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Junichi Zaitsu,
Takahiro Yamasaki, Issei Saeki,
Yohei Harima,
Takuya Iwamoto,
Yumiko Harima,
Toshihiko Matsumoto,
Yohei Urata,
Isao Hidaka,
Yoshio Marumoto,
Tsuyoshi Ishikawa,
Taro Takami,
Naoki Yamamoto,
Seiji Kaino,
Koichi Uchida,
Shuji Terai,
Isao Sakaida
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ABSTRACT: AIM: We recently reported that the iron chelator deferoxamine (DFO) is efficacious in advanced hepatocellular carcinoma (HCC) patients. Iron regulation may thus have an important impact in HCC therapy. Because transferrin is a native chelator that regulates iron homeostasis, it may act as an anti-cancer agent in a similar manner as DFO. The objective of this study was to evaluate serum transferrin as a prognostic predictor in advanced HCC patients undergoing hepatic arterial infusion chemotherapy (HAIC). METHODS: We retrospectively studied 44 patients receiving HAIC and analyzed various parameters for their possible use as prognostic predictors. RESULTS: The 1-, 2-, and 3-year cumulative survival rates were 36.4%, 18.2%, and 8.5%, respectively, and the median survival time (MST) was 7.0 months. The survival rates of patients who had serum transferrin ≥190 mg/dL (MST, 12.0 months) were significantly better than those of patients who had serum transferrin <190 mg/dL (MST, 4.9 months). Multivariate analysis identified serum transferrin ≥190 mg/dL [hazard ratio (HR), 0.282; 95% confidence interval (CI), 0.132-0.603; P = 0.001] and Child-Pugh score B (HR, 1.956; 95% CI, 1.034-3.700; P = 0.039) as independent prognostic predictors. There was a significant correlation between serum transferrin level and therapeutic effect (P < 0.001). CONCLUSIONS: Serum transferrin could be useful as a prognostic predictor in advanced HCC patients before HAIC treatment.
Hepatology Research 04/2013; · 2.20 Impact Factor
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ABSTRACT: BACKGROUND: Human hepatocellular carcinoma (HCC) is highly ubiquitinated. The ubiquitination is important to the generatation of HCC. The antitumor and antifibrosis effects of an ubiquitin-proteasome system inhibitor, bortezomib, on HCC with liver cirrhosis (LC) were analyzed in vitro and in vivo. METHODS: The effect of bortezomib was analyzed in the rat hepatocarcinogenesis model using a DEN and CDAA diet (DEN/CDAA model), which shows severe LC and generation of HCC. The decrease of GST-P-positive foci and HCC were analyzed in vivo. Cell death was analyzed by cell death detection kit. Liver fibrosis was checked by sirius-red staining and α-smooth muscle actin staining. The in vitro study involved 3 HCC cell lines (HepG2, HuH7, and HLF) and primary rat and human hepatocytes. The proliferation rate of the HCC cell line was analyzed using the MTT assay and FACS analysis. The toxicity of bortezomib was checked using the LDH release assay for primary human and rat hepatocytes. RESULTS: In the rat hepatocarcinogenesis model, bortezomib prevented the development of preneoplastic lesions during the early stages of hepatocarcinogenesis and specifically induced cell death in HCC. Furthermore, bortezomib inhibited cell proliferation and induced tumor-specific cell death in HCC cell lines with decrease of cyclin D1 and phospho-Rb expression. Further, bortezomib showed no hepatotoxicity of primary rat and human hepatocytes, suggesting that it might be an HCC-specific drug. Bortezomib also prevented the activation of hepatic stellate cells and inhibited the liver fibrosis of the DEN/CDAA model. CONCLUSIONS: Bortezomib appears to be an ideal target drug for HCC with LC.
