Language：English   Publishing type：Research paper (scientific journal)  

Extramammary Paget's disease (EMPD) is a rare skin cancer with no standard treatment for advanced-stage disease. Although docetaxel-based chemotherapy is common, no standard treatment exists. Pembrolizumab is approved for solid tumors with a high tumor mutation burden (TMB) and/or high microsatellite instability, and nivolumab was approved in Japan in February 2024 for unresectable advanced or recurrent epithelial skin malignancies. However, there is a lack of real-world data regarding the efficacy of anti-programmed cell death protein 1 (PD-1) therapy for EMPD. We present the case details of three EMPD patients treated with anti-PD-1 therapy after docetaxel treatment, with TMB values of 17.8, 14.3, and 5.0 mut/Mb, respectively, and we review similar reported cases. Even in the cases with a high TMB, the response to anti-PD-1 therapy was not sufficient. Most cases involve second-line or later treatments, so further research is needed to determine the precise effectiveness of anti-PD-1 therapy as a first-line treatment.

DOI： 10.1111/1346-8138.17500

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Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases.

DOI： 10.3390/cells13181549

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Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is an autosomal dominant disorder characterized by widespread skin hyperpigmentation, café-au-lait spots, and hypopigmented circular macules, resulting from KITLG variants. KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear. This report presents a unique FPHH case in a patient with a novel KITLG mutation (Ser78Leu). Notably, the patient showed multiple hypopigmented macules and striae along the lines of Blaschko. Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism. Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis. This case contributes to the understanding of the genetic mechanisms in FPHH.

DOI： 10.1111/1346-8138.17459

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BACKGROUND: Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan. METHODS: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed. RESULTS: A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1. CONCLUSION: The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.

DOI： 10.1007/s10147-024-02615-y

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Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants.

DOI： 10.1111/1346-8138.17434

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DOI： 10.1111/1346-8138.17401

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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DOI： 10.1111/1346-8138.17043

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Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma.

DOI： 10.1111/1346-8138.17002

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Epidermal keratinocytes, forming the outermost layer of the human body, serve as a crucial barrier against diverse external stressors such as ultraviolet radiation. Proper keratinocyte differentiation and effective responses to external stimuli are pivotal for maintaining barrier integrity. Heat is one such stimulus that triggers the synthesis of heat shock proteins (HSPs) when cells are exposed to temperatures above 42 °C. Additionally, activation of the transient receptor potential cation channel subfamily V member 1 (TRPV1) occurs at 42 °C. Here, we explore the interplay between TRPV1 signaling and HSP induction in human keratinocytes. Both heat and capsaicin, a TRPV1 agonist, induce expression of HSP27, HSP70, and HSP90 in keratinocytes. Interestingly, pharmacological inhibition of TRPV1 attenuates heat-induced HSP27 expression, but not that of HSP70 or HSP90. Furthermore, both heat and capsaicin stimulation result in distinct phosphorylation patterns of heat shock factor 1 (HSF1), with phosphorylation at serine 326 being a common feature. Notably, genetic manipulation to mimic dephosphorylation of HSF1 at serine 326 reduces HSP27 levels. Additionally, ΔNp63, a key regulator of epidermal differentiation, negatively modulates HSP27 expression independently of HSF1 phosphorylation status. While heat stimulation has no effect on ΔNp63 expression, capsaicin reduces its levels. The precise role of TRPV1 signaling in keratinocytes warrants further investigation for a comprehensive understanding of its impact on barrier function.

DOI： 10.1016/j.bbrc.2024.149817

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DOI： 10.1111/1346-8138.17149

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Language：Japanese   Publisher：(株)協和企画  

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DOI： 10.1111/1346-8138.17070

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/1346-8138.16977

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Ipilimumab plus nivolumab therapy is approved for patients with unresectable advanced esophageal squamous cell carcinoma (ESCC). Although a combination of immune checkpoint inhibitors (ICIs), compared to conventional chemotherapy, can improve overall survival in patients with advanced ESCC, this increases the incidence of immune-related adverse events (irAEs). Here, we describe an ESCC case that developed pemphigus vulgaris (PV), an extremely rare cutaneous irAE, during ipilimumab plus nivolumab treatment. The patient achieved a partial response to treatment. The PV was successfully managed after the cessation of ipilimumab and the use of a topical steroid. We should thus re-treat ESCC with nivolumab monotherapy. In the era of ICIs as standard cancer therapeutics, diagnostic criteria for blistering diseases need to be established to properly manage patients with cutaneous irAEs.

DOI： 10.3389/fimmu.2023.1259071

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The efficacy of combination therapy with an immune checkpoint inhibitor (ICI) and cytotoxic chemotherapeutic agents has been investigated in cancer, including melanoma. Before ICIs were introduced, dacarbazine or temozolomide (TMZ) were used to treat melanoma. Several studies using glioma or colorectal cancer cells showed that TMZ can increase the tumor mutation burden (TMB) and induce mismatch repair (MMR) deficiency associated with microsatellite instability (MSI). These could increase immunoreactivity to an ICI, but this has not been evaluated in melanoma cells. We investigated the effects of TMZ on MSI status and TMB in melanoma cells. To evaluate the TMB, we performed whole-exome sequencing using genomic DNA from the human melanoma cell lines Mel18, A375, WM266-4, G361, and TXM18 before and after TMZ treatment. Polymerase chain reaction amplification of five mononucleotide repeat markers, BAT25, BAT26, NR21, NR24, and MONO27, was performed, and we analyzed changes in the MSI status. In all cell lines, the TMB was increased after TMZ treatment (the change amount of TMB with ≤ 5% variant allele frequency [VAF] was 18.0-38.3 mutations per megabase) even in the condition without obvious cytological damage. MSI after TMZ treatment was not observed in any cells. TMZ increased TMB but did not change MSI status in melanoma cells.

