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Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT).The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments.Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo.Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

Hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) is highly malignant; therefore, continual, multidisciplinary treatments are essential.In this study, two 78- and 81-year-old men were treated with the Vater papilla-preserving strategy. Case 1 had advanced HCC with BDTT expanding to the common bile duct (B4) and portal vein tumor thrombus (PVTT) of the umbilical portion. He showed triple-positive tumor markers. He underwent an extended left hepatectomy without bile duct resection following percutaneous transhepatic biliary drainage and transarterial chemoembolization (TACE). Later, TACE in combination with percutaneous microwave ablation was performed to treat four intrahepatic recurrent HCCs. Case 2 had diffuse-type HCCs accompanied by BDTT (B4) and PVTT to the right portal vein. He underwent liver partition associated with portal vein ligation for staged hepatectomy without bile duct resection. Six months later, he developed a solitary recurrent BDTT with obstructive jaundice. After percutaneous transhepatic biliary drainage, he was treated with two TACE from the various feeding arteries. Both patients achieved complete responses and are doing well without viable tumors approximately 2 years after the initial treatment.The Vater papilla-preserving strategy is essential for obtaining long-term survival and recurrent-free status for patients with HCC with highly extended BDTT.

A 41-year-old Japanese man was admitted to our hospital with acute perimyocarditis 4 weeks after coronavirus disease 2019 (COVID-19) infection. Ten days after admission, the patient showed bilateral facial nerve palsy in the course of improvement of perimyocarditis under treatment with aspirin and colchicine. After prednisolone therapy, perimyocarditis completely improved, and the facial nerve palsy gradually improved. Acute perimyocarditis and facial nerve palsy can occur even 4 weeks after contracting COVID-19., Internal Medicine, 61 (15), pp. 2327-2332; 2022

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal type of cancer. The 5-year survival rate for patients with early-stage diagnosis can be as high as 20%, suggesting that early diagnosis plays a pivotal role in the prognostic improvement of PDAC cases. In the medical field, the broad availability of biomedical data has led to the advent of the "big data" era. To overcome this deadly disease, how to fully exploit big data is a new challenge in the era of precision medicine. Artificial intelligence (AI) is the ability of a machine to learn and display intelligence to solve problems. AI can help to transform big data into clinically actionable insights more efficiently, reduce inevitable errors to improve diagnostic accuracy, and make real-time predictions. AI-based omics analyses will become the next alterative approach to overcome this poor-prognostic disease by discovering biomarkers for early detection, providing molecular/genomic subtyping, offering treatment guidance, and predicting recurrence and survival. Advances in AI may therefore improve PDAC survival outcomes in the near future. The present review mainly focuses on recent advances of AI in PDAC for clinicians. We believe that breakthroughs will soon emerge to fight this deadly disease using AI-navigated precision medicine.

BACKGROUND: Liver inflammation is a reaction to disease-causing stress in the liver that induces fibrosis and cirrhosis. However, its prognostic impact after hepatectomy remains unclear. This study aimed to evaluate the prognostic and oncologic impacts of liver inflammation on patients after curative hepatectomy for hepatocellular carcinoma (HCC). METHODS: The study enrolled 500 consecutive patients with primary HCC who underwent curative and primary hepatectomy. Patient characteristics and prognoses were evaluated according to histologic liver inflammation assessed by the New Inuyama Classification. RESULTS: Severe liver inflammation (A3) was observed in 97 patients (19.4%) and nonsevere liver inflammation (A0-2) in 403 patients (80.6%). The patients with A3 had a significantly poorer prognosis than those with A0-2 in terms of relapse-free survival (p < 0.0001, log-rank) and overall survival (p = 0.0013, log-rank). The study showed that A3 is an independent poor prognostic factor (hazard ratio, 1.36; 95% confidence interval [Cl], 1.02-1.81; p = 0.039), and that Child-Pugh grade B and multiple tumors are associated with relapse-free survival. Furthermore, The significant predictors of early recurrence (within 2 years after hepatectomy) were A3 (odds ratio, 2.10; 95% CI, 1.25-3.55; p = 0.005), a des-I³-carboxyprothrombin level higher than 40 mAU/mL, and multiple tumors. CONCLUSIONS: Severe liver inflammation was associated with poor short- and long-term prognoses independently of cirrhosis. Controlling liver inflammation in the perioperative period may be essential to improving the prognosis of patients with HCC after hepatectomy.

