Education 【 display / non-display 】

Education 【 display / non-display 】

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  1986

  Hokkaido University   Faculty of Medicine  

Degree 【 display / non-display 】

Degree 【 display / non-display 】

• Doctor of Medicine

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 1990.02

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  2017.01

  Shinshu University School of Medicine  

• 1990.02

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  1991.01

  諏訪赤十字病院皮膚科  

• 1986.06

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  1988.08

  Resident in Dermatology, Shinshu University School of Medicine  

Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  THE JAPANESE DERMATOLOGICAL ASSOCIATION

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  The Japanese Society for Plgment Cell Research

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  日本癌学会

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  ESMO

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  日本癌治療学会

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Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Dermatology  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   University Hospital, Dermatology   Professor &Chairman  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• cancer immunology

• immune related adverse events

• dermoscopy

• genetics

• Ultrasonography

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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  [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  [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  [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  [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  [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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Books and Other Publications 【 display / non-display 】

Books and Other Publications 【 display / non-display 】

• WHO Classification of Skin Tumours, 4th edition 2018

  UHARA Hisashi( Part： Joint author, melanoma, melanocytic nevus, mongolian spot)

  World Health Organization  2018.09

Misc 【 display / non-display 】

Misc 【 display / non-display 】

• Comprehensive single-cell immune profiling of tumor-infiltrating lymphocytes in acral melanoma

  箕輪智幸, 箕輪智幸, 村田憲治, 廣橋良彦, 宇原久, 鳥越俊彦

  日本病理学会会誌   112 ( 1 )  2023

  J-GLOBAL

• 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

• 病理組織学的に顕著なロゼット様構造を呈したALK陽性atypical Spitz tumor

  箕輪 智幸, 肥田 時征, 堀本 浩平, 加藤 潤史, 神谷 崇文, 杉田 真太朗, 井戸川 雅史, 宇原 久

  日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  131 ( 5 ) 1417 - 1417  2021.05

• カスタムパネルシーケンスを用いた日本人メラノーマのドライバー遺伝子の検出

  肥田 時征, 井戸川 雅史, 堀本 浩平, 加藤 潤史, 佐藤 さゆり, 藤岡 茉生, 丹下 正一朗, 時野 隆至, 宇原 久

  日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  131 ( 5 ) 1363 - 1363  2021.05

• Immunotherapy for advanced melanoma: Current situation in Japan

  Junji Kato, Hisashi Uhara

  Japanese Journal of Clinical Oncology ( Oxford University Press )  51 ( 1 ) 3 - 9  2021.01

  Book review, literature introduction, etc.  

  　View Summary

  Treatment with immune checkpoint inhibitors provides long-term survival for patients with advanced melanoma. Improvements in the overall survival of advanced melanoma patients have been achieved with anti-PD-1 monotherapy and anti-PD-1+ CTLA4 combination therapy, but there are still many issues to resolve. Acral, mucosal and uveal melanoma have been less responsive to immune checkpoint inhibitors than cutaneous melanoma. For patients who have achieved a good response, it is still not known how long the anti-PD-1 therapy should be administered. Moreover, there is limited treatment for patients who relapse during or after adjuvant anti-PD-1 therapy. Here, we review the current evidence regarding the clinical effects of immunotherapy for advanced melanoma. Moreover, we review previous studies of acral, mucosal and uveal melanoma, and we discuss the recent findings regarding durable response after the cessation of anti-PD-1 therapy, and treatment options for recurrence after adjuvant therapy.

  DOI PubMed

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• Best Doctors in Japan (2010-)

  2010  

• 第72回日本皮膚科学会東部支部学術大会学会賞（Best Clinical Award）

  2008  

• Certificate of Recognition for Outstanding Posters in the Category Invasive&non invasive techniques - Diagnostic tools

  2007  

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• メラノーマにおける複数の変異遺伝子を候補とした個別化リキッドバイオプシー法の確立

  基盤研究(C)

  Project Year :

  2022.04

  -

  2025.03

   

  宇原 久

• Characterization of the intratumoral ecosystem in melanoma by single-cell RNA-seq analysis

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2019.04

  -

  2022.03

   

  UHARA HISASHI

  　View Summary

  The aim of the study is to establish of the method to obtain the single-cell gene expression of RNA in melanoma cells from the resected tumor samples. The method is planned according to the following steps (Hashimoto S, Scientic Reports 7;14225, 2017). In the first case, over expression of MAPK pathway-related molecules and HLA class 1 and lower expression of HLA class 2 and PD-L1 were observed in melanoma cells in 2 of 5 clusters. However, in next 5 examined cases, synthesis of cDNA of a single cell was not stable. We thought that melanin blocked the enzyme activity. We have tried several methods to remove melanin from tissue samples, however it has not been sufficient yet. Now, we test other methods including filters.

• 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。

• メラノーマ患者の血液循環腫瘍由来RNAを用いた病勢モニタリング法の確立

  Project Year :

  2016

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  2018

   

  宇原久

  Authorship： Principal investigator

• 血液循環腫瘍DNAを用いたメラノーマ患者の遺伝子解析

  Project Year :

  2014

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  2016

   

  芦田敦子

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Committee Memberships 【 display / non-display 】

Committee Memberships 【 display / non-display 】

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    評議員、予後統計調査委員会委員

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    代議員、ガイドライン作成委員会委員