Clinical significance of early interventional therapy of branched-chain amino acid granules in patients with hepatocellular carcinoma: Propensity score matching analysis
- Authors:
- Published online on: June 24, 2014 https://doi.org/10.3892/ijo.2014.2514
- Pages: 1082-1090
Abstract
Introduction
Hepatocellular carcinoma (HCC) is the most common carcinoma worldwide (1). Unlike most solid cancers, both the incidence and mortality rate for HCC patients are expected to increase substantially in many countries over the next 20 years, mostly as a result of infection with hepatitis C virus (HCV), in Japan, however, the incidence of non-B and non-C HCC has recently tended to increase (2,3). Treatment methods for HCC vary depending on the disease stage and liver function, and they include surgical resection (SR), liver transplantation, radiofrequency thermal ablation (RFA), percutaneous ethanol injection therapy, transcatheter arterial chemotherapy with or without embolization, systemic treatment with molecular-targeted therapy (MTT) such as sorafenib therapy and radiation therapy (RT) (4–7). HCC also carries a considerable risk of tumor recurrence even when curative treatment was performed at the initial therapy, with the tumor characteristics and any underlying liver disease important predictive factors affecting the risk of HCC recurrence (1,2,4,6).
Branched-chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low plasma level ratio of BCAAs to aromatic amino acids suggests liver cirrhosis (LC) physiologically, and BCAA supplementation was originally developed in order to normalize the patient’s amino acid profile and nutritional status (8–11). Most HCC patients have underlying various stages of LC including compensated or decompensated stages. LC patients with decreased plasma BCAA level can develop protein-energy malnutrition (PEM) with increased catabolism (12). PEM is associated with a high morbidity and mortality due to an increased risk of life-threatening complications, resulting in poor clinical outcome and deteriorated quality of life (QOL) (9). PEM in LC patients is already observed in the compensated phase with serum albumin level, which is a useful indicator of liver functional reserve, ≥3.6 g/dl (13). Supplementation with BCAA for the treatment of patients with liver disorder has been attracting attention. BCAA has a variety of pharmacological effects. BCAA treatment can correct malnutrition associated with LC (14,15) and long-term nutritional BCAA supplementation may be effective for increasing plasma BCAA levels, albumin synthesis and prevention of hepatic failure while it also improves surrogate markers in patients with advanced LC (16,17). On the other hand, dietary supplementation alone does not affect plasma BCAA levels in patients with LC (18).
BCAA granules (Livact; Ajinomoto Pharmaceutical, Tokyo, Japan) have been approved for its use in LC patients since 1996 in Japan, and BCAA granules are generally administered in LC patients with a serum albumin level ≤3.5 g/dl. Clinical evidence regarding the effect of this therapy is being accumulated (19–23). Thus, the 2008 Japanese guidelines for the treatment of patients with chronic liver diseases recommend that treatment with BCAA granules should be performed for decompensated LC with a serum albumin level ≤3.5 g/dl (19). In Japan, BCAA granules are widely used in clinical practice without serious adverse effects. In addition, we have previously demonstrated that BCAA treatment may improve OS and recurrence-free survival after RFA in patients with HCV-related HCC ≤3 cm in diameter with ≤3 nodules and a serum albumin level before RFA ≤3.5 g/dl (24). On the other hand, several investigators reported that for patients with chronic liver diseases including LC, it might be beneficial to initiate BCAA therapy in the compensatory stage or even earlier, which means ‘early intervention using BCAA therapy’, rather than starting BCAA therapy in the decompensatory stage (25–27). Thus, BCAA supplementation may be effective in improving clinical outcome in cirrhotic patients regardless of disease stage.
However, to our knowledge, whether this early intervention using BCAA granules in patients with HCC can contribute to prolongation of survival remains unclear. The objectives of the present study were to examine whether supplementation of BCAA granules in an early stage of underlying liver disease (pretreatment serum albumin level ≥3.6 g/dl) can improve overall survival (OS) after HCC therapy. For reducing selection biases, we used propensity score matching analysis.
