論文 - 肥田　時征

Dominant inheritance in hereditary angioedema associated with carboxypeptidase N deficiency.

Tokimasa Hida, Masashi Idogawa, Masae Okura, Takashi Tokino, Hisashi Uhara

Allergology international : official journal of the Japanese Society of Allergology    2025年04月  [査読有り]  [国際誌]

DOI PubMed

Genomic profiling and personalized treatment strategies for skin malignancies: findings from the center for cancer genomics and advanced therapeutics database.

Tokimasa Hida

International journal of clinical oncology    2025年03月  [査読有り]  [国内誌]

　概要を見る

Immune checkpoint inhibitors and molecular-targeted therapies have dominated recent cancer treatment. However, these treatments face challenges, such as primary and acquired resistance, indicating that not all patients benefit from them. Therefore, the search for new molecular targets is crucial. In addition, immune checkpoint inhibitors have exhibited racial differences in their effectiveness for certain neoplasms. Hence, understanding the genomic landscape of cancers in various racial groups is important. In Japan, health insurance has covered comprehensive genomic profiling since 2019, and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has accumulated genetic abnormalities along with clinical data of patients with various cancers. These data are crucial for advancing cancer research and drug development. This review discusses the genetic abnormalities of the major skin malignancies including melanoma, cutaneous squamous cell carcinoma (cSCC), and extramammary Paget's disease (EMPD), and proposes potential treatment strategies by comparing C-CAT data analysis with other genetic studies. The C-CAT data have emphasized unique genetic alterations in tumors of the Japanese population, particularly racial differences in tumor mutational burden in cutaneous melanoma and cSCC, indicating the importance of personalized treatment strategies that consider racial differences.

DOI PubMed

Efficacy of eribulin monotherapy for bone marrow carcinomatosis of breast cancer in a patient with Werner syndrome.

Akihito Fujimi, Yasuhiro Nagamachi, Naofumi Yamauchi, Riku Hasebe, Naoki Onoyama, Naotaka Hayasaka, Teppei Matsuno, Kazuhiko Koike, Yoshiro Gotoh, Kohji Ihara, Junji Kato, Takuji Nishisato, Kazuyuki Murase, Goro Kutomi, Tokimasa Hida, Hisashi Uhara, Kohichi Takada

Geriatrics & gerontology international    2025年01月  [査読有り]  [国内誌]

　概要を見る

Various complications and potential risks of serious adverse events lessens the intensity of chemotherapy in patients with Werner syndrome. Bone marrow carcinomatosis of breast cancer was developed in a patient with Werner syndrome. Eribulin proved well tolerated and effective in improving severe thrombocytopenia, leading to platelet transfusion-free status.

DOI PubMed

Joining PCMR: Aspirations for Editorial Contributions.

Tokimasa Hida

Pigment cell & melanoma research   38 ( 1 ) e70000  2025年01月  [国際誌]

DOI PubMed

The genomic landscape of cutaneous squamous cell carcinoma in Japan.

Junji Kato, Tokimasa Hida, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

The Journal of dermatology    2024年12月  [査読有り]  [国際誌]

　概要を見る

Comprehensive studies of the genetic profiles of cutaneous squamous cell carcinoma (cSCC) in Japanese patients have been lacking, although an understanding of these profiles is crucial for improving treatment outcomes. Since 2019, comprehensive genomic profiling (CGP) has been covered by Japan's health insurance, and the resulting data have been compiled into a comprehensive database by the country's Center for Cancer Genomics and Advanced Therapeutics (C-CAT). In this retrospective study, we used CGP data from the C-CAT database to analyze genomic characteristics of cSCC in Japanese patients. The patients' clinical and genomic data, including the chemotherapy regimens, tumor mutational burden (TMB), and survival status, were obtained. We analyzed the cases of 152 patients, with only those evaluated by the FoundationOne® CDx included for accuracy. Among the 152 patients, the most common gene oncogenic alterations were observed in TP53 (67%), CDKN2A (54%), TERT (49%), CDKN2B (33%), and NOTCH1 (18%). TMB-high (≥10 mut/Mb) was observed in 27% (n = 41) of the patients, with a median age of 75 years for this group. TMB-low (<10 mut/Mb) was observed in 73% (n = 111) of the patients; their median age was 67 years.

DOI PubMed

Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment.

Tomoyuki Minowa, Kenji Murata, Yuka Mizue, Aiko Murai, Munehide Nakatsugawa, Kenta Sasaki, Serina Tokita, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Toshiya Handa, Sayuri Sato, Kohei Horimoto, Junji Kato, Tokimasa Hida, Yoshihiko Hirohashi, Hisashi Uhara, Toshihiko Torigoe

Science translational medicine   16 ( 776 ) eadk8832  2024年12月  [査読有り]  [国際誌]

　概要を見る

Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.

DOI PubMed

Genetic Characteristics of Cutaneous, Acral, and Mucosal Melanoma in Japan.

Tokimasa Hida, Masashi Idogawa, Junji Kato, Yukiko Kiniwa, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Shoichiro Tange, Masae Okura, Ryuhei Okuyama, Takashi Tokino, Hisashi Uhara

Cancer medicine   13 ( 22 ) e70360  2024年11月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: Acral and mucosal melanomas are more prevalent in Asians than in Caucasians, unlike cutaneous melanomas, which are predominant in Caucasians. Recent studies have suggested that non-Caucasian cutaneous melanomas responded less to immune checkpoint inhibitors, highlighting the need for genetic profiling across ethnicities. This study aimed to elucidate the genetic characteristics of Japanese melanomas, which is an under-researched topic. METHODS: Single-nucleotide variants, indels, and copy number alterations in 104 Japanese melanoma patients (37 cutaneous, 52 acral, and 15 mucosal) were analyzed using custom panel sequencing. RESULTS: Driver events were detected in 94% of the cases. Among cutaneous melanoma cases, 76% had BRAF mutations, and 8% had NRAS mutations. In acral melanoma, BRAF (9%), NRAS (17%), KRAS (8%), KIT (19%), and NF1 (7%) mutations were detected. Major driver mutations in mucosal melanoma were detected in NRAS, KRAS, NF1, PTEN, GNAQ, and KIT. The median tumor mutational burden across all melanoma types was 4.6 mutations/Mb, with no significant difference between the cutaneous and acral/mucosal types. Of the 21 patients with both primary and metastatic lesions, 11 showed distinct mutations in each. Potentially actionable mutations were detected in 58 patients in addition to BRAF V600E/K mutations in 31. CONCLUSIONS: This study highlights distinct genetic abnormalities and actionable alterations in Japanese melanoma patients. This suggests a lower tumor mutational burden in East Asian cutaneous melanoma, which may affect the efficacy of immune checkpoint inhibitors. The heterogeneity of driver mutations across and within individuals highlights the need for personalized treatment approaches.

DOI PubMed

Extramammary Paget's disease treated with of anti-programmed cell death protein 1 therapy after docetaxel therapy failure.

Midori Narasaki, Junji Kato, Sayuri Sato, Tokimasa Hida, Kohei Horimoto, Yoshiyuki Matsui, Nobuaki Shigyo, Hisashi Uhara

The Journal of dermatology    2024年10月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

A case of familial progressive hyperpigmentation with or without hypopigmentation presenting with hypopigmented striae along the lines of Blaschko.

Tokimasa Hida, Masashi Idogawa, Aki Ishikawa, Masae Okura, Satoru Sasaki, Takashi Tokino, Hisashi Uhara

The Journal of dermatology    2024年09月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Genomic landscape of cutaneous, acral, mucosal, and uveal melanoma in Japan: analysis of clinical comprehensive genomic profiling data.