Background Bile duct adenomas (BDA) may be precursor lesions of small duct-type, including mass-forming type intrahepatic cholangiocarcinoma (ICC). Case report A 68-year-old woman was transferred to our facility for the treatment of a liver tumor, possibly metastasized from a pancreatic neuroendocrine tumor. Finally, two liver tumors were resected and histopathologically diagnosed as "BDA" and "ICC with a BDA-like component". In the BDA-like component, the MUC6 positive rate was notably lower and the Ki-67 positive rate was higher than the other BDAs and ICC component, respectively. The doubling time of the tumor volume in BDA was very long but was shortened (1,510 and 719 days). Distinct enlargement of the tumor and appearance of enhancement through diagnostic imaging was useful in diagnosing the transformation from a BDA to an ICC. Conclusion An "adenoma-carcinoma sequence" may exist in the transformation process from a BDA to an ICC.

Purpose Although early prediction of mortality is useful for the management of patients with colorectal perforations, no significant perioperative predictive factors have been identified. The purpose of this study was to identify useful prognostic factors for patients with colorectal perforation. Methods This single-center retrospective study included consecutive patients undergoing emergency surgery for colorectal perforation from January 2012 to December 2019. The primary outcome was combined 30 day and in-hospital mortality. Patient- and disease-related factors obtained perioperatively were evaluated for mortality prediction. A scoring system was developed to enhance clinical utility. Results Overall, 146 patients were included and 20 (14%) died after surgery. Multivariate logistic regression identified five predictive factors: age, hemodialysis, uncommon perforation etiology, plasma albumin level, and decreased platelet count. The area under the receiver operating curve for the scoring system using these parameters was 0.894 (95% CI 0.835–0.952). Patients at high-risk of mortality were classified by the proposed score with a sensitivity of 90.0% and negative predictive value of 98.0%. Conclusion This study identified five perioperative factors significantly associated with mortality of patients with colorectal perforation. Although these parameters predict mortality of patients with colorectal perforation using a score with high discrimination, further study is required to confirm these findings. Supplementary Information The online version contains supplementary material available at 10.1007/s00068-021-01719-8.

Background: Pancreatic cancer is a serious life-threatening disease due to its highly invasive and metastatic potential. Hyperglycemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). In this study, we elucidate the biological and clinical impact of hyperglycemia in PDAC progression. Methods: Biological impact of hyperglycemia on malignant behavior in PDAC was examined by in vitro and in vivoexperiment. Results: Hyperglycemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycemia enhanced chemoresistance by upregulating ABCB1 expression, and triggered PDAC switch into pure-basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterized by abundant stroma that harbors tumor-promoting properties and chemoresistance. Hyperglycemia promotes production of collagen fiber-related proteins (fibronectin, fibroblast activation protein, COL1A1, and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance, and a favorable tumor microenvironment even under hyperglycemic conditions in vitro and in vivo. Indeed, YAP/TAZ overexpression was significantly associated with worse prognostic outcomes in human PDAC patients. Conclusion: Hyperglycemia induce metabolic reprogramming into a glycolytic phenotype and promote EMT via the YAP/TAZ-Hedgehog signaling axis in PDAC. Hyperglycemia as an initial symptom may be the cause of highly invasive and metastatic potential by inducing YAP/TAZ overexpression, while YAP/TAZ could be a novel therapeutic target in PDAC patients. Citation Format: Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba. Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3709.

