Takashi Niizeki

Serum C‐reactive protein levels predict survival in hepatocellular carcinoma

Background/Aims: C‐reactive protein (CRP) was recently identified as a prognostic factor for patients with hepatocellular carcinoma (HCC) after surgical resection. We investigated the relationship between the serum levels of high sensitivity CRP (H‐CRP) and the prognosis of HCC patients.

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.

Effects of in‐hospital exercise on liver function, physical ability, and muscle mass during treatment of hepatoma in patients with chronic liver disease

Sarcopenia and physical disability assessed by a 6‐min walking test (6MWT) are associated with poor prognosis of patients with chronic liver disease (CLD). However, CLD patients with hepatocellular carcinoma (HCC) mostly rest in bed during hospitalization. We aimed to investigate the effects of therapeutic exercise on liver function, 6MWT, and skeletal muscle mass during HCC treatment in patients with CLD.

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.

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.

Intrahepatic cholangiocarcinoma with sarcomatous change producing granulocyte-colony stimulating factor.

To the editor: Granulocyte-colony stimulating factor (G-CSF) is a naturally occurring glycoprotein that stimulates the proliferation and maturation of precursor cells in bone marrow into fully differentiated neutrophils. Since G-CSF producing lung cancer was initially reported in 1977, G-CFS producing malignant neoplasms, such as hepatocellular carcinoma (HCC), bladder cancer, uterine cervix cancer, pancreatic cancer, and so forth, has been reported. Intrahepatic cholangiocarcinoma (ICC) is a relatively infrequent tumor in most populations, but is the second most common primary hepatic malignancy following HCC. Only five ICCs have been reported to show G-CSF production with marked leucocytosis. Herein, we report a case of ICC with sarcomatous change presenting marked leukocytosis and discuss the association between ICC and G-CSF with respect to hepatic stem/progenitor cells (HSPCs). A 62-year-old woman was hospitalized for a large mass with a maximal diameter of 8 cm in the left lobe of the liver. She had a history of chronic hepatitis type C, and had been examined periodically in our hospital for 20 years. When she underwent examination by ultrasonography 5 months prior to the admission, the mass lesion was not detected in the liver. Physical examination on admission revealed high fever (38.4°C), epigastralgia, hepatomegaly and non-pitting edema in the lower extremities. Laboratory data on admission showed mild leukocytosis (11 900/mL), mild anemia, hypoalbuminemia and elevation of C-reactive protein. Serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 were markedly elevated to 104.9 ng/mL (normal: <2.5 ng/mL) and 5983.7 U/mL (normal: <37 U/mL), respectively. Abdominal computed tomography showed a large low density mass measuring 10 ¥ 6 cm in the left lobe of the liver. Metastasis of lymph nodes or other organs was not detected. Based on these findings, she was clinically diagnosed with ICC and underwent chemotherapy using gemcitabine (1400 mg/day). However, chemotherapy had no effect. With the tumor progression, white blood cell count and CEA were elevated up to 50 500/mL and 227.0 ng/mL, respectively. She died of liver failure approximately 3 months after admission. Autopsy was performed. The liver weighed 2470 g. The cut surface showed a yellowish solid mass measuring 12.2 ¥ 8.5 cm with massive necrosis and hemorrhage in the left lobe of the liver. Innumerable small nodules had diffusely invaded the bilateral lobes of the liver. Histopathologically, the tumor was composed of two different components. One was an adenocarcinoma component, the other was a sarcomatous component. In the former component, tumor cells were proliferative in glandular fashion with mucin production in a relatively limited part (Fig. 1a: left side). The latter component showed that tumor cells with loose cohesiveness and marked pleomorphism were diffusely proliferative (Fig. 1a: right side). Numerous atypical mitoses were encountered. Neutrophils infiltration was evident inside tubular structures of adenocarcinoma component and around sarcomatous component. The expression of G-CSF was observed both adenocarcinoma and sarcomatous components immunohistochemically (Fig. 1b). Both components were positive for vimentin (Fig. 1c). All of the tumor cells were positive for cytokeratin (CK) 7, CK19, CK CAM 5.2 and negative for hepatocyte paraffin-1 and epithelial cell adhesion molecule. These findings indicate this tumor is a moderately differentiated adenocarcinoma with sarcomatous change. The inner rims of small ducts in the adenocarcinoma component were positive for CD56 and CD 133, which are representative markers of HSPCs (Fig. 1d). The tumor metastasized to bilateral lung diffusely, bronchopulmonary and para-aortic lymph nodes. Background non-carcinomatous hepatic tissue showed the formation of regenerative nodules and infiltration of mononuclear cells in the portal area, which corresponded to cirrhosis associated with hepatitis C virus infection. There were no apparent infection foci causing severe leucocytosis in other organs. The diagnostic criteria of G-CSF producing tumor are as follows: (i) extreme leukocytosis, (ii) elevated G-CSF activity, (iii) drop in white blood cell count after tumor resection, or (iv) proof of G-CSF production in the tumor. Our present case revealed marked leucocytosis. Moreover, G-CSF production was confirmed by immunohistochemical staining although the serum G-CSF level was not examined. It is reasonable to regard this tumor as a G-CSF producing tumor because leukocytosis deteriorated with the tumor progression and there were no other factors causing leukocytosis. The prognosis of patients with a G-CSF-producing tumor is extremely poor. ICC rarely causes marked leucocytosis. To the best of our knowledge searched by PubMed, only five cases of G-CSF producing ICC with marked leucocytosis have ever been reported (Table 1). Out of these, squamous cell carcinoma, adenosquamous cell carcinoma and adenocarcinoma were pathologically diagnosed in one, one and three cases, respectively. The average prognosis of them was 49 days. G-CSF was considered to be a major autocrine growth factor in rapid tumor proliferation and metastasis. Autocrine Pathology International 2013; 63: 233–235 doi:10.1111/pin.12051 bs_bs_banner

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.