DOI： 10.1111/1346-8138.16925

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Language：Japanese   Publisher：(株)協和企画  

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DOI： 10.1111/ijd.16771

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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DOI： 10.1111/1346-8138.16817

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Language：Japanese   Publisher：日本臨床皮膚科医会  

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BACKGROUND: Efficacy of anti-PD-1 antibody monotherapy (PD1) or anti-PD-1 plus anti-CTLA-4 combination therapy (PD1 +CTLA4) for melanoma is affected by its clinical subtype. The amount of tumor mutation burden (TMB) caused by cumulative sun damage (CSD) is occasionally used to explain this; however, their relationship in Japanese nonacral cutaneous melanoma (NACM) is still unclear. OBJECTIVE: To analyze the ICI efficacy and its relationship with CSD of the primary lesion in Japanese patients with NACM. METHODS: Japanese patients with advanced BRAF wild-type NACM who received first-line ICIs were recruited. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), and the degree of solar elastosis (SE) were evaluated. RESULTS: A total of 146 patients (PD1 group 113 and PD1 +CTLA4 group 33) were included. No significant differences in ORR were observed between the PD1 and PD1 +CTLA4 groups (35 % vs. 36 %; P = 0.67) or PFS and OS (median PFS 6.1 months vs. 8.5 months; P = 0.46, median OS 28.1 months vs. not reached; P = 0.59). Multivariate survival analysis revealed that PD1 +CTLA4 did not prolong the PFS and OS. The SE score had no effect on either PFS or OS. CONCLUSIONS: ICI efficacy was not as high as those reported in Western countries, and PD1 +CTLA4 did not present better clinical efficacy compared to PD1. Indicators of CSD did not serve as a predictor for clinical advantage. These findings may partially support the theory that ICI efficacy is affected by CSD; however, other unrecognized factors may also exist.

DOI： 10.1016/j.jdermsci.2023.03.008

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To study the molecular mechanisms responsible for inducing the spatial proliferation of malignant melanomas (MM), three-dimension (3D) spheroids were produced from several MM cell lines including SK-mel-24, MM418, A375, WM266-4, and SM2-1, and their 3D architectures and cellular metabolisms were evaluated by phase-contrast microscopy and Seahorse bio-analyzer, respectively. Several transformed horizontal configurations were observed within most of these 3D spheroids, and the degree of their deformity was increased in the order: WM266-4, SM2-1, A375, MM418, and SK-mel-24. An increased maximal respiration and a decreased glycolytic capacity were observed within the lesser deformed two MM cell lines, WM266-4 and SM2-1, as compared with the most deformed ones. Among these MM cell lines, two distinct cell lines, WM266-4 and SK-mel-24, whose 3D appearances were the closest and farthest, respectively, from being horizontally circular-shaped, were subjected to RNA sequence analyses. Bioinformatic analyses of the differentially expressed genes (DEGs) identified KRAS and SOX2 as potential master regulatory genes for inducing these diverse 3D configurations between WM266-4 and SK-mel-24. The knockdown of both factors altered the morphological and functional characteristics of the SK-mel-24 cells, and in fact, their horizontal deformity was significantly reduced. A qPCR analysis indicated that the levels of several oncogenic signaling related factors, including KRAS and SOX2, PCG1α, extracellular matrixes (ECMs), and ZO1 had fluctuated among the five MM cell lines. In addition, and quite interestingly, the dabrafenib and trametinib resistant A375 (A375DT) cells formed globe shaped 3D spheroids and showed different profiles in cellular metabolism while the mRNA expression of these molecules that were tested as above were different compared with A375 cells. These current findings suggest that 3D spheroid configuration has the potential for serving as an indicator of the pathophysiological activities associated with MM.

DOI： 10.3390/cells12050759

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DOI： 10.1093/bjd/ljac009

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It remains debatable whether melanoma with a clinical history of early childhood onset truly arises from a nevus. To clarify the clinical and genetic characteristics of melanoma detected at birth or several years afterwards, 249 melanoma cases seen at Shinshu University Hospital between 2006 and 2015 were retrospectively analyzed. Ten (4.0%) cases (median age 39.5 years, range 19-70 years; male/female 2/8; lesion site, 6 extremities, 2 trunk, 1 head, 1 face; cumulative sun damage [CSD] skin, 9 low-CSD, 1 high-CSD; detection at birth 3) had recorded early childhood onset. Median Breslow's tumor thickness in those cases was 6.0 mm (range: 0.4-17.5 mm). The frequency of lesions detected at <20 years of age was significantly higher for low-CSD melanoma (17.5%) than for high-CSD (3.3%) and acral (0.8%) melanoma. Although melanoma with a history of early childhood onset is rare, the characteristics of such cases should be established since most have progressed to an advanced stage at the initial visit.

DOI： 10.1111/1346-8138.16545

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Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14CRE/ERTIl9raΔ/Δ mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14CRE/ERTIl9raΔ/Δ mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14WTIl9rafl/fl mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14CRE/ERTIl9raΔ/Δ epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.

DOI： 10.1016/j.jid.2022.06.021

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DOI： 10.1111/ajd.13902

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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DOI： 10.5826/dpc.1203a123

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A major advance in drug discovery and targeted therapy directed at cancer cells may be achieved by the exploitation and immunomodulation of their unique biological properties. This review summarizes our efforts to develop novel chemo-thermo-immunotherapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, the utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) expression upon heat generation in MNP by exposure to an alternating magnetic field (AMF). This comprehensive review covers experimental in vivo and in vitro mouse melanoma models and preliminary clinical trials with a limited number of advanced melanoma patients. We also discuss the future directions of CTI therapy.