Tokimasa Hida, Junji Kato, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

International journal of clinical oncology    2024年09月  [査読有り]  [国内誌]

　概要を見る

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 PubMed

Mosaic SUFU mutation associated with a mild phenotype of multiple hereditary infundibulocystic basal cell carcinoma syndrome.

Marina Hamada, Tokimasa Hida, Masashi Idogawa, Shoichiro Tange, Takafumi Kamiya, Masae Okura, Toshiharu Yamashita, Takashi Tokino, Hisashi Uhara

The Journal of dermatology    2024年08月  [査読有り]  [国際誌]

担当区分：   責任著者

　概要を見る

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 PubMed

Genomic profiles of Merkel cell carcinoma in Japan.

Junji Kato, Tokimasa Hida, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

The Journal of dermatology    2024年07月  [査読有り]  [国際誌]

DOI PubMed

Distinct induction pathways of heat shock protein 27 in human keratinocytes: Heat stimulation or capsaicin through phosphorylation of heat shock factor 1 at serine 326 and/or suppression of ΔNp63.

Terufumi Kubo, Kenta Sasaki, Sayuri Sato, Tomoyuki Minowa, Tokimasa Hida, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Hisashi Uhara, Toshihiko Torigoe

Biochemical and biophysical research communications   708   149817 - 149817  2024年03月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Melanoma incidence on the non-weight-bearing areas of the sole.

Kazuki Furudate, Junji Kato, Kohei Horimoto, Sayuri Sato, Tokimasa Hida, Masahide Sawada, Tomoyuki Minowa, Hisashi Uhara

The Journal of dermatology    2024年02月  [査読有り]  [国際誌]

DOI PubMed

Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line.

Nami Nishikiori, Megumi Watanabe, Tatsuya Sato, Masato Furuhashi, Masae Okura, Tokimasa Hida, Hisashi Uhara, Hiroshi Ohguro

Cancers   16 ( 2 )  2024年01月  [査読有り]  [国際誌]

　概要を見る

To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM cell lines including SK-mel-24, A375, dabrafenib- and trametinib-resistant A375 (A375DT), and WM266-4. Upon exposure to 2 or 10 μM of ML329, cell viability was significantly decreased in WM266-4, SK-mel-24, and A375DT cells, but not A375 cells, in a dose-dependent manner, and these toxic effects of ML329 were most evident in WM266-4 cells. Extracellular flux assays conducted using a Seahorse bioanalyzer revealed that treatment with ML329 increased basal respiration, ATP-linked respiration, proton leakage, and non-mitochondrial respiration in WM266-4 cells and decreased glycolytic function in SK-mel-24 cells, whereas there were no marked effects of ML329 on A375 and A375DT cells. A glycolytic stress assay under conditions of high glucose concentrations also demonstrated that the inhibitory effect of ML329 on the glycolytic function of WM266-4 cells was dose-dependent. In addition, ML329 significantly decreased 3D-spheroid-forming ability, though the effects of ML329 were variable among the MM cell lines. Furthermore, the mRNA expression levels of selected genes, including STAT3 as a possible regulator of 3D spheroid formation, KRAS and SOX2 as oncogenic-signaling-related factors, PCG1a as the main regulator of mitochondrial biogenesis, and HIF1a as a major hypoxia transcriptional regulator, fluctuated among the MM cell lines, possibly supporting the diverse ML329 effects mentioned above. The findings of diverse ML329 effects on various MM cell lines suggest that MITF-associated biological activities are different among various types of MM.

DOI PubMed

Characterization of CD4 T-cell phenotype in human leukocyte antigen class II-positive acral melanoma.

Nayuha Shogase, Tomoyuki Minowa, Junji Kato, Kohei Horimoto, Sayuri Sato, Tokimasa Hida, Yoshihiko Hirohashi, Toshihiko Torigoe, Hisashi Uhara

The Journal of dermatology    2023年12月  [査読有り]  [国際誌]

DOI PubMed

Four cases of gnathostomiasis due to the ingestion of raw <i>Salangichthys microdon</i>

Takahiko Abe, Tokimasa Hida, Takafumi Kamiya, Kanako Ebata, Shintaro Sugita, Rie Kaneko, Mio Tanaka, Haruhiko Maruyama, Akira Suzuki, Hisashi Uhara

The Journal of Dermatology ( Wiley )   2023年10月  [査読有り]

担当区分：   責任著者

DOI

Effects of temozolomide on tumor mutation burden and microsatellite instability in melanoma cells.

Masahide Sawada, Tokimasa Hida, Takafumi Kamiya, Tomoyuki Minowa, Junji Kato, Masae Okura, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

The Journal of dermatology    2023年09月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Relationships between tumor thickness and the risk of sentinel node metastasis in acral and non-acral melanoma.

Junji Kato, Tokimasa Hida, Takafumi Kamiya, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Tomoyuki Minowa, Toshiya Handa, Sayuka Komatsu, Hisashi Uhara

International journal of dermatology    2023年06月  [査読有り]  [国際誌]

DOI PubMed

A Japanese patient with hereditary angioedema caused by deep intron variation in the SERPING1 gene.

Tokimasa Hida, Aki Ishikawa, Masae Okura, Mari Kishibe, Hisashi Uhara

The Journal of dermatology    2023年05月  [査読有り]  [国際誌]

DOI PubMed

3D Spheroid Configurations Are Possible Indictors for Evaluating the Pathophysiology of Melanoma Cell Lines.

Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Fumihito Hikage, Masato Furuhashi, Masae Okura, Tokimasa Hida, Hisashi Uhara

Cells   12 ( 5 )  2023年02月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Bacillus Calmette-Guérin-induced lupus vulgaris in a patient with Mendelian susceptibility to mycobacterial disease caused by a novel STAT1 variation.

Aika Shionoya, Yuko Yoto, Tokimasa Hida, Aki Ishikawa, Tadashi Hasegawa, Takeshi Tsugawa, Hisashi Uhara

The British journal of dermatology   188 ( 1 ) 142 - 143  2023年01月  [査読有り]  [国際誌]

DOI PubMed

Functional Interplay between IL-9 and Peptide YY Contributes to Chronic Skin Inflammation.

Shiori Kamiya, Ippei Ikegami, Masahiro Yanagi, Hiromi Takaki, Ryuta Kamekura, Taiki Sato, Keiju Kobayashi, Takafumi Kamiya, Yuka Kamada, Takaya Abe, Ken-Ichi Inoue, Tokimasa Hida, Hisashi Uhara, Shingo Ichimiya

The Journal of investigative dermatology   142 ( 12 ) 3222 - 3231  2022年12月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development.

Kazumasa Wakamatsu, Akira Ito, Yasuaki Tamura, Tokimasa Hida, Takafumi Kamiya, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito, Kowichi Jimbow

Cancers   14 ( 22 )  2022年11月  [査読有り]  [国際誌]

　概要を見る

Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo-dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma.

DOI PubMed

Linear lichen planus after COVID-19 vaccination.

Junji Kato, Takafumi Kamiya, Toshiya Handa, Eri Kobayashi, Tokimasa Hida, Toshiharu Yamashita, Hisashi Uhara

The Australasian journal of dermatology   63 ( 4 ) e385-e387  2022年11月  [査読有り]  [国際誌]

DOI PubMed

Difference in immunohistochemical findings among anti-PD-L1 antibodies and their relationships with CD4+ and CD8+ T cells in Japanese melanoma patients.

Daisuke Yoneta, Junji Kato, Takafumi Kamiya, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Tomoyuki Minowa, Tokimasa Hida, Shintaro Sugita, Hisashi Uhara

International journal of clinical oncology   27 ( 8 ) 1364 - 1371  2022年06月  [査読有り]  [国内誌]

　概要を見る

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 PubMed

Primary cutaneous diffuse large B-cell lymphoma, leg type, of the face that appeared on pre-existing T-cell pseudolymphoma clinically resembling actinic reticuloid.

