Publications by authors named "Takatoshi Shimauchi"

65 Publications

CD8 mycosis fungoides with optic nerve and central nervous system involvement.

J Dermatol 2021 Jun 8;48(6):e286-e287. Epub 2021 Apr 8.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.15885DOI Listing
June 2021

Outlines of the Japanese guidelines for the management of primary cutaneous lymphomas 2020.

J Dermatol 2021 Feb 27;48(2):e49-e71. Epub 2020 Nov 27.

Department of Dermatology, International University of Health and Welfare, Narita, Japan.

Since the publication of the Japanese "Guidelines for the management of cutaneous lymphomas" in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO-European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T-cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese "Guidelines for the management of cutaneous lymphomas".
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http://dx.doi.org/10.1111/1346-8138.15707DOI Listing
February 2021

Suprabasin-null mice retain skin barrier function and show high contact hypersensitivity to nickel upon oral nickel loading.

Sci Rep 2020 09 3;10(1):14559. Epub 2020 Sep 3.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.

Suprabasin (SBSN) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSN level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSN-null (Sbsn) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (CHS) responses to haptens than did WT mice. The blood nickel level after oral feeding of nickel was significantly higher in Sbsn mice than in WT mice, and CHS to nickel was elevated in Sbsn mice under nickel-loading condition. Our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high CHS to nickel, sharing the features of intrinsic AD.
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http://dx.doi.org/10.1038/s41598-020-71536-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471289PMC
September 2020

Secukinumab promotes engagement of cholecystokinin and its receptor in epidermal keratinocytes of psoriasis patients.

J Dermatol 2020 Dec 13;47(12):1454-1456. Epub 2020 Aug 13.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.15552DOI Listing
December 2020

Enhanced PD-L1 expression on tumor cells in primary cutaneous large T-cell lymphoma with CD30 expression as classic Hodgkin lymphoma mimics: A report of lymph node lesions of two cases.

Pathol Int 2020 Oct 12;70(10):804-811. Epub 2020 Aug 12.

Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Aichi, Japan.

Neoplastic PD-L1 (nPD-L1, clone SP142) expression remains unclear in cutaneous T-cell lymphoma (CTCL), although it is well-documented in classic Hodgkin lymphoma (CHL). Here, we report two cases of primary cutaneous large T-cell lymphoma (PCLTCL) with CD30 expression that developed secondary nodal lesions morphologically mimicking CHL, and describe their PD-L1 expression. Our two cases (52- and 60-year-old males) had long-standing clinical courses of CTCL. Their PCLTCL with CD30 expression developed nodal lesions, having a nodular growth pattern containing scattered CD30+ Hodgkin and Reed-Sternberg-like and/or lacunar cells that expressed CD15 but did not harbor Epstein-Barr virus. Their differential diagnosis from CHL was challenging. A diagnosis of PCLTCL with secondary nodal involvement featuring CHL mimicry was based on comparison of the primary and secondary lesions. In one case, shared expression of the same T-cell antigen was revealed by immunohistochemistry, and in the other, identical clonal TCR rearrangement was demonstrated by polymerase chain reaction (PCR). Interestingly, nPD-L1 was expressed on more than 50% of the tumor cells in the secondary nodal lesions, but on very few in the primary cutaneous lesions, in both cases. This is the first report of nPD-L1 expression greatly increasing with PCLTCL tumor progression to nodal involvement.
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http://dx.doi.org/10.1111/pin.13000DOI Listing
October 2020

Protective role of Galectin-7 for skin barrier impairment in atopic dermatitis.

Clin Exp Allergy 2020 08 14;50(8):922-931. Epub 2020 Jun 14.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: Atopic dermatitis (AD) patients have a barrier disorder in association with Th2 dominant skin inflammation. Galectin-7 (Gal-7), a soluble unglycosylated lectin, is highly expressed in the stratum corneum of AD patients. However, the biological significance of increased Gal-7 expression in AD skin lesions remains unclear.

Objective: We aimed to investigate the production mechanism and functional role of Gal-7 in AD patients and IL-4/IL-13-stimulated epidermal keratinocytes.

