Masaaki Hirano

Direct Interaction between Nucleolin and Hepatitis C Virus NS5B

Hepatitis C virus (HCV) NS5B is an RNA-dependent RNA polymerase (RdRP), a central catalytic enzyme in HCV replication. While studying the subcellular localization of a NS5B mutant lacking the C-terminal membrane-anchoring domain, NS5Bt, we found that expression of the green fluorescent protein (GFP)-fused form was exclusively nucleolar. Interestingly, the distribution of endogenous nucleolin changed greatly in the cells expressing GFP-NS5B, with nucleolin colocalized with GFP-NS5B in perinuclear regions in addition to the nucleolus, suggesting that NS5B retains the ability to bind nucleolin. The interaction between nucleolin and NS5B was demonstrated by GST pull-down assay. GST pull-down assay results indicated that C-terminal region of nucleolin was important for its binding to NS5B. Scanning clustered alanine substitution mutants library of NS5B revealed two sites on NS5B that binds nucleolin. NS5B amino acids 208–214 and 500–506 were both found to be indispensable for the nucleolin binding. We reported that the latter sequence is essential for oligomerization of NS5B, which is a prerequisite for the RdRP activity. C-terminal nucleolin inhibited the NS5B RdRP activity in a dose-dependent manner. Taken together, this indicates the binding ability of nucleolin may be involved in NS5B functions.

A Scoring System to Stratify Curability after Endoscopic Submucosal Dissection for Early Gastric Cancer: "eCura system".

Objectives:Although radical surgery is recommended for patients not meeting the curative criteria for endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) because of the potential risk of lymph node metastasis (LNM), this recommendation may be overestimated and excessive. We aimed to establish a simple scoring system for decision making after ESD.Methods:This multicenter retrospective study consisted of two stages. First, the risk-scoring system for LNM was developed using multivariate logistic regression analysis in 1,101 patients who underwent radical surgery after having failed to meet the curative criteria for ESD of EGC. Next, the system was internally validated by survival analysis in another 905 patients who also did not meet the criteria and did not receive additional treatment after ESD.Results:In the development stage, based on accordant regression coefficients, five risk factors for LNM were weighted with point values: three points for lymphatic invasion and 1 point each for tumor size >30 mm, positive vertical margin, venous invasion, and submucosal invasion ≥500 μm. Then, the patients were categorized into three LNM risk groups: low (0–1 point: 2.5% risk), intermediate (2–4 points: 6.7%), and high (5–7 points: 22.7%). In the validation stage, cancer-specific survival differed significantly among these groups (99.6, 96.0, and 90.1%, respectively, at 5 years; P<0.001). The C statistic of the system for cancer-specific mortality was 0.78.Conclusions:This scoring system predicted cancer-specific survival in patients who did not meet the curative criteria after ESD for EGC. ESD without additional treatment may be an acceptable option for patients at low risk.

Primary squamous cell carcinoma of the liver producing parathyroid hormone-related protein

We report here an autopsy case of primary squamous cell carcinoma of the liver in a 63-year-old man who had hypercalcemia and an elevated serum level of parathyroid hormone-related protein. At autopsy, primary squamous cell carcinoma of the liver was found, without distinct preceding or associated hepatic or biliary diseases; no extrahepatic primary focus of squamous cell carcinoma was found. Bone involvement was not demonstrated, either radiologically or pathologically. Immunohistochemically, parathyroid hormone-related protein was detectable in the squamous cell carcinoma cells and it may have been responsible for the hypercalcemia. Such a case has not been reported so far in the English-language or the Japanese literature.

Short-term outcomes of multicenter prospective cohort study of gastric endoscopic resection: ‘Real-world evidence’ in Japan

A Japanese multicenter prospective cohort study examining endoscopic resection (ER) for early gastric cancer (EGC) has been conducted using a Web registry developed to determine the short‐term and long‐term outcomes based on absolute and expanded indications. We hereby present the short‐term outcomes of this study.

The Role of an Undifferentiated Component in Submucosal Invasion and Submucosal Invasion Depth After Endoscopic Submucosal Dissection for Early Gastric Cancer

Background/Aims: The role of an undifferentiated component in submucosal invasion and submucosal invasion depth (SID) for lymph node metastasis (LNM) of early gastric cancer (EGC) with deep submucosal invasion (SID ≥500 μm from the muscularis mucosa) after endoscopic submucosal dissection (ESD) has not been fully understood. This study aimed to clarify the risk factors (RFs), including these factors, for LNM in such patients. Methods: We enrolled 513 patients who underwent radical surgery after ESD for EGC with deep submucosal invasion. We evaluated RFs for LNM, including an undifferentiated component in submucosal invasion and the SID, which was subdivided into 500–999, 1,000–1,499, 1,500–1,999, and ≥2,000 µm. Results: LNM was detected in 7.6% of patients. Multivariate analysis revealed that an undifferentiated component in submucosal invasion (OR 2.22), in addition to tumor size >30 mm (OR 2.51) and lymphatic invasion (OR 3.07), were the independent RFs for LNM. However, the SID was not significantly associated with LNM. Conclusion: An undifferentiated component in submucosal invasion was one of the RFs for LNM, in contrast to SID, in patients who underwent ESD for EGC with deep submucosal invasion. This insight would be helpful in managing such patients.