Degree 【 display / non-display 】

Degree 【 display / non-display 】

• MD, PhD

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2022.06

  -

  2024.03

  Sapporo Medical University   Department of Dermatology   Associate Professor

• 2014.04

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  2022.05

  Sapporo Medical University   Department of Dermatology   Assistant Professor

• 2005.08

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  2007.08

  St George's University of London   Basic Medical Sciences   Visiting Research Fellow

  Visiting Research Fellow

• 2005.04

  -

  2014.03

  Sapporo Medical University   Department of Dermatology   Instructor

  Instructor

• 2002.04

  -

  2005.03

  Sapporo Medical University   Department of Dermatology   Resident

  Resident

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Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

• 　

  　

  　

  THE JAPAN SOCIETY OF HUMAN GENETICS

• 　

  　

  　

  日本臨床皮膚科医会

• 　

  　

  　

  Japanese Skin Cancer Society

• 　

  　

  　

  JAPANESE DERMATOLOGICAL ASSOCIATION

• 　

  　

  　

  The Japanese Society of Recklinghausen disease

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Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Medical biochemistry   clinical genetics

• Life sciences   Dermatology   skin cancers

• Life sciences   Dermatology   melanogenesis

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   School of Medicine, Dept.of Dermatology   Associate Professor   病院教授  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• genodermatosis

• melanin

• melanoma

• genetics

• clinical genetics

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Papers 【 display / non-display 】

Papers 【 display / non-display 】

• 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  2024.12  [Refereed]  [International journal]

  　View Summary

  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  2024.11  [Refereed]  [International journal]

  　View Summary

  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    2024.10  [Refereed]  [International journal]

  　View Summary

  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    2024.09  [Refereed]  [International journal]

  　View Summary

  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    2024.09  [Refereed]  [Domestic journal]

  　View Summary

  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

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 【メラノーマ診療Up-To-Date】メラノーマの治療選択における包括的がんゲノムプロファイリング検査

  肥田 時征, 加藤 潤史, 井戸川 雅史, 宇原 久

  皮膚病診療 ( (株)協和企画 )  46 ( 1 ) 28 - 33  2024.01

  　View Summary

  ＜文献概要＞ポイント ●包括的がんゲノムプロファイリング(comprehensive genome profiling:CGP,別名:がん遺伝子パネル)検査は,標準治療の終了した(または終了見込みの)固形癌患者が保険診療で受けることができ,現在5種類から選択できる.●CGP検査のエキスパートパネルで非承認薬や適応外薬が推奨された場合,その薬を使用するためには治験,先進医療,臨床研究などに参加する必要がある.●メラノーマでは,BRAFのまれな変異,融合遺伝子,KIT変異などが治療標的として検出される可能性がある.

• 【新規知見の乏しい皮膚疾患】aquagenic wrinkling of the palmsの2例

  小松 彩友香, 肥田 時征, 黄倉 真恵, 宇原 久

  皮膚病診療 ( (株)協和企画 )  45 ( 9 ) 802 - 805  2023.09

  　View Summary

  ＜文献概要＞症例のポイント ・aquagenic wrinkling of the palmsは手掌を浸水させると容易に白色浸軟化し,ときおり疼痛を伴う後天性の疾患である.治療法は確立されていない.・掌蹠に角化を伴う場合,本邦で頻度の高い長島型掌蹠角化症も鑑別になるが,そのほかに特徴的な臨床症状を伴い,SERPINB7遺伝子に病原性バリアントが検出される.

• メラノーマの治療選択におけるがん遺伝子パネル検査

  肥田 時征

  日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  133 ( 5 ) 1275 - 1275  2023.05

• MYO5A-NTRK3融合遺伝子を検出したatypical Spitz tumor

  佐藤 さゆり, 肥田 時征, 井戸川 雅史, 黄倉 真恵, 宇原 久

  日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  132 ( 5 ) 1363 - 1363  2022.05

• Melanoma and Non-Melanoma Skin Cancers メラノーマ・皮膚癌 メラノーマのゲノム異常

  肥田 時征

  癌と化学療法 ( (株)癌と化学療法社 )  49 ( 4 ) 409 - 412  2022.04

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Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• Comprehensive analysis of genetic mutations and fusions in Japanese melanoma

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2021.04

  -

  2024.03

   

  肥田 時征, 井戸川 雅史

• 美白化合物のメラノーマ細胞障害作用を利用した新規メラノーマ治療薬の開発

  奨励研究

  Project Year :

  2019

  　

  　

   