The prediction of prognostic outcomes can provide the most suitable strategy for patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the clinical value of the preoperative tumor marker index (pre-TI) in predicting prognostic outcomes after resection for PDAC. For 183 patients who underwent pancreatic resection of PDAC, adjusted carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), pancreatic cancer-associated antigen-2 (DUpan-2), and s-pancreas-1 antigen (SPan-1) were retrospectively evaluated, and the positive number of these markers was scored as the pre-TI. A high pre-TI (≥ 2) was significantly associated with a larger tumor and lymph node metastases, and the patients with a high pre-TI had worse prognostic outcomes in terms of both relapse-free survival (RFS) (P

Bartter syndrome and Gitelman syndrome (GS) are autosomal recessive disorders usually caused by homozygous or compound heterozygous mutations in causative genes. In some patients, these two syndromes cannot be discriminated based on clinical features or mutation type; thus, a single disease concept, salt-losing tubulopathies (SLTs), has been used instead. Despite the existence of several SLT causative genes, cases of digenic heterozygous mutations in two different genes are extremely rare. Here, we report the case of a 36-year-old woman with renal insufficiency and hypokalemia caused by an SLT. To evaluate the SLT phenotype, we performed next-generation sequencing (NGS) with a gene panel including SLC12A3,SLC12A1, CLCNKB, and CLCNKA as well as laboratory examinations and diuretic loading tests. The results of the diuretic loading tests were consistent with a GS phenotype, while the NGS results showed that the patient had heterozygous mutations in SLC12A1 and CLCNKB. Both genes have been associated with BS,suggesting that the SLT was caused by digenic heterozygous mutations in two different genes. To date, only a few SLT cases caused by digenic heterozygous mutations in two different genes have been reported. The digenic SLT phenotype in the patient was presumably accelerated by moderate renal insufficiency., CEN case reports, 9(4), pp.375-379; 2020

Background An ectopic hepatocellular carcinoma (EHCC) arises from the ectopic liver which is defined as a hepatic organ or tissue not connected to surrounding tissues. EHCC is a rare disease and it is difficult to diagnose preoperatively. Furthermore, the clinical features are not fully elucidated. Case summary A retroperitoneal tumor (6 cm) was located at the dorsal side of the pancreas head on abdominal ultrasonography in an 81-year old woman positive for hepatitis C virus antibody. Contrast enhanced-computed tomography and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging showed viable HCC patterns with early enhancement and delayed washout. The tumor markers - serum alpha-fetoprotein and alpha-fetoprotein-L3% - were increased to 30.1 ng/mL and 83.1%, respectively. Protein induced by vitamin K absence or antagonist-II was within normal levels (17 mAU/mL). Positron emission tomography-computed tomography showed strong accumulation into the tumor (Standardized Uptake Value max: 13.8), and the tumor cytology following endoscopic ultrasound-guided fine needle aspiration showed poorly differentiated carcinoma. Tumor extirpation was performed, and operative findings showed that the retroperitoneal tumor was disconnected from the pancreas and the liver. Swollen lymph nodes near the tumor were histologically normal. On histological examination, the tumor was finally diagnosed as EHCC with Arginase-1 positive expression. Conclusion We report our experience of a rare EHCC which was difficult to diagnose, and we present a review of the literature.

Human fascioliasis is a rare parasitic disease outside of countries in which it is endemic. The diagnosis of hepatic-phase fascioliasis by diagnostic imaging alone is challenging. A 69-year-old female was referred to our hospital for the treatment of a solitary solid cystic mass lesion, 6 cm in diameter, accompanied with mild symptoms and minimal changes in laboratory parameters. Intrahepatic cholangiocarcinoma was suspected, and she underwent extended posterior sectionectomy. Four months later, she was re-admitted because of fatigue, high fever, and epigastric pain. Her eosinophil fraction and immunoglobulin E levels were extremely elevated (49.1% and 6833 IU/ml, respectively). She was found to have two new reticular cystic hepatic tumors. Serum dot enzyme-linked immunosorbent assay for parasites revealed strong positivity for Fasciola hepatica. Praziquantel was ineffective, and multi-cystic tumors rapidly developed in the left lateral section, requiring emergency left lateral sectionectomy. An F. hepatica helminth, approximately 3 cm in size, was observed on the cut liver surface during hepatic resection. Prophylactic triclabendazole (1,000 mg/day) was administered twice. She has been well for over 10 years without relapse of fascioliasis. In patients with hepatic tumors accompanied by inflammatory changes and eosinophilia, detailed medical history and serological testing by dot enzyme-linked immunosorbent assay for parasites are strongly recommended.