Methods: We assessed the Gal-7 expression levels in skin lesions and sera from AD patients. Gal-7 levels were also measured in monolayered normal human epidermal keratinocytes (NHEKs) and 3-dimensional (3D)-reconstructed epidermis in the presence or absence of IL-4/IL-13 with or without Stat3, Stat6 or Gal-7 gene silencing.

Results: Gal-7 was highly expressed in the stratum corneum or intercellular space of AD lesional epidermis as assessed by the stratum corneum proteome analysis and immunohistochemistry. A positive correlation was noted between serum Gal-7 level and transepidermal water loss in patients with AD. These clinical findings were corroborated by our in vitro data, which showed that IL-4/IL-13 facilitated the extracellular release of endogenous Gal-7 in both monolayered NHEKs and 3D-reconstructed epidermis. This machinery was caused by IL-4/IL-13-induced cell damage and inhibited by knockdown of Stat6 but not Stat3 in NHEKs. Moreover, we performed Gal-7 knockdown experiment on 3D-reconstructed epidermis and the result suggested that endogenous Gal-7 serves as a protector from IL-4/IL-13-induced disruption of cell-to-cell adhesion and/or cell-to-extracellular matrix adhesion.

Conclusion And Clinical Relevance: Our study unveils the characteristic of Gal-7 and its possible role as an alarmin that reflects the IL-4/IL-13-induced skin barrier impairment in AD.
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http://dx.doi.org/10.1111/cea.13672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496409PMC
August 2020

Indolent multipapular adult T-cell leukemia/lymphoma with phenotype of resident memory T cells.

J Dermatol 2020 Jul 8;47(7):e280-e281. Epub 2020 May 8.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.15380DOI Listing
July 2020

Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy.

J Dermatol 2020 Jun 24;47(6):636-640. Epub 2020 Mar 24.

Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Bexarotene is useful for both early and advanced cutaneous T-cell lymphoma (CTCL), and is sometimes applied to ultraviolet-tolerant early CTCL patients as one of the first-line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m cohort (conventional dose) was 76.2%, while that of the 150-300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional-dose cohort and 19.1 months for the low-dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional-dose cohort and 12.5% for the low-dose with NBUVB cohort. Our present study suggests that low-dose bexarotene plus NBUVB therapy is well-tolerated and could be one of the optimal therapies for advanced CTCL.
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http://dx.doi.org/10.1111/1346-8138.15322DOI Listing
June 2020

Skin Infiltration of Pathogenic Migratory and Resident T Cells Is Decreased by Secukinumab Treatment in Psoriasis.

J Invest Dermatol 2020 10 19;140(10):2073-2076.e6. Epub 2020 Mar 19.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1016/j.jid.2020.02.024DOI Listing
October 2020

Cutaneous lymphoma in Japan, 2012-2017: A nationwide study.

J Dermatol Sci 2020 Mar 25;97(3):187-193. Epub 2020 Jan 25.

Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: The types of cutaneous lymphoma (CL) and their incidences can vary among geographic areas or ethnic groups.

Objective: This study aimed to investigate the incidence of various CL types in Japan using epidemiological data from a nationwide registration system for CL.

Methods: A questionnaire was sent to participating hospitals, all of which had been approved to conduct residency programs for board-certified dermatologists by the Japanese Dermatological Association. Data from patients newly diagnosed with CL were collected electronically.

Results: Between 2012 and 2017, 2547 new patients with CL from the dermatological institutes were registered. In total, 2090 patients had primary CL and 453 had secondary CL. Those with primary CL included 1609 (77.0 %) patients with mature T- and natural killer (NK)-cell neoplasms, 442 (21.1 %) with B-cell neoplasms, and 39 (1.9 %) with blastic plasmacytoid dendritic cell neoplasms. Mycosis fungoides (MF) was the most common CL subtype in the present study (1003 patients, 48.0 %), and 72.4 % of MF patients had early-stage disease, similar to observations in previous studies on other cohorts. Primary cutaneous CD30+ T-cell lymphoproliferative disorders and adult T-cell leukemia/lymphoma were the second and third most common subtypes, respectively.

