Yoko Tsukuda

Efficacy of therapy for advanced hepatocellular carcinoma: intra-arterial 5-fluorouracil and subcutaneous interferon with image-guided radiation.

Background and Aim:  To evaluate the efficacy of intra‐arterial 5‐fluorouracil (5‐FU) and subcutaneous interferon (IFN) combined with image‐guided radiation therapy (IGRT) in advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT).

Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection.

Sofosbuvir (SOF), a nucleotide analog pro‐drug, targets hepatitis C virus (HCV) NS5B polymerase and shows potential for treating HCV infection, given its high efficacy and good barrier to resistance. However, in addition to the rare resistant‐associated variant (RAV) of non‐structural protein NS5B S282T, several new potential RAVs of SOF have been reported, especially related to HCV genotype 1b. However, the prevalence and characteristics of these RAVs have not been clarified.

Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus‐infected patients with renal impairment

Hepatitis C virus (HCV) infection is a risk factor for end‐stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct‐acting antiviral therapy for HCV‐infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment.

Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions.

Telaprevir‐based therapy for chronic hepatitis C patients is effective; however, the high prevalence of dermatological reactions is an outstanding issue. The mechanism and characteristics of such adverse reactions are unclear; moreover, predictive factors remain unknown. Granulysin was recently reported to be upregulated in the blisters of patients with Stevens–Johnson syndrome (SJS). Therefore, we investigated the risk factors for severe telaprevir‐induced dermatological reactions as well as the association between serum granulysin levels and the severity of such reactions.

A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma

In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Krüppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44High/CD133High and CD44Low/CD133Low cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44High/CD44High cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44High/CD133High subpopulation and, consistent with the up-regulation of CD44High/CD133High cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44High/CD133High subpopulation. When KLF5 was acetylated by TGF-β1, the KLF5-mediated CD44High/CD133High subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44High/CD133High subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.

A Prospective Observational Study on Effect of Short‐Term Periodic Steroid Premedication on Bone Metabolism in Gastrointestinal Cancer (ESPRESSO‐01)

This study is an evaluation of the effect of gastrointestinal cancer chemotherapy with short‐term periodic steroid premedication on bone metabolism. Primary endpoints were changes in bone mineral densities and metabolic bone turnover 16 weeks after initiation of chemotherapy.

Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection.

Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti‐HCV activity of l‐carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH‐1 or HCV replicon‐transfected Huh7.5.1 cells were treated with or without l‐carnitine to examine its anti‐HCV effects. The effects of l‐carnitine on HCV entry, HCV‐induced adipogenesis and lipid droplet formation, and HCV‐induced oxidative stress were examined. Treatment of JFH‐1‐infected cells with l‐carnitine inhibited HCV propagation in a concentration‐dependent manner. In contrast, l‐carnitine had no anti‐HCV activity in the HCV replicon system, which is lacking viral assembly. In addition, l‐carnitine did not affect HCV entry. However, l‐carnitine treatment decreased intracellular lipid droplets, which are crucial for HCV assembly in JFH‐1‐infected cells. The expression level of CPT‐1 was decreased in JFH‐1‐infected cells, and l‐carnitine treatment restored this expression. HCV‐infected cells exhibited increased production of reactive oxygen species and glutathione oxidation. l‐carnitine decreased oxidative stress induced by JFH‐1‐infection, as shown by glutathione/glutathione disulfide assays and MitoSOX staining. l‐carnitine exhibited anti‐HCV activity, possibly by inhibiting HCV assembly and through its anti‐adipogenic activity in HCV‐infected cells. Moreover, l‐carnitine has antioxidant properties in HCV‐infected hepatocytes. Overall, these results indicated that l‐carnitine may be an effective adjunctive agent in antiviral therapies to treat chronic hepatitis C. J. Med. Virol. 89:857–866, 2017.

Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study: FLV add-on SMV/Peg-IFN/RBV therapy

The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated‐interferon (Peg‐IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct‐acting antiviral‐containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add‐on treatment in Peg‐IFN and RBV combination therapy for HCV‐infected patients significantly improved the sustained virologic response (SVR), but the add‐on effect of FLV on SMV combination therapy is not well understood.

Update analysis: Thromboembolism in gastrointestinal tract cancer patients receiving chemotherapy.

e15156Background: We previously reported that TE incidence (TEi) was 14 % among Japanese gastrointestinal tract cancer (GTC) patients (pts) receiving chemotherapy (CTx), and it was significantly hi...

Thromboembolism incidence in patients with gastrointestinal tract cancer receiving chemotherapy: A single-institutional retrospective cohort analysis.

541 Background: Although cancer and its treatments are well-recognized risk factors for thromboembolism (TE), such as venous and pulmonary TE, there are very few data of the incidence of cancer associated TE in the Asian population. So we conducted a retrospective cohort study to investigate the TE incidence of gastrointestinal tract cancer (GTC) patients (pts) receiving chemotherapy in a Japanese community hospital’s daily practice setting. Methods: All the patients received chemotherapy for GTC in our hospital from January 2008 to May 2015 were identified through medical records review extracted by our hospital data warehouse. We analyzed the incidences of TE by reviewing all the reports of contrast-enhanced computed tomography performed on each patient during chemotherapy and identified the association between several clinicopathological factors and TE incidence using chi-square tests and logistic regression. Results: Five hundred fourteen Japanese GTC pts were analyzed on this study. Patient character...