Background/aim The aim of this study was to elucidate the clinical impact of coagulation disorders on outcomes after curative resection of pancreatic ductal adenocarcinoma. Patients and methods Preoperative coagulation activity in 135 patients, who had undergone curative resections for pancreatic ductal adenocarcinoma was retrospectively evaluated and the impact on survival outcomes analyzed. Results A prolonged prothrombin time-international normalized ratio (PT-INR) (≥1.1) was detected in 23/135 patients (17%). Univariate analysis that showed prolonged PT-INR was associated with worse relapse-free (hazard ratio=1.79, p=0.044) and overall (hazard ratio=2.18, p=0.004) survival. Multivariate analyses showed prolonged PT-INR, large tumor (>30 mm), and lymph node metastasis were independent predictors of poor overall survival. Conclusion Prolonged PT-INR may be a predictor of poor prognosis in patients with pancreatic ductal adenocarcinoma who have undergone curative resection. Coagulation disorders may be a therapeutic target for improving outcomes of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type as it is prone to metastases and is difficult to diagnose at an early stage. Despite advances in molecular detection, its clinical prognosis remains poor and it is expected to become the second leading cause of cancer-related deaths. Approximately 85% of patients develop glucose metabolism disorders, most commonly diabetes mellitus, within three years prior to their pancreatic cancer diagnosis. Diabetes, or glucose metabolism disorders related to PDAC, are typically associated with insulin resistance, and beta cell damage, among other factors. From the perspective of molecular regulatory mechanisms, glucose metabolism disorders are closely related to PDAC initiation and development and to late invasion and metastasis. In particular, abnormal glucose metabolism impacts the nutritional status and prognosis of patients with PDAC. Meanwhile, preliminary research has shown that metformin and statins are effective for the prevention or treatment of malignancies; however, no such effect has been shown in clinical trials. Hence, the causes underlying these conflicting results require further exploration. This review focuses on the clinical significance of glucose metabolism disorders in PDAC and the mechanisms behind this relationship, while also summarizing therapeutic approaches that target glycolysis.

Background The liver is the digestive organ where metastatic adenocarcinoma of unknown primary site is most often observed. Case report A 74-year-old man was diagnosed with a growing gallbladder tumor and multiple liver tumors limited to the left lateral sector. Liver tumors were suggested to be primary or secondary adenocarcinoma with no relation to the gallbladder tumor. Also for diagnostic purposes, laparoscopic full-thickness resection of the gallbladder, laparoscopic lateral sectionectomy and lymph node sampling were performed. The final histopathological diagnosis was hyperplastic polyp of the gallbladder and metastatic poorly differentiated adenocarcinoma of the liver. Liver tumors were suspected to originate from the stomach, duodenum, or small intestine; however, the primary sites could not be identified. The patient has been closely followed up without any chemotherapy 3 months after surgery. Conclusion Laparoscopic surgery can be strongly recommended for patients with multiple liver tumors of unknown origin concomitant with a gallbladder tumor.

A number of peptide toxins isolated from animals target potassium ion (K

PURPOSE The pulmonary function test (PFT) has played an essential role in diagnosing and managing interstitial lung disease (ILD) but has its contraindications and difficult conditions to perform. Therefore, the present study aimed to evaluate dynamic chest radiography (DCR) ability to predict forced vital capacity (FVC) and other PFT parameters of ILD patients. METHOD The prospective observational study included 97 patients who underwent DCR at Tenri Hospital (Tenri, Japan) between June 2019 and April 2020. Twenty-five patients with stable disease status underwent DCR twice to evaluate test-retest reliability using the intraclass correlation coefficient. From the lung field areas measured by DCR, lung volumes at maximum inspiration (V.ins) and expiration (V.exp) were estimated. Correlation coefficients between the measured values of DCR and PFT parameters were calculated. Multilinear models for predicting FVC and other PFT parameters were developed. RESULTS Intraclass correlation coefficients between first and second measurements of V.ins and V.exp were 0.94 (95% CI: 0.89-0.97, p