Conclusion: Compared to that in our previous cohort (2007-2011), the number of registered T- and NK-cell CL cases decreased, whereas that of B-cell CL cases increased from 44.8-73.7 patients/year. These results provide insight into CL trends within the Japanese population, which might contribute to a better understanding of the disease.
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http://dx.doi.org/10.1016/j.jdermsci.2020.01.010DOI Listing
March 2020

An intuitive explanation of dermoscopic structures by digitally reconstructed pathological horizontal top-down view images.

Sci Rep 2019 12 27;9(1):19875. Epub 2019 Dec 27.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.

Dermoscopy is a convenient tool to diagnose melanocytic lesions, especially nevus and melanoma. Various pigmented structures, including pigment network, dots and globules, and streaks, are observed in dermoscopy. Usually, 2D vertical images are used to explain the correlation of dermoscopy and histopathology. However, because the image of dermoscopy is horizontal, it is difficult for the horizontal view of dermoscopy to refer to the vertical view of histopathology. In our study, we digitally reconstructed 2D horizontal top-down view images and 3D aerial images from 50-100 serial 2D vertical sections by using high-speed scanner and 3D software in 6 cases of melanocytic lesion. Our new technology intuitively explained the histopathological structures corresponding to the dermoscopic structures. This technique could be used as a good educational tool for beginners.
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http://dx.doi.org/10.1038/s41598-019-56522-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934765PMC
December 2019

Decreased expression of suprabasin induces aberrant differentiation and apoptosis of epidermal keratinocytes: Possible role for atopic dermatitis.

J Dermatol Sci 2019 Sep 27;95(3):107-112. Epub 2019 Jul 27.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: Suprabasin (SBSN), a secreted protein, is expressed in various epithelial tissues. The role of SBSN in epidermal differentiation and atopic dermatitis (AD) pathology remains largely unknown.

Objective: To evaluate the effects of SBSN on epidermal keratinocytes and its role in AD.

Methods: We examined the SBSN expression levels in the stratum corneum and the epidermis by proteome analysis and immunohistochemistry, respectively. The serum SBSN concentration was measured by ELISA. These values were compared between AD and healthy control. Morphological changes in the epidermis were investigated in SBSN-knockdown three-dimensional human living skin equivalent (LSE) model with or without IL-4/IL-13.

Results: Epidermal SBSN expression was decreased in AD lesional skin compared to healthy skin, as assessed by the stratum corneum proteome analysis and immunohistochemistry. The SBSN serum levels were significantly lower in AD patients than in normal subjects (P<0.05). The SBSN-deficient LSE exhibited compact stratum corneum, immature stratum granulosum, and increased keratinocyte apoptosis. Th2 cytokines, IL-4 and IL-13, did not affect SBSN expression in LSE. There were no differentiation-associated makers that were affected by the SBSN knockdown. SBSN deficiency-induced apoptosis of keratinocytes was exaggerated by IL-4/IL-13, and accordingly, the addition of recombinant SBSN induced significant keratinocyte proliferation (P<0.05).

Conclusion: Our data demonstrated that SBSN regulates normal epidermal barrier. Th2 cytokines unaffect SBSN expression in keratinocytes, but promote SBSN deficiency-induced apoptosis. It is suggested that SBSN has an anti-apoptotic activity, and its deficiency is involved in the pathogenesis of AD.
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http://dx.doi.org/10.1016/j.jdermsci.2019.07.009DOI Listing
September 2019

Cholecystokinin Downregulates Psoriatic Inflammation by Its Possible Self-Regulatory Effect on Epidermal Keratinocytes.

