Efficacy of oral cholecalciferol on rhododendrol-induced vitiligo: A blinded randomized clinical trial.

Rhododendrol (RD), 4-(4-hydroxyphenyl)-2-butanol, inhibits melanin synthesis and has been used for skin-whitening cosmetic products. RD has been very effective in lightening skin pigmentation, but some persons have developed so-called RD vitiligo, in which vitiligo starts on the face, neck and hands where topical RD has been applied and even extended over skin areas where RD has not been applied. RD vitiligo lesions in some patients have lasted for years and have been resistant to conventional vitiligo treatments.

The Expression of Matrix Metalloproteinases in Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-expressing Cancer of Apocrine Origin.

Unlabelled: Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive tumor entity. Since there is no conventional therapy for advanced PCAC, exploratory treatments are sometimes used. As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD).

Increased serum production of soluble CD163 and CXCL5 in patients with moyamoya disease: Involvement of intrinsic immune reaction in its pathogenesis.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is still unknown, intrinsic immune reactions such as autoimmune response has been implicated in the pathogenesis of MMD. Recently, the RING finger protein 213 (RNF213) was found to be an important risk gene for MMD, and is predominantly expressed in blood cells and the spleen.

Phase I study of nivolumab combined with IFN-β for patients with advanced melanoma.

The efficacy of nivolumab is greater than that of other anti-melanoma drugs, so nivolumab-based combined therapies that enhance anti-tumor immune responses in patients with metastatic melanoma are of great interest to dermato-oncologists. As we have previously reported, IFN-β enhances the anti-tumor immune response of anti-PD-1 antibodies against B16F10 melanoma . To explore the potential of this property of IFN-β as part of a combination therapy for the treatment of metastatic melanoma patients, we performed a phase 1 trial, using a traditional rule-based 3 + 3 design, on patients with advanced melanoma.

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages.

Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte-derived M2 macrophages.

Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas.

Background/aim: Tumor-associated macrophages (TAMs), together with splenic CD11b cells, help maintain the tumor microenvironment. The immunomodulatory compound imiquimod (IQM) stimulates innate immune cells, including macrophages, to induce antitumor effects. In order to elucidate the effects of IQM on the tumor microenvironment, we investigated the immunomodulatory effect of IQM during melanoma growth by using the B16F10 melanoma model.

The Immunological Roles of Periostin/Tumor-Associated Macrophage Axis in Development of Dermatofibrosarcoma Protuberans.

Background/aim: Dermatofibrosarcoma protuberance (DFSP) is a fibrohistiocytic tumor of intermediate malignancy characterized by slow infiltrative growth and a high tendency to recur locally. Periostin is involved in modulating cell function and inducing the production of proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) from tumor-associated macrophages (TAMs) to promote fibrosis and tumor growth. This study aimed to examine the cancer stroma of DFSP, focusing on TAMs-related proteins and MMPs.

Phospho-STAT5B Expression Is a Prognostic Marker for Merkel Cell Carcinoma.

Background/aim: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Although recent reports suggest that tumor-infiltrating leukocytes (TILs), especially CD8 T-cells, contribute to the pathogenesis of MCC, it is difficult for a single Institute with a small number of patients with MCC to determine the threshold number of CD8 cells. Therefore, clearer and easier methods of evaluating prognostic factors of MCC are needed.

Retrospective Investigation of Cutaneous Squamous Cell Carcinoma on the Lip Treated with Peplomycin Administered Through a Superficial Temporal Artery.

Background: Continuous intra-arterial (IA) administration of peplomycin (PEP) through a tumor-feeding artery is one of the most effective treatments for cutaneous squamous cell carcinoma (cSCC) in cosmetic areas.

Patients And Methods: In order to determine the effective and safe dose of PEP and the curative rate of IA-PEP, we retrospectively investigated a case series of 24 patients with cSCC on the lips who were treated with IA-PEP.

Results: IA-PEP reduced the tumor mass in all 24 cases (100%).

M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site.

Since bacillus Calmette-Guérin (BCG) is an attenuated strain of , lupus vulgaris (LV) is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages.

A possible interaction between periostin and CD163 skin-resident macrophages in pemphigus vulgaris and bullous pemphigoid.

Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are autoimmune blistering diseases, and substantial numbers of CD163 tissue-associated macrophages (TAMs) are detected in both diseases. PV and BP possess different subsets of helper T cells, suggesting that the cytokine profiles of PV and BP might be different. The purpose of this study was to investigate the microenvironment of lesional skin and serum of PV and BP patients, focusing on the immunomodulatory factors related to TAMs, such as periostin (POSTN), chemokines, cytokines and matrix metalloproteinases (MMPs).

RANKL-Expressing Ectopic Extramammary Paget's Disease on the Lower Abdomen.

Ectopic extramammary Paget's disease (EMPD) is a rare variant of EMPD that develops in nonapocrine regions. Since reports about ectopic EMPD are limited, little is known about the biological and immunological background of ectopic EMPD. In this report, we present a case of ectopic EMPD on the lower abdomen that expressed RANKL but lacked the expression of MMP7.

Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma.

Background: Tumor-associated M2 macrophages (TAMs) produce chemokines that affect the formation of cutaneous T-cell lymphoma (CTCL) by stromal factors. Since IFNs are an effective treatment for advanced-stage mycosis fungoides (MF), we hypothesized that IFNs might modulate M2 macrophages.

