Issei Saeki

Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis

BackgroundHuman 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.MethodsThe 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.ResultsIn 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.ConclusionsBortezomib appears to be an ideal target drug for HCC with LC.

Effect of a late evening snack using branched‐chain amino acid‐enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

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).

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: Is the addition of subcutaneous interferon‐α‐2b beneficial?

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)‐ α‐2b in patients with advanced HCC.

Pilot study of combination therapy with transcatheter arterial infusion chemotherapy using iodized oil and percutaneous radiofrequency ablation during occlusion of hepatic blood flow for hepatocellular carcinoma.

Objective: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. Patients and Methods: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. Results: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. Conclusions: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.

Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma

AIM To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies. METHODS In the basic study, the effect of DFX was investigated in three hepatoma cell lines (HepG2, Hep3B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity (according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced. RESULTS Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro. In the murine model, DFX treatment significantly suppressed the development of liver tumors (P < 0.01), and significantly upregulated the mRNA expression levels of hepcidin (P < 0.05), transferrin receptor 1 (P < 0.05), and hypoxia inducible factor-1α (P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%. CONCLUSION We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.

Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib

Although sorafenib is expected to have a chemopreventive effect on hepatocellular carcinoma (HCC) recurrence, there are limitations to its use because of adverse effects, including effects on liver function. We have reported that the iron chelator, deferoxamine can prevent liver fibrosis and preneoplastic lesions. We investigated the influence of administering a new oral iron chelator, deferasirox (DFX), on the effects of sorafenib. We used the choline-deficient l-amino acid-defined (CDAA) diet-induced rat liver fibrosis and HCC model. We divided rats into four groups: CDAA diet only (control group), CDAA diet with sorafenib (sorafenib group), CDAA diet with DFX (DFX group), and CDAA diet with DFX and sorafenib (DFX + sorafenib group). Liver fibrosis and development of preneoplastic lesions were assessed. In addition, we assessed adverse effects such as changes in body and liver weight, skin damage (eruption, dryness, and hair loss), which is defined as hand-foot skin syndrome, in the sorafenib and DFX + sorafenib groups. The combination of DFX + sorafenib markedly prevented liver fibrosis and preneoplastic lesions better than the other treatments. Furthermore, the combination therapy significantly decreased adverse effects compared with the sorafenib group. In conclusion, the combination therapy with DFX and sorafenib may be a useful adjuvant therapy to prevent recurrence after curative treatment of HCC.

Clinical characteristics and prognosis of non-B non-C hepatocellular carcinoma patients with modest alcohol consumption

Alcoholic hepatocellular carcinoma (ALD‐HCC) accounts for the majority of non‐B non‐C HCC (NBNC‐HCC) cases. Although alcohol is a potent carcinogen, there have been few reports on the influence of modest alcohol consumption in NBNC‐HCC. This study aimed to investigate the clinical characteristics and prognosis of NBNC‐HCC patients with modest alcohol consumption.

A new therapeutic assessment score for advanced hepatocellular carcinoma patients receiving hepatic arterial infusion chemotherapy.

Background & Aims Hepatic arterial infusion chemotherapy (HAIC) is an option for treating advanced hepatocellular carcinoma (HCC). Because of the poor prognosis in HAIC non-responders, it is important to identify patients who may benefit from continuous HAIC treatment; however, there are currently no therapeutic assessment scores for this identification. Therefore, we aimed to establish a new therapeutic assessment score for such patients. Methods We retrospectively analyzed 90 advanced HCC patients with elevated baseline alpha-fetoprotein (AFP) and/or des-gamma-carboxy prothrombin (DCP) levels and analyzed various parameters for their possible use as predictors of response and survival. AFP and DCP responses were assessed after half a course of HAIC (2 weeks); a positive-response was defined as a reduction of ≥ 20% from baseline. Results Multivariate analysis identified DCP response (odds ratio 16.03, p < 0.001) as an independent predictor of treatment response. In multivariate analysis, Child-Pugh class A (hazard ratio [HR] 1.99, p = 0.018), AFP response (HR 2.17, p = 0.007), and DCP response (HR 1.90, p = 0.030) were independent prognostic predictors. We developed an Assessment for Continuous Treatment with HAIC (ACTH) score, including the above 3 factors, which ranged from 0 to 3. Patients stratified into two groups according to this score showed significantly different prognoses (≤1 vs. ≥2 points: median survival time, 15.1 vs. 8.7 months; p = 0.003). Conclusions The ACTH score may be useful in the therapeutic assessment of HCC patients receiving HAIC.

Serum transferrin as a predictor of prognosis for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma

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 anticancer 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).

Efficacy of iron chelator deferoxamine for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma patients refractory to current treatments

The prognosis of advanced hepatocellular carcinoma (HCC) remains poor. For patients with advanced HCC, the multikinase inhibitor sorafenib is recommended as the current standard of care. In contrast, hepatic arterial infusion chemotherapy (HAIC) is one of the recommended treatments in Japan. However, in Japan, the use of sorafenib versus hepatic arterial infusion chemotherapy for first-line treatment remains unclear, because there have been no randomized controlled trials comparing HAIC with sorafenib. HAIC can substantially prolong survival in patients with complete and partial response, while non-responders may be suitable candidates for sorafenib therapy. Nonetheless, HAIC non-responders with deteriorated liver function currently have no treatment options. We have shown the efficacy of an alternative therapy, the iron chelator deferoxamine, for advanced HCC patients with deteriorated liver function. Iron chelators may have future therapeutic possibilities in this patient population.