J Immunol 2019 05 22;202(9):2609-2615. Epub 2019 Mar 22.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Cholecystokinin (CCK) is a peptide hormone that functions in digestive organs and the CNS. We previously showed that CCK downregulates peripheral pruritus by suppressing degranulation of mast cells. In this study, we demonstrated that CCK octapeptide (CCK8) was constitutively expressed in the epidermis of normal skin, whereas its expression was lost in acanthotic lesions of psoriasis. In contrast, CCKA receptor (CCKAR), a high-affinity receptor for CCK, was constitutively expressed in the epidermis of psoriatic skin lesions. Expression of CCK was also reduced in skin lesions of an imiquimod (IMQ)-induced psoriatic mouse model. Notably, the expression level of CCK inversely correlated with the severity of epidermal inflammation, raising the possibility that CCK from epidermal keratinocytes suppresses the psoriatic inflammation. To verify this hypothesis, we investigated the effects of sulfated CCK octapeptide (CCK8S) on the development of IMQ-induced psoriatic inflammation. i.p. injection of CCK8S suppressed the IMQ-induced psoriatic inflammation accompanied by reduced mRNA expression of IL-17, IL-22, and IL-6 but not of IL-23. The suppressive effect of CCK8S was completely restored by administration of CCKAR antagonist. In vitro studies showed that exogenous CCK8S suppressed IL-6 production in CCKAR-expressing cultured human keratinocytes, and blocking the endogenous CCK signaling with CCKAR antagonist markedly enhanced IL-6 production. When keratinocytes were stimulated with IL-17, the expression of endogenous CCK was significantly decreased. These findings suggest that CCK physiologically functions as a negative regulator of keratinocyte-based inflammation in an autocrine or paracrine manner, although decreased CCK may pathologically contribute to continuous and aggravated skin lesions such as psoriasis.
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http://dx.doi.org/10.4049/jimmunol.1801426DOI Listing
May 2019

Voriconazole-photoinduced polyomavirus-negative Merkel cell carcinoma.

J Dermatol 2019 08 12;46(8):e287-e288. Epub 2019 Mar 12.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.14849DOI Listing
August 2019

Unknown primary Merkel cell carcinoma responding well to first-line treatment with avelumab.

J Dermatol 2019 08 25;46(8):e273-e275. Epub 2019 Feb 25.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.14827DOI Listing
August 2019

Nation-wide survey of advanced non-melanoma skin cancers treated at dermatology departments in Japan.

J Dermatol Sci 2018 Dec 3;92(3):230-236. Epub 2018 Nov 3.

Prognosis and Statistical Investigation Committee, Japanese Skin Cancer Society, Japan; Department of Dermatology and Plastic Surgery, Kumamoto University, Japan.

Background: There are limited treatment options for advanced non-melanoma skin cancers (NMSCs). To overcome this issue, we need to conduct clinical studies, however, there is a lack of information on how many patients with advanced NMSCs are treated annually in Japan.

Objective: To investigate the actual number of advanced NMSC patients in Japan.

Methods: A questionnaire survey was sent to 668 institutes to educe information on: 1) the numbers of patients with squamous cell carcinoma (SCC), extramammary Paget disease (EMPD), other skin origin carcinomas, and cutaneous angiosarcoma (CAS) admitted in 2016 and 2017; 2) the preferred first- and second-line chemotherapies; and 3) the anticipated for future development.

Results: Questionnaires were returned from 383 (57.3%) institutes. They reported a total of 1765 patients over the 2 years. The annual number patients with SCC, EMPD, other skin carcinomas, and CAS was 323.5, 192.5, 126, and 240.5, respectively. We estimated the annual number of patients for all 668 institutes to be 1255.6. Current first- and second-line treatment for NMSCs were chemotherapy regimens, but immune checkpoint inhibitors were the most anticipated new drugs for SCC and CAS, while chemotherapy was still the most anticipated treatment for EMPD.

Conclusion: Considering that during 2017, the number of deaths in Japan due to NMSC was reported to be 948, our estimated annual number of patients with NMSCs, 1255.6 seems to be an accurate estimation. As most of the treatment options for advanced NMSCs are outdated, the results of this study should be used to propose clinical studies.
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http://dx.doi.org/10.1016/j.jdermsci.2018.10.004DOI Listing
December 2018

Induction of plasmablasts by follicular helper T cell-CXCL13 axis upon occurrence of herpes zoster.