Objective: To prove our hypothesis, we stimulated monocyte-derived M2 macrophages with IFN-α2a or IFN-γ and examined the mRNA expression of chemokines.

Merkel Cell Carcinoma with Spontaneous Regression: A Case Report and Immunohistochemical Study.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma that only rarely regresses spontaneously. Since little is known about the immunological mechanisms involved in the spontaneous regression of MCC, we describe a case of MCC with spontaneous regression and employed immunohistochemical staining for cytotoxic and immunosuppressive molecules to investigate possible mechanisms involved in the spontaneous regression of MCC. Interestingly, compared to conventional MCC, tumor-infiltrating lymphocytes in MCC with spontaneous regression contained higher numbers of CD8(+) cells and granulysin-bearing cells and lower numbers of CD206(+) cells.

Periostin in the Cancer Stroma of Mycosis Fungoides Palmaris et Plantaris: A Case Report and Immunohistochemical Study.

Mycosis fungoides palmaris et plantaris (MFPP) is a rare variant of mycosis fungoides limited to the palms and soles. Although little is known about the pathogenesis of MFPP, this variant of mycosis fungoides presents a relatively good prognosis. In this report, we describe an 85-year-old Japanese man with MFPP.

Plexiform Fibrohistiocytic Tumor on the Ear: Case Report and Immunohistochemical Investigation of Stromal Factor.

Plexiform fibrohistiocytic tumor (PFT) is a rare mesenchymal neoplasm of intermediate malignant potential with a high local recurrence rate. In this report, we describe a case of PFT on the ear, which showed a dense deposition of periostin (POSTN) in the stromal areas of the tumor. In addition, dense infiltration of CD163+CD206- tumor-associated macrophages (TAMs) was detected in the same areas as POSTN.

Tumor-associated macrophages in skin: How to treat their heterogeneity and plasticity.

Immunosuppressive tumor-associated macrophages (TAMs) promote an immunosuppressive environment in the tumor-bearing host, together with regulatory T cells (Tregs). TAMs compose cancer stroma in skin cancers including melanomas and non-melanomas. The majority of tumor-associated macrophages (TAMs) are alternatively activated M2 macrophages that favor tumor development, and they comprise one of the main populations of inflammatory cells in skin cancers.

RANKL expression is a useful marker for differentiation of pagetoid squamous cell carcinoma in situ from extramammary Paget disease.

Background: Pagetoid squamous cell carcinoma in situ (SCCIS) is a histopathologic variant of SCCIS composed of cells that display an abundant, pale-staining cytoplasm in a pagetoid distribution within the epidermis. As pagetoid SCCIS is sometimes difficult to differentiate from extramammary Paget disease (EMPD) histopathologically, specific markers for pagetoid SCCIS or EMPD are needed by dermatopathologists.

Methods: In this report, we employed immunohistochemical staining for receptor of activated nuclear factor kappa ligand (RANKL) and programmed death-ligand 1 (PD-L1) in six cases each of pagetoid SCCIS and EMPD.

Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease.

Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease with an unknown etiology and is characterized by an abnormal vascular network at the base of the brain. Recent studies identified the RNF213 gene (RNF213) as an important susceptibility gene for MMD; however, the mechanisms underlying the RNF213 abnormality related to MMD have not yet been elucidated. We previously reported that Rnf213-deficient mice and Rnf213 p.

Contact immunotherapy enhances the therapeutic effects of nivolumab in treating in-transit melanoma: Two cases reports.

Because nivolumab significantly prolongs survival in patients with metastatic melanoma, enhancing its antitumor immune response is of great interest to dermato-oncologists. In this report, we describe two cases of metastatic melanoma successfully treated with nivolumab in combination with contact immunotherapy, using contact sensitizing agents, such as squaric acid dibutylester and diphencyprone. In addition, immunohistochemical staining supported one of the possible mechanisms of this combination therapy.

Adult Onset of BRAF(V600E)-Mutated Langerhans Cell Histiocytosis with Cutaneous Involvement Successfully Diagnosed by Immunohistochemical Staining.

Langerhans cell histiocytosis (LCH) is characterized by the clonal proliferation of Langerhans cells; it is categorized as a single-system disease with single or multifocal lesions, and as a multi-system disease with or without the risk of organ involvement. Although the skin is not categorized as a risk organ, the precise diagnosis of skin lesions is necessary to determine the protocol for the treatment of LCH. In this report, we describe a 28-year-old Japanese man with adult onset of BRAF(V600E)-mutated LCH with cutaneous involvement successfully diagnosed by immunohistochemical staining.

Immunomodulatory effect of peritumorally administered interferon-beta on melanoma through tumor-associated macrophages.

An imbalance of immunosuppressive cells and cytotoxic cells plays an important role in the tumor-bearing host. Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Since interferon beta (IFN-β) has been clinically used for the treatment of malignant melanoma, we investigated the immunomodulatory effect of IFN-β during melanoma growth to elucidate the effects of IFN-β on the tumor microenvironment by using the B16F10 melanoma model.

The possible interaction between periostin expressed by cancer stroma and tumor-associated macrophages in developing mycosis fungoides.

Mycosis fungoides (MF) starts as an indolent disease, progresses from a patch stage to confluent plaques and ultimately develops skin tumors. Tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment in MF. The purpose of this study was to elucidate the involvement of TAMs in the lesional skin of different stages of MF.