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Introduction: Single distant metastases after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) are rare. There are no guidelines for treating patients without liver tumors after resecting lung metastases. Case Presentation: Here, we report a patient with HCC recurring as a single lung metastasis 14 months after RFA. A 76-year-old woman with primary biliary cholangitis without hepatitis B virus or hepatitis C virus infection had been treated by RFA for a single 16-mm-sized HCC lesion in liver S8. Fourteen months thereafter, despite lack of intrahepatic recurrence, a single new 26-mm-sized mass was found in S10 of the right lung. The patient underwent right lower lobectomy. The histopathological diagnosis was HCC metastasis. Because no residual disease could be found, she was followed up without any additional treatment after surgery. She remains alive with no signs of recurrence 3 years later. Conclusion: HCC patients who relapse with lung metastases but without intrahepatic recurrence after RFA are extremely rare, especially when RFA is used to treat HCC lesions

ABSTRACT Background Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1‐mutated synchronous and metachronous PACC. Case A 58‐year‐old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab‐paclitaxel therapy was administered as first‐line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second‐ line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC‐related cancers was initiated. Conclusion We diagnosed a 58‐year‐old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.

ABSTRACT Background SMARCA4 is a component gene of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex; undifferentiated tumors associated with its functional deletion have been described in several organs. However, no established treatment for these tumors currently exists. Case In this study, we report a case of a SMARCA4‐deficient undifferentiated urothelial carcinoma with high PD‐L1 expression that was effectively treated with nivolumab after early relapse following treatment for non‐invasive bladder cancer. The histological morphology of the rhabdoid‐like undifferentiated tumor of unknown primary led us to suspect a SWI/SNF‐deficient tumor, and subsequent immunostaining led to the diagnosis of a SMARCA4‐deficient undifferentiated tumor. This effort also led to the identification of the developmental origin of this SMARCA4‐deficient undifferentiated tumor as a non‐invasive bladder cancer. We also carried out a detailed immune phenotypic assay on peripheral T cells. In brief, a phenotypic change of CD8+T cells from naive to terminally differentiated effector memory cells was observed. Conclusion Regardless of the organ of cancer origin or cancer type, SWI/SNF‐deficient tumors should be suspected in undifferentiated and dedifferentiated tumors, and immune checkpoint inhibitors may be considered as a promising treatment option for this type of tumor. The pathogenesis of SMARCA4‐deficient anaplastic tumors awaits further elucidation for therapeutic development.

Abstract The scale of volcanic eruptions influences the effects of wide-ranging disasters involving ashfall, such as the disruption of lifelines and paralysis of urban functions. This highlights the importance of vehicle availability on ash-covered roads for disaster management personnel involved in rescue and recovery efforts and for citizens who must evacuate or continue their social lives. We conducted tests to scientifically verify the running ability of vehicles on ash-covered roads. Results revealed that all-wheel-drive vehicles showed better running performance than two-wheel-drive vehicles, which get stuck when ashfall thickness exceeds 10 cm. Most of the vehicle’s drive power is consumed as energy to scrape ash grains from under the tires, hindering sufficient propulsion. In addition, the tires sink into the ash layer, which increases driving resistance and causes the vehicle to get stuck. Running ability on ash-covered roads is mainly determined by the relation between the “drive system” of the vehicle and the “thickness of ash” on the roads. In addition, road surface conditions, including ash thickness, could change in time and space because of traffic volume and weather conditions.

The identification of chromosomal abnormalities accompanied by copy number alterations is important for understanding tumor characteristics. Testing methodologies for copy number abnormality have limited sensitivity, resulting in their use only for the sample provided at the time of diagnosis or recurrence of malignancy, but not for the monitoring of minimal residual disease (MRD) during and after therapy. We developped the “DimShift” technology which enable to measure the copy number of target gene/chromosome in each cell, which is given by the single cell droplet PCR. Qualitative result of DimShift given by peripheral blood was perfectly concordant with that of bone marrow. These findings and performances are promising to be the new methodology for MRD detection in malignant diseases utilizing bone marrow as well as peripheral blood.