  黄倉 真恵, 宇原 久, 肥田 時征

  　View Summary

  BRAF遺伝子変異を有するメラノーマには分子標的薬が奏効するものの、のちに薬剤耐性が生じる場合が多い。本研究は、分子標的薬の耐性をアスコルビン酸、ロドデノールの併用で克服できるかどうかを検討した。結果、アスコルビン酸はBRAF/MEK阻害剤耐性メラノーマ細胞株SK-me1-23DT, ロドデノールはBRAF/MEK阻害剤耐性メラノーマ細胞株A375DTに強い細胞障害を誘発した。以上の結果から、アスコルビン酸とロドデノールは、分子標的薬(BRAF/MEK阻害薬)による耐性を克服しうる治療薬の候補となり得ることがわかった。

• Identification and analysis of tumor-associated genes of melanoma by functional assay

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2013.04

  -

  2016.03

   

  Yamashita Toshiharu

  　View Summary

  We aimed to examine the epigenetically silenced miRNA and its involvement in the induction of apoptosis of cultured melanoma cells. A screen for miRNAs induced by 5-aza-2’deoxycytidine (5-aza-dC) and interferon-beta (IFN-β) in TXM18 melanoma cells identified six species of miRNAs including miR-7, miR-203, miR-215 and miR-596. The CpG island of the miR-596 gene was strongly methylated in all melanoma cell lines tested (n = 20) whereas methylation levels were limited in melanocytes (n=4). Transfection of a precursor of miR-596 into melanoma cells induced growth suppression, indicating that the effect of 5-aza-dC plus IFN-β is in part due to induction of miR-596. Methylation levels of miR-596 were significantly higher in clinical specimens of melanoma as compared to benign melanocytic nevi.

• Analysis of melanosome transfer between melanocytes and keratinocytes

  Grant-in-Aid for Young Scientists (B)

  Project Year :

  2011

  -

  2013

   

  HIDA Tokimasa

  　View Summary

  A new co-culture method for melanocytes and keratinocytes has been developed. By using this method, melanosomal transfer from melanocytes to keratinocytes could be visualized with electron and optical microscopes and the melanin content of transferred melanosomes could be analyzed. The effect of inhibitors of melanin synthesis on melanosomal transfer could also be analyzed. To apply the result for clinical practice, the melanin distribution in the nipple skin of patients with pigmented mammary Paget's disease was examined with histopathology, immunohistochemistry and dermoscopy. It was suggested that tumor cells transferred melanin from reactive melanocytes are subject to passive elimination from the epidermis and form characteristic dermoscopic patterns. This finding is useful in diagnosing pigmented mammary Paget's disease.

• Development of novel melanoma therapy targeting SIRT1

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2010

  -

  2012

   

  YAMASITA Tosiharu, HORIO Yosiyuki, HIDA Tokimasa

  　View Summary

  SIRT1 was localized in the cytoplasm of melanoma cells and the SIRT1 inhibitor nicotinamide suppressed their migration. SIRT1 was detected with F -actin in the protuberance of the cell membrane and accumulated with PIP-3 and AKT. Nicotinamide inhibited the peritoneal invasion and lymph node metastasis of transplanted B16F1 cells in C57BL mice and extended their life span. These results indicate that SIRT1 inhibition may be applicable for the suppression of metastatic melanoma.

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Presentations 【 display / non-display 】

Presentations 【 display / non-display 】

• Mutation landscape of melanomas among Japanese: Custom panel sequencing of 77 cases

  Hida T, Idogawa M, Kato J, Horimoto K, Sato S, Kiniwa Y, Okura M, Okuyama R, Tokino T, Uhara H

  25th World Congress of Dermatology 

  Presentation date： 2023.07

  Event date：

  2023.07

  　

  　

• Copy number variations and fusion genes in driver mutation-negative melanoma

  Hida T, Idogawa M, Kato J, Horimoto K, Sato S, Kiniwa Y, Sugita S, Okura M, Okuyama R, Tokino T, Uhara H

  25th International Pigment Cell Conference 

  Presentation date： 2023.05

  Event date：

  2023.05

  -

  2023.06

• 線状の脱色素斑を伴ったfamilial progressive hyperpigmentation with or without hypopigmentationの１例

  肥田時征, 宇原 久

  第31回日本色素細胞学会学術大会 

  Presentation date： 2022.11

  Event date：

  2022.11

  　

  　

• 教育講演. 神経線維腫症1型 up date

  肥田 時征  [Invited]

  第424回日本皮膚科学会北海道地方会 

  Presentation date： 2020.12

  Event date：

  2020.12

  　

  　

• 教育講演．メラノーマの分子生物学的背景

  肥田時征  [Invited]

  第121回日本皮膚科学会総会 

  Presentation date： 2022.06

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Committee Memberships 【 display / non-display 】

Committee Memberships 【 display / non-display 】

• 2024

  -

  Now

    Councilor

• 2021

  -

  Now

    Director

• 2020

  -

  Now

    Councilor

• 2018.04

  -

  Now

    特別委員

• 2017.12

  -

  Now

    Councilor