A case of Langerhans cell sarcoma on the scalp: Whole‐exome sequencing reveals a role of ultraviolet in the pathogenesis

Langerhans cell sarcoma (LCS) is a high‐grade neoplasm with overtly malignant cytological features and a Langerhans cell phenotype. The underlying genetic features are poorly understood, and only a few alterations, such as those of the MARK pathway‐related genes, CDKN2A and TP53 have been reported. Here we present a 70‐year‐old male with LCS on the scalp and pulmonary metastasis. The multinodular tumor, 3.0 cm in diameter, consisted of diffusely proliferated pleomorphic cells with numerous mitoses (53/10 HPFs). Immunohistochemically, the tumor cells were positive for CD1a, Langerin and PD‐L1, and the Ki‐67 labeling index was 50%. These pathological features were consistent with LCS, and were also observed in the metastatic tumor. Whole‐exome sequencing revealed that both the primary and metastatic tumors harbored a large number of mutations (>20 mutations/megabase), with deletion of CDKN2A and TP53 mutation, and highlighted that the mutational signature was predominantly characteristic of ultraviolet (UV) exposure (W = 0.828). Our results suggest, for the first time, that DNA damage by UV could accumulate in Langerhans cells and play a role in the pathogenesis of LCS. The high mutational burden and PD‐L1 expression in the tumor would provide a rationale for the use of immune checkpoint inhibitors for treatment of unresectable LCS

Identification and characterization of neural crest-derived cells in adult periodontal ligament of mice

Cells derived from the neural crest (NC) contribute to the development of several adult tissues, including tooth and periodontal tissue. Here, two transgenic lines, Wnt1-Cre/ZEG and P0-Cre/ZEGwere analyzed to determine the fate and distribution of neural crest cells (NCCs) in adult mouse periodontal ligament (PDL)

The surveillance of colistin resistance and mobilized colistin resistance genes in multidrug-resistant Enterobacteriaceae isolated in Japan

Background: The plasmid-mediated bacterial colistin-resistant gene, mcr, is of global concern in clini-cal healthcare. However, there are few reports of surveillance for mcr in Japan. The aim of this study was to assess the prevalence of colistin resistance by identifying nine mcr genes in extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) isolates in Japan.Methods: A total of 273 ESBL and CRE clinical isolates were collected from patients in five tertiary hospi-tals from August 2016 to March 2017. Minimum inhibitory concentration (MIC) of colistin was measured using the microdilution method. Polymerase chain reaction (PCR) was performed to detect mcr-1 to mcr-9 genes in all strains. Whole-genome sequencing (WGS) analysis was conducted for any mcr-genes identi-fied that had not been previously reported in patients from Japan.Results: The rate of colistin resistance was 7.7% in all strains, with a higher rate in the CRE strains than in the ESBL-producing strains (20.4% versus 1.1%). The mcr-5 and mcr-9 gene were detected in one ESBL-producing Escherichia coli strain (1/273, 0.37%) and three CRE strains (3/273, 1.1%), respectively. As theESBL-producing E. coli strain was the first clinical strain with mcr-5 in Japan, WGS analysis was performed for the strain. The sequence type of the mcr-5-positive strain was ST1642 and it carried two distinct plasmids, ESBL gene-carrying pN-ES-6-1, and mcr-5.1-carrying pN-ES-6-2.Conclusions: The results of this study showed that the frequency of colistin resistance and mcr-positive strains is not high in Japan. As the MIC for colistin was low in the mcr-5.1 and mcr-9 gene-positive strain, continuous monitoring of mcr genes is necessary

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

The definition of healthcare-associated pneumonia (HCAP) is insufficient for the medical environment in Japan: a comparison of HCAP and nursing and healthcare-associated pneumonia (NHCAP)

