineages coincides with the increase of large-race pig importation from Europe and the USA after 1960. The epidemic phase of 3a and 3b strains from 1960 to 1980 could be related to increased opportunity for HEV infection arising from large-scale pig breeding since 1960. Our observations revealed new findings concerning the close relationship between the epidemic history of Japan-indigenous genotype 3 HEV and the improvement of the Japanese pig industry. Infection control in pig farms should be an effective method of preventing HEV infection in humans.
Liver international: official journal of the International Association for the Study of the Liver 12/2011; 32(4):675-88. · 3.82 Impact Factor
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Chiaki Masuda,
Kaoru Dohi,
Yuko Sakurai,
Yuri Bessho,
Harumi Fukuda,
Shinobu Fujii,
Tadafumi Sugimoto,
Masaki Tanabe,
Katsuya Onishi, Katsuya Shiraki,
Masaaki Ito,
Tsutomu Nobori
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ABSTRACT: We evaluated the impact of chronic kidney disease (CKD) on the presence and severity of aortic stenosis (AS) in patients at high risk for coronary artery disease (CAD).
One hundred and twenty consecutive patients who underwent invasive coronary angiography were enrolled. Aortic valve area (AVA) was calculated by the continuity equation using transthoracic echocardiography, and was normalized by body surface area (AVA index).
Among all 120 patients, 78% had CAD, 55% had CKD (stage 3: 81%; stage 4: 19%), and 34% had AS (AVA < 2.0 cm²). Patients with AS were older, more often female, and had a higher frequency of CKD than those without AS, but the prevalence of CAD and most other coexisting conventional risk factors was similar between patients with and without AS. Multivariate linear regression analysis indicated that only CKD and CAD were independent determinants of AVA index with standardized coefficients of -0.37 and -0.28, respectively. When patients were divided into 3 groups (group 1: absence of CKD and CAD, n = 16; group 2: presence of either CKD or CAD, n = 51; and group 3: presence of both CKD and CAD, n = 53), group 3 had the smallest AVA index (1.19 ± 0.30*# cm²/m², *p < 0.05 vs. group 1: 1.65 ± 0.32 cm²/m², and #p < 0.05 vs. group 2: 1.43 ± 0.29* cm²/m²) and the highest peak velocity across the aortic valve (1.53 ± 0.41*# m/sec; *p < 0.05 vs. group 1: 1.28 ± 0.29 m/sec, and #p < 0.05 vs. group 2: 1.35 ± 0.27 m/sec).
CKD, even pre-stage 5 CKD, has a more powerful impact on the presence and severity of AS than other conventional risk factors for atherosclerosis in patients at high risk for CAD.
Cardiovascular Ultrasound 11/2011; 9:31. · 1.26 Impact Factor
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ABSTRACT: BACKGROUND: We aimed to evaluate therapeutic outcomes of radiofrequency (RF) ablation following intra-arterial iodized-oil injection for hepatocellular carcinomas (HCCs) invisible on ultrasonographic (US) images. MATERIALS AND METHODS: Informed consent was waived for this retrospective study approved by our institutional review board. Sixty-seven consecutive patients with 150 HCCs (mean diameter 1.3 ± 0.6 cm; range 0.5-4.2 cm) received 90 RF sessions following intra-arterial iodized-oil injection. Each patient had at least one HCC invisible on US images. Computed tomography (CT) fluoroscopy-guided RF ablation was performed within 1 week after the injection of iodized oil from feeding arteries of each tumor. Technical success was defined as a planned electrode placement and completion of ablation protocol. Technical success, complications, changes in liver function, local tumor progression, and survival were evaluated. RESULTS: All HCCs became visible on CT fluoroscopy after iodized-oil injection, and RF ablation was technically successful in all sessions (technical success rate, 100%, 90/90). Major complications occurred in 6 RF sessions (6.7%, 6/90), including hemorrhage (2.2%, 2/90), portal thrombosis (2.2%, 2/90), and pneumothorax (2.2%, 2/90). No significant deterioration in Child-Pugh score was found. The mean follow-up period was 23.2 ± 18.0 months. The cumulative local tumor progression rates and overall survival rates were, respectively, 3.9 and 82.7% at 1 year, 5.3 and 45.3% at 3 years, and 5.3 and 26.4% at 5 years. CONCLUSION: CT fluoroscopy-guided RF ablation following intra-arterial iodized-oil injection is a feasible, safe, and useful therapeutic option for HCCs invisible on US images.