DOI： 10.3390/ijms23126457

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BACKGROUND: The immunohistochemical evaluation of programmed death ligand 1 (PD-L1) is important for selecting treatments. Several antibodies are available for such evaluations, but data regarding the differences in the antibodies' positivity are limited in melanoma, particularly the acral and mucosal types. We investigated the differences in melanoma tissues' PD-L1 expression among the commonly used PD-L1 antibodies and then evaluated the relationship between PD-L1+ tumor cells and tumor-infiltrating lymphocytes (TILs). PATIENTS AND METHODS: We examined 56 primary lesions and 8 metastatic lymph node samples from 56 Japanese patients with melanoma (28 acral melanoma, 8 mucosal melanoma, 18 cutaneous melanoma, 2 unknown). Immunohistochemical staining was performed using three primary antibodies against PD-L1 (E1L3N, SP142, and 28-8). PD-L1-positive staining in tumor cells was defined as ≥ 1% expression. RESULTS: The positive rates were 25.0% for 28-8, 34.0% for E1L3N, and 34.0% for SP142 in 64 samples. The positive rates of acral melanoma were 10.7% for 28-8, 21.4% for E1L3N, and 21.4% for SP142. The positive rate of mucosal melanoma for which all three antibodies reacted was 12.5%. The positive rates of cutaneous melanoma were 55.6% for 28-8, 66.7% for E1L3N, and 66.7% for SP142. Significant relationships were observed among the PD-L1+ tumor cells, CD4+ TILs, and CD8+ TILs (p < 0.001). CONCLUSION: The staining results by E1L3N, SP142, and 28-8 antibodies were within the allowable range, although the positive rates by E1L3N and P142 were slightly higher than that of 28-8. CD4+ TILs and CD8+ TILs were quantitatively correlated with PD-L1-positive tumor cells.

DOI： 10.1007/s10147-022-02189-7

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Other Link： https://link.springer.com/article/10.1007/s10147-022-02189-7/fulltext.html

DOI： 10.1007/s10147-022-02189-7

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DOI： 10.1111/1346-8138.16380

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DOI： 10.1111/bjd.21276

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1346-8138.16331

DOI： 10.1111/1346-8138.16331

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DOI： 10.1111/cod.14001

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DOI： 10.1111/1346-8138.16180

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DOI： 10.1111/ajd.13607

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A sebaceous nevus is a congenital skin hamartoma caused by postzygotic HRAS or KRAS mosaic mutations. With age, affected individuals may develop secondary tumors within a sebaceous nevus. RAS mutations are harbored from the onset of sebaceous nevus, and further mutations can be expected to be required in order to explain the initiation of secondary tumors. However, genetic analyses of the secondary tumors have not been conducted. Herein, we describe the rare coexistence of a poroma and a trichoblastoma arising in a sebaceous nevus. This is the first report of an investigation of multiple genes in a secondary tumor in an SN. First, HRAS c.37G>C, which is the common mutation in sebaceous nevus, was detected in all three lesions (sebaceous nevus, poroma, and trichoblastoma). Next, to elucidate the potential second-hit mutations in the secondary poroma and trichoblastoma, we applied a panel sequencing for skin cancers that was newly developed in our institution. Our comparison of the mutational profile of 95 skin cancer-related genes in each of the three lesions newly revealed TP53 p.R158P in the poroma and NOTCH2 p.G329S in the trichoblastoma. TP53 p.R158P has been determined as a pathogenic mutation in other tumors, and NOTCH2 p.G329S was a novel mutation. We identified two novel mutations that may have contributed to the pathogenesis of the secondary tumor's development. The roles of the mutations remain unclear.

DOI： 10.1111/1346-8138.15919

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We report the 5-year follow-up results from a single-arm, open-label, multicenter phase II study (ONO-4538-08) conducted in Japan. Twenty-four patients with treatment-naïve, recurrent, or unresectable stage III/IV malignant melanoma received 3 mg/kg nivolumab every 2 weeks until progressive disease or unacceptable toxicity occurred. The 5-year overall survival (OS) rate was 26.1%. Five years after the start of nivolumab treatment, there were six survivors. The 5-year OS rate was 66.7% for patients with a superficial spreading type, 14.3% for acral lentiginous type, and 16.7% for mucosal type. The 5-year progression-free survival rate was 17.2%. No new cases of partial response or complete response were observed after 3 years, and overall response and disease control rates were similar to those reported at 3 years. The treatment-related adverse events reported between the 3- and 5-year follow-up periods were anemia (grade 2), white blood cell count decrease (grade 2), and psoriasiform dermatitis (grade 2) in one patient each. No new grade 3 or higher treatment-related adverse events occurred in this period. In conclusion, first-line treatment with nivolumab in Japanese patients with unresectable or metastatic melanoma resulted in confirmed long-term survival. No new safety signals were reported in the studied population.

DOI： 10.1111/1346-8138.15804

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DOI： 10.1684/ejd.2021.3997

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BACKGROUND: Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53-like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified. OBJECTIVE: In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD-associated molecules regulated by ΔNp63 in keratinocytes. METHODS: The immunohistochemical expression profiles of ΔNp63 and AD-related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD-related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method. RESULTS: In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier-related proteins including filaggrin, caspase-14, claudin-1, and claudin-4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL-1β and IL-33, pro-inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL-13 exposure increased the thickness of the three-dimensional culture of keratinocytes. IL-13 interfered with ΔNp63 downregulation during calcium-induced keratinocyte differentiation. IL-13 modulated some barrier-related and inflammation-related molecules, which were regulated by ΔNp63. CONCLUSIONS: We have shown that ΔNp63 modulated AD-related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL-4/IL-13. IL-13-ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation.

DOI： 10.1002/iid3.427

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(株)医学書院  

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Palmoplantar pustulosis (PPP) is characterized by sterile pustules on the palms and soles. A strong association between PPP and tobacco smoking has been reported, and it has been speculated that the IL-17A pathway may play an important role in PPP. Recent studies have suggested that IL-36 plays a pivotal role in the pathogenesis of psoriasis and its subtypes. The relationships among IL-36, smoking, and PPP have not been examined. Here, we investigated the relationships among the smoking index, severity of the clinical condition of PPP, and in vitro dynamics of IL-36 in human tonsillar epithelial cells under the condition of exposure to a cigarette smoke extract. The results demonstrated that the Palmoplantar Pustulosis Area and Severity Index was strongly and positively correlated with the smoking index in female patients. Immunohistochemical examinations showed that IL-36γ was highly expressed in tonsillar epithelial cells from patients with PPP but not in those from patients with recurrent tonsillitis without PPP. The in vitro study revealed that IL-17A synergistically induced a release of IL-36γ under cigarette smoke extract exposure. These results suggest that local production of IL-36γ by epithelial cells induced by cigarette smoke exposure plays an important role in the pathogenesis of PPP.