Clin Immunol 2018 10 16;195:93-100. Epub 2018 Aug 16.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Electronic address:

Herpes zoster (HZ) is a recurrent varicella zoster virus (VZV) infection. Follicular helper T (Tfh) cells produce IL-21 and CXCL13, which contributes to the differentiation of plasmablasts. Plasmablasts are involved in the VZV-specific antibody production. We investigated the kinetics of circulating plasmablasts and circulating Tfh (cTfh) cells in 43 HZ patients. Plasma IL-21 and CXCL13 levels were also measured. We found an increase of circulating plasmablasts during the clinical course of HZ. The frequency of circulating plasmablasts positively correlated with VZV-specific IgG titers, frequency of activated cTfh cells, and plasma CXCL13 levels, but did not correlate with plasma IL-21 levels. In a representative case, the kinetics peaked in the order of cTfh cells, CXCL13, plasmablasts, and VZV IgG titer. These results suggest that cTfh-CXCL13 may have a crucial role in the differentiation of B cells into VZV-specific IgG-producing plasmablasts, resulting in boosting immunity against VZV reactivation.
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http://dx.doi.org/10.1016/j.clim.2018.08.003DOI Listing
October 2018

Dendritic Cells Promote the Spread of Human T-Cell Leukemia Virus Type 1 via Bidirectional Interactions with CD4 T Cells.

J Invest Dermatol 2019 01 23;139(1):157-166. Epub 2018 Jul 23.

Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; Division of Dermatology, Women's College Hospital, Toronto, Canada; Division of Dermatology, Department of Medicine, University of Toronto, Canada. Electronic address:

Human T-cell leukemia virus type 1 (HTLV-1) propagates within and between individuals via cell-to-cell transmission, and primary infection typically occurs across juxtaposed mucosal surfaces during breastfeeding or sexual intercourse. It is therefore likely that dendritic cells (DCs) are among the first potential targets for HTLV-1. However, it remains unclear how DCs contribute to virus transmission and dissemination in the early stages of infection. We show that an HTLV-1-infected cell line (MT-2) and naturally infected CD4 T cells transfer p19 viral particles to the surface of allogeneic DCs via cell-to-cell contacts. Similarly organized cell-to-cell contacts also facilitate DC-mediated transfer of HTLV-1 to autologous CD4 T cells. These findings shed light on the cellular structures involved in anterograde and retrograde transmission and suggest a key role for DCs in the natural history and pathogenesis of HTLV-1 infection.
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http://dx.doi.org/10.1016/j.jid.2018.06.188DOI Listing
January 2019

Isolated Adrenocorticotropic Hormone Deficiency in Melanoma Patients Treated with Nivolumab.

Acta Derm Venereol 2018 Jul;98(7):704-705

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, 431-3192 Hamamatsu, Japan.

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http://dx.doi.org/10.2340/00015555-2902DOI Listing
July 2018

Lymphatic transit rate as a predictive parameter for nodal metastasis in primary limb malignant melanoma.

J Dermatol Sci 2018 Apr 24;90(1):27-34. Epub 2017 Dec 24.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: The status of sentinel lymph node (SLN) is one of the most predictive prognostic factors in patients with clinically localized malignant melanomas (MMs). However, since the positive SLN metastatic rate is as low as 20%, it is desirable to minimize SLN biopsy performance with imaging. By dynamic lymphoscintigraphy, we have proposed the lymphatic transit rate (LTR), the value that the distance between the primary lesion and SLN is divided by scintigraphic saturation time. LTR represents the scintigraphic saturation velocity and can be used for evaluation of metastasis of skin cancers.

Methods: Dynamic lymphoscintigraphy data from 36 lymph nodes in 36 patients with primary MM on the limb were analyzed. The initial sites of the MMs were the lower limb in 24 patients and the upper limb in 12 patients. Histopathologically, nodal metastasis was found in 10 patients.

Results: In the lower limb MM, the mean LTRs were 3.49 cm/min in histologically non-metastatic SLNs and 4.49 cm/min in histologically metastatic SLNs (P = 0.0056). In the upper limb MM, the mean LTRs were 2.59 cm/min in non-metastatic SLNs and 3.94 cm/min in metastatic SLNs (P = 0.0162). Thus, significantly higher LTRs were obtained in the metastatic SLNs. All SLNs with LTR < 4.0 cm/min in the lower limb MM and those with LTR < 3.0 cm/min in the upper limb MM were non-metastatic.

