Kazuya Kariyama

Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma

Background: Advanced hepatocellular carcinoma (HCC) in humans is characterized by hypervascularity. In the present study, the expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF‐2) and endostatin were analyzed in patients with chronic liver disease to clarify the effect of these major angiogenic factors.

Complications of radiofrequency ablation for hepatocellular carcinoma in a multicenter study: An analysis of 16 346 treated nodules in 13 283 patients

Aim:  We surveyed multiple centers to identify types and frequency of complications and mortality rate associated with radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC).

Expression of MAGE, GAGE and BAGE genes in human liver diseases : utility as molecular markers for hepatocellular carcinoma

BACKGROUND/AIMS The MAGE, GAGE and BAGE genes encode tumor antigens recognized by autologous cytotoxic T lymphocytes. The aim of this study was to evaluate the possibility of using these genes as molecular markers and as the targets of specific immunotherapy for human hepatocellular carcinoma (HCC). METHODS The expressions of MAGE-1, MAGE-3, GAGE1-6, GAGE1-2 and BAGE mRNA in 33 surgically resected HCC samples and 26 of their corresponding non-cancerous samples (11 liver cirrhosis and 15 chronic hepatitis) were studied by a reverse-transcription polymerase chain reaction, and were compared with clinicopathological parameters. The expression of MAGE-1 was also examined in 16 biopsied HCC samples. RESULTS MAGE-1, MAGE-3, GAGE1-6, GAGE1-2 and BAGE mRNA were expressed in 67%, 39%, 36%, 30%, and 21% of the HCC, respectively. At least one transcript was detected in 88% of the HCC, while no expression was observed in the non-cancerous livers. There was no significant correlation between the expression of any of the tumor antigens examined and the differentiation stage or size of the HCC. Especially, MAGE-1 was highly expressed in small HCC with a diameter of less than 2 cm and in well-differentiated HCC (81% and 70%, respectively), and was also expressed even in alpha-fetoprotein-negative and PIVKA-II-negative HCC (58% and 76%, respectively). The MAGE-1 expression was detected in 69% of biopsied HCC samples and the expression was high in both small and well-differentiated HCC. CONCLUSIONS These tumor-specific antigens can be useful as molecular markers and as the possible target molecules for the specific immunotherapy of human HCC.

Expression of telomerase-associated protein 1 and telomerase reverse transcriptase in hepatocellular carcinoma.

To know whether two protein components of human telomerase (human telomerase-associated protein 1 (hTEP1) and human telomerase reverse transcriptase (hTERT) are useful markers for telomerase activation in human liver diseases, we examined mRNA levels of these and telomerase activity in human liver samples. Twenty-three human hepatocellular carcinomas (HCCs) and corresponding adjacent livers were analysed for hTEP1 and hTERT expression by semiquantitative reverse transcription-polymerase chain reaction, and for telomerase activity by a telomeric repeat amplification protocol assay. Thirteen liver samples (ten HCCs and three dysplastic nodules) that were biopsied with 21-gauge needles were analysed for hTERT expression. hTEP1 was expressed in all samples examined. No correlation between hTEP1 expression and telomerase activity was observed. hTERT expression significantly correlated with telomerase activity (P< 0.001). The positivity of hTERT for HCC and corresponding non-cancerous liver was 100% and 30.4% respectively (P< 0.001). Seventy-four per cent (17/23) of HCCs showed strong hTERT expression, but none of the non-cancerous liver tissues did. hTERT expression of the 21-gauge needle biopsied specimens showed no significant difference from that of the surgical samples. The present study revealed that hTERT is strongly expressed in most HCCs, and that hTERT but not hTEP1 is a key component regulating telomerase activity in human liver.