DOI： 10.1016/j.jid.2020.09.028

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DOI： 10.1111/1346-8138.15544

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DOI： 10.1684/ejd.2020.3861

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DOI： 10.1016/j.alit.2020.04.011

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DOI： 10.1111/1346-8138.15463

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Melanogenesis is the biological and biochemical process of melanin and melanosome biosynthesis. Melanin is formed by enzymic reactions of tyrosinase family proteins that convert tyrosine to form brown-black eumelanin and yellow-red pheomelanin within melanosomal compartments in melanocytes, following the cascades of events interacting with a series of autocrine and paracrine signals. Fully melanized melanosomes are delivered to keratinocytes of the skin and hair. The symbiotic relation of a melanocyte and an associated pool of keratinocytes is called epidermal melanin unit (EMU). Microphthalmia-associated transcription factor (MITF) plays a vital role in melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes for promoting melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis. Diseases involving alterations of EMU show various forms of pigmentation phenotypes. This review introduces four major topics of melanogenesis cascade that include (1) melanocyte development and differentiation, (2) melanogenesis and intracellular trafficking for melanosome biosynthesis, (3) melanin pigmentation and pigment-type switching, and (4) development of a novel therapeutic approach for malignant melanoma by elucidation of melanogenesis cascade.

DOI： 10.3390/ijms21176129

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Nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open-label, uncontrolled phase II study that investigated the long-term efficacy and safety in treatment-naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3-week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2-week intervals. The median follow-up period was 20.8 months (range, 5.2-35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5-62.6). Median progression-free survival was not reached (95% CI, 3.02-not reached), and median overall survival was also not reached (95% CI, 19.52-not reached). The 30-month progression-free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune-related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long-term treatment-free survival (659 and 590 days, respectively). Long-term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.

DOI： 10.1111/1346-8138.15514

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Treatment strategies for advanced melanoma are dramatically changing, due to immune-checkpoint inhibitors and BRAF/MEK inhibitors. Nevertheless, reliable serum markers for evaluation of treatment responses and the outcome are still limited. Some previous reports suggested that serum neuron-specific enolase (sNSE) may be a useful marker for melanoma; however, its usefulness is controversial. Moreover, NSE has not been examined in vitro by using melanoma cell lines. We retrospectively evaluated sNSE and serum lactate dehydrogenase (sLDH) levels at the initial diagnosis and during therapy in 33 melanoma patients of various stages. We analyzed the NSE concentrations in cell lysates and supernatants from melanoma cell lines by enzyme-linked immunosorbent assay. The median sNSE was significantly higher in stage IV patients compared with stages I/II and III (16.3, 12.7 and 12.1 ng/mL, respectively). sNSE was elevated in 20% (2/10) of stage III and 61.1% (11/18) of stage IV patients but not in stages I/II. sNSE and sLDH tended to correspond to the total tumor volume (P = 0.48 and 0.58; 95% confidence intervals, 0.005-0172 and 0.776-0.836, respectively). The coincidence rate of sNSE and sLDH in stage IV at the initial diagnosis was 11 of 18 (61.1%). Of the remaining patients, elevated sNSE but not sLDH was observed in five patients (27.8%) and elevated sLDH but not sNSE was observed in two (11.1%). Four of the five patients showing elevated sNSE and normal sLDH were of the mucosal type. NSE was detected in both supernatant and cell lysate of all four melanoma cell lines (0.30-237.32 ng/mL and 137-483.04 ng/mg, respectively). Two cell lines with a high supernatant NSE level contained many dead cells in the supernatant. The combination of sNSE and sLDH could contribute to the early detection of distant metastasis and disease condition evaluations for advanced melanoma patients.

DOI： 10.1111/1346-8138.15502

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DOI： 10.1111/1346-8138.15509

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Cholinergic urticaria (CholU) decreases affected individuals' quality of life because they must avoid stimuli including exercise and hot bathing. Although case reports have indicated that regular sweating activities are effective for CholU with hypohidrosis, little evidence is available. This retrospective medical record review examined CholU patients who received any form of treatment at our hospital. Twenty-seven cases (78% men; median age 22 years, range 12-70 years) were analyzed. Fourteen (52%) patients had acquired idiopathic generalized anhidrosis (AIGA). Among the 12 patients receiving sweating therapy (4 with, 8 without AIGA), improvement of symptoms was confirmed in 11 (92%; sweating therapy alone: n = 5, with H1 blocker: n = 5, with steroid pulse: n = 1) including 8 (67%) showing complete response (CR). In this sweating-therapy group, CR was achieved by six of the eight (75%) patients without AIGA and two of the four (50%) patients with AIGA. Among the 15 patients without sweating therapy, symptom improvement was observed in 9 (60%; steroid pulse: n = 7, H1 blocker: n = 2) including 1 (7%) achieving CR. Sweating therapy was safely undertaken except in one case in which the patient showed angioedema and anaphylaxis. Regular sweating activities could be a potential therapeutic option for CholU patients.

DOI： 10.1111/dth.13647

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Treatment with immune checkpoint inhibitors has improved prognosis among patients with cutaneous melanoma, but there are still unmet medical needs in Japan, especially for mucosal melanoma and acral lentiginous melanoma (ALM) subtypes. Ipilimumab, a fully human monoclonal antibody that specifically blocks cytotoxic T-lymphocyte-associated antigen 4 and potentiates antitumor T-cell response, was approved in Japan in 2015 for the treatment of radically unresectable malignant melanoma. This postmarketing surveillance (prospective, non-interventional, multicenter, observational study) evaluated the safety (occurrence of adverse drug reactions [ADR]) and efficacy (overall survival [OS]) of ipilimumab in a real-world setting in Japan. All patients with radically unresectable malignant melanoma undergoing treatment with ipilimumab in Japan during the registration period between August 2015 and February 2017 were enrolled. In total, 547 patients were analyzed; 67.5% were 60 years old or more, 85.7% had an Eastern Cooperative Oncology Group performance status of 0-1, 50.3% had melanoma of the skin (mainly of the ALM subtype) and 73.5% had negative BRAF mutation status. Most patients had experienced recurrence and received multiple treatments. The overall incidence of ADR and serious ADR was 69.5% and 40.8%, respectively. The most common ADR and serious ADR were liver disorder, colitis and diarrhea. The most common ADR of special interest were liver-related ADR (22.5%), skin-related ADR (22.1%), gastrointestinal-related ADR (20.3%) and endocrine system-related ADR (16.3%). Most of these events had recovered or were in remission by the last evaluation. The median OS was 7.52 months (95% confidence interval, 6.47-8.74). Median OS was 6.31 and 8.44 months in patients with mucosal melanoma and melanoma of the skin; 9.43 and 3.75 months in patients with and without ADR; and 10.32 and 6.11 months in patients with and without serious ADR, respectively. Ipilimumab was tolerable and showed efficacy in improving OS for these patients.