Journal of Gastroenterology 09/2012; · 4.16 Impact Factor
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Takahiro Yamasaki, Issei Saeki,
Yohei Harima,
Junichi Zaitsu,
Masaki Maeda,
Haruko Tanimoto,
Takuya Iwamoto,
Isao Hidaka,
Yohei Urata,
Tsuyoshi Ishikawa,
Taro Takami,
Yuhki Yamaguchi,
Koichi Uchida,
Shuji Terai,
Isao Sakaida
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ABSTRACT: Transcatheter arterial infusion chemotherapy (TAI) using a combination of iodized oil (lipiodol) and degradable starch microspheres (DSMs) has been reported to be superior to TAI with either lipiodol or DSMs separately for the treatment of hepatocellular carcinoma (HCC), based on the results of a prospective randomized study. In the study reported here, we investigated the predictors influencing response and survival in HCC patients receiving TAI using lipiodol and DSMs.
A total of 50 HCC patients [Child-Pugh A/B, 34/16 patients; maximum tumor size 2.9 cm (mean); tumor number <5/≥5 = 29/21 patients] were administered a mixture of cisplatin and lipiodol, followed by the injection of DSMs.
According to the criteria of the Liver Cancer Study Group of Japan, the response [complete response (CR) + partial response (PR)] rate and CR rate were 72 and 38%, respectively [CR, 19 patients; PR, 17; stable disease, 9; progressive disease, 5]. The 1-, 2-, 3-, and 4-year cumulative survival rates were 85, 67, 41, and 35%, respectively, and the median survival time was 32.6 months. Multivariate analysis identified tumor number <5 nodules [odds ratio 10.651, 95% confidence interval (CI) 2.168-52.317; P = 0.004] as an independent predictor of response and des-γ-carboxyprothrombin level <100 mAU/mL [hazard ratio (HR), 0.268, 95% CI 0.091-0.786, P = 0.017] and therapeutic effect CR or PR (HR 0.255, 95% CI 0.099-0.659; P = 0.005) as independent predictors of survival.
Transcatheter arterial infusion chemotherapy using lipiodol and DSMs might be considered as a potential intervention in HCC patients, especially those with tumors of <5 nodules.
Journal of Gastroenterology 02/2012; 47(6):715-22. · 4.16 Impact Factor
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ABSTRACT: We designed a novel transcatheter arterial infusion chemotherapy (TAI) using iodized oil (lipiodol) and degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) patients. In this study, we investigated the efficacy of TAI using lipiodol and DSM in a prospective randomized trial.
We randomly divided 45 patients with HCC into 3 groups: TAI using lipiodol (lipiodol group, n = 15), TAI using DSM (DSM group, n = 15), and TAI using lipiodol and DSM (lipiodol + DSM group, n = 15). In the lipiodol group, a mixture of cisplatin and lipiodol was administered. In the DSM group, a mixture of cisplatin and DSM was administered. In the lipiodol + DSM group, a mixture of cisplatin and lipiodol was administered, followed by DSM.
The response rates were 40% in the lipiodol group, 53.4% in the DSM group, and 80% in the lipiodol + DSM group, respectively. The response rate tended to improve in the lipiodol + DSM group (lipiodol group vs. lipiodol + DSM group, P = 0.07). The median progression-free survival time was 177 days in the lipiodol group, 287 days in the DSM group, and 377 days in the lipiodol + DSM group. The progression-free survival in the lipiodol + DSM group was significantly better than those in the DSM group (P = 0.020) and the lipiodol group (P = 0.035). There were no serious adverse effects among the 3 groups.
TAI using lipiodol and DSM was superior to TAI using lipiodol only and TAI using DSM only because of improvements in therapeutic effects and progression-free survival.
Journal of Gastroenterology 03/2011; 46(3):359-66. · 4.16 Impact Factor
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ABSTRACT: Aim: A late evening snack (LES) is recommended for protein-energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched-chain amino acid (BCAA)-enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). Methods: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75-g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. Results: Non-protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early-stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. Conclusions: LES using BCAA-enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.
