研究者詳細 - 天谷　雅行

論文 - 天谷　雅行

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Streptococcus pyogenes upregulates arginine catabolism to exert its pathogenesis on the skin surface

Hirose Y., Yamaguchi M., Sumitomo T., Nakata M., Hanada T., Okuzaki D., Motooka D., Mori Y., Kawasaki H., Coady A., Uchiyama S., Hiraoka M., Zurich R.H., Amagai M., Nizet V., Kawabata S.

Cell Reports （Cell Reports） 34 （ 13 ） 2021年03月

The arginine deiminase (ADI) pathway has been found in many kinds of bacteria and functions to supplement energy production and provide protection against acid stress. The Streptococcus pyogenes ADI pathway is upregulated upon exposure to various environmental stresses, including glucose starvation. However, there are several unclear points about the advantages to the organism for upregulating arginine catabolism. We show that the ADI pathway contributes to bacterial viability and pathogenesis under low-glucose conditions. S. pyogenes changes global gene expression, including upregulation of virulence genes, by catabolizing arginine. In a murine model of epicutaneous infection, S. pyogenes uses the ADI pathway to augment its pathogenicity by increasing the expression of virulence genes, including those encoding the exotoxins. We also find that arginine from stratum-corneum-derived filaggrin is a key substrate for the ADI pathway. In summary, arginine is a nutrient source that promotes the pathogenicity of S. pyogenes on the skin.

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Single nucleotide variations in genes associated with innate immunity are enriched in Japanese adult cases of face and neck type atopic dermatitis

Yasuda-Sekiguchi F., Shiohama A., Fukushima A., Obata S., Mochimaru N., Honda A., Kawasaki H., Kubo A., Ebihara T., Amagai M., Sasaki T.

Journal of Dermatological Science （Journal of Dermatological Science） 101 （ 2 ） 93 - 100 2021年02月

ISSN 09231811

Background: Atopic dermatitis (AD) is heterogenous in terms of phenotype as well as genetic and environmental factors, while its associated genetic factors and pathophysiology are not fully understood. Objective: We identify novel genetic factors enriched in a subgroup of AD patients with characteristic clinical features. Methods: We clinically subgrouped 18 AD patients who exhibited distinctive characteristic of persistent skin eruption areas on the face and neck from 92 Japanese adult AD patients and identified disease-associated genetic factors enriched within the subgroup. Targeted resequencing and subsequent genetic association analyses were used to identify novel enriched genetic variations in the subgroup compared with the other AD patients. Results: Targeted resequencing of 648 skin associated genes revealed an enrichment of 12 single nucleotide variations (SNVs) in patients with face and neck AD (n = 18) compared with the general Japanese population in the database. Subsequent allele frequency comparison between the face and neck AD and non - face and neck AD subgroups revealed enrichment of five SNVs. Multivariate analysis using genotype data revealed that three SNVs in theTLR1, TIRAP, and PSAPL1 genes, two of the three genes are involved in the Toll-like receptor pathway, were significantly enriched in patients with face and neck AD. Conclusion: These findings revealed that the SNVs in genes associated with the innate immune pathway are enriched in a subgroup of AD. The combinational approach of clinical subgrouping and genotyping is valuable for detecting novel disease-associated genetic factors.

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【最近の水疱症】天疱瘡の寛解後に発症した水疱性類天疱瘡

田原海, 古市祐樹, 舩越建, 久保亮治, 天谷雅行, 山上淳

皮膚病診療（(株)協和企画） 43 （ 2 ） 116 - 119 2021年02月

ISSN 0387-7531

＜文献概要＞症例のポイント　・天疱瘡の長期寛解後に水疱性類天疱瘡(bullous pemphigoid:BP)とネフローゼ症候群を発症し,またその罹患後に間質性肺炎で死亡した1例を報告した.・同一患者に,2種類の自己免疫性水疱症が時を経て発症した.またネフローゼ症候群,間質性肺炎の発症メカニズムに,水疱性類天疱瘡と共通した自己免疫反応の存在が示唆された.詳細な関連や機構については不明な点が多く,今後のさらなる症例の蓄積が必要である.