Poly­(vinyl alcohol) (PVA) has been widely used in industrial and consumer products. In this study, we aimed to address this challenge by synthesizing well-defined multiarm poly­(vinyl acetate) (PVAc) through the use of nonhydrolyzable vinyl ether-type multifunctional RAFT agents. The control over molecular weights was achieved by the RAFT process to afford polymers with dominant head-to-head linkages at the terminal. Especially, quantitative end-functionalization of the synthesized PVAc was performed using Michael thiol–ene or disulfide exchange reactions. Consequently, saponification of the PVAc enabled the synthesis of end-functionalized multiarm PVA in an efficient manner. This straightforward approach afforded well-defined functional PVAs, which enable further chemical modification, thus widening the utility of PVA in a range of applications, such as precisely controlled network synthesis and bioconjugation.

Ipilimumab plus nivolumab therapy is approved for patients with unresectable advanced esophageal squamous cell carcinoma (ESCC). Although a combination of immune checkpoint inhibitors (ICIs), compared to conventional chemotherapy, can improve overall survival in patients with advanced ESCC, this increases the incidence of immune-related adverse events (irAEs). Here, we describe an ESCC case that developed pemphigus vulgaris (PV), an extremely rare cutaneous irAE, during ipilimumab plus nivolumab treatment. The patient achieved a partial response to treatment. The PV was successfully managed after the cessation of ipilimumab and the use of a topical steroid. We should thus re-treat ESCC with nivolumab monotherapy. In the era of ICIs as standard cancer therapeutics, diagnostic criteria for blistering diseases need to be established to properly manage patients with cutaneous irAEs.

Abstract Background and Aim Reliable predictors for hepatocellular carcinoma (HCC) are urgently needed. The psoas muscle index (PMI) is a simple and rapid method for evaluating muscle atrophy. Furthermore, the neutrophil/lymphocyte ratio (NLR) is a prognostic factor that is easy to calculate in everyday clinical practice. We aimed to investigate the value of the PMI and NLR as prognostic factors for patients receiving nonsurgical HCC therapy, hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial chemoembolization (TACE), or molecular targeted drugs such as sorafenib (SOR) and lenvatinib (LEN). Methods We enrolled 87 patients with HCC who were treated with HAIC, TACE, SOR, or LEN. The primary endpoint was overall survival (OS) with variable PMI or NLR status. For Barcelona Clinic Liver Cancer (BCLC)‐B patients, useful prognostic factors were examined by comparing the OS between stratified groups. Prognostic factors including PMI and NLR were evaluated by univariate and multivariate analysis. Results Analysis of HAIC or TACE (HAIC/TACE) and SOR or LEN (SOR/LEN) patients showed significant differences in OS between low and high PMI. In patients treated with TACE, there was a significant difference in OS between low and high NLR. For BCLC‐B and low PMI, the prognosis was significantly worse for SOR/LEN than for TACE, although there was no difference for high PMI, suggesting that PMI may be useful for treatment selection. In addition, the prognostic formula composed of PMI, NLR, and up‐to‐seven criteria developed in the present study may be useful. Conclusion PMI and NLR are considered to be independent prognostic factors for HCC.

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.