Yuna Hosokawa, Takafumi Kamiya, Shintaro Sugita, Tokimasa Hida, Kohichi Takada, Yasuyuki Sumikawa, Hiroyuki Takahashi, Hisashi Uhara

The Journal of dermatology   49 ( 6 ) e206-e207  2022年06月  [査読有り]  [国際誌]

DOI PubMed

[Ⅰ. Genomic Alterations of Melanoma].

Tokimasa Hida

Gan to kagaku ryoho. Cancer & chemotherapy   49 ( 4 ) 409 - 412  2022年04月  [国内誌]

PubMed

Anogenital skin necrosis with fibrin thrombosis induced by crotamiton.

Toshiya Handa, Takafumi Kamiya, Yuji Kan, Tokimasa Hida, Yasuyuki Sumikawa, Tomoyuki Minowa, Hisashi Uhara

Contact dermatitis   86 ( 3 ) 221 - 223  2022年03月  [査読有り]  [国際誌]

DOI PubMed

Case of immunoglobulin (Ig)M/IgG immune complex vasculitis associated with multicentric Castleman's disease.

Aika Shionoya, Tokimasa Hida, Hiroshi Ikeda, Shintaro Sugita, Keiko Segawa, Tadashi Hasegawa, Hisashi Uhara

The Journal of dermatology   48 ( 12 ) e614-e615  2021年12月  [査読有り]  [国際誌]

担当区分：   責任著者

DOI PubMed

Genetic analyses of a secondary poroma and trichoblastoma in a HRAS-mutated sebaceous nevus.

Tomoyuki Minowa, Takafumi Kamiya, Tokimasa Hida, Masae Okura, Junji Kato, Masashi Idogawa, Shoichiro Tange, Tomomi Hirano, Takashi Tokino, Hisashi Uhara

The Journal of dermatology   48 ( 8 ) 1268 - 1272  2021年08月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

IL-13 modulates ∆Np63 levels causing altered expression of barrier- and inflammation-related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis.

Terufumi Kubo, Sayuri Sato, Tokimasa Hida, Tomoyuki Minowa, Yoshihiko Hirohashi, Tomohide Tsukahara, Takayuki Kanaseki, Kenji Murata, Hisashi Uhara, Toshihiko Torigoe

Immunity, inflammation and disease   9 ( 3 ) 734 - 745  2021年04月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

ALK-positive atypical Spitz tumour with conspicuous rosette-like structures.

Tomoyuki Minowa, Tokimasa Hida, Kohei Horimoto, Junji Kato, Takafumi Kamiya, Shintaro Sugita, Masashi Idogawa, Toshiaki Saida, Tadashi Hasegawa, Takashi Tokino, Hisashi Uhara

European journal of dermatology : EJD   31 ( 2 ) 256 - 258  2021年04月  [査読有り]  [国際誌]

担当区分：   責任著者

DOI PubMed

Neurofibromatosis type 1 without cutaneous neurofibromas: a rare genotype-phenotype correlation?

Tokimasa Hida, Masashi Idogawa, Aki Ishikawa, Miyako Mizukami, Junji Kato, Yasuyuki Sumikawa, Masae Okura, Takashi Tokino, Hisashi Uhara

European journal of dermatology : EJD   30 ( 5 ) 608 - 609  2020年10月  [査読有り]  [国際誌]

DOI PubMed

Elucidation of Melanogenesis Cascade for Identifying Pathophysiology and Therapeutic Approach of Pigmentary Disorders and Melanoma.

Tokimasa Hida, Takafumi Kamiya, Akinori Kawakami, Jiro Ogino, Hitoshi Sohma, Hisashi Uhara, Kowichi Jimbow

International journal of molecular sciences   21 ( 17 )  2020年08月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Usefulness of neuron-specific enolase as a serum marker of metastatic melanoma.

Sayuri Sato, Junji Kato, Masahide Sawada, Kohei Horimoto, Masae Okura, Tokimasa Hida, Hisashi Uhara

The Journal of dermatology    2020年07月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Homozygous promoter variant of SLC45A2 causes diverse hair color and patterns.

Tokimasa Hida, Katsuhiko Tsukamoto, Masae Okura, Hisashi Uhara

The Journal of dermatology    2020年07月  [査読有り]  [国際誌]

DOI PubMed

Koebner phenomenon of vitiligo associated with Coffin-Siris syndrome.

Tokimasa Hida, Aki Ishikawa, Miyako Mizukami, Hisashi Uhara

European journal of dermatology : EJD   30 ( 3 ) 310 - 311  2020年06月  [査読有り]  [国際誌]

DOI PubMed

Genetic analyses of mosaic neurofibromatosis type 1 with giant café-au-lait macule, plexiform neurofibroma and multiple melanocytic nevi.

Tokimasa Hida, Masashi Idogawa, Masae Okura, Shintaro Sugita, Taro Sugawara, Yasushi Sasaki, Takashi Tokino, Toshiharu Yamashita, Hisashi Uhara

The Journal of dermatology   47 ( 6 ) 658 - 662  2020年04月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH).

Masashi Idogawa, Tokimasa Hida, Toshiaki Tanaka, Noriaki Ohira, Shoichiro Tange, Yasushi Sasaki, Hisashi Uhara, Naoya Masumori, Takashi Tokino, Hiroshi Natori

Cancer biology & therapy   21 ( 4 ) 315 - 319  2020年04月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Association between PD-L1 expression and lymph node metastasis in cutaneous squamous cell carcinoma.

Shiori Kamiya, Junji Kato, Takafumi Kamiya, Toshiharu Yamashita, Yasuyuki Sumikawa, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Hitomi Takahashi, Masahide Sawada, Terufumi Kubo, Toshihiko Torigoe, Hisashi Uhara

Asia-Pacific journal of clinical oncology   16 ( 2 ) e108-e112  2020年04月  [査読有り]  [国際誌]

　概要を見る

AIM: To clarify the relationship between programmed cell death ligand 1 (PD-L1) expression in cutaneous squamous cell carcinoma (cSCC) and clinicopathological variables. METHODS: We examined PD-L1 expression in tumor cells (TCs) and tumor infiltrating immune cells (ICs) in 46 cases of cSCC by immunohistochemistry. In each case, we employed two methods-intensity and proportion scores-to evaluate PD-L1 expression in TCs. For the evaluation of PD-L1 expression in ICs, only the proportion score was used. Association between PD-L1 expression and clinicopathological variables was analyzed using Fisher's exact test. RESULTS: High intensity scores in TCs were observed in 18 of the 46 cases (39.1%) and low intensity scores were observed in 28 cases (60.9%). Applying the proportions, using cut-off values of ≥1% and 50%, positive scores in TCs were observed in 36 (78.3%) and 20 cases (43.5%), respectively. PD-L1-positive ICs were observed in 29 (63%) and seven cases (15.2%), using cut-off values of ≥1% and 10%, respectively. The high intensity scores in TCs correlated with lymph node metastasis (P = 0.008) and female gender (P = 0.017), although positive proportions in TCs or ICs were not significantly related to lymph node metastasis. A multivariate analysis showed that high intensity of PD-L1 expression in TCs was an independent risk factor for lymph node metastasis. CONCLUSIONS: The results suggested that high intensity of PD-L1 expression in TCs is associated with lymph node metastasis in cSCC.

DOI PubMed

Prognostic Factors and Long-Term Efficacy of Tonsillectomy in 17 Patients with Pustulotic Arthro-Osteitis.