Patients and methods
Patients
A total of 1,134 consecutive treatment-naïve patients diagnosed with HCC with pretreatment serum albumin level ≥3.6 g/dl were admitted to the Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Japan, between 2004 and 2013. We divided these patients into two groups according to pretreatment serum albumin level (cut-off serum albumin level, 4.0 g/dl). There were 470 patients with pretreatment serum albumin level ≥3.6 g/dl and <4.0 g/dl at the initial treatment for HCC. Of these, BCAA granules were prescribed in 120 patients at the initial therapy for HCC and the remaining 350 patients did not receive such therapy at the initial therapy for HCC. Since this study was a retrospective observational study, covariate adjustment using the propensity score was performed. One hundred and eleven pairs were thus selected for analysis in this cohort (cohort 1) (Fig. 1). Similarly, there were 664 patients with pretreatment serum albumin level ≥4.0 g/dl at the initial treatment for HCC. Of these, BCAA granules were prescribed in 63 patients at the initial therapy for HCC and the remaining 601 patients did not receive such therapy at the initial therapy for HCC. After using the propensity score matching, 61 pairs were selected for analysis in this cohort (cohort 2) (Fig. 1). We compared the OS rate between the BCAA group and the control group in each cohort.
Prior to therapy for HCC, written informed consent was obtained from all patients. The ethics committee of our department approved the protocol for HCC therapy. The present study comprised a retrospective analysis of patients’ medical records in our database and all treatments were performed in an open-label manner.
Diagnosis of HCC and HCC therapy
HCC was diagnosed based on the results from abdominal ultrasound and dynamic computed tomography (CT) scan (hyperattenuation during the arterial phase in the entire or part of the tumor, and hypoattenuation in the portal-venous phase) and/or magnetic resonance imaging mainly as recommended by the American Association for the Study of Liver Diseases (28). Arterial and portal phase dynamic CT images were obtained ~30 and 120 sec after injection of contrast material. For all patients, abdominal angiography combined with CT (angio-CT) was performed before therapy for HCC after obtaining informed consent from them for performing abdominal angiography. This was performed based on the fact that this technique was useful for detecting small satellite nodules as reported by Yamasaki et al (29). Then, we confirmed HCC using CT during hepatic arteriography (CTHA) and CT during arterial-portography (CTAP). As for HCC therapy, the most appropriate treatment modality for each patient was selected through discussion with surgeons, hepatologists and radiologists (30,31). In the present analysis, there was no patient treated with liver transplantation and there was no treatment related death.
BCAA granule treatment
The patient’s attending physician determined whether treatment with BCAA granules would be performed in individual patients considering their intent to receive the treatment after providing sufficient information regarding BCAA treatment to them. In the BCAA group, BCAA granules, containing 952 mg of L-isoleucine, 1,904 mg of L-leucine and 1,144 mg of L-valine per sachet, were orally administered to subjects at a dose of one sachet three times daily after meals ≥1 month after initial therapy for HCC. We confirmed in our database that patients in the BCAA group were prescribed BCAA granules regularly.
Follow-up after initial therapy for HCC
Follow-up observation consisted of regular blood tests and monitoring of tumor markers, including α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), which was measured using a chemiluminescent enzyme immunoassay (Lumipulse PIVKAII Eisai, Eisai, Tokyo, Japan). Dynamic CT scan was performed every 3–4 months after initial therapy for HCC. In particular, for patients in the BCAA group, we confirmed that BCAA granules were taken properly at every hospital visit. When HCC recurrence or disease progression was detected based on radiologic findings, most appropriate therapy was performed in each patient.
Statistical analysis
The primary end-point is OS. Continuous variables were compared by unpaired t-test, and categorical variables were compared by Fisher’s exact test. Data were analyzed using univariate and multivariate analyses. The cumulative OS rate was calculated by Kaplan-Meier method and tested by log-rank test. A Cox proportional hazard model was used for multivariate analyses of factors with P<0.1 in univariate analysis. These statistical methods were used to estimate the interval from each initial therapy for HCC. Data were analyzed using SPSS software (SPSS Inc., Chicago, IL, USA) for Microsoft Windows. Data are expressed as mean ± standard deviation. A P-value <0.05 was considered to be statistically significant.