Clinical utility of SARS-CoV-2 whole genome sequencing in deciphering source of infection

Takenouchi T., Iwasaki Y.W., Harada S., Ishizu H., Uwamino Y., Uno S., Osada A., Abe K., Hasegawa N., Murata M., Takebayashi T., Fukunaga K., Saya H., Kitagawa Y., Amagai M., Siomi H., Kosaki K.

Journal of Hospital Infection （Journal of Hospital Infection） 107 40 - 44 2021年01月

ISSN 01956701

Coronavirus disease 2019 (COVID-19) caused by human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide problem. From the standpoint of hospital infection control, determining the source of infection is critical. We conducted the present study to evaluate the efficacy of using whole genome sequencing to determine the source of infection in hospitalized patients who do not have a clear infectious contact history. Recently, we encountered two seemingly separate COVID-19 clusters in a tertiary hospital. Whole viral genome sequencing distinguished the two clusters according to the viral haplotype. However, the source of infection was unclear in 14 patients with COVID-19 who were clinically unlinked to clusters 1 or 2. These patients, who had no clear history of infectious contact within the hospital (‘undetermined source of infection’), had haplotypes similar to those in cluster 2 but did not have two of the mutations used to characterize cluster 2, suggesting that these 14 cases of ‘undetermined source of infection’ were not derived from cluster 2. Whole viral genome sequencing can be useful for confirming that sporadic COVID-19 cases with an undetermined source of infection are indeed not part of clusters at the institutional level.

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Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin

Takahashi H., Nomura H., Iriki H., Kubo A., Isami K., Mikami Y., Mukai M., Sasaki T., Yamagami J., Kudoh J., Ito H., Kamata A., Kurebayashi Y., Yoshida H., Yoshimura A., Sun H.W., Suematsu M., O’Shea J.J., Kanno Y., Amagai M.

Science Immunology （Science Immunology） 6 （ 64 ） 2021年

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor–β (TGF-β), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-β signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27–treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

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Stratification of atopic dermatitis patients by patterns of response to proactive therapy with topical tacrolimus: low serum IgE levels and inadequately controlled disease activity at the start of treatment predict its failure

Kasai H., Kawasaki H., Fukushima-Nomura A., Yasuda-Sekiguchi F., Amagai M., Ebihara T., Tanese K.

Annals of Medicine （Annals of Medicine） 53 （ 1 ） 2205 - 2214 2021年

ISSN 07853890

Purpose: Topical calcineurin inhibitors (TCIs) are an important anti-inflammatory drug for treating atopic dermatitis (AD). However, those treatment responses are variable. In this study, we stratified AD patients by patterns of response to remission maintenance therapy (proactive therapy) with topical tacrolimus, a typical TCI. Thereafter, we explored patient features that predict the success or failure of proactive therapy using TCI (TCI proactive therapy). Methods: A single-arm open-label clinical study aimed to evaluate the efficacy of TCI proactive therapy was conducted in 31 patients with AD. Patients were treated with TCS to induce remission (remission-induction period) followed by daily TCI ointment (0.1% tacrolimus) application for 4 weeks (maintenance therapy period), and twice-weekly application for 12 weeks (proactive therapy period). Based on its results, treatment outcomes were correlated with the patients’ clinical and laboratory findings. Results: Of the 31 patients enrolled in the study, 21 successfully completed maintenance therapy (TCI responders). Among them, 13 completed (proactive-completed group) and 8 failed proactive therapy (proactive-dropout group). At the beginning of maintenance therapy, the serum IgE level was significantly higher in the TCI responders than in those who failed maintenance therapy (p = 0.049). At the beginning of proactive therapy, the mean-SCORing Atopic Dermatitis (SCORAD) score was significantly different between the proactive-completed (11.7 ± 4.6) and proactive-dropout (16.6 ± 4.2) groups (p = 0.025). In proactive-dropout group patients, worsened disease activity correlated well with the elevation of serum lactate dehydrogenase (LDH) and Thymus and activation-regulated chemokine (TARC) levels and peripheral eosinophil count. Conclusion: AD patients were stratified into three different response patterns to TCI proactive therapy. Patients with less involvement of IgE in the pathogenesis and inadequate remission induction by TCS may not be expected to respond well to TCI proactive therapy.Key messages AD patients can be stratified into three types according to their pattern of responsiveness to TCI proactive therapy. The efficacy of TCI proactive therapy is lower in AD patients with lower serum IgE levels. TCI proactive therapy should be done after the achievement of adequate remission induction by TCS.