Abstract The destruction caused by ballistic ejecta from the phreatic eruptions of Mt. Ontake in 2014 and Mt. Kusatsu-Shirane (Mt. Moto-Shirane) in 2018 in Japan, which resulted in numerous casualties, highlighted the need for better evacuation facilities. In response, some mountain huts were reinforced with aramid fabric to convert them into shelters. However, a number of decisions must be made when working to increase the number of shelters, which depend on the location where they are to be built. In this study, we propose a method of using high-strength steel to reinforce wooden buildings for use as shelters. More specifically, assuming that ballistic ejecta has an impact energy of 9 kJ or more, as in previous studies, we developed a method that utilizes SUS304 and SS400 unprocessed steel plates based on existing impact test data. We found that SUS304 is particularly suitable for use as a reinforcing material because it has excellent impact energy absorption characteristics due to its high ductility as well as excellent corrosion resistance. With the aim of increasing the structural strength of steel shelters, we also conducted an impact test on a shelter fabricated from SS400 deck plates (i.e., steel with improved flexural strength provided by work-hardened trapezoidal corrugated plates). The results show that the shelter could withstand impact with an energy of 13.5 kJ (2.66 kg of simulated ballistic ejecta at 101 m/s on impact). In addition, from the result of the impact test using the roof-simulating structure, it was confirmed the impact absorption energy is further increased when artificial pumice as an additional protective layer is installed on this structure. Observations of the shelter after the impact test show that there is still some allowance for deformation caused by projectile impact, which means that the proposed steel shelter holds promise, not only structurally, but also from the aspects of transportation and assembly. Hence, the usefulness of shelters that use steel was shown experimentally. However, shelter construction should be suitable for the target environment.

Abstract Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh +/+), heterozygous (Mutyh +/−), and MUTYH-null (Mutyh −/−) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh −/− mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.

Introduction: Liver transplantation for hepatocellular carcinoma (HCC) has been established as a curative therapy of underlying liver disease and cancer. However, the role of liver transplantation remains controversial for patients with HCC beyond Milan criteria. Case Presentation: A man in his 50s who was diagnosed as having two foci of HCC and advanced liver cirrhosis was referred to our hospital for further examination and treatment. Both foci of HCC were located in segment 8 of the liver and measured 39 and 9 mm. Endoscopy showed esophageal varices that had a high risk of bleeding. After endoscopic ligation of the esophageal varices, he underwent transcatheter arterial chemoembolization (TACE) for downstaging of the advanced HCCs. No further liver deterioration was observed after TACE, and HCC staging was successfully downstaged to within the Milan criteria. One hundred ten days after TACE, he underwent liver transplantation; at 2.5 years after transplantation, he remains alive without HCC recurrence. Discussion/Conclusion: There are only a few treatment options available for patients with advanced HCC and severe liver damage. Multidisciplinary treatment such as locoregional treatments and prophylaxis of variceal bleeding may result in tumor downstaging, enabling radical liver transplantation without further exacerbation of liver damage.

Background: Benzodiazepines (BZDs) and analgesics are widely used for conscious sedation during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP). However, endoscopic procedures are sometimes discontinued because of BZD-induced disinhibitory reactions such as excessive movement. We evaluated the usefulness of dexmedetomidine (DEX) for BZD-induced disinhibition in ERCP. Methods: Between February 2018 and August 2019, 22 patients who underwent EUS or ERCP were enrolled. All patients showed BZD-induced excessive movement at the first examination (BZD group) and received DEX at the second examination (DEX group). The initial DEX dose was 6 μg/kg/h for a 10-min loading, followed by 0.4 μg/kg/h during the procedure. BZDs and analgesics were administered before scope insertion. An additional sedative was administered to achieve a Ramsay sedation scale (RSS) of 4–5. Sedative effect, procedure completion rate, and changes in circulatory and respiratory dynamics were evaluated. Results: Mean RSS scores were significantly higher ( p

Generation and subsequent analysis of mutants is critical to understanding the functions of genes and proteins. Here we describe TIM, an efficient, cost-effective, CRISPR-based targeted insertional mutagenesis method for the model organism Chlamydomonas reinhardtii. TIM utilizes delivery into the cell of a Cas9-guide RNA (gRNA) ribonucleoprotein (RNP) together with exogenous double-stranded (donor) DNA. The donor DNA contains gene-specific homology arms and an integral antibiotic-resistance gene that inserts at the double-stranded break generated by Cas9. After optimizing multiple parameters of this method, we were able to generate mutants for six out of six different genes in two different cell-walled strains with mutation efficiencies ranging from 40% to 95%. Furthermore, these high efficiencies allowed simultaneous targeting of two separate genes in a single experiment. TIM is flexible with regard to many parameters and can be carried out using either electroporation or the glass-bead method for delivery of the RNP and donor DNA. TIM achieves a far higher mutation rate than any previously reported for CRISPR-based methods in C. reinhardtii and promises to be effective for many, if not all, non-essential nuclear genes.