Propensity score analysis
To compare the OS between BCAA group patients and control group patients, a propensity score model was used with an attempt to reduce potential biases in survival analysis (32,33). Possible variables associated with long-term survival of HCC patients, including age, sex, HCC stage, maximum tumor size, cause of liver disease, serum albumin level, aspartate aminotransferase (AST) value and alanine aminotransferase (ALT) value were included comprehensively for propensity score generation. With these selected variables, a logistic regression was applied to generate a continuous propensity score from 0 to 1. One-to-one matches between BCAA group patients and control group patients were introduced into the subsequent analysis.
Results
Patient demographic characteristics and survival (cohort 1)
Baseline demographic characteristics of patients in cohort 1 are shown in Table I. There were 111 patients in the BCAA group and 111 patients in the control group, respectively. In terms of baseline demographic characteristics, no significant differences were noted between the BCAA group and the control group, showing that balance of baseline characteristics in the two groups was obtained in the matched sample. As an initial therapy for HCC, in the BCAA group, SR was performed in 35 patients, percutaneous ablative therapies in 52, transcatheter arterial chemotherapy with or without embolization in 22, MTT in one and RT in one, whereas in the control group, SR was performed in 23 patients, percutaneous ablative therapies in 64, transcatheter arterial chemotherapy with or without embolization in 21 and MTT in three (P=0.201).
Table IBaseline characteristics between the BCAA group and the control group in HCC patients with pretreatment serum albumin level ≥3.6g/dl and <4.0 g/dl after propensity score matching. |
The median follow-up period was 2.9 years (range, 0.5–7.0 years) in the BCAA group and 2.6 years (range, 0.1–7.6 years) in the control group. Thirty-nine patients (35.2%) in the BCAA group died during the follow-up period. The causes of death were HCC progression (24 patients), liver failure (12 patients) and miscellaneous (3 patients). Sixty patients (54.1%) in the control group died during the follow-up period. The causes of death were HCC progression (40 patients), liver failure (14 patients) and miscellaneous (6 patients).
The 1-, 3- and 5-year OS rates after each initial therapy for HCC were 97.2, 75.5 and 56.3%, respectively, in the BCAA group and 87.2, 64.5 and 38.8%, respectively, in the control group (P=0.072) (Fig. 2), indicating that the OS rate in the BCAA group tended to be higher compared to that in the control group.
Univariate and multivariate analysis of factors contributing to OS (cohort 1)
In patients with pretreatment serum albumin level of ≥3.6 and <4.0 g/dl, using univariate analyses of factors contributing to OS, HCC stage (P<0.001), maximum tumor size ≥2.5 cm (P=0.004), AST ≥50 IU/l (P=0.004), ALT ≥40 IU/l (P=0.018), alkaline phosphatase (ALP) ≥330 IU/l (P=0.013), γ glutamyl transpeptidase (GGT) ≥70 IU/l (P=0.005), AFP ≥100 ng/ml (P=0.001) and DCP ≥100 mAU/ml (P<0.001) were found to be significant factors (Table II). The multivariate analyses involving nine factors with P<0.1 in the univariate analysis showed that only HCC stage was a significant independent predictor linked to OS (P=0.001). The hazard ratios (HRs), 95% confidence interval (CI) and P-value for nine factors are detailed in Table II.
Table IIUnivariate and multivariate analysis of factors contributing to overall survival in HCC patients with pretreatment serum albumin level ≥3.6 and <4.0 g/dl (cohort 1). |
Patient demographic characteristics and survival (cohort 2)
Baseline demographic characteristics of patients in cohort 2 are shown in Table III. They included 61 patients in the BCAA group and 61 patients in the control group, respectively. In terms of baseline demographic characteristics, no significant differences were noted between the BCAA group and the control group, demonstrating that balance of baseline characteristics in the two groups was obtained in the matched sample. As an initial therapy for HCC, in the BCAA group, SR was performed in 31 patients, percutaneous ablative therapies in 15 and transcatheter arterial chemotherapy with or without embolization in 15, whereas in the control group, SR was performed in 20 patients, percutaneous ablative therapies in 19, transcatheter arterial chemotherapy with or without embolization in 21 and MTT in one (P=0.160).