DOI： 10.1111/1346-8138.15388

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BACKGROUND: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the real-world efficacy of anti-PD-1 antibodies in advanced AM. PATIENTS AND METHODS: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, Response Evaluation Criteria in Solid Tumors), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. RESULTS: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within normal level in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH levels showed a significantly stronger association with better OS than abnormal levels (median OS 24.9 vs 10.7 months; P<0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group (6/70 patients [8.6%] vs 26/123 patients [21.1%]; P=0.026). Moreover, the median OS in this group was significantly poorer (12.8 vs 22.3 months; P=0.03). CONCLUSIONS: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

DOI： 10.1016/j.annonc.2020.05.031

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DOI： 10.1684/ejd.2020.3778

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

Ichushi

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Neurofibromatosis type 1 (NF1) is a genodermatosis caused by heterozygous germ line variations in the NF1 gene. A second-hit NF1 aberration results in the formation of café-au-lait macules, cutaneous neurofibroma and plexiform neurofibroma (PNF). Mosaic NF1 (mNF1), caused by a postzygotic NF1 mutation, is characterized by localized or generalized NF1-related manifestations. Although NF1 and mNF1 are associated with pigmentary skin lesions, clinically recognizable melanocytic nevi that developed over PNF have not been reported. Here, we report the first case of multiple melanocytic nevi that developed on a giant café-au-lait macule and PNF. The PNF had biallelic NF1 deletions, a whole deletion of NF1 and a novel intragenic deletion involving exons 25-30. The deletions were not detected in the blood, which resulted in the diagnosis of mNF1. Furthermore, the nevus cells had not only biallelic NF1 deletions but also NRAS Q61R, a common mutation found in congenital melanocytic nevi. These analyses revealed the coexistence of the two different mosaic diseases, mNF1 and congenital melanocytic nevi. For a diagnosis of cases with atypical NF1-like symptoms, genetic analyses using blood and lesional tissues are useful and aid in genetic counseling.

DOI： 10.1111/1346-8138.15327

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：Japanese   Publisher：日本レックリングハウゼン病学会  

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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DOI： 10.1111/1346-8138.15166

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In this case study, we aimed to evaluate the disease condition of patients with pustulotic arthro-osteitis (PAO) at 36-month post-tonsillectomy. A retrospective analysis of the cases of 17 patients with PAO who were resistant to initial systemic treatments and underwent tonsillectomy at our hospital in 2006-2016 was conducted. The patients' disease condition at 1-, 24-, and 36-month post-tonsillectomy was assessed by the visual analog scale (VAS) score for osteoarthropathic pain, the disease duration, the area of palmoplantar lesions, and the Palmoplantar Pustular Psoriasis Area Severity Index (ppPASI). In the minimum follow-up of 36-month post-tonsillectomy in 17 patients, the median ppPASI and VAS scores decreased from 12 to 1 and from 80 to 20, respectively. Thirteen patients with ≥70% improvement in their VAS scores maintained the same good condition after ≥36 months, whereas four patients with <70% improvement in their VAS scores did not show remarkable improvement after that time point. Furthermore, we found that the improvement in VAS score was not associated with the disease duration or the patients' pre-tonsillectomy ppPASI values. Tonsillectomy might be an alternative treatment option for patients with PAO. Long-term efficacy against pain can be predicted by evaluating a patient's improvement at 1-month post-tonsillectomy.

DOI： 10.5152/eurasianjmed.2019.19099

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Melanoma is one of the most lethal and malignant cancers and its incidence is increasing worldwide, and Japan is not an exception. Although there are numerous therapeutic options for melanoma, the prognosis is still poor once it has metastasized. The main concern after removal of a primary melanoma is whether it has metastasized, and early detection of metastatic melanoma would be effective in improving the prognosis of patients. Thus, it is very important to identify reliable methods to detect metastases as early as possible. Although many prognostic biomarkers (mainly for metastases) of melanoma have been reported, there are very few effective for an early diagnosis. Serum and urinary biomarkers for melanoma diagnosis have especially received great interest because of the relative ease of sample collection and handling. Several serum and urinary biomarkers appear to have significant potential both as prognostic indicators and as targets for future therapeutic methods, but still there are no efficient serum and urinary biomarkers for early detection, accurate diagnosis and prognosis, efficient monitoring of the disease and reliable prediction of survival and recurrence. Levels of 5-S-cysteinyldopa (5SCD) in the serum or urine as biomarkers of melanoma have been found to be significantly elevated earlier and to reflect melanoma progression better than physical examinations, laboratory tests and imaging techniques, such as scintigraphy and echography. With recent developments in the treatment of melanoma, studies reporting combinations of 5SCD levels and new applications for the treatment of melanoma are gradually increasing. This review summarizes the usefulness of 5SCD, the most widely used and well-known melanoma marker in the serum and urine, compares 5SCD and other useful markers, and finally its application to other fields.

DOI： 10.3390/ijms21020432

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Angiomyolipoma (AML) is classified as a perivascular epithelioid cell neoplasm, mostly occurring in the kidney. Twenty percent of patients with renal AML have tuberous sclerosis complex (TSC) caused by germline variation in the TSC1 or TSC2 gene. In this paper, we report the first case of renal AML harboring somatic missense mutations of the TSC2 gene and concomitant copy-neutral loss of heterozygosity (CN-LOH). The patient presented with solitary renal AML and pulmonary lymphangiomyomatosis and without other findings suggestive of TSC. Exome sequencing analysis of the renal AML, however, identified a pathogenic somatic missense mutation in the TSC2 gene (NM_000548:c.5228G>A:p. R1743Q), although no other somatic mutation was detected. Furthermore, no germline mutation in TSC1 or TSC2 was detected. Interestingly, the mutant allele ratio was too high for a somatic heterozygous mutation without loss of heterozygosity (LOH). Furthermore, no copy number variation was detected around the TSC2 locus (16p13.3). To clarify the allelic status, we analyzed heterozygous single-nucleotide polymorphisms (SNPs) in chromosome 16. In these SNPs, an unbalanced allele ratio was accumulated inside the 16p13.3 region. These results suggested copy-neutral LOH (CN-LOH). Consequently, we concluded that the missense mutation of the TSC2 gene and CN-LOH of the TSC2 locus caused renal AML.