Yuji Kan, Yasuyuki Sumikawa, Tokimasa Hida, Saeko Ajiki, Hisashi Uhara

The Eurasian journal of medicine   52 ( 1 ) 103 - 105  2020年02月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Significance of 5‐S‐Cysteinyldopa as a Marker for Melanoma

Kazumasa Wakamatsu, Satoshi Fukushima, Akane Minagawa, Toshikazu Omodaka, Tokimasa Hida, Naohito Hatta, Minoru Takata, Hisashi Uhara, Ryuhei Okuyama, Hironobu Ihn

International Journal of Molecular Sciences   21 ( 2 ) 432  2020年01月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Current clinical issue of skin lesions in patients with inflammatory bowel disease.

Tomoya Iida, Tokimasa Hida, Minoru Matsuura, Hisashi Uhara, Hiroshi Nakase

Clinical journal of gastroenterology   12 ( 6 ) 501 - 510  2019年12月  [査読有り]  [国内誌]

　概要を見る

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 PubMed

Durable response after cessation of anti-programmed death 1 therapy in four melanoma patients.

Toshiya Handa, Junji Kato, Yasuyuki Sumikawa, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Mao Fujioka, Tomoyuki Minowa, Yoshiyuki Matsui, Hisashi Uhara

The Journal of dermatology   46 ( 12 ) e461-e462 - e462  2019年12月  [査読有り]  [国際誌]

DOI PubMed

Docetaxel therapy for classic Kaposi's sarcoma.

Yuna Hosokawa, Junji Kato, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Hiroshi Sasaki, Yoshiyuki Matsui, Toshiya Handa, Hisashi Uhara

Asia-Pacific journal of clinical oncology   15 ( 3 ) 181 - 182  2019年06月  [査読有り]  [国際誌]

DOI PubMed

Efficacy of combined radiotherapy and anti-programmed death 1 therapy in acral and mucosal melanoma.

Junji Kato, Tokimasa Hida, Masanori Someya, Sayuri Sato, Masahide Sawada, Kohei Horimoto, Mao Fujioka, Tomoyuki Minowa, Yoshiyuki Matsui, Takaaki Tsuchiya, Mio Kitagawa, Kensei Nakata, Koh-Ichi Sakata, Toshihiko Torigoe, Hisashi Uhara

The Journal of dermatology   46 ( 4 ) 328 - 333  2019年04月  [査読有り]  [国際誌]

　概要を見る

Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti-programmed death 1 (PD-1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti-PD-1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti-PD-1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti-PD-1 therapy could be effective in some patients with mucosal melanoma.

DOI PubMed

Xeroderma pigmentosum group D: Report of a novel combination of ERCC2 variations and its phenotype.

Tokimasa Hida, Masae Okura, Keiju Kobayashi, Toshiharu Yamashita, Chikako Nishigori, Hisashi Uhara

The Journal of dermatology   46 ( 3 ) e81-e82 - e82  2019年03月  [査読有り]  [国際誌]

DOI PubMed

A case of childhood-onset cutaneous mastocytosis with loss of wild-type KIT allele.

Hida T, Okura M, Kamiya T, Yamamoto M, Hori T, Uhara H

Journal of the European Academy of Dermatology and Venereology : JEADV    2019年02月  [査読有り]

DOI PubMed

Successful rechallenge with nivolumab therapy after radiotherapy in mucosal melanoma.

Junji Kato, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Keiju Kobayashi, Masahide Sawada, Mao Fujioka, Takaaki Tsuchiya, Masanori Someya, Hisashi Uhara

The Journal of dermatology   46 ( 2 ) e72-e73 - e73  2019年02月  [査読有り]  [国際誌]

DOI PubMed

Halo formations around senile hemangiomas in diffuse plane normolipemic xanthomatosis associated with monoclonal gammopathy.

Tokimasa Hida, Hiroki Takahashi, Kohichi Takada, Hisashi Uhara

JAAD case reports   4 ( 10 ) 1034 - 1036  2018年11月  [査読有り]  [国際誌]

DOI PubMed

Transient hypogammaglobulinemia of infancy with no evidence of immunodeficiency other than atopic dermatitis: A case report and review of literature

Minowa T, Sumikawa Y, Hida T, Uhara H

J Cutan Immunol Allergy ( JOHN WILEY & SONS LTD )  1 ( 5 ) 174 - 175  2018年11月  [査読有り]

DOI

Nevus cells of cardiofaciocutaneous syndrome bear BRAF germ-line and somatic double mutations.

Tokimasa Hida, Sayuri Sato, Masae Okura, Hisashi Uhara

European journal of dermatology : EJD   28 ( 5 ) 704 - 705  2018年10月  [査読有り]  [国際誌]

DOI PubMed

Prognostic role of platelet to lymphocyte and lymphocyte to monocyte ratios in advanced melanoma treated with anti-programmed death-1.

Tomoyuki Minowa, Junji Kato, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Hisashi Uhara

European journal of dermatology : EJD   28 ( 5 ) 705 - 707  2018年10月  [査読有り]  [国際誌]

DOI PubMed

A case of subepidermal autoimmune bullous disease with autoantibodies against 200 and 290-kDa antigens

M. Sawada, T. Hida, H. Ujiie, H. Iwata, H. Uhara

Journal of the European Academy of Dermatology and Venereology   32 ( 9 ) e354 - e355  2018年09月  [査読有り]

担当区分：   責任著者

DOI PubMed

Novel COL7A1 mutation in a family with bullous dermolysis of the newborn: Phenotypic variability associated with a COL7A1 mutation within the same family.

Shota Takashima, Satoru Shinkuma, Yasuyuki Fujita, Ken Natsuga, Toshifumi Nomura, Tokimasa Hida, Shuku Ishikawa, Hideki Nakamura, Riichiro Abe, Hiroshi Shimizu

The Journal of dermatology   45 ( 9 ) e260-e261 - e261  2018年09月  [査読有り]  [国際誌]

DOI PubMed

Prognostic role of neutrophil to lymphocyte ratio in advanced melanoma treated with anti-programmed death-1 therapy.

Tomoyuki Minowa, Junji Kato, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Hisashi Uhara

The Journal of dermatology   45 ( 9 ) e250-e251 - e251  2018年09月  [査読有り]  [国際誌]

DOI PubMed

Cytokeratin 19 expression is a risk factor for metastasis in cutaneous squamous cell carcinoma

J. Kato, T. Hida, S. Sugita, T. Hasegawa, S. Kamiya, K. Horimoto, S. Sato, M. Sawada, H. Uhara

Journal of the European Academy of Dermatology and Venereology ( Blackwell Publishing Ltd )  32 ( 7 ) e299 - e301  2018年07月  [査読有り]

DOI

Granulocyte colony-stimulating factor-producing melanoma treated with the combination of dabrafenib and trametinib

T. Minowa, J. Kato, T. Hida, K. Horimoto, S. Sato, M. Sawada, H. Takahashi, H. Uhara

International Journal of Dermatology ( Blackwell Publishing Ltd )  57 ( 7 ) e31 - e33  2018年07月  [査読有り]

DOI PubMed

Cytokeratin 19 expression as a risk factor for metastasis in cutaneous squamous cell carcinoma.

Uhara Hisashi, Kato Junji, Hida Tokimasa

JOURNAL OF CLINICAL ONCOLOGY   36 ( 15 )  2018年05月  [査読有り]

DOI

Rechallenge With Nivolumab After Vemurafenib Treatment of Initially Nivolumab-Resistant Advanced Melanoma.

Junji Kato, Tokimasa Hida, Takafumi Kamiya, Sayuri Sato, Hitomi Takahashi, Toshihiko Torigoe, Hisashi Uhara

JAMA dermatology   154 ( 5 ) 621 - 622  2018年05月  [査読有り]  [国際誌]

DOI PubMed

Dermoscopic features distinctive for extraocular sebaceous carcinoma.