Table IIIBaseline characteristics between the BCAA group and the control group in HCC patients with pretreatment serum albumin level ≥4.0 g/dl after propensity score matching. |
The median follow-up period was 2.3 years (range, 0.2–7.8 years) in the BCAA group and 2.9 years (range, 0.3–8.4 years) in the control group. Twenty-four patients (39.3%) in the BCAA group died during the follow-up period. The causes of death were HCC progression (22 patients) and liver failure (2 patients). Twenty-eight patients (45.9%) in the control group died during the follow-up period. The causes of death were HCC progression (24 patients), liver failure (2 patients) and miscellaneous (2 patients).
The 1-, 3- and 5-year OS rates after each initial therapy for HCC were 83.2, 60.7 and 54.0%, respectively, in the BCAA group and 91.8, 66.0 and 44.5%, respectively, in the control group (P=0.871) (Fig. 3).
Univariate and multivariate analysis of factors contributing to OS (cohort 2)
In patients with serum albumin level of ≥4.0 g/dl, using univariate analyses of factors contributing to OS, HCC stage (P<0.001), maximum tumor size ≥4.0 cm (P<0.001), AST ≥50 IU/l (P=0.024), ALP ≥300 IU/l (P<0.001), GGT ≥70 IU/l (P=0.009), total bilirubin ≥1.0 mg/dl (P=0.045), AFP ≥100 ng/ml (P=0.013) and DCP ≥100 mAU/ml (P<0.001) were found to be significant factors (Table IV). The multivariate analyses involving nine factors with P<0.1 in the univariate analysis showed that HCC stage (P=0.019), ALP ≥300 IU/l (P=0.023) and AFP ≥100 ng/ml (P=0.019) were significant independent predictors linked to OS. The HRs, 95% CI and P-value for nine factors are detailed in Table IV.
Table IVUnivariate and multivariate analysis of factors contributing to overall survival in HCC patients with pretreatment serum albumin level ≥4.0 g/dl (cohort 2). |
Subgroup analysis according to HCC stage
Since HCC stage was an independent predictor associated with OS in both cohort 1 and 2, we further performed subgroup analyses according to HCC stage. In cohort 1 patients, there were 74 patients with HCC stage I or II in the BCAA group and 77 patients with HCC stage I or II in the control group. In terms of OS, no significant difference was observed in the two groups (P=0.353) (Fig. 4A). In cohort 1 patients, there were 37 patients with HCC stage III or IV in the BCAA group and 34 patients with HCC stage III or IV in the control group. In terms of OS, the difference in the two groups reached significance (P=0.017) (Fig. 4B). On the other hand, cohort 2 patients included 32 and 29 patients with HCC stage I or II and III or IV in the BCAA group and 34 and 27 patients with HCC stage I or II and III or IV in the control group. Regardless of HCC stage, no significant difference was found in terms of OS (P=0.785 for HCC stage I or II and P=0.572 for HCC stage III or IV) (Fig. 5).
Discussion
BCAA granules have a variety of pharmacological effects. Kawaguchi et al (8,35) and Kawaguchi and Sata (34) showed that BCAA granules can improve albumin synthesis, insulin resistance, immune function and patients’ QOL while they can reduce liver related complications and occurrence of HCC. In addition, BCAA supplementation can help in the management of HCC patients since most HCC patients have underlying LC (24,27,36,37). However, whether early interventional therapy using BCAA granules in patients with HCC can improve survival remains unclear. An interesting issue is when is the optimal timing of nutritional support such as BCAA granules in patients with HCC. Hence, we conducted these comparative studies.