DOI： 10.1080/15384047.2019.1702406

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DOI： 10.1111/1346-8138.15087

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Inflammatory bowel disease (IBD) is associated with a number of extraintestinal complications, including skin lesions. Most reports have shown that skin lesions are found in 10-15% of IBD cases, although this depends on the definition of skin lesions. The representative skin lesions in patients with IBD are erythema nodosum, pyoderma gangrenosum, Sweet's syndrome, and so on. These lesions are often associated with IBD progression, and intestinal lesions in particular require appropriate treatment. Recently, another clinical issue regarding skin lesions in patients with IBD, a so-called paradoxical reaction, during the treatment with anti-tumor necrosis factor (TNF)-α agents has emerged. These reactions are termed paradoxical reactions because the skin lesions sometimes resemble psoriasis, although the anti-TNF-α agents have been historically used to treat psoriasis. Paradoxical reactions are reportedly found in approximately 5-10% of patients using anti-TNF-α agents and are no longer rare. Now that the use of biologics is at its culmination, reports regarding paradoxical reactions are predicted to increase in number; thus, we must recognize skin lesions with IBD patients including this type of adverse events and manage them appropriately while consulting with dermatologists.

DOI： 10.1007/s12328-019-00958-y

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DOI： 10.1111/1346-8138.15095

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The multinational phase 3 CheckMate 238 trial compared adjuvant therapy with nivolumab versus ipilimumab among patients with resected stage III or IV melanoma (N = 906). In this Japanese subgroup analysis of CheckMate 238 (n = 28; nivolumab, n = 18; ipilimumab, n = 10), both the 12- and 18-month recurrence-free survival rates were 56% for nivolumab and 30% for ipilimumab (hazard ratio, 0.66; 97.56% confidence interval, 0.19-2.24; P = 0.4390). No new safety signals were reported for Japanese patients. Results were consistent with those from the CheckMate 238 global population, indicating that nivolumab has the potential to be a treatment option for Japanese patients with resected melanoma who are at high risk of recurrence.

DOI： 10.1111/1346-8138.15103

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To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) in terms of the overall response rate (ORR), progression-free survival (PFS), and disease control rate (DCR). Overall survival (OS) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events (CTCAE). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil-to-lymphocyte ratio (NLR) and high C-reactive protein (CRP) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.

DOI： 10.1111/1346-8138.15073

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

Ichushi

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Language：Japanese   Publisher：(株)北隆館  

Ichushi

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long-term follow up of a single-arm, open-label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post-hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment-related adverse events (TRAE), including select immune-related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the ORR was 66.7% (90% CI: 34.7, 88.3) for superficial spreading, 33.3% (90% CI: 11.7, 65.3) for mucosal, and 28.6% (90% CI: 10.0, 59.1) for acral lentiginous tumors. The median OS was 32.9 months, the 3-year OS rate was 43.5%, and the 3-year PFS rate was 17.2%. A long-term response was observed in all the tumor types. The most common TRAE included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long-term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type.

DOI： 10.1111/cas.14015

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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DOI： 10.1111/ajco.13139

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Importance: It is challenging to differentiate melanoma from melanocytic nevus on the volar skin in the absence of typical dermoscopic patterns. Objective: To identify the frequency and clinical and dermoscopic characteristics of melanocytic lesions on the volar skin not displaying a parallel furrow pattern, lattice-like pattern, fibrillar pattern, or parallel ridge pattern on results of dermoscopy. Design, Setting, and Participants: In this retrospective cohort study, a total of 504 melanocytic lesions on the volar skin were evaluated in the Shinshu University Hospital department of dermatology between January 1, 2000, and December 31, 2012. Dermoscopic images were independently assessed by 3 dermoscopists for the presence of established dermoscopic criteria. Statistical analysis was performed from October 1, 2017, to April 30, 2018. Main Outcomes and Measures: Frequency of dermoscopic criteria and corresponding clinical (patient age and size and location of lesion) and histopathologic features. Results: Of 504 lesions, 110 (21.8%) (melanocytic nevus, 97; melanoma, 8; and equivocal melanocytic lesion, 5) from 108 patients (68 female and 40 male patients; mean age, 40.1 years [range, 1-86 years]) did not show a parallel furrow pattern, lattice-like pattern, fibrillar pattern, or parallel ridge pattern. Among them, the mean patient age was significantly higher for melanoma than for melanocytic nevus (65.3 vs 38.0 years; P < .001), as was mean maximum lesion diameter (11.8 vs 5.7 mm; P < .001). Melanomas and equivocal melanocytic lesions tended to be distributed on weight-bearing areas of the foot sole, such as the heel, while nevi were spread over non-weight-bearing regions. Dermoscopically, 95 melanocytic nevi (97.9%) were symmetrical in 1 or 2 axes while melanomas were not. A total of 91 melanocytic nevi (93.8%) had 1 or 2 colors per lesion, and 4 melanomas (50.0%) had more than 2 colors. Vascular structures were seen in 3 melanocytic nevi (3.1%) and 3 melanomas (37.5%). Blue-white structures were seen in 18 melanocytic nevi (18.6%) and 3 melanomas (37.5%). Dots and globules were seen in 22 melanocytic nevi (22.7%) and 4 melanomas (50.0%). Vascular structures, blue-white structures, and dots and globules were irregularly distributed in the melanomas. Ulcer, hyperkeratosis, and irregular streaks were observed only in melanomas. Conclusions and Relevance: More than one-fifth of melanocytic lesions on the volar skin did not display typical dermoscopic patterns. Asymmetry, numerous colors (≥3), and other melanoma-specific dermoscopic findings were more frequently observed for melanomas. Clinical information, including patient age and lesion size and location, was helpful in differentiating melanoma from melanocytic nevus. Further prospective clinical studies are warranted to clarify the diagnostic accuracy of dermoscopy combined with clinical information.