Conclusion: LTR is a useful predictive indicator for nodal metastasis and SLN biopsy performance in MMs.
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http://dx.doi.org/10.1016/j.jdermsci.2017.12.013DOI Listing
April 2018

Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment.

J Dermatol Sci 2018 Jan 2;89(1):33-39. Epub 2017 Nov 2.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: Sensitive skin is a condition of cutaneous hypersensitivity to environmental factors. Lactic acid stinging test (LAST) is commonly used to assess sensitive skin and composed of four distinct sensations (pain, burning sensation, itch, and crawly feeling). A link between sensitive skin and barrier dysfunction has been proposed in atopic dermatitis (AD) patients. However, clinical and laboratory factors that are associated with sensitive skin remain unelucidated.

Objective: To investigate relationship between sensitive skin and AD-associated markers.

Methods: Forty-two Japanese AD patients and 10 healthy subjects (HS) were enrolled. AD patients were divided into extrinsic (EAD; high IgE levels) and intrinsic (IAD; normal IgE levels) types. We conducted 1% LAST by assessing the four distinct sensations and calculated the frequencies of sensitive skin in EAD, IAD, and HS. We also performed clinical AD-related tests, including transepidermal water loss (TEWL), visual analogue scale (VAS) of pruritus, and quality of life, and measured laboratory markers, including blood levels of IgE, CCL17/TARC, lactate dehydrogenase (LDH) and eosinophil counts, and concentration levels of serum Th1/Th2 cytokines. Filaggrin (FLG) mutations were examined in 21 patients. These values were subjected to correlation analyses with each of the four sensation elements.

Results: According to the standard criteria for LAST positivity, the frequencies of LAST-positive subjects were 54.8% and 10.0% in AD and HS, respectively (P=0.014). EAD patients showed a significantly (P=0.026) higher frequency of positive LAST (65.6%) than did IAD patients (20.0%). Among the four LAST sensation elements, the crawly feeling and pain scores positively correlated with VAS of pruritus, total serum IgE, mite-specific IgE, CCL17/TARC, and/or LDH. There was no association of the LAST scores with serum Th1/Th2 cytokine levels. Notably, neither TEWL nor FLG mutations correlated with LAST positivity or any sensation scores.

Conclusions: The frequency of sensitive skin is higher in EAD than in IAD. Sensitive skin is associated with AD severity, but not necessarily with barrier condition.
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http://dx.doi.org/10.1016/j.jdermsci.2017.10.011DOI Listing
January 2018

TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells.

J Invest Dermatol 2016 10 29;136(10):1981-1989. Epub 2016 Jun 29.

Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address:

Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2). We demonstrate that transforming growth factor-β signaling confers this potent HIV-1 restriction in MDLC during their differentiation and blocking of mothers against decapentaplegic homolog 2 (SMAD2) signaling in MDLC restores cells' infectivity. Interestingly, maturation of MDLC with a toll-like receptor 2 agonist or transforming growth factor-α significantly increases cells' susceptibility to HIV-1 infection, which may explain why HIV-1 acquisition is increased during coinfection with sexually transmitted infections. In conclusion, we report a SAMHD1-independent post-entry restriction in MDLC and LC isolated from epidermis, which inhibits HIV-1 replication. A better understanding of HIV-1 restriction and propagation from LC to CD4(+) T cells may help in the development of new microbicides or vaccines to curb HIV-1 infection at its earliest stages during mucosal transmission.
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http://dx.doi.org/10.1016/j.jid.2016.05.123DOI Listing
October 2016

Clinical categories of exaggerated skin reactions to mosquito bites and their pathophysiology.

J Dermatol Sci 2016 Jun 30;82(3):145-52. Epub 2016 Apr 30.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.