In our results, in cohort 1 (patients with pretreatment serum albumin level ≥3.6 and <4.0 g/dl), the OS rate in the BCAA group tended to be higher compared to that in the control group and in subgroup analysis in patients with HCC stage III or IV, which means advanced stage of HCC, the OS rate in the BCAA group was significantly higher compared to that in the control group, although in other analyses, no significant difference in the two groups was found. These results suggest that early interventional therapy using BCAA granules can be a treatment option for some selected patients.
In general, in patients with advanced stage HCC, curative therapies are difficult to perform due to tumor characteristics. Hence, repeated therapies for HCC will be needed in these patients. However, these repeated therapies can lead to deterioration of liver functional reserve as reflected by hypoalbuminemia (24,27). BCAA supplementation actually improves hypoalbuminemia. Moreover, Kawaguchi et al reported that BCAA granules may suppress hepatic neovascularization and hepatocarcinogenic activity and Yoshiji et al demonstrated that BCAA therapy significantly suppressed glucose- and insulin-induced angiogenesis in the presence of vascular endothelial growth factor (VEGF) (8,22). Angiogenesis is a key process in tumor growth and VEGF, which stimulates angiogenesis, appears to be essential for HCC progression (8,22). Our present results may be associated with these observations. On the other hand, advanced malignancy can result in muscle wasting and systemic catabolism, with BCAA treatment having the potential to improve these poor conditions (36).
As described above, in cohort 2 patients (pretreatment serum albumin level ≥4.0 g/d), the difference in the BCAA and control groups did not reach significance in the analyses in terms of OS. Very early intervention using BCAA granules might not be beneficial for improving OS. Curative treatment at the initial therapy for HCC, close surveillance for HCC recurrence and adequate therapy for recurrence will be more important than nutritional therapy in these patients for prolonging OS.
This study included several limitations. First, this is a retrospective observational study although propensity score matching analyses were performed for reducing selection biases in this study. Second, our patient cohorts included heterogeneous patient populations with various stages of HCC and various causes of underlying liver diseases. Third, BCAA treatment adherence in each individual, antiviral therapies such as interferon therapy for patients with HCV or nucleoside analogue therapy for those with hepatitis B virus during observation period were not included in the present analyses, leading to bias (38–40). Hence, further studies with well selected patient population will be needed. However, our study results demonstrated that early interventional therapy using BCAA granules may be effective in some selected patients.
We concluded that in HCC patients with pretreatment serum albumin level ≥3.6g/dl, early BCAA supplementation can be a treatment option for improving clinical outcome.
Acknowledgements
We would like to thank Haruko Takada for the data collection.
References
El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 142:1264–1273. 2012. View Article : Google Scholar : PubMed/NCBI | |
Lencioni: Loco-regional treatment of hepatocellular carcinoma. Hepatology. 52:762–773. 2010. View Article : Google Scholar : PubMed/NCBI | |
Nishikawa H and Osaki Y: Non-B, non-C hepatocellular carcinoma (Review). Int J Oncol. 43:1333–1342. 2013.PubMed/NCBI | |
Llovet JM: Update treatment approach to hepatocellular carcinoma. J Gastoenterol. 40:225–235. 2005. View Article : Google Scholar : PubMed/NCBI | |
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D and Bruix J: SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI | |
El-Serag HB: Hepatocellular carcinoma. N Engl J Med. 365:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI | |
Wo JY, Dawson LA, Zhu AX and Hong TS: An emerging role for radiation therapy in the treatment of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Surg Oncol Clin North Am. 23:353–368. 2014. View Article : Google Scholar : PubMed/NCBI | |