Kohei Horimoto, Junji Kato, Yasuyuki Sumikawa, Tokimasa Hida, Takafumi Kamiya, Sayuri Sato, Hitomi Takahashi, Masahide Sawada, Toshiharu Yamashita, Hisashi Uhara

The Journal of dermatology   45 ( 4 ) 487 - 490  2018年04月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Imiquimod 5% cream as a therapeutic option for extramammary Paget's disease.

Masahide Sawada, Junji Kato, Toshiharu Yamashita, Akihiro Yoneta, Tokimasa Hida, Kohei Horimoto, Sayuri Sato, Hisashi Uhara

The Journal of dermatology   45 ( 2 ) 216 - 219  2018年02月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Successful TS-1 monotherapy as the second-line treatment for advanced extramammary Paget's disease: A report of two cases.

Junji Kato, Tokimasa Hida, Toshiharu Yamashita, Shiori Kamiya, Kohei Horimoto, Sayuri Sato, Hitomi Takahashi, Masahide Sawada, Mao Yamada, Hisashi Uhara

The Journal of dermatology   45 ( 1 ) 80 - 82  2018年01月  [査読有り]  [国際誌]

　概要を見る

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 PubMed

Case of diffuse panbronchiolitis developed in a patient with epidermodysplasia verruciformis.

Naomi Kitayama, Satoshi Nakamizo, Yumi Nonomura, Yo Kaku, Yuichiro Endo, Teruki Dainichi, Masae Okura, Tokimasa Hida, Toshiharu Yamashita, Atsushi Otsuka, Kenji Kabashima

The Journal of dermatology ( WILEY )  44 ( 12 ) e363-e364 - e364  2017年12月  [査読有り]  [国際誌]

DOI PubMed

An adult case of cardiofaciocutaneous syndrome with BRAF mutation.

Sayuri Sato, Tokimasa Hida, Masae Okura, Aki Ishikawa, Toshiharu Yamashita

European journal of dermatology : EJD ( JOHN LIBBEY EUROTEXT LTD )  27 ( 4 ) 412 - 413  2017年08月  [査読有り]  [国際誌]

担当区分：   責任著者

DOI PubMed

Psoriasiform mycosis fungoides masquerading as tumourous plaques.

Yasuyuki Yamaguchi, Yasuyuki Fujita, Yu Hirata, Machiko Nishimura, Satoru Shinkuma, Ken Natsuga, Toshifumi Nomura, Tokimasa Hida, Naoko Kato, Hiroshi Shimizu

European journal of dermatology : EJD ( JOHN LIBBEY EUROTEXT LTD )  27 ( 3 ) 295 - 296  2017年06月  [査読有り]  [国際誌]

DOI PubMed

Serum cytokeratin 19 fragment 21-1 is a useful tumor marker for the assessment of extramammary Paget's disease.

Junji Kato, Yasuyuki Sumikawa, Tokimasa Hida, Takafumi Kamiya, Kohei Horimoto, Shiori Kamiya, Sayuri Sato, Hitomi Takahashi, Masahide Sawada, Toshiharu Yamashita

The Journal of dermatology ( WILEY )  44 ( 6 ) 666 - 670  2017年06月  [査読有り]  [国際誌]

　概要を見る

Cytokeratin 19 fragment 21-1 (CYFRA 21-1) has been used as a tumor marker for several malignancies. However, to date, no studies have assessed whether CYFRA 21-1 could be a useful marker for extramammary Paget's disease (EMPD). The present study aimed to evaluate the significance of CYFRA 21-1 as a serum tumor marker for EMPD progression. Concentrations of serum CYFRA 21-1 and carcinoembryonic antigen (CEA) in 13 cases of EMPD were measured prior to undergoing treatment at Sapporo Medical University Hospital from January 2014 to May 2016. Four of the 13 patients had lymph node metastases at diagnosis, but none had distant metastases. Immunohistochemistry indicated that all 13 primary tumors and four metastatic tumors in lymph nodes were positive for cytokeratin 19. Although none of the 13 patients showed high serum CEA levels, six patients (46.2%) had elevated serum CYFRA 21-1. Furthermore, CYFRA 21-1 was reduced in association with post-treatment tumor reduction in all six patients. Among these six patients, four developed recurrence and metastasis during the follow-up period. CYFRA 21-1 was re-elevated in all four of these patients; however, serum CEA was elevated only in the patient with distant metastasis. These results suggest that CYFRA 21-1 is more sensitive compared with CEA, and can be useful as a tumor marker for evaluating tumor progression and treatment efficacy in patients with EMPD.

DOI PubMed

Clinical and epidemiological analysis in 149 cases of rhododendrol-induced leukoderma.

Momoko Yoshikawa, Yasuyuki Sumikawa, Tokimasa Hida, Takafumi Kamiya, Kimi Kase, Yasue Ishii-Osai, Junji Kato, Yuji Kan, Shiori Kamiya, Yuki Sato, Toshiharu Yamashita

The Journal of dermatology ( WILEY )  44 ( 5 ) 582 - 587  2017年05月  [査読有り]  [国際誌]

　概要を見る

Rhododendrol-induced leukoderma is an acquired depigmentation that develops mainly at the contact site after repeated use of skin-whitening cosmetics containing rhododendrol. In most cases, cessation of further depigmentation or occurrence of repigmentation is observed after discontinuing the use of cosmetics. However, some patients develop vitiligo vulgaris through the spread of depigmentation into the non-exposed areas. Our study aims to investigate the patient-specific factors that may affect the extent of depigmentation or repigmentation, as well as development of vitiligo vulgaris. The degree of depigmentation of the face, neck and hands where exposed to rhododendrol was scored using photographs over time. The relationships between depigmentation score at first visit/improvement rate of depigmentation score and patient demographics were evaluated and three important clinical observations were made. First, repigmentation of the face was superior compared with that of the hands and neck, suggesting a possible role for the migration and differentiation of melanocyte stem cells from hair follicles, as a mechanism of repigmentation. Second, the intensity of rhododendrol exposure did not contribute to differences in the severity of depigmentation. This suggested a possibility of underlying genetic susceptibility to melanocyte cytotoxicity or immune reaction. Third, depigmentation score at first visit and past history of atopic dermatitis were significantly high in patients who developed vitiligo vulgaris. This suggested that severe chemical damage of melanocytes by rhododendrol leads to a higher risk of developing vitiligo vulgaris through the possible involvement of an immune reaction. These clinical observations may help to further understand the pathogenesis of rhododendrol-induced leukoderma.

DOI PubMed

Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination.

Mirei Shiki, Tokimasa Hida, Kokichi Sugano, Rie Kaneko, Takafumi Kamiya, Akihiro Sakurai, Toshiharu Yamashita

European journal of dermatology : EJD ( JOHN LIBBEY EUROTEXT LTD )  27 ( 1 ) 54 - 58  2017年02月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: Muir-Torre syndrome (MTS) is characterized by sebaceous neoplasms with internal malignancies and regarded as a variant of hereditary nonpolyposis colorectal cancer (HNPCC). Pathogenic variations of MTS have been identified in the MSH2, MLH1, and MSH6 genes, with the majority of variations located in MSH2. OBJECTIVES: To present an MTS patient who was the only individual with skin malignancies within a cancer-prone pedigree and to show the usefulness of RNA-based genetic analysis in the investigation of MTS. MATERIALS & METHODS: A 77-year-old man who had operated X-ray equipment at his workplace in his twenties was clinically diagnosed with MTS and investigated by RNA-based analysis, multiplex ligation-dependent probe amplification, and genomic DNA sequencing. RESULTS: The patient had suffered from sebaceous tumours, squamous cell carcinomas of the skin, and colon cancer. The patient's family history was remarkable for visceral malignant diseases. Genetic analysis revealed homologous recombination between two Alu elements within intron 4 and 5 of the MLH1 gene. The rearrangement caused a 1,222-bp deletion, including the entire exon 5. Deletion of exon 5 has previously been reported only in two patients with HNPCC, and not in patients with MTS. CONCLUSION: For the genetic analysis of MTS, the possibility of rare copy number variations of MLH1, as well as MSH2 variations, should be considered. RNA-based screening using puromycin is recommended in order to identify such variations. It remains unclear why only the proband among the pedigree had skin malignancies, however, the skin carcinogenesis might have been related to occupational radiation exposure.

