研究者詳細 - 肥田　時征

論文 - 肥田　時征

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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]

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]

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.

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]

Joining PCMR: Aspirations for Editorial Contributions.

Tokimasa Hida

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

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]

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.

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]

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.

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]

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.

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]

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.

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]

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.

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]

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.

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

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.

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]

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]

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.

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]

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]

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.

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]

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

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]

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.

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]

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]

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