Kawaguchi T, Izumi N, Charlton MR and Sata M: Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 54:1063–1070. 2011. View Article : Google Scholar : PubMed/NCBI | |
No authors listed. Nutritional status in cirrhosis. Italian Multicentre Cooperative Project on Nutrition in Liver Cirrhosis. J Hepatol. 21:317–335. 1994.PubMed/NCBI | |
Kuroda H, Ushio A, Miyamoto Y, Sawara K, Oikawa K, Kasai K, Endo R, Takikawa Y, Kato A and Suzuki K: Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial. J Gastroenterol Hepatol. 25:1550–1555. 2010. | |
Kasugai H, Osaki Y, Oka H, Kudo M and Seki T: Osaka Liver Cancer Study Group: Severe complications of radiofrequency ablation therapy for hepatocellular carcinoma: an analysis of 3,891 ablations in 2,614 patients. Oncology. 72(Suppl 1): 72–75. 2007. View Article : Google Scholar | |
Lautz HU, Selberg O, Körber J, Bürger M and Müller MJ: Protein-calorie malnutrition in liver cirrhosis. Clin Investig. 70:478–486. 1992. View Article : Google Scholar : PubMed/NCBI | |
Kato M, Miwa Y, Tajika M, Hiraoka T, Muto Y and Moriwaki H: Preferential use of branched-chain amino acids as an energy substrate in patients with liver cirrhosis. Intern Med. 37:429–434. 1998. View Article : Google Scholar : PubMed/NCBI | |
Kajiwara K, Okuno M, Kobayashi T, Honma N, Maki T, Kato M, Ohnishi H, Muto Y and Moriwaki H: Oral supplementation with branched chain amino acids improves survival rate of rats with carbon tetrachloride-induced liver cirrhosis. Dig Dis Sci. 43:1572–1579. 1998. View Article : Google Scholar | |
Yosida T, Muto Y, Moriwaki H and Yamato M: Effect of long-term oral supplementation with branched chain amino acid granules on the prognosis of liver cirrhosis. J Gastroenterol. 24:692–698. 1989.PubMed/NCBI | |
Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, Roffi L, Martines D and Abbiati R: Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy: a randomized double blind casein-controlled trial. J Hepatol. 11:92–101. 1990. View Article : Google Scholar : PubMed/NCBI | |
Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F and Abbiati R: Italian BCAA Study Group: Nutritional supplementation with branched chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 124:1792–1801. 2003. View Article : Google Scholar | |
Keshavarzian A, Meek J, Sutton C, Emery VM, Hughes EA and Hodgson HJ: Dietary protein supplementation from vegetable sources in the management of chronic portal systemic encephalopathy. Am J Gastroenterol. 79:945–949. 1984. | |
Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi N, Tanaka E, Chayama K, Sakisaka S, Takehara T, Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka K, Seike M, Yotsuyanagi H and Ueno Y: Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis, Ministry of Health, Labour and Welfare of Japan: Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan. Hepatol Res. 40:8–13. 2010. | |
Saito Y, Saito H, Nakamura M, Wakabayashi K, Takagi T, Ebinuma H and Ishii H: Effect of the molar ratio of branched-chain to aromatic amino acids on growth and albumin mRNA expression of human liver cancer cell lines in a serum-free medium. Nutr Cancer. 39:126–131. 2001. View Article : Google Scholar | |
Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H and Ohashi Y: Long-Term Survival Study (LOTUS) Group: Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res. 35:204–214. 2006. | |
Yoshiji H, Noguchi R, Kitade M, Kaji K, Ikenaka Y, Namisaki T, Yoshii J, Yanase K, Yamazaki M, Tsujimoto T, Akahane T, Kawaratani H, Uemura M and Fukui H: Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol. 44:483–491. 2009. View Article : Google Scholar : PubMed/NCBI | |
Sugiyama K, Yu L and Nagasue N: Direct effect of branched-chain amino acids on the growth and metabolism of cultured human hepatocellular carcinoma cells. Nutr Cancer. 31:62–68. 1998. View Article : Google Scholar | |
