Background Extramammary Paget’s disease (EMPD) is a rare skin cancer whose etiology and pathogenesis remain unclear. Because of limited treatment options, patients with advanced stages have a poor prognosis; therefore, identifying novel biomarkers for early detection and evaluation of therapeutic efficacy is necessary. Objective To investigate the association between anterior gradient 2 (AGR2) expression and clinical features in patients with EMPD and the potential involvement of AGR2 in the pathogenesis of EMPD. Methods Sixty-two tissue samples and 60 serum samples were evaluated using immunohistochemistry and enzyme-linked immunosorbent assay. In vitro experiments were performed using the EMPD cell line, KS-EMPD-1, to assess the effects of silencing AGR2 on cell growth, invasion, and migration. Results Patients with AGR2 overexpression in tumor tissues tended to have a poor prognosis; however, the difference was not statistically significant. Serum AGR2 concentrations were significantly higher in patients with EMPD with or without metastasis than in healthy controls and decreased after treatment. AGR2 knockdown decreased cell number and induced apoptosis in EMPD cells, suggesting that AGR2 may influence the viability of EMPD cells via apoptosis. Conclusion AGR2 is overexpressed in patients with EMPD and plays an important role in the pathogenesis of EMPD.

Overexpression of brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) has been reported in estrogen receptor α-positive breast cancer (BC) tissues, with high BIG3 expression strongly associated with poor prognosis in patients with BC. This study investigated the expression pattern of BIG3 in patients with extramammary Paget's disease (EMPD) and evaluated its clinical significance. Sixty-one tissue and 30 serum samples were collected from patients with EMPD. Immunohistochemistry showed that most EMPD tissues were positive for BIG3 (57/61, 93.4%), and strong BIG3 intensity correlated with the degree of invasiveness, lymph node/distant metastasis, and overall survival. Serum BIG3 levels in EMPD patients with invasive lesions were significantly higher than those in patients with in situ lesions and correlated with the serum concentration of cytokeratin 19 fragment. Therefore, BIG3 expression may serve as a prognostic marker in patients with EMPD.

Extramammary Paget disease (EMPD) is a rare malignancy that primarily arises in apocrine gland-bearing areas such as the genital, perianal, and axillary regions. The clinical and biological heterogeneity of EMPD, together with a lack of evidence from large-scale studies, has made it difficult to establish standardized approaches to diagnosis and treatment. To address these issues, the 2025 Japanese Guidelines for the Management of EMPD were developed, providing evidence-based recommendations tailored to the healthcare context in Japan. These guidelines were constructed using the Minds Guideline Development Manual 2020 (ver. 3.0), adhering to systematic review principles and incorporating both Japan and international research findings. A multidisciplinary panel of dermatologists, oncologists, surgeons, and other specialists developed the guidelines through a consensus-based process, which included structured discussions and grading of evidence. The primary focus of this condensed version is on six critical clinical questions, which address key aspects of EMPD management, including the role of mapping biopsy in diagnosis, the use of sentinel lymph node biopsy in cases of suspected dermal invasion, the efficacy of nonsurgical therapies when surgery is not an option, the efficacy of lymph node dissection for multiple regional lymph node metastases, the efficacy of radiation therapy after regional lymph node dissection, and systemic treatment options for advanced disease. The recommendations aim to improve diagnostic accuracy, optimize therapeutic approaches, and support clinical decision-making by providing a clear framework for the management of EMPD. By focusing on these critical areas, the guidelines strive to enhance patient outcomes and contribute to the advancement of evidence-based care for this rare and challenging malignancy.

A deficiency in DNA mismatch repair (MMR) leads to microsatellite instability (MSI), which is associated with a favorable response to immune checkpoint inhibitors (ICIs), and the Promega MSI Analysis System is approved as a companion diagnostic tool for it. In this study, we investigated the MMR status in patients with primary cutaneous lymphoma (PCL) diagnosed at our hospital. MSI was found in 1 of the 29 patients (3.4%), an 87-year-old man diagnosed with subcutaneous panniculitis-like T-cell lymphoma. Only the NR-21 marker was present in both tumor and normal tissue, indicating that the MMR status was MSI-low, and he had a germline mutation of SLC7A8. Our study showed that most PCLs are microsatellite stable tumors. This study is a single-center small-sample investigation and requires validation in larger cohorts.