DOI PubMed

Diagnosis of eight groups of xeroderma pigmentosum by genetic complementation using recombinant adenovirus vectors.

Toshiharu Yamashita, Masae Okura, Yasue Ishii-Osai, Tokimasa Hida

The Journal of dermatology   43 ( 10 ) 1167 - 1173  2016年10月  [査読有り]  [国際誌]

　概要を見る

Because patients with xeroderma pigmentosum (XP) must avoid ultraviolet (UV) light from an early age, an early diagnosis of this disorder is essential. XP is composed of seven genetic complementation groups, XP-A to -G, and a variant type (XP-V). To establish an easy and accurate diagnosis of the eight disease groups, we constructed recombinant adenoviruses that expressed one of the XP cDNA. When fibroblasts derived from patients with XP-A, -B, -C, -D, -F or -G were infected with the adenovirus expressing XPA, XPB, XPC, XPD, XPF or XPG, respectively, and UV-C at 5-20 J/m2 was irradiated, cell viability was clearly recovered by the corresponding recombinant adenoviruses. In contrast, XP-E and XP-V cells were not significantly sensitive to UV irradiation and were barely complemented by the matched recombinant adenoviruses. However, co-infection of Ad-XPA with Ad-XPE increased survival rate of XP-E cells after UV-C exposure. When XP-V cell strains, including one derived from a Japanese patient, were infected with Ad-XPV, exposed to UV-B and cultured with 1 mmol/L of caffeine, flow cytometry detected a characteristic decrease in the S phase in all the XP-V cell strains. From these results, the eight groups of XP could be differentiated by utilizing a set of recombinant adenoviruses, indicating that our procedure provides a convenient and correct diagnostic method for all the XP groups including XP-E and XP-V.

DOI PubMed

Biochemical effects of the flavanol-rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species.

Kazuya Hagiwara, Masae Okura, Yasuyuki Sumikawa, Tokimasa Hida, Atsushi Kuno, Yoshiyuki Horio, Toshiharu Yamashita

The Journal of dermatology   43 ( 10 ) 1174 - 1183  2016年10月  [査読有り]  [国際誌]

　概要を見る

An ingredient of fruit polyphenol, resveratrol, is known to have an inhibitory effect on melanogenesis. In order to examine the functional differences between resveratrol and other fruit polyphenols, we compared biochemical effects of a resveratrol-free polyphenol, flavanol-rich lychee fruit extract (FRLFE), with other phenolic compounds including resveratrol. FRLFE as well as hydroquinone and resveratrol suppressed growth of B16F1 melanoma cells more significantly than rhododendrol or arbutin. Resveratrol suppressed mushroom tyrosinase at the lowest concentration (23.0 μmol/L) among the compounds tested. FRLFE and hydroquinone suppressed tyrosinase at almost the same concentration (half maximal inhibitory concentration [IC50 ], 83.5 and 94.6 μmol/L, respectively), which was higher than rhododendrol, ascorbic acid and arbutin (IC50 , 245, 345 and 421 μmol/L, respectively). Western blot analysis revealed that although resveratrol decreased expressions of tyrosinase and tyrosinase-related protein 1, FRLFE did not affect their expressions. Both FRLFE and resveratrol suppressed antimycin A-mediated reactive oxygen species (ROS) production in melanocytic cells. Resveratrol-mediated ROS suppression was inhibited by nicotinamide, a SIRT1 inhibitor. However, FRLFE-mediated suppression was not affected by nicotinamide. Moreover, FRLFE directly decreased superoxide in vitro, as detected by superoxide dismutase-like scavenging activity assay. These results suggest that FRLFE can protect melanocytes from cytotoxicity caused by an excess amount of melanin and ROS in a different manner from resveratrol.

DOI PubMed

Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis.

Tokimasa Hida, Akihiro Yoneta, Kazumasa Wakamatsu, Kenji Yanagisawa, Yasue Ishii-Osai, Yuji Kan, Junji Kato, Toshiharu Yamashita

The Australasian journal of dermatology   57 ( 2 ) 145 - 9  2016年05月  [査読有り]  [国際誌]

　概要を見る

TNM staging is mainly used to evaluate the prognosis of melanoma patients. Serum biomarkers such as 5-S-cysteinyldopa (5-S-CD) have occasionally been used but most do not respond until the tumour burden becomes high. Recently, circulating melanoma cells (CMC) have been reported as a possible new biomarker to detect metastasis, monitor treatment response and predict prognosis. The object of this exploratory study was to evaluate the efficacy of CMC to detect metastasis and predict prognosis by cross-sectional and prospective observational analyses, respectively. Altogether 15 patients with stages II-IV melanoma were enrolled and CMC were enumerated by CellSearch system with cut-off values of two cells/7.5 mL. Serum 5-S-CD and lactate dehydrogenase (LDH) were also measured. The sensitivity of CMC and 5-S-CD for the detection of metastasis was 33 and 50%, respectively. The combination of CMC and 5-S-CD showed a sensitivity of 67%, the best performance among CMC, 5-S-CD, LDH and any combination of two of the markers. Additionally, a 30-month prospective observation showed that CMC could segregate patients with poorer prognosis. The median survival time for the patients with <2 CMC and those with ≥2 CMC was 19.5 and 4.5 months, respectively. The limitation of this study is the small sample size. These preliminary results indicate CMC may complement the efficacy of 5-S-CD to detect metastasis and can be a prognostic marker. Although there is still room for improvement to maximise the sensitivity, the CellSearch system is reproducible, standardised and suitable for multi-centre studies.

DOI PubMed

Nagashima-type palmoplantar keratosis caused by compound heterozygous mutations in SERPINB7.

Tokimasa Hida, Masae Okura, Takafumi Kamiya, Toshiharu Yamashita

European journal of dermatology : EJD   25 ( 2 ) 202 - 3  2015年04月  [査読有り]  [国際誌]

DOI PubMed

A case of oculocutaneous albinism type 4: aberrant expression of SLC45A2 transcript with exon skipping.

Tokimasa Hida, Masae Okura, Toju Tanaka, Toshiharu Yamashita

The Journal of dermatology ( WILEY-BLACKWELL )  41 ( 11 ) 1019 - 21  2014年11月  [査読有り]  [国際誌]

DOI PubMed

Pigmented mammary Paget's disease presenting with dermoscopic features of multiple dots.

Tokimasa Hida, Toshiharu Yamashita

The Australasian journal of dermatology ( WILEY-BLACKWELL )  55 ( 4 ) 260 - 2  2014年11月  [査読有り]  [国際誌]

DOI PubMed

Development of sarcoidosis during β-interferon therapy for melanoma.

Shiki M, Hida T, Yamashita T

The Journal of dermatology ( WILEY-BLACKWELL )  41 ( 9 ) 862 - 3  2014年09月  [査読有り]  [国際誌]

担当区分：   責任著者

DOI PubMed

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome: a case with a novelp63 mutation associated with abnormal keratohyalin granules

Tokimasa Hida, Kimi Kase, Takahiro Hamada, Mitsuhiro Matsuda, Takashi Hashimoto, Toshiharu Yamashita

EUROPEAN JOURNAL OF DERMATOLOGY ( JOHN LIBBEY EUROTEXT LTD )  24 ( 4 ) 495 - 497  2014年07月  [査読有り]

DOI PubMed

Influence of isoflavone intake and equol-producing intestinal flora on prostate cancer risk.