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Sars-cov-2 infection among medical institution faculty and healthcare workers in tokyo, japan

Nishimura T., Uwamino Y., Uno S., Kashimura S., Shiraki T., Kurafuji T., Morita M., Noguchi M., Azegami T., Yamada-Goto N., Murai-Takeda A., Yokoyama H., Kuwabara K., Kato S., Matsumoto M., Hirata A., Iida M., Harada S., Ishizaka T., Misawa K., Murata M., Saya H., Amagai M., Kitagawa Y., Takeuchi T., Mori M., Takebayashi T., Hasegawa N.

Internal Medicine （Internal Medicine） 60 （ 16 ） 2569 - 2575 2021年

ISSN 09182918

Objective To consider effective measures against severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) infection in medical institutions, this study estimated the SARS-CoV-2 infection rate among healthcare workers (HCWs) in Tokyo, Japan, and determined the specific findings for mild coronavirus disease 2019 (COVID-19) cases. Methods This study analyzed the results of serologic tests to detect immunoglobulin G antibodies against SARS-CoV-2 and evaluated the demographic and clinical characteristics of the faculty and HCWs at a Tokyo medical institution in August 2020. The demographic and clinical characteristics of participants with antibody-positive results were compared to those of participants with antibody-negative results. Materials This study recruited 2,341 faculty and HCWs at a Tokyo medical institution, 21 of whom had a COVID-19 history. Results Of the 2,320 participants without a COVID-19 history, 20 (0.862%) had positive serologic test results. A fever and dysgeusia or dysosmia occurred with greater frequency among the participants with positive test results than in those with negative results [odds ratio (OR), 5.475; 95% confidence interval (CI), 1.960-15.293 and OR, 24.158; 95% CI, 2.693-216.720, respectively]. No significant difference was observed in the positivity rate between HCWs providing medical care for COVID-19 patients using adequate protection and other HCWs (OR, 2.514; 95% CI, 0.959-6.588). Conclusion To reduce the risk of COVID-19 spread in medical institutions, faculty and HCWs should follow standard and necessary transmission-based precautions, and those with a fever and dysgeusia or dysosmia should excuse themselves from work as soon as possible.

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Identification of b.1.346 lineage of sars-cov-2 in japan: Genomic evidence of re-entry of clade 20c

Abe K., Shimura T., Takenouchi T., Iwasaki Y.W., Ishizu H., Uwamino Y., Uno S., Gotoh J., Tachikawa N., Takeuchi Y., Katayama J., Nozaki H., Fujii S., Seki S., Nakamura M., Uda K., Misumi T., Ishihara J., Yamada K., Kanai T., Murai S., Araki K., Ebihara T., Siomi H., Hasegawa N., Kitagawa Y., Amagai M., Suematsu M., Kosaki K.

Keio Journal of Medicine （Keio Journal of Medicine） 70 （ 2 ） 44 - 50 2021年

ISSN 00229717

SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a de-centralized network of hospitals offers significant advantages as a highly responsive system for monitor-ing regional molecular epidemiologic trends.

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Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model

Ono R., Watanabe T., Kawakami E., Iwasaki M., Tomizawa-Murasawa M., Matsuda M., Najima Y., Takagi S., Fujiki S., Sato R., Mochizuki Y., Yoshida H., Sato K., Yabe H., Kato S., Saito Y., Taniguchi S., Shultz L., Ohara O., Amagai M., Koseki H., Ishikawa F.

EBioMedicine （EBioMedicine） 41 584 - 596 2019年03月

© 2019 The Authors Background: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. Methods: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 + CD38 − CD45RA − haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34 − cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. Findings: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. Interpretation: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.

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Rituximab therapy for refractory autoimmune bullous diseases: A multicenter, open-label, single-arm, phase 1/2 study on 10 Japanese patients

Kurihara Y., Yamagami J., Funakoshi T., Ishii M., Miyamoto J., Fujio Y., Kakuta R., Tanikawa A., Aoyama Y., Iwatsuki K., Ishii N., Hashimoto T., Nishie W., Shimizu H., Kouyama K., Amagai M.