Hepatology Research 06/2010; 40(6):574-84. · 2.20 Impact Factor
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ABSTRACT: Aim: We previously reported the benefits of hepatic arterial infusion chemotherapy (HAIC) using cisplatin (CDDP), 5-fluorouracil (5-FU) [low-dose FP], and leucovorin/isovorin for advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy with HAIC and subcutaneous interferon (IFN)- alpha-2b in patients with advanced HCC. Methods: Of the 48 patients, 31 received low-dose FP with leucovorin/isovorin (HAIC group) and 17 received combination therapy comprising low-dose FP with isovorin and subcutaneous IFN-alpha-2b (combination group). Prognostic factors were evaluated by univariate and multivariate analyses of the patient and the disease characteristics. Results: There were no significant differences in the response rate (patients with complete or partial response/all patients; P = 0.736) and survival (P = 0.399) between both groups. Univariate analysis revealed that IFN therapy was not a significant prognostic factor. Multivariate analysis showed 3 variables, namely, Child-Pugh score (P = 0.010), alpha-fetoprotein level (P = 0.0047), and additional therapy (P = 0.002), to be significant prognostic factors. Conclusions: We considered that combination therapy with HAIC and subcutaneous interferon (IFN)-alpha-2b was not beneficial for advanced HCC.
Hepatology Research 12/2008; 39(3):223-30. · 2.20 Impact Factor
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ABSTRACT: We have reported that radiofrequency (RF) ablation with balloon occlusion of the hepatic artery (balloon-occluded RF ablation) increases the coagulation area compared with standard RF ablation. In this study, we evaluated the efficacy and safety of combination therapy with transcatheter arterial infusion chemotherapy (TAI) using iodized oil and balloon-occluded RF ablation in patients with hepatocellular carcinoma.
We studied 12 patients with 12 HCC nodules (mean tumor diameter, 27.3 mm). All patients were classified as Child-Pugh Class A. Immediately after TAI using iodized oil, we performed balloon-occluded RF ablation.
One treatment session of the combination therapy was done for 10 of 12 nodules (83%). The greatest long-axis and short-axis dimensions of the area coagulated after the combination therapy were 48.8+/- 5.5 mm and 41.9 +/- 4.1 mm, respectively. During follow-up (mean, 33.4 months), there was no local recurrence. The 1, 2, and 3-year survival rates were 100%, 92%, and 83%, respectively. No fatal complications were observed.
The combination therapy is an effective and safe treatment under favorable liver reserve capacity. Using the combination therapy, it is possible to finish one treatment session for patients with HCC nodules measuring less than 3 cm in greatest dimension.
American journal of clinical oncology 09/2008; 31(4):311-6. · 2.21 Impact Factor
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ABSTRACT: Background/Aims: We previously reported that combination therapy comprising hepatic arterial infusion chemotherapy (HAIC) with 3 drugs, namely, cisplatin (CDDP), 5-fluorouracil (5-FU) (low-dose FP) and isovorin and interferon (IFN)-α-2b was not beneficial for patients with advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy comprising HAIC and pegylated interferon (PEG-IFN)-α-2b in advanced HCC patients by comparing our results with previous data. Methodology: From a total of 29 patients, 12 received HAIC and PEGIFN- α-2b (PEG-IFN group) and 17 received HAIC and IFN-α-2b (IFN group). There were no significant differences in clinical characteristics between the 2 groups. Results: The response rate was 33.3% (complete response (CR)=1; partial response (PR)=3) in the PEGIFN group and 47.1% (PR=8) in the IFN group. The 1-, 2- and 3-year cumulative survival rates were 50%, 25% and 8%, respectively, in the PEG-IFN group, whereas they were 53%, 18% and 12%, respectively, in the IFN group. There were no significant differences in the response rate (p=0.251) and survival (p=0.938) between the two groups. Conclusions: We found that combination therapy comprising HAIC using low-dose FP with isovorin and PEG-IFN-α-2b was not beneficial for advanced HCC.
Hepato-gastroenterology 59(114):533-7. · 0.66 Impact Factor