DOI： 10.1001/jamadermatol.2018.5926

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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DOI： 10.1111/1346-8138.14805

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Language：Japanese   Publisher：日本皮膚病理組織学会  

Ichushi

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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DOI： 10.1001/jamadermatol.2018.5379

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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DOI： 10.1111/jdv.15501

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Dermoscopy is a widely used non-invasive technique for diagnosing skin tumors. In melanocytic tumors, e.g., melanoma and basal cell carcinoma (BCC), the effectiveness of dermoscopic examination has been fully established over the past two decades. Moreover, dermoscopy has been used to diagnose non-melanocytic tumors. Here, we review novel findings from recent reports concerning dermoscopy of melanoma and non-melanoma skin cancers including BCC, sebaceous carcinoma, actinic keratosis, Bowen's disease, squamous cell carcinoma (SCC), Merkel cell carcinoma (MCC), extramammary Paget's disease (EMPD), and angiosarcoma.

DOI： 10.3389/fmed.2019.00180

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AIM: The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma. METHODS: In this multicentre, single-arm study, treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. RESULTS: The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2-27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III-IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III-IV AEs were high but manageable with appropriate medical attention and treatment. TRIAL REGISTRATION: JapicCTI-152869.

DOI： 10.1016/j.ejca.2018.09.025

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

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DOI： 10.1016/j.jdcr.2018.08.012

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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DOI： 10.1002/cia2.12037

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DOI： 10.1093/annonc/mdy289.023

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

Ichushi

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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DOI： 10.1111/1346-8138.14297

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

Ichushi

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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DOI： 10.1200/JCO.2018.36.15_suppl.e21603

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

DOI： 10.1111/1346-8138.14227

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We examined dermoscopic features of three cases of extraocular sebaceous carcinoma and reviewed the literatures. The yellowish structures, polymorphous vessels and ulceration were common findings in our cases and all cases of the previous reports. The appearance of whitish-pink areas has not been described previously. Our results suggested that the combination of four dermoscopic features, whitish-pink areas, yellowish structures, polymorphous vessels and ulceration might be distinctive in extraocular sebaceous carcinoma.

DOI： 10.1111/1346-8138.14170

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Language：Japanese   Publisher：日本皮膚病理組織学会  

Ichushi

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Ichushi

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s10147-018-1246-y

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A wide local excision is the standard treatment for extramammary Paget's disease (EMPD), though this treatment often leads to permanent anogenital mutilation and functional impairment. The purpose of our study is to evaluate the efficacy and safety of the topical application of imiquimod 5% cream for non-invasive EMPD. We examined nine patients with EMPD. Eight of the nine patients were treated with imiquimod 5% cream three times per week for 16 weeks; one case was treated for 6 weeks. The response rate was 100% including five complete remissions. Local irritation was observed in three patients, which was controlled by a provisional withdrawal of the treatment. These results suggest that imiquimod 5% cream may be considered an alternative therapeutic option for the treatment of non-invasive EMPD.

DOI： 10.1111/1346-8138.14117

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Language：Japanese   Publisher：日本レックリングハウゼン病学会  

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There is no standard chemotherapeutic treatment for advanced extramammary Paget's disease, though the effectiveness of some chemotherapy regimens, including docetaxel, has been reported. In this report, we report that TS-1 monotherapy was effective in two patients with advanced extramammary Paget's disease after docetaxel treatment failure. TS-1 monotherapy may be useful as the second-line treatment for patients with advanced extramammary Paget's disease.

DOI： 10.1111/1346-8138.14017

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medical Journals/Acta D-V  

DOI： 10.2340/00015555-2748

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1093/annonc/mdx667.002

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DOI： 10.1111/bjd.15318

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DOI： 10.1212/WNL.0000000000004359

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Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation through overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI-142533.).

DOI： 10.1111/cas.13241

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DOI： 10.1111/cas.13241

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Language：Japanese   Publisher：日本皮膚病理組織学会  

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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Language：Japanese   Publisher：日本皮膚病理組織学会  

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Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.

DOI： 10.1111/cas.13226

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(一社)日本皮膚悪性腫瘍学会  

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DOI： 10.1515/cclm-2016-0634

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PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.

DOI： 10.1007/s00280-016-3237-x

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BACKGROUND: Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE: A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS: We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS: We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION: IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

DOI： 10.1016/j.jdermsci.2016.11.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s10147-016-0976-y

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Language：English   Publisher：(一社)日本癌学会  

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DOI： 10.1111/1346-8138.13338

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000449033

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DOI： 10.1016/j.jdermsci.2016.06.004

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Language：Japanese   Publisher：(一社)日本臨床免疫学会  

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01882&link_issn=&doc_id=20160905390193&doc_link_id=%2Fdy4jjoci%2F2016%2F003904%2F193%2F0423-0423%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2016%2F003904%2F193%2F0423-0423%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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DOI： 10.1007/s10147-015-0944-y

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DOI： 10.1111/1346-8138.13260

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DOI： 10.1111/1346-8138.13200

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DOI： 10.1111/all.12836

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

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DOI： 10.1111/1346-8138.13082

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

DOI： 10.1093/jjco/hyv199

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DOI： 10.1093/jjco/hyv158

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DOI： 10.2340/00015555-2194

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DOI： 10.1016/j.jdermsci.2015.07.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

DOI： 10.1016/j.jdermsci.2015.04.003

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01174&link_issn=&doc_id=20150805360004&doc_link_id=10.14924%2Fdermatol.125.1587&url=https%3A%2F%2Fdoi.org%2F10.14924%2Fdermatol.125.1587&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

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DOI： 10.1016/j.jdermsci.2015.03.014

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DOI： 10.1097/PGP.0000000000000169

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DOI： 10.1111/1346-8138.12873

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J01559&link_issn=&doc_id=20150610070009&doc_link_id=10.11477%2Fmf.1412204475&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1412204475&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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Language：Japanese   Publisher：(株)全日本病院出版会  