Journal of Dermatology （Journal of Dermatology） 46 （ 2 ） 124 - 130 2019年02月

ISSN 03852407

© 2018 Japanese Dermatological Association This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m 2 of body surface area). The primary end-points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19-positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.

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Identification of a human papillomavirus type 58 lineage in multiple Bowen's disease on the fingers: Case report and published work review

Kobayashi K., Tanese K., Kubo A., Matsumoto-Mochimaru N., Sasaki A., Kameyama K., Amagai M., Umegaki-Arao N.

Journal of Dermatology （Journal of Dermatology） 45 （ 10 ） 1195 - 1198 2018年10月

ISSN 03852407

© 2018 Japanese Dermatological Association Human papillomavirus (HPV) has been detected in some cases of Bowen's disease, particularly on the fingers and genitalia. HPV-58 is classified as a high-risk mucosal type and accounts for a high percentage of cervical cancer in Asia. Moreover, several HPV-58 lineages, including sublineage A1, have a high prevalence in Asia. However, the nature of HPV-58-associated skin cancer is still unknown. Here, we report a case of a Japanese patient with multiple Bowen's disease on the fingers. A 33-year-old man presented with multiple reddish-brown scaly plaques on his left middle finger and right ring finger. All lesions were surgically excised, and the diagnosis of Bowen's disease was made. We performed Sanger sequencing using DNA extracted from paraffin-embedded samples and identified HPV-58 sublineage A1. Additionally, we review previous reports on HPV-58-associated skin cancers, including our case, showing a high regional prevalence in Asia. Further studies would be needed to reveal the relationship between HPV-58 lineages and carcinogenesis in the skin.

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Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis

Yamagami J., Nakamura Y., Nagao K., Funakoshi T., Takahashi H., Tanikawa A., Hachiya T., Yamamoto T., Ishida-Yamamoto A., Tanaka T., Fujimoto N., Nishigori C., Yoshida T., Ishii N., Hashimoto T., Amagai M.

Journal of Investigative Dermatology （Journal of Investigative Dermatology） 138 （ 7 ） 1473 - 1480 2018年07月

査読有り, ISSN 0022202X

© 2018 The Authors Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease.

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Characterization of centriole duplication in human epidermis, Bowen's disease, and squamous cell carcinoma

Watanuki S., Fujita H., Kouyama K., Amagai M., Kubo A.

Journal of Dermatological Science （Journal of Dermatological Science） 91 （ 1 ） 9 - 18 2018年07月

共著, 査読有り, ISSN 09231811

© 2018 Background: Centrosomes contain two centrioles: a pre-existing mature centriole and a newly formed immature centriole. Each centriole is duplicated once within a cell cycle, which is crucial for proper centrosome duplication and cell division. Objective: To describe the centrosome duplication cycle in human epidermis, Bowen's disease (BD), and squamous cell carcinoma (SCC). Methods: Immunofluorescent staining of centriolar proteins and Ki-67 was used to evaluate cell cycles and the number of centrioles. Centrobin and Outer dense fiber of sperm tails 2 (ODF2) were used as markers for immature and mature centrioles, respectively. Results: Normal human primary epidermal keratinocytes in a monolayered culture have one centrobin+ centriole (CTRB1+ cells) supposed in G0/G1 phases or have two centrobin+ centrioles (CTRB2+ cells) supposed in S−G2 phase. In a three-dimensional culture and in vivo human epidermis, the majority of suprabasal cells were CTRB2+ cells, in spite of their non-proliferative Ki-67− nature. The tumor mass of BD and SCC contained CTRB1+ cells and Ki-67+ proliferating and Ki-67− non-proliferative CTRB2+ cells. Clumping cells in BD had increased numbers of centrioles, with an approximate 1:1 to 2:1 ratio of centrobin+ to ODF2+ centrioles. Conclusions: The cell cycle arrest of suprabasal cells is distinct from the G0 arrest of monolayered epithelial cells. Tumor mass of BD and SCC contained non-proliferative cells with the characteristics of the suprabasal cells of normal epidermis. A constant ratio of the number of centrobin+ to ODF2+ centrioles indicates that multiple centrioles were induced by cell division failure rather than centriole overduplication in clumping cells.

