Shigeo Shimose

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.

Long-term outcome of elderly patients (75 years or older) with hepatocellular carcinoma.

The aim of this study was to evaluate the long‐term outcome of elderly patients with hepatocellular carcinoma (HCC) aged 75 years or older.

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.

Inhibition of hypoxia-inducible factor via upregulation of von Hippel-Lindau protein induces “angiogenic switch off” in a hepatoma mouse model

“Angiogenic switch off” is one of the ideal therapeutic concepts in the treatment of cancer. However, the specific molecules which can induce “angiogenic switch off” in tumor have not been identified yet. In this study, we focused on von Hippel-Lindau protein (pVHL) in hepatocellular carcinoma (HCC) and investigated the effects of sulfoquinovosyl-acylpropanediol (SQAP), a novel synthetic sulfoglycolipid, for HCC. We examined mutation ratio of VHL gene in HCC using 30 HCC samples and we treated the HCC-implanted mice with SQAP. Thirty clinical samples showed no VHL genetic mutation in HCC. SQAP significantly inhibited tumor growth by inhibiting angiogenesis in a hepatoma mouse model. SQAP induced tumor “angiogenic switch off” by decreasing hypoxia-inducible factor (HIF)-1, 2α protein via pVHL upregulation. pVHL upregulation decreased HIFα protein levels through different multiple mechanisms: (i) increasing pVHL-dependent HIFα protein degradation; (ii) decreasing HIFα synthesis with decrease of NF-κB expression; and (iii) decrease of tumor hypoxia by vascular normalization. We confirmed these antitumor effects of SQAP by the loss-of-function experiments. We found that SQAP directly bound to and inhibited transglutaminase 2. This study provides evidence that upregulation of tumor pVHL is a promising target, which can induce “angiogenic switch off” in HCC.

Epirubicin is More Effective than Miriplatin in Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma

Background: Transcatheter arterial chemoembolization (TACE) is a standard therapy used in the treatment of intermediate hepatocellular carcinoma (HCC). Recently, balloon-occluded TACE (B-TACE) has been developed. Purpose: This study aimed to clarify the effects of B-TACE in patients with HCC, with a focus on which drug is suitable to suspend in Lipiodol for B-TACE. Methods: We retrospectively evaluated 35 patients with HCC treated with B-TACE. Factors associated with enhanced time to progression (TTP) after B-TACE were evaluated using univariate and multivariate analyses. Results: A total of 35 patients with HCC (40 nodules) were treated with B-TACE between June 2013 and August 2016. Epirubicin was used in 25 nodules and miriplatin was used in 15 nodules. Epirubicin (15.1 months) was significantly better than miriplatin (3.2 months) in prolonging the local TTP after B-TACE (p = 0.0293). Epirubicin showed a positive tendency in TE4 (100% tumor necrosis) rate when compared with miriplatin (p = 0.058). Achievement of TE4 was the only significant factor associated with better TTP after B-TACE. Epirubicin- and TACE-naïve statuses were significant factors in achieving TE4 with B-TACE. Conclusion: To enhance the TTP with B-TACE, TE4 should be achieved. Epirubicin is a more optimal anticancer drug (as a Lipiodol suspension) than miriplatin for achieving TE4 with B-TACE.

Profiles Associated with Sarcopenia in Hepatoma Patients Underwent Transcatheter Arterial Chemoembolization: A Data-Mining Analysis

Sarcopenia is a prognostic factor in patients with hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) may aggravate sarcopenia because of post‐embolization syndrome. The aims of this study are to investigate changes in skeletal muscle mass after TACE and its risk profiles in patients with HCC.

Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis-related cytokines after treatment with sodium-glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus: Regression of HCC after SGLT2 inhibitor treatment

Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event, and the pathogenesis remains unclear. Here, we present a case of spontaneous regression of HCC after treatment with sodium‐glucose cotransporter 2 inhibitor (SGLT2i) in a cirrhotic patient with diabetes mellitus (DM). A 68‐year‐old man regularly visited our hospital for follow‐up of HCC after treatment with transcatheter arterial chemoembolization, and management of liver cirrhosis and type 2 DM. Contrast‐enhanced computed tomography scan showed a hypervascular tumor in the liver and elevated serum α‐fetoprotein levels, indicating the recurrence of HCC. Simultaneously, the hemoglobin A1c value increased to 8.0%; therefore, he was treated with SGLT2i (canagliflozin 100 mg/day). Ten weeks after the initiation of SGLT2i treatment, he was admitted to our hospital for treatment of recurrent HCC. However, the hypervascular tumor had disappeared, and the elevated serum α‐fetoprotein level had decreased to normal limits, indicating spontaneous regression of HCC. In addition, an angiogenesis array analysis revealed downregulated protein expression of matrix metalloproteinase‐8, angiopoietin‐1/2, platelet‐derived growth factor‐AA, and prolactin at 10 weeks after SGLT2i treatment. In this report, we first describe a case of spontaneous regression of HCC with reduction in angiogenesis‐related cytokines after SGLT2i treatment.