Mosquito bites are skin irritating reactions, which usually resolve spontaneously without intensive medical care. However, in certain situations, mosquito bites may form a more vicious reaction, sometimes accompanying fever and systemic symptoms. In such cases, the presence of rare hematological disorders, abnormalities in eosinophils and/or association with Epstein-Barr virus (EBV) may underlie. Importantly, hypersensitivity to mosquito bites (HMB), which is characterized by necrotic skin reactions to mosquito bites with various systemic symptoms, is often observed in association with EBV infection and natural killer (NK) cell lymphoproliferative disorder. Exaggerated skin reaction to mosquito bites is also seen in Wells' syndrome. While strong Th2-skewing immune dysregulation is apparent in the patients, they also show robust CD4(+) T cell proliferation in response to mosquito salivary gland extracts, indicating close association between Wells' syndrome and mosquito bites. Similar skin reaction to mosquito bites is also noticed in certain types of B cell neoplasm, although the role of B cells in this peculiar reaction to mosquito bites is yet to be elucidated. In this review, we will discuss the current knowledge of exaggerated reaction toward mosquito bites seen in conjunction with these unique hematological disorders, and examine the scientific studies and observations reported in previous literatures to organize our current understanding of the pathogenesis of this distinct disorder.
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http://dx.doi.org/10.1016/j.jdermsci.2016.04.010DOI Listing
June 2016

Human T-lymphotropic virus 1 (HTLV-1)-associated lichenoid dermatitis induced by CD8+ T cells in HTLV-1 carrier, HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T-cell leukemia/lymphoma.

J Dermatol 2015 Oct 15;42(10):967-74. Epub 2015 Jun 15.

Department of Dermatology and Wound Healing, School of Medicine, Cardiff University, Cardiff, UK.

Human T-lymphotropic virus type 1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and carrier. ATLL is a mature CD4+ CD25+ CCR4+ T-cell neoplasm, and approximately half of patients have direct skin involvement manifesting patch, plaque, tumor, multiple papules, erythroderma and purpura. However, there exist secondary eruptions without tumor cell infiltration in patients with ATLL or HAM/TSP and carriers of HTLV-1. To clarify the presence of reactive skin eruptions in HTLV-1-infected individuals, we reviewed our patients with HTLV-1-associated diseases. In 2002-2012, we saw 50 ATLL or HAM/TSP patients and HTLV-1 carriers presenting with skin lesions. We retrospectively selected cases that histologically showed lichenoid tissue reactions with predominant infiltration of CD8+ T cells, but not CD4+ tumor cells. The cases included erythroderma (HTLV-1 carrier), lichen planus (HTLV-1 carrier), alopecia areata (HAM/TSP), chronic actinic dermatitis (HTLV-1 carrier to acute ATLL conversion) and discoid lupus erythematosus (smoldering ATLL). They were graft-versus-host disease-like, major secondary lesions and seen in HTLV-1 carriers and patients with HAM/TSP and smoldering ATLL. We coin the term HTLV-1-associated lichenoid dermatitis (HALD) to encompass the conditions. HALD may occur in association with the elevated immunity toward HTLV-1-infected CD4+ T cells, thus sharing the pathogenetic role of cytotoxic T cells with HAM/TSP.
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http://dx.doi.org/10.1111/1346-8138.12980DOI Listing
October 2015

Manipulated microenvironment in human papilloma virus-infected epithelial cells: is the CD40-CD154 pathway beneficial for host or virus?

J Invest Dermatol 2014 Dec;134(12):2866-2868

Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, School of Medicine, Cardiff University and University Hospital of Wales, Cardiff, UK. Electronic address:

In this issue, Tummers et al. (2014) demonstrate that high-risk human papilloma viruses (hrHPVs) attenuate the magnitude of responses to CD40 ligation and the epithelial cells' (ECs) capacity to attract leukocytes. These results suggest that hrHPVs can escape from host immune surveillance by modulating pro-inflammatory responses in infected ECs, resulting in persistent infections and potential carcinogenesis.
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http://dx.doi.org/10.1038/jid.2014.357DOI Listing
December 2014

Epstein-Barr virus-associated T-cell lymphoproliferative disorder affecting skin and lung in an elderly patient.