Nishikawa H, Osaki Y, Iguchi E, Koshikawa Y, Ako S, Inuzuka T, Takeda H, Nakajima J, Matsuda F, Sakamoto A, Henmi S, Hatamaru K, Ishikawa T, Saito S, Nasu A, Kita R and Kimura T: The effect of long-term supplementation with branched-chain amino acid granules in patients with hepatitis C virus-related hepatocellular carcinoma after radiofrequency thermal ablation. J Clin Gastroenterol. 47:359–366. 2013. View Article : Google Scholar | |
Nishiguchi S and Habu D: Effect of oral supplementation with branched-chain amino acid granules in the early stage of cirrhosis. Hepatol Res. 30S:36–41. 2004. View Article : Google Scholar : PubMed/NCBI | |
Habu D, Nishiguchi S, Nakatani S, Kawamura E, Lee C, Enomoto M, Tamori A, Takeda T, Tanaka T and Shiomi S: Effect of oral supplementation with branched-chain amino acid granules on serum albumin level in the early stage of cirrhosis: a randomized pilot trial. Hepatol Res. 25:312–318. 2003. View Article : Google Scholar : PubMed/NCBI | |
Nishikawa H, Osaki Y, Inuzuka T, Takeda H, Nakajima J, Matsuda F, Henmi S, Sakamoto A, Ishikawa T, Saito S, Kita R and Kimura T: Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol. 18:1379–1384. 2012. View Article : Google Scholar | |
Bruix J and Sherman M: Practice Guidelines Committee, American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma. Hepatology. 42:1208–1236. 2005. View Article : Google Scholar | |
Yamasaki T, Kurokawa F, Shirahashi H, Kusano N, Hironaka K and Okita K: Percutaneous radiofrequency ablation therapy with combined angiography and computed tomography assistance for patients with hepatocellular carcinoma. Cancer. 91:1342–1348. 2001. View Article : Google Scholar | |
Park JW, Amarapurkar D, Chao Y, Chen PJ, Geschwind JF, Goh KL, Han KH, Kudo M, Lee HC, Lee RC, Lesmana LA, Lim HY, Paik SW, Poon RT, Tan CK, Tanwandee T, Teng G and Cheng AL: Consensus recommendations and review by an International Expert Panel on Interventions in Hepatocellular Carcinoma (EPOIHCC). Liver Int. 33:327–337. 2013. View Article : Google Scholar | |
Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, Kojiro M and Makuuchi M: HCC Expert Panel of Japan Society of Hepatology. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 29:339–364. 2011. View Article : Google Scholar | |
Austin PC: A comparison of 12 algorithms for matching on the propensity score. Stat Med. 33:1057–1069. 2014. View Article : Google Scholar : PubMed/NCBI | |
D’Agostino RB Jr: Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 17:2265–2281. 1998. | |
Kawaguchi T and Sata M: Importance of hepatitis C virus-associated insulin resistance: therapeutic strategies for insulin sensitization. World J Gastroenterol. 16:1943–1952. 2010. View Article : Google Scholar : PubMed/NCBI | |
Kawaguchi T, Yamagishi S and Sata M: Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatis c virus-associated insulin resistance. Curr Med Chem. 16:4843–4857. 2009. View Article : Google Scholar | |
Choudry HA, Pan M, Karinch AM and Souba WW: Branched-chain amino acid-enriched nutritional support in surgical and cancer patients. J Nutr. 136(Suppl 1): S314–S318. 2006.PubMed/NCBI | |
Ichikawa K, Okabayashi T, Maeda H, Namikawa T, Iiyama T, Sugimoto T, Kobayashi M, Mimura T and Hanazaki K: Oral supplementation of branched-chain amino acids reduces early recurrence after hepatic resection in patients with hepatocellular carcinoma: a prospective study. Surg Today. 43:720–726. 2013. View Article : Google Scholar | |
Takaguchi K, Moriwaki H, Doyama H, Iida M, Yagura M, Shimada N, Kang M, Yamada H and Kumada H: Effects of branched-chain amino acid granules on serum albumin level and prognosis are dependent on treatment adherence in patients with liver cirrhosis. Hepatol Res. 43:459–466. 2013. View Article : Google Scholar : PubMed/NCBI | |
Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, Tagger A, Colombo M, Bonino F, Majno P and Llovet JM: HCC Italian Task Force: Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 44:1543–1554. 2006. View Article : Google Scholar : PubMed/NCBI | |
Nishikawa H, Nishijima N, Arimoto A, Inuzuka T, Kita R, Kimura T and Osaki Y: Effect of nucleoside analog use in patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Res. May 24–2013.(Epub ahead of print). View Article : Google Scholar |