Yukiko Sugiyama, Naoya Masumori, Fumimasa Fukuta, Akihiro Yoneta, Tokimasa Hida, Toshiharu Yamashita, Machiko Minatoya, Yoshie Nagata, Mitsuru Mori, Hirokazu Tsuji, Hideyuki Akaza, Taiji Tsukamoto

Asian Pacific journal of cancer prevention : APJCP   14 ( 1 ) 1 - 4  2013年  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: The age-adjusted incidence rate of prostate cancer (PCa) has been reported to be lower among Asians than Western populations. A traditional Japanese meal, high in soybean products or isoflavones, may be associated with a decreased risk of PCa. Equol, which is converted from daidzein by human intestinal flora, is biologically more active than any other isoflavone aglycone. MATERIALS AND METHODS: We reviewed not only recent epidemiological studies on association of isoflavones with PCa risk, but also recent research on human intestinal bacteria responsible for converting daidzein into equol. Studies were systematically searched from the database published within the last 5 years of from 2008-2012. RESULTS: Five out of 6 articles showed significant association of isoflavones with a decreased risk of PCa, and two of them consistently showed that equol-producers carry a significantly reduced risk of PCa. Furthermore, 5 human intestinal bacteria that can convert daidzein into equol were identified in the last 5 years. CONCLUSIONS: If equol can reduce risk of PCa, a possible strategy for reducing the risk of PCa may be to increase the proportion of equol-producers by changing the intestinal flora to carrying an equol-producing bacterium with dietary alteration or probiotic technology.

DOI PubMed

Etanercept-induced lichen planus-like eruptions following the lines of Blaschko

Momoko Utsu, Tokimasa Hida, Hiroki Takahashi, Toshiharu Yamashita

EUROPEAN JOURNAL OF DERMATOLOGY ( JOHN LIBBEY EUROTEXT LTD )  22 ( 4 ) 544 - 545  2012年07月  [査読有り]

担当区分：   責任著者

DOI PubMed

Pigmented mammary Paget's disease mimicking melanoma: report of three cases

Tokimasa Hida, Akihiro Yoneta, Takahiro Nishizaka, Tousei Ohmura, Yasuyo Suzuki, Hidekazu Kameshima, Toshiharu Yamashita

EUROPEAN JOURNAL OF DERMATOLOGY ( JOHN LIBBEY EUROTEXT LTD )  22 ( 1 ) 121 - 124  2012年01月  [査読有り]

　概要を見る

Pigmented mammary Paget's disease (PMPD) is a rare subtype of mammary Paget's disease. The differential diagnosis of PMPD and melanoma is difficult clinically and sometimes histopathologically. Here we present three cases of PMPD with a variable-sized lesion. All cases showed an irregular-shaped black-brown macule, one of which was accompanied by nipple retraction. Dermoscopically, all cases showed reticular pigmentation with or without irregular black dots, regression structures and streaks, which were indistinguishable from those of melanoma. In all but one of the cases, preoperative examinations confirmed the presence of a subcutaneous mammary lesion. All patients underwent a total mastectomy with the histopathological results indicating invasive ductal carcinoma. These cases emphasize how difficult it is to distinguish PMPD from melanoma. Dermoscopic features also mimic those of melanoma, but the reticular pigmentation seen in all cases could be a feature specific to PMPD. For suspicious cases, histopathological assessment using immunohistochemistry is highly recommended.

DOI PubMed

Rab7 is a critical mediator in vesicular transport of tyrosinase-related protein 1 in melanocytes.

Tokimasa Hida, Hitoshi Sohma, Yasuo Kokai, Akinori Kawakami, Kuninori Hirosaki, Masae Okura, Noriko Tosa, Toshiharu Yamashita, Kowichi Jimbow

The Journal of dermatology   38 ( 5 ) 432 - 41  2011年05月  [査読有り]  [国際誌]

　概要を見る

How melanosomal proteins such as enzymic proteins (tyrosinase and tyrosinase-related proteins, Tyrps) and structural protein (gp100) are transported from Golgi to melanosomal compartments is not yet fully understood. A number of small GTPases have been found to be associated with melanosomes and we have identified one of them, Rab7, a regulator of vesicular transport, organelle motility, phospholipid signaling and cytosolic degradative machinery, as being involved in the transport of Tyrp1 from Golgi to stage I melanosomes. This study further characterizes the role of Rab7 as a regulator of differential sorting of melanosomal proteins in this process. Murine melanocytes were transiently transfected with a plasmid encoding either wild-type (Rab7WT), constitutively active (Rab7Q67L) or dominant-negative (Rab7N125I and Rab7T22N) Rab7. Through immunocytostaining and confocal laser scanning microscopy, we quantitatively compared the bio-distribution of melanosomal proteins between Rab7WT-expressing cells and mutant Rab7-expressing cells. We also characterized their differential elimination from melanosomal compartments by Rab7 by utilizing a proteasome inhibitor, MG132. Our findings indicate that Rab7 plays an important role in differential sorting of tyrosinase, Tyrp1 and gp100 in early melanogenesis cascade, and that it is more specifically involved with Tyrp1 than tyrosinase and gp100 in the trafficking from Golgi to melanosomes and the specific exit from the degradative process.

DOI PubMed

Cytokeratin expression patterns in multiple infundibulocystic basal cell carcinoma.

Tokimasa Hida, Kenji Saga, Tetsunori Kimura

Journal of cutaneous pathology   38 ( 3 ) 309 - 13  2011年03月  [査読有り]  [国際誌]

　概要を見る

Infundibulocystic basal cell carcinoma (IBCC) is a variant of basal cell carcinoma. Sporadic cases usually represent a solitary tumor and multiple IBCC is rare. There have been no reports in which the tumor differentiation is characterized immunohistochemically. We report a case of multiple IBCC which developed on a patient's scalp by performing histopathological and immunohistochemical examinations, using monoclonal antibodies against cytokeratins (CKs). A 76-year-old female had noticed multiple small papules on her scalp. She noticed that the tumors were growing when she underwent systemic chemotherapy for metastatic lung cancer. Routine histopathological specimens from skin biopsies revealed findings typical of IBCC. The tumor cells expressed CK14 and CK17. However, CK1 and CK10 were expressed only in a few cells in the inner area of the tumors. The present case is unique in two points. First, multiple tumors developed on the patient's scalp during the systemic chemotherapy for the lung cancer. Second, the tumor showed CK expression patterns characteristic to infundibular and trichilemmal epithelia.

DOI PubMed

Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway.

Tokimasa Hida, Kazumasa Wakamatsu, Elena V Sviderskaya, Andrew J Donkin, Lluis Montoliu, M Lynn Lamoreux, Bin Yu, Glenn L Millhauser, Shosuke Ito, Gregory S Barsh, Kowichi Jimbow, Dorothy C Bennett

Pigment cell & melanoma research   22 ( 5 ) 623 - 34  2009年10月  [査読有り]  [国際誌]

　概要を見る

Melanocortin-1 receptor (MC1R) and its ligands, alpha-melanocyte stimulating hormone (alphaMSH) and agouti signaling protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells. Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (A(y)/a and Mc1r(e)/ Mc1r(e)) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by alphaMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrn(mg-3J/mg-3J) or Mgrn1(md-nc/md-nc)) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP-MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.

DOI PubMed

Macrophage inhibitory cytokine-1: a new player in melanoma development.