We applied a real-time tsunami inundation forecast system to a disaster response plan. We developed a standard operating procedure (SOP) for a tsunami disaster response based on a Plan, Do, Check, Action cycle to effectively use tsunami observation and prediction information provided by a real-time tsunami inundation forecast system during an initial response to a tsunami disaster. In the Plan stage, we ran a workshop on the tsunami disaster response to confirm the current tsunami disaster response plan and develop a timeline plan for a tsunami disaster. In the Do stage, we conducted a tabletop exercise (TTX) for a tsunami disaster using a real-time tsunami prediction system. In the Check stage, we ran a workshop on an after-action review of the TTX. In the Action stage, we applied the SOPs of the real-time tsunami prediction system to the tsunami disaster management plan and conducted a second TTX. As a result, we verified the information provided by a real-time tsunami prediction system to apply the system to a tsunami disaster management plan for real municipalities. It was confirmed that the SOP that we developed allows a real-time tsunami inundation forecast system to enable government staff to safely and effectively respond during a disaster.

In the present study, we characterized CFAP70, a candidate of cilia-related protein in mice. As this protein has a cluster of tetratricopeptide repeat (TPR) domains like many components of the intraflagellar transport (IFT) complex, we investigated the domain functions of particular interest in ciliary targeting and/or localization. RT-PCR and immunohistochemistry of various mouse tissues demonstrated the association of CFAP70 with motile cilia and flagella. A stepwise extraction of proteins from swine tracheal cilia showed that CFAP70 bound tightly to the ciliary axoneme. Fluorescence microscopy of the cultured ependyma expressing fragments of CFAP70 demonstrated that the N-terminus rather than the C-terminus with the TPR domains was more important for the ciliary localization. When CFAP70 was knocked down in cultured mouse ependyma, reductions in cilia beating frequency were observed. Consistent with these observations, a Chlamydomonas mutant lacking the CFAP70 homolog, FAP70, showed defects in outer dynein arm (ODA) activity and a reduction in flagellar motility. Cryo-electron tomography revealed that the N-terminus of FAP70 resided stably at the base of the ODA. These results demonstrated that CFAP70 is a novel regulatory component of the ODA in motile cilia and flagella, and that the N-terminus is important for its ciliary localization.

α- and β-tubulin have an unstructured glutamate-rich region at their C-terminal tails (CTTs). The function of this region in cilia and flagella is still unclear, except that glutamates in CTTs act as the sites for posttranslational modifications that affect ciliary motility. The unicellular alga Chlamydomonas possesses only two α-tubulin and two β-tubulin genes, each pair encoding an identical protein. This simple gene organization might enable a complete replacement of the wild-type tubulin with its mutated version. Here, using CRISPR/Cas9, we generated mutant strains expressing tubulins with modified CTTs. We found that the mutant strain in which four glutamate residues in the α-tubulin CTT had been replaced by alanine almost completely lacked polyglutamylated tubulin and displayed paralyzed cilia. In contrast, the mutant strain lacking the glutamate-rich region of the β-tubulin CTT assembled short cilia without the central apparatus. This phenotype is similar to mutant strains harboring a mutation in a subunit of katanin, the function of which has been shown to depend on the β-tubulin CTT. Therefore, our study reveals distinct and important roles of α- and β-tubulin CTTs in the formation and function of cilia. [ABSTRACT FROM AUTHOR]