Expression of MAGE-1 and -3 genes and gene products in human hepatocellular carcinoma

SummaryMAGE gene family encodes peptides recognized by autologous cytotoxic T lymphocytes in a major histocompatibility complex (MHC) class-I restricted fashion. In the present study, we have performed reverse-transcription polymerase chain reaction (RT-PCR) for the genes, as well as immunohistochemical analysis and Western blotting of MAGE-1 and -3 proteins in 33 surgically resected hepatocellular carcinomas (HCCs). MAGE-1 and -3 mRNAs were constitutively expressed exclusively in 78 and 42% of HCCs respectively. On immunohistochemistry with monoclonal antibodies, 77B for MAGE-1 and 57B for MAGE-3, MAGE-1 and -3 proteins were recognized in cytoplasm of only six among 33 (18%) and two of 29 HCCs (7%) respectively. The distribution pattern was mostly focal in HCC nodules. By contrast, the Western blot analysis revealed that the MAGE-1 (46 kDa) and -3 proteins (48 kDa) were expressed in 80 and 60% of 15 HCCs examined respectively. The proteins of MAGE-1 and -3 were also expressed exclusively in HCCs regardless of the histological grading and clinical staging. Our results indicate that the detection of the genes by RT-PCR or the proteins by Western blotting is useful for differentiating early HCCs from non-cancerous lesions, and that the peptides derived from MAGE-1 and -3 proteins might be suitable targets for immunotherapy of human HCC.

Percutaneous Radiofrequency Ablation for Treatment of Hepatocellular Carcinoma in the Caudate Lobe

OBJECTIVE This study aimed to evaluate the efficacy and safety of percutaneous radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC) in the caudate lobe, where RFA is considered to be difficult. MATERIALS AND METHODS Of a total of 810 patients treated by ultrasound-guided radiotherapy between July 2002 and May 2010, medical records of 50 consecutive patients with HCC in the caudate lobe were reviewed in this retrospective study. Twenty-two tumors were found to be in the paracaval portion and 28 in the Spiegel lobe. We retrospectively reviewed the procedures, treatment effect, and complications. RESULTS For all paracaval tumors and eight Spiegel lobe tumors, we used the intercostal approach, and for the remaining Spiegel tumors (n = 20) we used the pass-the-left approach. We found that all tumors were successfully treated, and the local recurrence rate after 2 years was 12%. Cases of mortality or major complications after RFA were absent. CONCLUSION RFA appears to be an effective treatment modality for HCC in the caudate lobe.

Albumin-Bilirubin (ALBI) Grade as Part of the Evidence-Based Clinical Practice Guideline for HCC of the Japan Society of Hepatology: A Comparison with the Liver Damage and Child-Pugh Classifications

Aim/Background: The purpose of this study was to evaluate the validity of 3 classifications for assessing liver function, the liver damage and Child-Pugh classifications and the newly proposed albumin-bilirubin (ALBI) grade, in order to examine the feasibility of evaluating hepatic function using ALBI grade with the hepatocellular carcinoma (HCC) treatment algorithm used in Japan. Methods: We analyzed the medical records of 3,495 Japanese HCC patients admitted from 2000 to 2015, which were comprised of 1,580 patients hospitalized in the Ehime Prefecture area and used as a training cohort (Ehime group), and 1,915 others who were used for validation (validation group). ALBI score used for grading (≤-2.60 = grade 1, greater than -2.60 to ≤-1.39 = grade 2, greater than -1.39 = grade 3) as well as clinical features and prognosis (Japan Integrated Staging [JIS], modified JIS, ALBI-TNM [ALBI-T] score) were retrospectively investigated. Results: For prediction of liver damage A, the values for sensitivity and specificity, positive predictive and negative predictive values, and positive and negative likelihood ratios of ALBI-1 and Child-Pugh A were similar among the 2 groups. Akaike information criterion results showed that prognosis based on ALBI grade/ALBI-T score was better than that based on liver damage/modified JIS score and Child-Pugh/JIS score (22,291.8/21,989.4, 22,379.6/22,076.0, 22,392.1/22,075.1, respectively). The cutoff values for ALBI score for indocyanine green retention rate at 15 min (ICG-R15) <10, <20, and <30% were -2.623 (area under the curve [AUC]: 0.798), -2.470 (AUC: 0.791), and -2.222 (AUC: 0.843), respectively. The distribution of ICG-R15 (<10%, 10 to <20%, 20 to <30%, and ≥30%) for ALBI grade 1 was similar to that for liver damage A. There were only small differences with regard to therapeutic selection with the Japanese HCC treatment algorithm between liver damage and ALBI grade. Conclusion: ALBI grade is a useful and easy classification system for assessment of hepatic function for therapeutic decision making.

Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma

Background:We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort.Methods:In the current retrospective cohort study, we measured serum levels of the eightcytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS).Results:Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21–2.81), and OS (HR, 1.95; 95% CI, 1.21–3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30–3.06) and OS (HR, 1.94; 95% CI, 1.19–3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis.Conclusion:High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.

Radiofrequency Ablation for the Treatment of Hepatocellular Carcinoma with Decompensated Cirrhosis

Background: Radiofrequency ablation (RFA) is used to treat early-stage hepatocellular carcinoma (HCC), but is sometimes avoided in patients with decompensated liver cirrhosis because of the possible side effect of deterioration of liver function. Aims: In this study, we report the safety and effects of RFA for treating HCC patients with Child-Pugh B/C liver cirrhosis. Methods: Sixty-six consecutive HCC patients with Child-Pugh B/C cirrhosis, who were treated by RFA, were enrolled in this study. We analyzed patient outcomes, the complications of RFA, and changes in liver function and tumor markers. Results: Fifty-six patients were classified as Child-Pugh class B, and 10 were classified as class C. The overall survival rates in patients with Child-Pugh B and C cirrhosis were 82 and 83% at 1 year and 47 and 31% at 3 years, respectively. Serum total bilirubin (T.Bil), albumin, prothrombin time, ascites, and encephalopathy were unchanged at 1, 3, and 6 months after RFA in patients with Child-Pugh B cirrhosis; however, serum T.Bil levels increased significantly at 6 months after RFA in 6/10 (60%) patients with Child-Pugh C cirrhosis. Hemothorax and rupture of esophageal varices were observed in 2 patients; however, there were no complications related to poor liver function. Conclusion: RFA is a useful modality for treating HCC in patients with poor liver function such as Child-Pugh B and C, but careful monitoring after RFA must be needed.

Proposed New Sub-Grouping for Intermediate-Stage Hepatocellular Carcinoma Using Albumin-Bilirubin Grade

Aim: We retrospectively evaluated the efficacy of albumin-bilirubin (ALBI) grade, which has been proposed as a new classification for hepatic function, for evaluation of the prognosis of intermediate-stage hepatocellular carcinoma (Barcelona Clinic Liver Cancer criteria stage B, BCLC-B). Patients and Methods: We enrolled 754 naïve BCLC-B patients (multiple tumors) and retrospectively analyzed their clinical features [surgical resection (hepatectomy), n = 170; radiofrequency ablation (RFA), n = 110; percutaneous ethanol injection, n = 7; transcatheter arterial chemoembolization, n = 396; others, n = 25; best supportive care, n = 46]. Four sub-groups were defined for the Modified Intermediate Stage of Liver Cancer (MICAN) criteria as follows: B1 (ALBI-1/within up-to-7 criteria), B2 (ALBI-2/within up-to-7 criteria), B3 (ALBI-1 and ALBI-2/multiple and beyond up-to-7 criteria), and B4 (ALBI-3/any). Results: The median survival time of patients classified as B1 (n = 94), B2 (n = 175), B3 (n = 452), and B4 (n = 33) was 65.1, 48.1, 29.6, and 14.6 months, respectively (p < 0.01 for each). Those in B1 treated with hepatectomy and RFA comprised 67.0%, while that ratio was 51.4% in B2, 28.3% in B3, and 12.1% in B4. Conclusion: The MICAN criteria based on ALBI grade are simple and useful for prediction of prognosis and therapy decision-making in the heterogeneous population of BCLC-B patients.