Recently, cell-free DNA (cfDNA) has gained attention as a diagnostic and prognostic biomarker for various conditions, including autoimmune and inflammatory skin diseases. However, reports of cfDNA use in patients with systemic sclerosis (SSc) are limited. The purpose of this study was to investigate the clinical significance of cfDNA in patients with SSc and assess the circulating DNA levels of key cytokines associated with SSc fibrosis. Serum samples were obtained from 64 patients with SSc, 9 with very early SSc, and 20 healthy controls (HC). Circulating DNA copies were quantified using droplet digital polymerase chain reaction analysis. The DNA copies of interleukin (IL)-6, IL-8, Janus kinase 2 (JAK2), and connective tissue growth factor were significantly higher in patients with SSc than in the HCs. Although not statistically significant, circulating IL-6 DNA copies were higher in patients with SSc than in patients with very early SSc. Receiver operating characteristic analysis indicated that IL-6 DNA copies could distinguish patients with SSc from both the HCs and patients with very early SSc (area under the curve > 0.7 in both cases). Disease type dcSSc and reduced %FVC were significant independent predictors of higher circulating IL-6 and JAK2 DNA copies in multivariate logistic regression analysis. cfDNA, including circulating IL-6 and JAK2 DNA in sera, may serve as valuable indicators for diagnosis and fibrosis progression in patients with SSc.

In this study, we investigated whether circulating S100A7 and S100A15 DNA copies in cell-free DNA (cfDNA) are elevated in patients with psoriasis and atopic dermatitis (AD) and their levels are correlated with clinical findings. Serum cfDNA was obtained from 124 psoriasis patients and 45 AD patients. Circulating S100A7 and S100A15 DNA copies in psoriasis and AD patients were significantly higher than in healthy controls. Although circulating S100A7 and S100A15 DNA copies showed a significant positive correlation with the Psoriasis Severity and Area Index (PASI) scores in patients with severe psoriasis (PASI ≥ 10), in AD patients there was no significant correlation between their levels and disease severity. Furthermore, in psoriasis patients, circulating S100A15 DNA copies were significantly decreased in patients after treatment compared with patients before treatment.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

Psoriasis vulgaris (PsV) is an immune-mediated inflammatory skin disorder with complex genetic architecture. Most genome-wide association studies (GWASs) of PsV have been limited to analyzing common single-nucleotide variants in Europeans, lacking diversity in the variant spectrum and ancestral background. To investigate the contribution of rare variants (RVs) and structural variants (SVs), we perform a whole-genome sequencing study involving 1,415 PsV cases and 3,968 controls in Japanese. A GWAS signal at IFNLR1 is fine-mapped to a 3.3-kb deletion SV disrupting an epithelium-specific putative enhancer, which is validated by PacBio long-read sequencing. Gene-based RV analyses identify two susceptibility genes: IFIH1 (p = 9.8 × 10-6) and CERCAM (p = 4.1 × 10-7). Notably, IL36RN, a causative gene for generalized pustular psoriasis, a rare and lethal multi-systemic inflammatory disorder, is associated with common PsV (p = 1.2 × 10-4). Finally, Cercam knockout (Cercam-/-) in an imiquimod-induced psoriasis mouse model aggravates dermatitis with elevated T cell retention in the subepidermis. Our study elucidates the overlooked genetic basis of PsV.

