Masahito Nakano

Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection.

Background Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection. Methods A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). Results There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97–46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80–37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC. Conclusions Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.

Efficacy, Safety, and Survival Factors for Sorafenib Treatment in Japanese Patients with Advanced Hepatocellular Carcinoma

Background: Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC. Aims: The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib. Methods: Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively. Results: Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival. Conclusions: This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage.

Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study

Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. However, its therapeutic effect in advanced HCC patients with extrahepatic metastasis remains uncertain. This study aimed to prospectively assess the efficacy, safety, and survival risk factors and evaluate the prognostic impact of sorafenib treatment in advanced HCC patients with or without extrahepatic metastasis. Between May 2009 and March 2014, 312 consecutive advanced HCC patients who received sorafenib were enrolled in this study. We evaluated their characteristics and compared the clinical outcomes of those with and without extrahepatic metastasis. Of the enrolled patients, 245 (81%) received sorafenib treatment for more than 1 month, with a median duration of 3.6 months. Eighteen patients demonstrated partial response to sorafenib therapy, 127 had stable disease, and 134 had progressive disease at the first radiologic assessment. The median survival time (MST) and progression‐free survival (PFS) were 10.3 and 3.6 months, respectively. Multivariate analysis identified gender, Child‐Pugh class, baseline serum des‐gamma‐carboxy prothrombin level, and treatment duration as independent risk factors for survival. Extrahepatic metastasis was detected in 178 patients. However, the MST, PFS, and therapeutic effect were comparable between patients with and without extrahepatic metastasis. The independent risk factors for decreased overall survival in patients with extrahepatic metastasis were similar to those affecting all patients. Our results indicated that sorafenib could be administered for hepatic reserve and as long‐term treatment for advanced HCC patients regardless of their extrahepatic metastasis status.

Adipocytokine involvement in hepatocellular carcinoma after sustained response to interferon for chronic hepatitis C

Aim:  Interferon (IFN) dramatically reduces the risk of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to chronic hepatitis C (CH‐C). However, HCC still develops in some patients after SVR. To evaluate metabolic factors in patients with HCC occurring after SVR and to determine whether insulin resistance and adipocytokines were involved in this etiology.

Diffusion-weighted magnetic resonance imaging predicts malignant potential in small hepatocellular carcinoma

BACKGROUND Poor differentiation and microvascular invasion are indicators of poor outcome after hepatectomy for patients with small hepatocellular carcinoma (HCC). AIMS We investigated whether gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging (MRI) could predict these factors before hepatectomy. METHODS Between July 2008 and April 2012, 75 patients who underwent hepatectomy for small HCCs (diameter: ≤3cm, tumor number: ≤3) were consecutively enrolled. In gadoxetic acid-enhanced MRI, the signal intensity in the tumor was corrected to that in the paraspinous muscles, and the relative enhancement was calculated. In diffusion-weighted imaging, we measured the apparent diffusion coefficient (ADC). We then investigated the correlations between relative enhancement or ADC and histological grade, microvascular invasion and recurrence-free survival. RESULTS Poorly differentiated HCCs showed significantly lower ADC than well-differentiated and moderately differentiated HCCs. There was no significant difference in the hepatobiliary phase. Only ADC was an independent predictor of microvascular invasion, and the best cut-off point of its prediction was 1.175×10(-3)mm(2)/s. Additionally, the recurrence-free survival was significantly shorter in low-ADC group than in high-ADC group. CONCLUSION ADC is useful for predicting poorly differentiated HCCs and microvascular invasion, and low ADC is associated with increased recurrence risk for small HCCs after hepatectomy.

Serum albumin level is a notable profiling factor for non-B, non-C hepatitis virus-related hepatocellular carcinoma: A data-mining analysis

Various factors are underlying for the onset of non‐B, non‐C hepatitis virus‐related hepatocellular carcinoma (NBNC‐HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC‐HCC using a data‐mining technique.

Recent progress in the management of hepatocellular carcinoma detected during a surveillance program in Japan

Aim:  This study explored recent improvements in the management of hepatocellular carcinoma (HCC) diagnosed during surveillance.

