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We aimed to investigate novel emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages in Japan that harbor variants in the spike protein receptor-binding domain (RBD). The total nucleic acid contents of samples from 159 patients with coronavirus disease 2019 (COVID-19) were subjected to whole genome sequencing. The SARS-CoV-2 genome sequences from these patients were examined for variants in spike protein RBD. In January 2021, three family members (one aged in their 40s and two aged under 10 years old) were found to be infected with SARS-CoV-2 harboring W152L/E484K/G769V mutations. These three patients were living in Japan and had no history of traveling abroad. After identifying these cases, we developed a TaqMan assay to screen for the above hallmark mutations and identified an additional 14 patients with the same mutations. The associated virus strain was classified into the GR clade (Global Initiative on Sharing Avian Influenza Data [GISAID]), 20B clade (Nextstrain), and R.1 lineage (Phylogenetic Assignment of Named Global Outbreak [PANGO] Lineages). As of April 22, 2021, R.1 lineage SARS-CoV-2 has been identified in 2,388 SARS-CoV-2 entries in the GISAID database, many of which were from Japan (38.2%; 913/2,388) and the United States (47.1%; 1,125/2,388). Compared with that in the United States, the percentage of SARS-CoV-2 isolates belonging to the R.1 lineage in Japan increased more rapidly over the period from October 24, 2020 to April 18, 2021. R.1 lineage SARS-CoV-2 has potential escape mutations in the spike protein RBD (E484K) and N-terminal domain (W152L); therefore, it will be necessary to continue to monitor the R.1 lineage as it spreads around the world.

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.

It has been thought that there is a strong relationship between inflammation and carcinogenesis so that the development of cancer occurs with chronic inflammation in many organs. An in‐depth understanding of the mechanism by which inflammation can lead to carcinogenesis may enable the development of drugs targeted at important molecules, providing a powerful tool for preventing cancer development. In this review, we focused on a signal transduction system, the nuclear factor‐kappaB (NF‐κB) pathway, which is thought to play a role in the process leading from inflammation to carcinogenesis, and may thus serve as a candidate for targeted intervention. (Cancer Sci 2008; 99: 836–842)

Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.

BackgroundTumor metastases to lymph nodes and distant organs are associated with worse prognosis in gastric cancer. However, little is known about the genetic profiles, subclonal architecture, and evolutional processes across primary tumors and metastases.MethodsWe analyzed the genetic alterations of 106 multiregional samples including primary tumors, lymph node metastases, and visceral metastases from 10 patients with advanced gastric cancer. Histologically different portions were obtained by laser-capture microdissection. We reconstructed the subclonal architectures and inferred the primary to lymph or visceral metastatic seeding patterns.ResultsThe different histological portions in primary tumors had common mutations, suggesting common ancestral tumor origins transformed into distinct histological types. In almost all cases, TP53 mutations were identified as clonal mutations across primary tumors and metastases. Subclonal reconstruction and phylogenetic analysis showed primary tumors were classified into monoclonal or polyclonal tumors. All monoclonal primary tumors disseminated as metastases with the same tumor composition (100%, 26/26 samples). In contrast, polyclonal primary tumors mainly spread as metastases by way of polyclonal seeding (84%: 37/44 samples).ConclusionsClonal mutations were maintained at both the primary and metastatic sites and genetic divergence of these was low. These findings shed light on the genetic basis of primary tumor dissemination and metastatic processes in advanced gastric cancer.

Background & AimHepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation.MethodsAll publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation.RecommendationsWe recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.

Background The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients. Methods After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan–Meier method and Cox proportional hazard regression. Results The proportion of patients with non-viral etiologies increased from 10.0 % in 1991 to 24.1 % in 2010. Of the patients, 92 % were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m 2 in 39 %. Diabetes was most prevalent in NAFLD (63 %), followed by unclassified etiology (46 %) and ALD (45 %). Approximately 80 % of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2 %, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m 2 showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score. Conclusions Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis.

Radiofrequency ablation (RFA) is widely performed for hepatocellular carcinoma (HCC). However, there has been no report on 10-year outcome of RFA. The objective of this study was to report a 10-year consecutive case series at a tertiary referral center. We performed 2,982 RFA treatments on 1,170 primary HCC patients and analyzed a collected database. Final computed tomography images showed complete tumor ablation in 2,964 (99.4%) of 2,982 treatments performed for the 1,170 primary HCC patients. With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% (95% confidence interval (CI): 56.7-63.9%) and 27.3% (95% CI: 21.5-34.7%), respectively. Multivariate analysis demonstrated that age, antibody to hepatitis C virus (anti-HCV), Child-Pugh class, tumor size, tumor number, serum des-γ-carboxy-prothrombin (DCP) level, and serum lectin-reactive α-fetoprotein level (AFP-L3) were significantly related to survival. Five- and 10-year local tumor progression rates were both 3.2% (95% CI: 2.1-4.3%). Serum DCP level alone was significantly related to local tumor progression. Five- and 10-year distant recurrence rates were 74.8% (95% CI: 71.8-77.8%) and 80.8% (95% CI: 77.4-84.3%), respectively. Anti-HCV, Child-Pugh class, platelet count, tumor size, tumor number, serum AFP level, and serum DCP level were significantly related to distant recurrence. There were 67 complications (2.2%) and 1 death (0.03%). RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.