International Journal of Clinical Oncology 10/2011; · 1.41 Impact Factor
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ABSTRACT: The purpose of this study is to evaluate the treatment effect and prognostic factors of radiofrequency ablation (RFA) combined with chemoembolization for patients with recurrent hepatocellular carcinomas (HCCs) after hepatectomy.
Fifty-five consecutive patients who received combination therapy as a curative treatment of recurrent HCCs after hepatectomy were included in this retrospective study. The mean maximum tumor diameter was 2.2 cm (range, 1.0-4.8 cm). Under CT fluoroscopic guidance, RFA was performed 1-2 weeks after chemoembolization. Technique effectiveness rates, complications, local tumor progression rates, survival rates, and prognostic factors were evaluated.
Tumor enhancement disappeared on contrast-enhanced CT images in all patients after 72 RFA sessions (technique effectiveness rate, 100%). Pneumothorax requiring chest drainage was the only major complication that developed in one RFA session (1%). Four of 55 patients (7%) showed local tumor progression. New tumors emerged in the untreated liver in 27 patients (49%) during the mean follow-up of 35 months (range, 1-82 months). The 5-year overall and recurrence-free survival rates after combination therapy were 74% (95% CI, 54-87%) and 28% (95% CI, 14-45%), respectively. The presence of a single tumor at initial hepatectomy and a low α-fetoprotein level (≤ 100 ng/mL) at recurrence were significantly favorable independent factors affecting overall and recurrence-free survival.
For treatment of recurrent HCCs after hepatectomy, RFA combined with chemoembolization is a useful therapeutic option. This study identified prognostic factors that will help to stratify patients with recurrent HCCs after hepatectomy.
American Journal of Roentgenology 08/2011; 197(2):488-94. · 2.78 Impact Factor
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Masahiro Suzuki,
Kazushi Sugimoto,
Junichiro Tanaka,
Masahiko Tameda,
Yuji Inagaki,
Satoko Kusagawa,
Keiichiro Nojiri,
Tetsuya Beppu,
Kentaro Yoneda,
Norihiko Yamamoto,
Masaaki Ito,
Misao Yoneda,
Kazuhiko Uchida,
Koujiro Takase, Katsuya Shiraki
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ABSTRACT: To investigate the expression and significance of glypican-3 (GPC3) in human hepatocellular carcinoma (HCC).
DNA chips were used to measure the expression of mRNAs for members of the glypican and syndecan families of heparan sulfate proteoglycans (HSPGs) in normal liver tissue, non-tumor tissues and HCC. GPC3 protein expression was investigated by immunohistochemical staining in the tissues samples and Western blotting in human HCC cell lines. In addition, the levels of GPC3 protein in the blood were determined by ELISA.
Only the expression of GPC3 was found to be markedly elevated in HCCs. In the human HCC cell lines, GPC3 expression was consistently observed, and was mainly located in the cell membrane and cytoplasm. Immunohistochemistry showed a tendency for overall staining of the cytoplasm of cells in the liver carcinoma tissues, but the cell membrane was preferentially stained in poorly differentiated HCC when compared with well-differentiated HCC. Moreover, the cell membrane was preferentially stained in metastatic lesions of HCC when compared with primary HCC lesions. Non-tumor tissues and cholangiocellular carcinoma tissues were not stained. In addition, using HepG2 cells, AG490 and piceatannol, which are signal transducer and activator of transcription 3 (STAT3) inhibitors, each increased the amount of GPC3 mRNA expressed. Assay of the circulating levels of GPC3 protein in chronic liver disease and HCC found that serum GPC3 protein levels were significantly elevated in the latter.
GPC3 is highly expressed in HCC, and its expression pattern differs according to the degree of cell differentiation. In addition, the expression of GPC3 is regulated by Janus kinase-STAT signaling. GPC3 shows potential as a tumor biomarker for HCC that can be used for molecularly targeted therapy.