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アレルギー疾患研究、臨床研究アトピー性皮膚炎と皮膚バリア障害

福島彩乃川崎洋天谷雅行

医学のあゆみ 265 （ 9 ） 812 - 817 2018年06月

共著

Unique clinical and serological features of bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors

Horikawa, H. Kurihara, Y. Funakoshi, T. Umegaki-Arao, N. Takahashi, H. Kubo, A. Tanikawa, A. Kodani, N. Minami, Y. Meguro, S. Itoh, H. Izumi, K. Nishie, W. Shimizu, H. Amagai, M. Yamagami, J.

Br J Dermatol 178 （ 6 ） 1462 - 1463 2018年06月

査読有り

Combination of low-dose total skin electron beam therapy and subsequent localized skin electron beam therapy as a therapeutic option for advanced-stage mycosis fungoides

Kinoshita-Ise, M. Ouchi, T. Izumi, E. Kawaguchi, O. Nagao, K. Amagai, M. Funakoshi, T.

Clinical and Experimental Dermatology 43 （ 4 ） 437 - 440 2018年06月

共著, 査読有り

Assessment of the methods used to detect HER2-positive advanced extramammary Paget’s disease

Hirai I., Tanese K., Nakamura Y., Otsuka A., Fujisawa Y., Yamamoto Y., Hata H., Fujimura T., Matsushita S., Yoshino K., Kameyama K., Amagai M., Funakoshi T.

Medical Oncology （Medical Oncology） 35 （ 6 ） online1 - 8 2018年06月

共著, 査読有り, ISSN 13570560

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a therapeutic target in various cancers. Certain patients with advanced extramammary Paget’s disease (EMPD) have also been reported to express HER2, which is therefore considered a therapeutic target for EMPD. However, an accurate methodology to determine HER2-positive EMPD has not been established. To assess the optimal methods for detection of HER2-positive EMPD, 73 EMPD samples were analyzed by immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), and the HER2 testing algorithm for breast cancer of the American Society of Clinical Oncology/College of American Pathologists, which combined the results of IHC staining and FISH. The results showed discordance in the rate of positive IHC staining and FISH results. While 68.6% (24/35) of the metastatic samples showed equivocal or positive IHC staining, only 37.1% (13/35) were positive by FISH. To assess the accuracy of these methods, the degree of HER2 expression detected by each method was correlated with the staining profiles of activated downstream signaling pathways involving phosphorylated p44/42 MAPK (Thr202/Tyr204) (p-ERK1/2) and phosphorylated AKT (Ser473) (p-AKT). Among 16 lymph node metastasis samples, all HER2-positive samples as determined by the testing algorithm stained positively for both p-ERK1/2 and p-AKT. On the other hand, 10-14.3% of the samples determined by FISH or IHC showed negative staining for p-ERK1/2 and p-AKT. The results showed that combining the results of IHC and FISH according to the HER2 testing algorithm is a useful method for accurately evaluating HER2-positive EMPD.

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女性化乳房様を呈し、皮膚悪性腫瘍を疑った嚢胞内乳癌の男性例

八谷美穂梅垣知子江原佳恵舩越建高橋麻衣子天谷雅行

皮膚科の臨床 60 （ 5 ） 726 - 727 2018年05月

共著

Bone Marrow-Derived Stem Cells Migrate into Intraepidermal Skin Defects of a Desmoglein-3 Knockout Mouse Model but Preserve their Mesodermal Differentiation

Hunefeld, C. Mezger, M. Muller-Hermelink, E. Schaller, M. Muller, I. Amagai, M. Handgretinger, R. Rocken, M.

J Invest Dermatol 138 （ 5 ） 1157 - 1165 2018年05月

共著, 査読有り

A familial case of nail patella syndrome with a heterozygous in-frame indel mutation in the LIM domain of LMX1B

Mukai, M. Fujita, H. Umegaki-Arao, N. Sasaki, T. Yasuda-Sekiguchi, F. Isojima, T. Kitanaka, S. Amagai, M. Kubo, A.

J Dermatol Sci 90 （ 1 ） 90 - 93 2018年04月

査読有り

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