Extramammary Paget disease (EMPD) is a rare skin cancer with an estimated incidence rate of 0.13 per 100 000 population/year in Caucasians and 0.28 in Asians. Although distant metastases have been reported in 10%-20% of EMPD cases, standardized systemic chemotherapy has not been established. Prospective clinical trials are essential to establish standard treatments for advanced EMPD. Therefore, this retrospective study examined a substantial number of patients with EMPD to assess the efficacy of systemic chemotherapy. This study included 164 patients with advanced EMPD who underwent treatment at 16 Japanese institutions. Treatment efficacy was evaluated in a cohort of 138 patients, after excluding 26 patients without lesions outside the radical irradiation field from the 164 patients. The efficacy of each treatment was evaluated by determining the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using Kaplan-Meier analysis. Multivariate analysis was performed to account for potential confounding factors, such as age, sex, and performance status. The patients received the following treatments: docetaxel hydrate (DOC) (65.9%); tegafur/gimeracil/oteracil potassium, DOC (S-1/DOC) (9.8%); fluorouracil and cisplatin (FP) (15.9%); and other drugs (8.5%). DOC is the most commonly used in Japan. The ORRs in the DOC, S-1/DOC, and FP groups were 51.6%, 78.6%, and 27.8%, respectively. Logistic regression analysis revealed that, compared with the DOC group, the odds ratio for the ORR of the S-1/DOC group was 3.29 (95% CI: 1.49-7.25, p = 0.003). However, no significant differences in OS or PFS were observed between the treatment groups (p = 0.122 and p = 0.422, respectively). This study provides valuable information on EMPD and may serve as a useful historical control for the future evaluation of new treatments for EMPD.

Systemic sclerosis (SSc) is a multisystem connective tissue disease. Skin fibrosis, the hallmark of this disease, is defined as the excess deposition and accumulation of extracellular matrix, mainly type 1 collagen, in the dermis. SLC39A7 is an intracellular zinc transporter that plays a unique role in connective tissue formation. Therefore, we investigated the expression and role of SLC39A7 in SSc. Using immunohistochemical staining we demonstrated the overexpression of SLC39A7 in the skin of SSc patients. Quantitative real-time PCR and western blot data analysis showed that both SLC39A7 mRNA and protein levels were significantly upregulated in dermal fibroblasts from SSc patients compared to healthy controls. We used the shRNA lentiviral particle transduction system to stably knockdown the expression of SLC39A7 in SSc fibroblasts. The results showed that knockdown of SLC39A7 suppressed the production of type 1 collagen. These findings provide evidence that SLC39A7 is involved in the pathogenesis of SSc and that SLC39A7 plays a positive role in its progression.

The Journal of DermatologyEarly View LETTER TO THE EDITOR Effectiveness of trabectedin for radiation-induced angiosarcoma of the breast refractory to several anticancer drugs Erina Matsuzaki, Erina Matsuzaki Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorIkko Kajihara, Corresponding Author Ikko Kajihara [email protected] orcid.org/0000-0002-3080-1621 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Correspondence Ikko Kajihara, Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan. Email: [email protected]Search for more papers by this authorMai Tomiguchi, Mai Tomiguchi Department of Breast and Endocrine Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorToshihiro Kimura, Toshihiro Kimura Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSeina Araki, Seina Araki Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSoichiro Sawamura, Soichiro Sawamura orcid.org/0000-0003-1697-9316 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorKatsunari Makino, Katsunari Makino Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorJun Aoi, Jun Aoi orcid.org/0000-0002-0988-2471 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorShinichi Masuguchi, Shinichi Masuguchi Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSatoshi Fukushima, Satoshi Fukushima Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this author Erina Matsuzaki, Erina Matsuzaki Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorIkko Kajihara, Corresponding Author Ikko Kajihara [email protected] orcid.org/0000-0002-3080-1621 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Correspondence Ikko Kajihara, Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan. Email: [email protected]Search for more papers by this authorMai Tomiguchi, Mai Tomiguchi Department of Breast and Endocrine Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorToshihiro Kimura, Toshihiro Kimura Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSeina Araki, Seina Araki Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSoichiro Sawamura, Soichiro Sawamura orcid.org/0000-0003-1697-9316 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorKatsunari Makino, Katsunari Makino Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorJun Aoi, Jun Aoi orcid.org/0000-0002-0988-2471 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorShinichi Masuguchi, Shinichi Masuguchi Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSatoshi Fukushima, Satoshi Fukushima Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this author First published: 17 February 2024 https://doi.org/10.1111/1346-8138.17159Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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