With population aging, the number of frail patients with pancreatic cancer has increased. The Clinical Frailty Scale (CFS) is a simple and validated tool to assess frailty, and higher scores predict worse clinical outcomes after cardiovascular surgery. In this retrospective study, we aimed to examine the association of preoperative frailty with prognosis after resection for pancreatic cancer. We retrospectively analyzed data from 142 consecutive patients undergoing resection for pancreatic cancer between April 2010 and December 2018. We used the CFS: 1 (very fit) to 9 (terminally ill) to assess frailty and examined associations of the CFS scores with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs), controlling for potential confounders. Of the 142 patients, 113 (80%) had CFS scores of ≤ 3, 13 (9.2%) scores of 4, and 16 (11%) scores of ≥ 5. Scores of ≥ 5 on the CFS were associated with worse CSS (univariable HR: 2.62, 95% confidence interval [CI]: 1.19–5.18, P = 0.019; multivariable HR: 2.49, 95% CI 1.05–5.34, P = 0.039) and OS (univariable HR: 2.42, 95% CI 1.19–4.46, P = 0.016; multivariable HR: 2.25, 95% CI 1.05–4.43, P = 0.038). The association between CFS scores and RFS was not significant in multivariable analysis (univariable HR: 2.11, 95% CI 1.08–3.79, P = 0.030; multivariable HR: 1.47, 95% CI 0.71–2.83, P = 0.29). Higher scores on the CFS are associated with worse CSS and OS after resection for pancreatic cancer. Preoperative measurement of frailty may improve risk assessment among patients with pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.

Achieving multiple physical properties from a single material through three-dimensional (3D) printing is important for manufacturing applications. In addition, industrial-level durability and reliability is necessary for realizing individualized manufacturing of devices using 3D printers. We investigated the properties of architected materials composed of ultraviolet (UV)-cured urethane elastomers for use as insoles. The durability and reliability of microlattice and metafoam architected materials were compared with those composed of various foamed materials currently used in medical insoles. The hardness of the architected materials was able to be continuously adjusted by controlling the design parameters, and the combination of the two materials was effective in controlling rebound resilience. In particular, the features of the architected materials were helpful for customizing the insole properties, such as hardness, propulsive force, and shock absorption, according to the user’s needs. Further, using elastomer as a component led to better results in fatigue testing and UV resistance compared with the plastic foam currently used for medical purposes. Specifically, polyethylene and ethylene vinyl acetate were deformed in the fatigue test, and polyurethane was mechanically deteriorated by UV rays. Therefore, these architected materials are expected to be reliable for long-term use in insoles.

A number of peptide toxins isolated from animals target potassium ion (K+) channels. Many of them are particularly known to inhibit voltage-gated K+ (KV) channels and are mainly classified into pore-blocking toxins or gating-modifier toxins. Pore-blocking toxins directly bind to the ion permeation pores of KV channels, thereby physically occluding them. In contrast, gating-modifier toxins bind to the voltage-sensor domains of KV channels, modulating their voltage-dependent conformational changes. These peptide toxins are useful molecular tools in revealing the structure-function relationship of KV channels and have potential for novel treatments for diseases related to KV channels. This review focuses on the inhibition mechanism of pore-blocking and gating-modifier toxins that target KV channels.

In late March 2020, we faced a nosocomial outbreak of novel coronavirus disease 2019 (COVID-19) at Keio University Hospital, Tokyo, Japan. Presently, COVID-19 is an unprecedented worldwide biohazard, and a nosocomial outbreak can occur in any hospital at any time. Therefore, we reviewed the literature regarding hospital preparedness, the initial management of COVID-19, and the surveillance of healthcare workers (HCWs) to find information that would be generally useful for physicians when confronted with COVID-19. In terms of hospital preparedness, each hospital should develop an incident management system and establish a designated multidisciplinary medical team. To initiate case management, COVID-19 should be suspected based on patient symptoms and/or high-risk history and then should be confirmed by viral testing, such as reverse transcription polymerase chain reaction (RT-PCR) analysis. Although some patients will become critically ill, the guidelines for respiratory failure and septic shock for non-COVID-19 cases can be followed for supportive treatment. Antiviral medications should be carefully selected because the available information is confused by the large volume of preprint literature and unreliable data. HCWs who have come into contact with patients with COVID-19 can generate new in-hospital clusters of COVID-19 cases. Quarantine following contact tracking with risk stratification is effective in preventing transmission, and the essentials of medical surveillance include monitoring different types of symptoms, delegation of supervision, and continuation of surveillance regardless of the RT-PCR results. Preparation for COVID-19 is recommended before the first COVID-19 case is encountered.