Toshiharu Yamashita, Akihiro Yoneta, Tokimasa Hida

The Journal of investigative dermatology   129 ( 2 ) 262 - 4  2009年02月  [査読有り]  [国際誌]

　概要を見る

Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the TGF-beta superfamily. Although it has been reported to exhibit both tumorigenic and antitumorigenic activities, Boyle et al. report in this issue that MIC-1 expression was correlated with the tumorigenicity of melanoma cells. The elucidation of signaling pathways around MIC-1 might contribute to prospective targeting therapy for melanoma.

DOI PubMed

Spontaneous regression of bowenoid papulosis in a patient with acquired immunodeficiency syndrome after an increase in peripheral CD4+ T lymphocytes.

Akinori Kawakami, Kenji Saga, Ichiro Ono, Tokimasa Hida, Kowichi Jimbow, Toshiharu Yamashita

International journal of dermatology   48 ( 2 ) 210 - 2  2009年02月  [査読有り]  [国際誌]

DOI PubMed

Fulminant bowel-associated dermatosis-arthritis syndrome that clinically showed necrotizing fasciitis-like severe skin and systemic manifestations

A Kawakami, K Saga, T Hida, K Jimbow, H Takahashi

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY ( BLACKWELL PUBLISHING )  20 ( 6 ) 751 - 753  2006年07月  [査読有り]

DOI PubMed

Testicular swelling as the presenting sign of cutaneous malignant melanoma

T Hida, K Saga, J Ogino, M Kagaya, A Kamada, R Kaneko, K Jimbow, R Inoue, A Takahashi

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY ( BLACKWELL PUBLISHING )  20 ( 3 ) 351 - 353  2006年03月  [査読有り]

DOI PubMed

Exploitation of melanin and melanosome biogenesis for better management of malignant melanoma

Kowichi Jimbow, Toshiharu Yamashita, Hidenobu Matsusaka, Kuninori Hirosaki, Akihiro Yoneta, Asako Kamada, Hiroyoshi Inoue, Tokimasa Hida, Akinori Kawakami, Takafumi Kamiya, Jiro Ogino, Tomoaki Takada, Makito Sato, Akiko Sakemoto, Ichiro Ono

Sapporo Medical Journal ( 札幌医科大学 )  74 ( 3 ) 23 - 31  2005年08月

　概要を見る

Management of malignant melanoma is a difficult challenge for physicians and basic scientists because cutaneous melanoma grows in the highly vascular tissue of epidermo-dermal interface and occurs at any age of generation. It can easily spread to distant organs and practically no treatment modality is available except for early diagnosis and surgical excision. In this report we review our current research efforts in establishing novel diagnostic and therapeutic approaches for malignant melanoma by exploiting our knowledge of basic biology in melanin and melanosome biogenesis. This is based upon the fact that melanin and melanosome biogenesis is biological property uniquely expressed in melanocytes, and highly accelerated and altered in their neoplastic counterpart, malignant melanoma. It is immediately apparent if one looks at the past literatures that rapid and significant progress of cancer management has been made if the biological property unique to cancer cells is exploited.

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Local administration of hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds.

Ichiro Ono, Toshiharu Yamashita, Tokimasa Hida, Hai-Ying Jin, Yoshinori Ito, Hirobumi Hamada, Yoshikiyo Akasaka, Toshiharu Ishii, Kowichi Jimbow

The Journal of surgical research   120 ( 1 ) 47 - 55  2004年07月  [査読有り]  [国際誌]

　概要を見る

Hepatocyte growth factor (HGF) has a number of biological activities, e.g., mitogenic, motogenic, antiapoptotic, antifibrous, and morphogenic. It also has angiogenic and angioprotective activities for endothelial cells. The aim of this study was to characterize the role of HGF in wound healing by administering the HGF gene locally to acute incisional skin wounds created on the backs of rats. To create wounds, the backs of Wistar rats were clipped and three 2-cm-long incisional wounds were made deep to the fascia. The wounds contained pannicrus carnosum and were created at intervals of 2 cm. After suturing, the HGF gene was then administered intradermally. Apoptotic cells in wound lesions were identified by TUNEL method as well as by immunological detection of active caspase-3. In the HGF-treated animals, we found almost complete suppression of apoptosis and well-organized wound healing. Histopathological examination revealed that the proliferation of fibroblasts was suppressed and that scar formation was less apparent in the HGF-treated animals compared to the controls. It is thought that administration of the HGF gene immediately after surgery may enhance the healing process through suppressing apoptosis, which occurred in the controls 1 week after suturing the incisional wound. In addition, locally increased HGF expression due to the introduction of the HGF gene to cells around wounds enhances dermal regeneration, possibly by promoting regeneration of dermal tissue, which results in less scarring due to its antifibrotic effect. Thus, HGF supplementation through gene therapy may be an effective strategy for treating wounds, as it increases the regeneration of the dermis to allow for "scarless wound healing."

DOI PubMed

Combined administration of basic fibroblast growth factor protein and the hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds

Ono, I, T Yamashita, T Hida, HY Jin, Y Ito, H Hamada, Y Akasaka, T Ishii, K Jimbow

WOUND REPAIR AND REGENERATION ( BLACKWELL PUBLISHING INC )  12 ( 1 ) 67 - 79  2004年01月  [査読有り]

　概要を見る

Hepatocyte growth factor (HGF) is a ligand for the c-Met receptor tyrosine kinase. This study was aimed to characterize the role of the HGF gene combined with basic fibroblast growth factor (bFGF) protein in wound healing by administering both of them locally to acute incisional skin wounds created on the backs of rats. The bFGF protein and the HGF gene were administered intradermally after incisional surgery. Apoptotic cells in wound lesions were identified by the terminal deoxynucleotide transferase-mediated nick-end labeling method, as well as by immunological detection of active caspase-3. While there was almost complete suppression of apoptosis with well-organized wound healing in animals treated with the HGF gene, the combination of bFGF protein and the HGF gene paradoxically resulted in less scarring along with the promotion of apoptosis. Histopathological examination revealed that scar formation was least apparent in rats treated with both bFGF and the HGF gene compared with controls or those treated with the bFGF or the HGF gene alone. It is thought that the combined administration of bFGF and the HGF gene immediately after skin incision may make the healing process occur closer to tissue regeneration through the induction of apoptosis, which occurred 1 week after surgery. HGF supplementation through gene therapy combined with bFGF protein may be an effective strategy for treating wounds, as it increases the apparent regeneration of the dermis to allow for "scarless wound healing."

DOI PubMed

Carney complex: report of a Japanese case associated with cutaneous superficial angiomyxomas, labial lentigines, and a pituitary adenoma.

Hiroyuki Takahashi, Tokimasa Hida

The Journal of dermatology   29 ( 12 ) 790 - 6  2002年12月  [査読有り]  [国際誌]

　概要を見る

We report the case of a 12-year-old female patient who manifested multiple cutaneous angiomyxomas and labial pigmented lesions. Although the familial history was not confirmed in the present case, autosomal dominant inheritance has been reported to be involved in the pathogenesis of this condition. In addition to the cutaneous complications, magnetic resonance (MR) images revealed the presence of a pituitary adenoma, which provoked an elevation of serum growth hormone (GH) level. On the other hand, no significant symptoms such as cardiac myxoma, myxoid fibroadenoma of the breast, or adrenocortical complaints suggesting Cushing syndrome, were detected. In the Japanese literature, only a few cases of this disorder have been described in the form of brief reports. There have been only a few similar cases described in the dermatological field, except for one report diagnosed as Carney complex in 1990. Therefore, the present case seems to be the first Japanese case of typical Carney complex manifesting major clinical complications, including angiomyxomas, lentigines, and a pituitary adenoma, which induced endocrine overactivity.

DOI PubMed