Usefulness of short‑term eltrombopag treatment as a supportive treatment in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia: A report of two cases

Eltrombopag is an oral thrombopoietin (TPO) receptor agonist that increases platelet counts in patients with idiopathic thrombocytopenic purpura and in patients with liver cirrhosis. When cirrhotic patients with thrombocytopenia undergo elective invasive procedures, eltrombopag treatment reduces the requirement for platelet transfusions. However, TPO is known to have proliferative effects on hepatic progenitor cells and hepatic sinusoidal endothelial cells, which indicates that eltrombopag may accelerate tumor progression. Thus, the effect of eltrombopag on hepatocellular carcinoma (HCC) progression is an important issue. The current study describes two cases of HCC with cirrhosis-related thrombocytopenia. A two-week administration of eltrombopag increased platelet counts from 4.8 to 11.3×104 /μl in case 1 and 4.5 to 23.2×104 /μl in case 2. However, no changes were identified in the serum levels of tumor markers or HCC size following eltrombopag administration in the two cases. These HCCs were curatively treated by radiofrequency ablation without platelet transfusions or serious bleeding. Thus, short-term eltrombopag administration may not accelerate HCC proliferation and may be beneficial for invasive HCC treatment in cirrhotic patients with thrombocytopenia.

Clinical effects and safety of intra‑arterial infusion therapy of cisplatin suspension in lipiodol combined with 5‑fluorouracil versus sorafenib, for advanced hepatocellular carcinoma with macroscopic vascular invasion without extra‑hepatic spread: A prospective cohort study

Although sorafenib and hepatic arterial infusion chemotherapy (HAIC) have been proven to improve prognosis in hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion (MVI), the most appropriate approach remains unclear. The present multicenter, non-randomized, prospective cohort study aimed to compare the efficacy and safety of HAIC and sorafenib in patients with advanced HCC and MVI, without extra-hepatic spread (EHS) and Child-Pugh class A disease. The present study was performed between April 2008 and March 2014, and 64 HCC patients with MVI, without EHS and Child-Pugh class A disease were registered. Of these patients, 44 were treated with HAIC and 20 with sorafenib. HAIC involved cisplatin (50 mg fine powder in 5-10 ml lipiodol) and a continuous infusion of 5-fluorouracil (FU) (1,500 mg/5 days), which is referred to as new 5-FU and cisplatin therapy (NFP). The primary outcome was progression-free survival, and the secondary outcome was overall survival (OS). Clinical factors influencing OS and the therapeutic effect were identified using univariate and multivariate analyses. There were no differences in clinical factors between the two groups. The median progression-free survival was 5.1 and 9.5 months in the sorafenib and NFP groups, respectively (P=0.001). The complete response (CR) or partial response (PR) rates were 10 and 71% in the sorafenib and NFP groups, respectively (P<0.001). The median OS in the sorafenib and NFP groups was 13.2 and 30.4 months, respectively (P=0.013). Multivariate analysis revealed that the independent predictors of survival were Child-Pugh score (5, P=0.022, 95% CI, 0.191-0.892), grade of portal vein invasion (brunch, P=0.009, 95% CI, 0.220-0.752), and therapeutic effect (CR or PR, P<0.001, 95% CI, 0.220-0.752), and the independent predictor of therapeutic effect was therapeutic regimen (NFP, P<0.001, 95% CI, 0.006-0.199). NFP should be the first choice for patients with advanced HCC and MVI, without EHS and Child-Pugh A disease.

Alternative treatments in advanced hepatocellular carcinoma patients with progressive disease after sorafenib treatment: a prospective multicenter cohort study

Sorafenib is an oral multikinase inhibitor that has been approved to treat advanced hepatocellular carcinoma (HCC), though it is unclear how much benefit advanced HCC patients with progressive disease (PD) derive from sorafenib treatment. This study aimed to assess survival risk factors and evaluate therapeutic strategies for advanced HCC patients with PD after sorafenib treatment. We analyzed the clinical data and treatment outcomes for 315 consecutive advanced HCC patients treated with sorafenib. Univariate analyses of overall survival identified therapeutic effect as an independent risk factor in all patients. Among all patients, 141 developed PD. Of those, 58 (41%) were treated with sorafenib monotherapy, 70 (50%) with agents other than sorafenib, and 13 (9%) were not treated at all. The median survival time was 6.1 months for PD patients with sorafenib monotherapy and 12.2 months for those administered alternative treatments (p < 0.0001). Our results indicated that sorafenib treatment may have negative long-term therapeutic effects in advanced HCC patients with PD, and that alternative treatments should be considered for these patients after sorafenib administration.