Case series Patients: Male, 72-year-old • Male, 70-year-old Final Diagnosis: Acute respiratory distress syndrome (ARDS) • COVID-19 • COVID-19 pneumonia Symptoms: Cough • fever • malaise • nausea • respiratory distress • vomiting Medication: — Clinical Procedure: — Specialty: Critical Care Medicine • Infectious Diseases • Radiology Objective: Rare disease Background: Patients with coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome corona-virus 2 can rapidly progress to acute respiratory distress syndrome (ARDS). Because clinical diagnosis of ARDS includes several diseases, understanding the characteristics of COVID-19-related ARDS is necessary for precise treatment. We report 2 patients with ARDS due to COVID-19-associated pneumonia. Case Report: Case 1 involved a 72-year-old Japanese man who presented with respiratory distress and fever. Computed tomography (CT) revealed subpleural ground-glass opacities (GGOs) and consolidation. Six days after symptom onset, reverse transcription-polymerase chain reaction (RT-PCR) testing confirmed the diagnosis of COVID-19-associated pneumonia. He was intubated and received veno-venous extracorporeal membrane oxygenation (ECMO) 8 days after symptom onset. Follow-up CT revealed large diffuse areas with a crazy-paving pattern and consolidation, which indicated progression of COVID-19-associated pneumonia. Following treatment with antiviral medications and supportive measures, the patient was weaned off ECMO after 20 days. Case 2 involved a 70-year-old Asian man residing in Canada who presented with cough, malaise, nausea, vomiting, and fever. COVID-19-associated pneumonia was diagnosed based on a positive result from RT-PCR testing. The patient was then transferred to the intensive care unit and intubated 8 days after symptom onset. Follow-up CT showed that while the initial subpleural GGOs had improved, diffuse GGOs appeared, similar to those observed upon diffuse alveolar damage. He was administered systemic steroid therapy for ARDS and extubated after 6 days. Conclusions: Because the pattern of symptom exacerbation in COVID-19-associated pneumonia cases seems inconsistent, individual treatment management, especially the CT-based treatment strategy, is crucial.

Background Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Results We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis. Conclusions The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of KV channels.

Background IgG4-related disease (IgG4-RD) is an immune-mediated disorder in which abundant IgG4-positive plasma cells infiltrate affected organs. There have been reported four cases of probable IgG4-RD presenting as a submucosal tumor of the stomach. We herein report the first case of definite IgG4-RD presenting as a submucosal tumor of the stomach resected with laparoscopic endoscopic cooperative surgery (LECS). Case presentation A 70-year-old woman with a 6-year history of autoimmune pancreatitis was referred to our department because a 15-mm submucosal tumor in the greater curvature of the lower part of the stomach had been identified via upper gastrointestinal endoscopy. Endoscopic ultrasonography showed a 10-mm low-echoic lesion derived from the submucosal layer of the stomach. A fine-needle aspiration biopsy was attempted, but the tumor was too hard for sampling. F-fluorodeoxyglucose (FDG) positron emission tomography showed an FDG uptake, suggesting a possibility of malignant disease. As the diagnosis could not be confirmed, LECS for both the diagnosis and curative treatment was performed. A histopathological examination showed a tumor with IgG4-positive lymphoplasmacytic infiltration and fibrosis. The ratio of IgG4+/IgG+ lymphoplasmacytic cells was > 80%. A laboratory examination showed elevation of the serum IgG4 levels preoperatively. Thus, the final diagnosis was IgG4-RD of the stomach. No recurrence was observed within 1 year after surgery. Conclusions We encountered a case of definite IgG4-RD presenting as a gastric SMT in which a correct diagnosis was achieved by a minimally invasive LECS technique. IgG4-RD may present as a gastric lesion and should be taken into consideration as a differential diagnosis.