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Language：Japanese   Publisher：角化症研究会事務局  

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DOI： 10.1007/s10147-014-0686-2

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DOI： 10.2340/00015555-1865

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DOI： 10.1111/pcmr.12297

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Tohoku University Medical Press  

DOI： 10.1620/tjem.234.57

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Language：Japanese   Publisher：(一社)茨城県医師会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

DOI： 10.1007/s10147-013-0573-2

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DOI： 10.2340/00015555-1836

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.76.345

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DOI： 10.1111/1346-8138.12179

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DOI： 10.1111/j.1440-0960.2011.00873.x

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DOI： 10.1007/s10147-012-0411-y

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DOI： 10.1111/j.1468-3083.2012.04547.x

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DOI： 10.2340/00015555-1587

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DOI： 10.1016/j.jdermsci.2012.09.002

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DOI： 10.1111/j.1440-0960.2011.00746.x

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DOI： 10.1111/j.1524-4725.2011.02217.x

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DOI： 10.1111/j.1346-8138.2011.01340.x

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DOI： 10.1038/bjc.2012.12

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Various microscopic classifications of metastatic sentinel lymph nodes (SLN) have been reported along with predictors of additional lymph node positivity and their correlations with the prognosis. The purpose of this study was to re-evaluate these classifications in the Japanese population. We selected the following three classifications, based on the procedural simplicity of the measurements: maximum diameter (maximum diameter of the largest tumor lesion in the SLN; <0.1, 0.1-1.0, >1.0 mm), invasion depth (depth of tumor invasion measured from the capsule in the SLN; SI ≤ 0.3 mm, SII >0.3 to ≤ 1.0 mm, SIII >1.0 mm), and microanatomic location (microanatomic location of the tumor deposits within the SLN; "subcapsular", "parenchymal", "combined", "multifocal", "extensive"). A retrospective study, using prescribed survey forms, was carried out. Among the 450 patients, including the 149 cases with SLN metastasis, an additional lymph node positivity rate of 0% could be predicted only in patients with a maximum diameter category of less than 0.1 mm. As compared with that in the SLN metastasis-negative cases, however, the prognosis was poorer in cases with SLN metastasis, even those with lesions falling under the maximum diameter category of less than 0.1 mm, invasion depth category of SI (≤ 0.3 mm) and microanatomic location category of subcapsular. The prognosis is particularly poor for the microanatomic location category of extensive, which should thus be regarded as a macrometastasis. A prospective study with standardized procedures, including pathological evaluation, is needed in order to confirm our conclusion.

DOI： 10.1111/j.1346-8138.2011.01318.x

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：Japanese   Publisher：The Japanese Skin Cancer Society  

We report a 44-year-old man with brain, lung and retroperitoneum metastasis from malignant melanoma treated with dacarbazine. The primary lesion was not detected. He received stereotactic radiosurgery for the brain metastasis, followed by single-dose dacarbazine (250mg/m²/day &times; 5 days). After 3 courses, a 55.8% reduction in lung metastasis was observed, without serious adverse reaction. After 6 courses, the lung metastasis was removed surgically. Four months after surgical resection, new metastatic lesions were detected in the mediastinum, pancreas, and mesentery. He was treated with stereotactic radiosurgery for increased brain metastasis, followed by one single course of dacarbazine (250mg/m²/day &times; 5 days) and 2 single courses of cisplatin (100mg/m²/day &times; 1 day). He died 20 months after the first consultation with us. The combination therapy composed of single dacarbazine, stereotactic radiosurgery and surgery might have contributed to durable survival without serious adverse effect in this case.[<i>Skin Cancer (Japan)</i> 2011 ; 26 : 139-142]

DOI： 10.5227/skincancer.26.139

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/DAD.0b013e318201ac8f

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2340/00015555-1020

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1346-8138.2010.01175.x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1346-8138.2010.01174.x

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

DOI： 10.1111/j.1346-8138.2010.00920.x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10147-009-0894-3

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jaad.2008.09.029

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jns.2008.08.006

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00384-008-0529-6

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jaad.2007.08.026

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1600-0560.2007.00859.x

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Language：Japanese   Publisher：Japanese Dermatological Association  

Objective: To establish the relationship between tumor thickness (TT) and metastatic rate of the sentinel lymph nodes (SLN) in Japanese patients with melanoma. Methods: A retrospective review of 259 patients who underwent successful SLN mapping and biopsy in 13 facilities in Japan from April of 2003 to June of 2006. The data were analyzed with the χ² or Fisherʼs tests. Result: The metastatic rate of SLN in each T-classification category was as follows: pTis: 0% (0/36), pT1: 11.3% (6/56), pT2: 21.0% (13/63), pT3: 34.0% (35/103), and pT4: 62.4% (63/101). Two of T1 cases with SLN metastasis were T1b, and the remaining 4 cases with SLN metastasis were T1a, in which TT was 1.0, 0.8, 0.55, and 0.50 mm. Metastatic rates of SLN in patients with primary lesions over 4 mm in thickness were as follows: 4.01–5 mm: 40.0%, 5.01–6 mm: 57.9%, 6.01–7 mm: 53.8%, 7.01–8 mm: 62.5%, 8.01–9 mm: 87.5%, 9.01–10 mm: 87.5%, and 10 mm<: 72.0%. The metastatic rates of SLN were significantly higher in cases with ulcerated primary lesions than in those without ulceration in T1–T4 and T1–T3 groups (p<0.001). Conclusion: In melanoma patients with thicker primary lesions, the indication for SLN biopsy should be decided taking into consideration the predictive metastatic rates and locations of SLN. Further study is needed to define criteria for performing SLN biopsy in patients with melanomas less than 1.0 mm thick.

DOI： 10.14924/dermatol.118.3083

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

DOI： 10.1093/jjco/hyn114

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1524-4725.2007.33256.x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1346-8138.2007.00324.x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000093854

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Language：Japanese   Publisher：(株)協和企画  

Ichushi

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mosby Inc.  

DOI： 10.1067/mjd.2002.122754

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/00008390-200206000-00008

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Language：English   Publishing type：Research paper (scientific journal)  

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