J Dermatol 2014 Sep 11;41(9):837-40. Epub 2014 Aug 11.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

A 70-year-old man presented with papular skin lesions and was diagnosed with Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD). The patient showed infiltration of a large number of EBV-encoded RNA-positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV-infected γδ T cells and CD8(+) T cells in the blood and skin, as assessed by EBV-terminal repeat Southern blot, T-cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV-associated T/natural killer (NK)-LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection (CAEBV), and the latter group typically suffers from extranodal NK/T-cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients.
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http://dx.doi.org/10.1111/1346-8138.12585DOI Listing
September 2014

DC-T cell virological synapses and the skin: novel perspectives in dermatology.

Exp Dermatol 2015 Jan 11;24(1):1-4. Epub 2014 Nov 11.

Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, School of Medicine, Cardiff University and University Hospital of Wales, Cardiff, UK.

Virological synapses (VS) increase cell-to-cell viral transmission and facilitate propagation of human immunodeficiency virus type 1 (HIV-1) and human T-cell leukaemia virus type 1 (HTLV-1). VS formation also plays a more general role in viral replication and dissemination. VS have been observed in vitro and ex vivo between uninfected T cells and T cells infected with HIV-1 or HTLV-1. In addition, dendritic cells (DC) infected with HIV-1 also play an important role in viral transmission to uninfected CD4+ T cells via VS formation. Recent studies revealed that several DC subsets are also infected with HTLV-1. These findings may help explain the rapid dissemination of both viruses within secondary lymphoid tissues in vivo. VS also explain, at least in part, why HIV-1 can propagate in the mucosal sites during sexual transmission. Furthermore, in the case of HTLV-1, VS can potentially explain some of the features of HTLV-1-associated dermatitis as infected T cells in the skin contribute to the pathogenesis of this condition.
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http://dx.doi.org/10.1111/exd.12511DOI Listing
January 2015

VEGF-A promotes IL-17A-producing γδ T cell accumulation in mouse skin and serves as a chemotactic factor for plasmacytoid dendritic cells.

J Dermatol Sci 2014 May 13;74(2):116-24. Epub 2014 Jan 13.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: IL-17-producing CD4(+) T (Th17) cells and their cytokines, IL-17A and IL-22, are deeply involved in the pathogenesis of psoriasis by stimulating epidermal keratinocytes to proliferate and to produce cytokines/chemokines and vascular endothelial growth factor (VEGF)-A. Plasmacytoid dendritic cells (pDCs), infiltrating in psoriatic lesions, are known to exacerbate the Th17-mediated pathogenesis of psoriasis.

Objective: To address the initiative role of VEGF-A in the development of psoriasis and the pDC accumulation.

Methods: Numerical changes and VEGF receptor 1 (VEGFR1) and VEGFR2 expressions were investigated in skin-infiltrating T cells and pDCs of K14-VEGF-A transgenic (Tg) and wild type (WT) mice. The chemotactic properties of VEGF-A for purified splenic pDCs were also evaluated by real-time chemotaxis assay.

Results: By flow cytometry and immunohistochemistry, we observed that the number of dermal IL-17A(+) γδ T cells, but not CD4(+) T cells, was increased in VEGF-A Tg mice, suggesting that the main source of IL-17A was γδ T cells. Moreover, we identified pDCs as 440c(+) cells by immunohistochemistry and as PDCA-1(+)B220(+) cells by flow cytometry, and found that pDCs infiltrated at a higher frequency in VEGF-A Tg than WT mice. pDCs, but not γδ T cells, isolated from the skin expressed VEGFR1 and VEGFR2. Freshly isolated splenic pDCs expressed both receptors after 48-h cultivation. pDCs did not produce cytokines in response to VEGF-A, however, they had a strong velocity of chemotaxis toward VEGF-A at a comparable level to chemerin.

Conclusions: These findings suggest that VEGF-A functions as not only a downstream enhancer but also an upstream initiator by chemoattracting pDCs in psoriatic lesions.
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http://dx.doi.org/10.1016/j.jdermsci.2013.12.013DOI Listing
May 2014