Healthcare-associated pneumonia (HCAP) is a new concept of pneumonia, which was proposed in the ATS/IDSA guidelines. The guidelines explain that HCAP patients should be treated with broad-spectrum antimicrobial drugs directed at multidrug-resistant pathogens. However, in Japan, there are many elderly people who received in-home care service. These patients seemed to be consistent with the concept of HCAP, but they did not meet the definition of HCAP. Therefore, the Japanese Respiratory Society modified the definition of HCAP according to the medical environmental in Japan. We retrospectively observed HCAP patients and nursing home and healthcare-associated pneumonia (NHCAP) patients who were hospitalized during 24 months at the Japanese Red Cross Nagasaki Genbaku Hospital (Nagasaki, Japan). Patient background, disease severity, identified pathogens, initial antibiotic regimens, and outcomes were compared. A total of 108 patients (77 HCAP and 31 NHCAP except HCAP patients) were evaluated. Of NHCAP except HCAP patients, 27 (87.1 %) were above 3 in the ECOG PS score. There were almost no significant differences between the two groups in characteristics, pneumonia severity, identified bacteria, initial antibiotic regimens, and response rate of initial antibiotic therapy. Although the in-hospital mortality of HCAP patients and NHCAP except HCAP patients was 9.1 % and 19.4 %, respectively, this difference did not reach statistical significance (P > 0.05). Our study suggested that, in the criteria of HCAP, some Japanese patients, who were consistent with the concept of HCAP, were classified as community-acquired pneumonia (CAP). Therefore, there is a need to change the definition of HCAP according to the medical environment in Japan

Endothelial dysfunction, carotid artery plaque burden, and conventional exercise-induced myocardial ischemia as predictors of coronary artery disease prognosis

<p>Abstract</p> <p>Background</p> <p>While both flow-mediated vasodilation (FMD) in the brachial artery (BA), which measures endothelium-dependent vasodilatation, and intima-media thickness (IMT) in the carotid artery are correlated with the prognosis of coronary artery disease (CAD), it is not clear which modality is a better predictor of CAD. Furthermore, it has not been fully determined whether either of these modalities is superior to conventional ST-segment depression on exercise stress electrocardiogram (ECG) as a predictor. Thus, the goal of the present study was to compare the predictive value of FMD, IMT, and stress ECG for CAD prognosis.</p> <p>Methods and Results</p> <p>A total of 103 consecutive patients (62 ± 9 years old, 79 men) with clinically suspected CAD had FMD and nitroglycerin-induced dilation (NTG-D) in the BA, carotid artery IMT measurement using high-resolution ultrasound, and exercise treadmill testing. The 73 CAD patients and 30 normal coronary patients were followed for 50 ± 15 months. Fifteen patients had coronary events during this period (1 cardiac death, 2 non-fatal myocardial infarctions, 3 acute heart failures, and 9 unstable anginas). On Kaplan-Meier analysis, only FMD and stress ECG were significant predictors for cardiac events.</p> <p>Conclusion</p> <p>Brachial endothelial function as reflected by FMD and conventional exercise stress testing has comparable prognostic value, whereas carotid artery plaque burden appears to be less powerful for predicting future cardiac events.</p

Influence of antimicrobial regimen on decreased in-hospital mortality of patients with MRSA bacteremia

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important causes of bacteremia. Recently, several epidemiological and microbiological changes have become evident in MRSA infections. The purposes of this study were to assess clinical characteristics of patients with MRSA bacteremia and microbiological changes in MRSA. We conducted a retrospective observational study on patients with MRSA bacteremia who were hospitalized between 2008 and 2011. We used univariate and multivariate analysis to evaluate the predictors associated with 30-day mortality. The 7-day and 30-day mortality rates were 12.0% and 25.3%, respectively. According to multivariate analysis, the independent predictors that associated with 30-day mortality were leukopenia, low serum albumin, high sequential organ failure assessment (SOFA) score, and quinolone use within 30 days. Compared to previous data (2003-2007), the SOFA score of the new data set remained unchanged, but in-hospital mortality decreased significantly. In particular, the mortality associated with use of vancomycin (VCM) was significantly lower. Although the minimuminhibitory concentration of VCM required to inhibit the growth of 90% of organisms (MIC90) had not changed, the trough value of VCM changed significantly; a VCM trough value of 10 or greater was significantly higher compared to previous data. Of the staphylococcal cassette chromosome mec (SCCmec) types, SCCmec II values decreased significantly, and SCCmec I and IV values increased significantly. Our results indicate that changes in VCM usage might contribute to decreased in-hospital mortality

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In 1992 the World Health Organization advocated that follicular keratocysts, which may envelop an adjacent unerupted tooth, be classified as an entity different from dentigerous cysts in the classification of odontogenic cysts. However after follicular keratocysts were distinguished from dentigerous cysts, follicular keratocysts have still been erroneously reported as dentigerous cytsts with a keratinizing lining. This reviews Japanese cases of follicular keratocysts, including two cases occurring at the maxilla that have been diagnosed at this hospital