Anticancer research 12/2010; 30(12):5055-61. · 1.73 Impact Factor
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Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 11/2010; 9(4):e31-2. · 5.64 Impact Factor
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Junichiro Tanaka,
Kazushi Sugimoto, Katsuya Shiraki,
Masahiko Tameda,
Satoko Kusagawa,
Keiichiro Nojiri,
Tetsuya Beppu,
Kentaro Yoneda,
Norihiko Yamamoto,
Kazuhiko Uchida,
Takahiro Kojima,
Yoshiyuki Takei
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ABSTRACT: Toll-like receptor 9 (TLR9) is a pattern-recognition receptor that is involved in immune signaling and plays a crucial role in cell survival through recognition of various bacterial and viral components including unmethylated CpG-DNA. TLR9 expression and function in cancer cells are not well understood. We investigated the expression of TLR9, and the function of TLR9 signaling, in hepatocellular carcinoma (HCC) cells following stimulation with CpG-oligodeoxynucleotides (ODNs). Positive immunohistochemical staining for TLR9 was observed in 85.7% of HCC tissues. Western blot analysis revealed that TLR9 was expressed both on the cell membrane and in the cytoplasm of HCC cell lines. Full-length TLR9 was predominantly expressed on the membrane rather than in the cytoplasm, whereas multiple cleaved forms of TLR9 were predominantly expressed in the cytoplasm rather than on the membrane. Cell surface stimulation of TLR9 promoted cell proliferation, and, furthermore, the TLR9 agonists, CpG-ODNs, reduced the cytotoxicity of the anti-cancer drug adriamycin (ADM) via up-regulation of apoptosis inhibitors such as survivin, Bcl-xL, XIAP and cFLIP, in HCC cell lines. Although cell surface stimulation of TLR9 did not activate either the NF-kappaB signaling pathway or the type-I IFN secretion pathway, gene chip microarray analysis indicated that TLR9 agonists closely regulated multiple oncology-related genes and transcription factors involved in tumorigenesis and cancer progression. In conclusion, our results indicate that functional cell surface expression of TLR9 in human HCC may play an important role in tumorigenesis and cancer progression.
International Journal of Oncology 10/2010; 37(4):805-14. · 2.40 Impact Factor
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Tetsuya Beppu,
Kazushi Sugimoto, Katsuya Shiraki,
Masahiko Tameda,
Satoko Kusagawa,
Keiichiro Nojiri,
Junichiro Tanaka,
Norihiko Yamamoto,
Yoshiyuki Takei,
Haruyuki Takaki,
Junji Uraki,
Atsuhiro Nakatsuka,
Koichiro Yamakado,
Kan Takeda
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ABSTRACT: The aim of this study was to elucidate the importance of three tumor markers, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), for detecting and predicting the recurrence of hepatocellular carcinomas (HCCs). A total of 108 patients with initial non-advanced HCC who underwent curative radiofrequency ablation (RFA) in our hospital were enrolled in this study. The effectiveness of the three tumor markers for detecting recurrence and recurrence-free survival was analyzed. Positivity of these three makers was not markedly increased at the first or second recurrence. In addition, there was no significant correlation between the initial and recurrent levels of each tumor marker. The tumor marker that was positive at the time of initial HCC was not necessarily positive at recurrence. The tumor marker levels at recurrence were not correlated with pre-ablation levels. No significant correlation was found in the tumor marker values between pre-ablation and the time of recurrence. On multivariate analysis, high AFP-L3 levels (>/=10%) were significantly predictive of recurrence-free survival. All three tumor markers should be routinely measured to detect recurrence during follow-up after RFA. Especially high AFP-L3 levels should be followed closely.
International Journal of Molecular Medicine 09/2010; 26(3):425-33. · 1.98 Impact Factor
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Keiichiro Nojiri,
Kazushi Sugimoto, Katsuya Shiraki,
Satoko Kusagawa,
Junichiro Tanaka,
Tetsuya Beppu,
Norihiko Yamamoto,
Yoshiyuki Takei,
Akira Hashimoto,
Atsuya Shimizu,
Shigeru Omori,
Masahiko Tameda,
Koujiro Takase
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ABSTRACT: The risk factors for the development of hepatocellular carcinoma (HCC) in patients who have achieved a long-term sustained viral response (SVR) to interferon (IFN) are not fully understood. This study aimed to investigate the characteristics of patients who developed HCC after 10 years of achieving SVR. We retrospectively studied 5 patients with HCC which developed more than 10 years after the termination of IFN therapy. The clinical characteristics at the induction of IFN therapy were male gender, a mean age of 51.6±9.1 years, while 2 patients were moderate alcohol consumers. None of the 5 patients were positive for either HBs Ag or anti-HBc Ab. A histological examination at the initial IFN therapy showed the activity scores to be A2 in all cases, and the fibrosis scores at least F2. The clinical parameters at the diagnosis of HCC included fluctuating transaminase levels in all cases. These levels scarcely fell below the upper limits even after SVR was achieved. In 3 patients, liver tissues were obtained at the treatment of HCC. These tissues showed marked improvement in both activities and fibroses, but severe steatosis in 1 patient. To conclude, chronic hepatitis C patients who respond to IFN therapy should undergo long-term follow-up, even after the eradication of HCV, with special attention particularly to patients who had elevated transaminase levels and steatosis.
Oncology letters 05/2010; 1(3):427-430. · 0.11 Impact Factor