Human fascioliasis is a rare parasitic disease outside of countries in which it is endemic. The diagnosis of hepatic-phase fascioliasis by diagnostic imaging alone is challenging. A 69-year-old female was referred to our hospital for the treatment of a solitary solid cystic mass lesion, 6 cm in diameter, accompanied with mild symptoms and minimal changes in laboratory parameters. Intrahepatic cholangiocarcinoma was suspected, and she underwent extended posterior sectionectomy. Four months later, she was re-admitted because of fatigue, high fever, and epigastric pain. Her eosinophil fraction and immunoglobulin E levels were extremely elevated (49.1% and 6833 IU/ml, respectively). She was found to have two new reticular cystic hepatic tumors. Serum dot enzyme-linked immunosorbent assay for parasites revealed strong positivity for Fasciola hepatica. Praziquantel was ineffective, and multi-cystic tumors rapidly developed in the left lateral section, requiring emergency left lateral sectionectomy. An F. hepatica helminth, approximately 3 cm in size, was observed on the cut liver surface during hepatic resection. Prophylactic triclabendazole (1,000 mg/day) was administered twice. She has been well for over 10 years without relapse of fascioliasis. In patients with hepatic tumors accompanied by inflammatory changes and eosinophilia, detailed medical history and serological testing by dot enzyme-linked immunosorbent assay for parasites are strongly recommended.

Aim: The objective of this study was to examine the clinical and biological significance of CD44 expression in conversion hepatectomy for initially unresectable colorectal liver metastases. Methods: Fifty-four patients who received chemotherapy followed by hepatectomy (conversion hepatectomy) for initially unresectable liver metastases were enrolled. CD44 expression and its clinical significance were examined in 52 resected specimens; two specimens revealed no residual cancer cells. The biological significance of CD44 expression in the chemoresistance response to fluorouracil, oxaliplatin or irinotecan, three major anti-cancer agents for colon cancer in the clinical setting, was examined using colon cancer cell lines. Results: Membrane CD44 expression in the residual cancer cells after chemotherapy for colorectal liver metastases was detectable in 19 patients (37%), and was significantly associated with high proliferative activity represented by Ki-67 expression (P = 0.003). CD44 expression was also significantly associated with shorter disease-free survival and worse overall survival after hepatectomy (hazard ratio and P-values were 2.570, 0.007 and 3.457, 0.026, respectively). In SW480 and HT29 colon cancer cells, siRNA-mediated CD44 knockdown attenuated cell growth. Additionally, CD44 knockdown overcame chemoresistance in response to fluorouracil and oxaliplatin with enhanced apoptosis and p27 upregulation, respectively. For irinotecan, CD44 knockdown showed no additional effect in chemoresistance. Conclusions: CD44 enhances chemoresistance in response to anti-cancer drugs (fluorouracil and oxaliplatin) in colon cancer cells. CD44 expression in liver metastases after chemotherapy implies the presence of occult micrometastases and is a worse prognostic factor in patients with conversion hepatectomy for initially unresectable colorectal liver metastases.

The oxygen electrode reactions (oxygen reduction reaction (ORR) and oxygen evolution reaction (OER)) of the pyrochlore-type metal oxide containing Bi and Ru (BRO) were investigated. In this study, we report that the correlation between the calcination temperature and the bifunctional catalytic activity of BRO in a KOH aqueous solution. BRO was prepared by the co-precipitation method in aqueous medium using Bi(NO3)3, RuCl3, and NaOH and following the calcination at 500–700 °C. The characterization was carried out by synchrotron XRD and temperature-programmed reduction technique. It was found that the oxygen contents of BRO decreased with rising the calcination temperature. The catalytic behavior of BRO towards ORR and OER was evaluated by hydrodynamic voltammetry using a rotating disk electrode and a rotating ring-disk electrode technique. Tafel slopes for the ORR and OER decreased with an increase in the calcination temperature from 500 to 600 °C, while the onset potentials for both reactions were almost same. The results of this study suggest that the oxygen content of BRO is one of the factors that determine the catalytic activity for the oxygen electrode reactions.