Details of a Researcher - UHARA Hisashi

Papers - UHARA Hisashi

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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 2025.04 [International journal]

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 2025.01 [Domestic journal]

The genomic landscape of cutaneous squamous cell carcinoma in Japan.

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

The Journal of dermatology 2024.12 [International journal]

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 2024.12 [International journal]

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 2024.11 [International journal]

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 2024.10 [International journal]

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

Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review.

Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshiyuki Yano, Hiromu Suzuki, Akihiro Miyazaki, Kohichi Takada, Hisashi Uhara, Masato Furuhashi, Fumihito Hikage

Cells 13 ( 18 ) 2024.09 [International journal]

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

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]

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 2024.09 [Domestic journal]

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 2024.08 [International journal]

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 2024.07 [International journal]

当科における円形脱毛症に対するバリシチニブの治療経験

畠山瑞季, 菅裕司, 松田宇充, 濱田茉里奈, 織田美琴, 安食さえ子, 熊谷綾子, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 134 ( 6 ) 1657 - 1657 2024.05

ざ瘡症状が遷延した慢性再発性多発性骨髄炎(CRMO)の1例

半田稔也, 菅裕司, 熊谷綾子, 肥田時征, 宇原久, 木澤敏毅, 岡田葉平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 134 ( 6 ) 1660 - 1660 2024.05

Analysis of the immune microenvironment in the indolent form of primary cutaneous extranodal natural killer/T-cell lymphoma: A case report.

Risako Maeda, Tomoyuki Minowa, Junji Kato, Kohei Horimoto, Sayuri Sato, Yoshihiko Hirohashi, Toshihiko Torigoe, Hisashi Uhara

The Journal of dermatology 51 ( 4 ) e137-e138 2024.04 [International journal]

Long-term follow-up results from KEYNOTE-041: Phase 1b study of pembrolizumab in Japanese patients with advanced melanoma.

Kenji Yokota, Tatsuya Takenouchi, Yasuhiro Fujisawa, Satoshi Fukushima, Hiroshi Uchi, Takashi Inozume, Yoshio Kiyohara, Hisashi Uhara, Kazuhiko Nakagawa, Hiroshi Furukawa, Shirong Han, Masaru Watanabe, Kazuo Noguchi, Naoya Yamazaki

The Journal of dermatology 2024.03 [International journal]

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

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 2024.03 [International journal]

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 2024.02 [International journal]

【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

＜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.

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 2023.12 [International journal]

SJS進展型TENを発症した小児患者の2例

勝賀瀬なゆは, 菅裕司, 熊谷綾子, 小松彩友香, 小栗瑛実, 箕輪智幸, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 133 ( 12 ) 2853 - 2853 2023.11

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 ) 2023.10

Pemphigus vulgaris as an immune-related adverse event in recurrent metastatic esophageal squamous cell carcinoma treated with ipilimumab plus nivolumab: a case report and literature review

Hajime Nakamura, Aika Shionoya, Yohei Arihara, Naotaka Hayasaka, Tomohiro Kubo, Makoto Usami, Shintaro Sugita, Hisashi Uhara, Kohichi Takada

Frontiers in Immunology ( Frontiers Media SA ) 14 2023.09

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

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 2023.09 [International journal]

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.

【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

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 2023.06 [International journal]

メラノーマ細胞におけるtumor mutation burden及びmicrosatellite instabilityに対するtemozolomideの影響

澤田匡秀, 肥田時征, 神谷崇文, 箕輪智幸, 加藤潤史, 黄倉真恵, 井戸川雅史, 時野隆至, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 39回 229 - 229 2023.06

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 2023.05 [International journal]

SUFUの体細胞変異を検出したbasaloid follicular hamartomaの1例

浜田茉里奈, 肥田時征, 神谷宗文, 井戸川雅史, 山下利春, 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 ) 133 ( 5 ) 1403 - 1404 2023.05

北海道在住者におけるシラウオ生食による皮膚爬行症

阿部貴彦, 肥田時征, 神谷崇文, 江畑加奈子, 杉田真太朗, 兼古理恵, 鈴木昭, 田中美緒, 丸山治彦, 宇原久

日本臨床皮膚科医会雑誌 ( 日本臨床皮膚科医会 ) 40 ( 3 ) 471 - 471 2023.05

Analyzing the relationship between the efficacy of first-line immune checkpoint inhibitors and cumulative sun damage in Japanese patients with advanced BRAF wild-type nonacral cutaneous melanoma: A retrospective real-world, multicenter study.

Takashi Inozume, Kenjiro Namikawa, Hiroshi Kato, Shusuke Yoshikawa, Yukiko Kiniwa, Koji Yoshino, Satoru Mizuhashi, Takamichi Ito, Tatsuya Takenouchi, Shigeto Matsushita, Yasuhiro Fujisawa, Takamitsu Matsuzawa, Satoru Sugihara, Jun Asai, Hiroshi Kitagawa, Takeo Maekawa, Taiki Isei, Masahito Yasuda, Naoya Yamazaki, Hisashi Uhara, Yasuhiro Nakamura

Journal of dermatological science 110 ( 1 ) 19 - 26 2023.03 [International journal]

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

経カテーテル的大動脈弁植え込み術後の親水性ポリマー塞栓の1例

竹林文彦, 菅裕司, 佐藤知世, 肥田時征, 宇原久, 櫻田心太郎, 村上直人

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 133 ( 3 ) 541 - 541 2023.03

シラウオ生食後の皮膚爬行症の1例

阿部貴彦, 肥田時征, 宇原久, 杉田真太朗, 兼古理恵, 田中美緒, 丸山治彦

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 133 ( 3 ) 542 - 542 2023.03

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 ) 2023.02 [International journal]

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.

抗PD-1抗体が著効したNF1変異型末端型メラノーマの1例

松田宇充, 加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 黄倉真恵, 宇原久, 井戸川雅史, 時野隆至

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 133 ( 2 ) 271 - 272 2023.02

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 2023.01 [International journal]

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 2022.12 [International journal]

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.

Clinical history analysis of Japanese melanoma cases and characteristics of melanoma with childhood onset.

Akane Minagawa, Hisashi Uhara, Atsuko Ashida, Hiroshi Koga, Ryuhei Okuyama

The Journal of dermatology 49 ( 12 ) 1334 - 1337 2022.12 [International journal]

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

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 2022.11 [International journal]

抗PD-1抗体が著効したNF1-mutant acral melanoma肝転移の1例

松田宇充, 加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 黄倉真恵, 宇原久, 井戸川雅史, 時野隆至

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 132 ( 12 ) 2699 - 2699 2022.11

顔面に多発したbasaloid follicular hamartomaの1例

濱田茉里奈, 肥田時征, 神谷崇文, 宇原久, 井戸川雅史, 山下利春

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 132 ( 12 ) 2704 - 2704 2022.11

顔に繰り返した壊疽性膿皮症の1例

松田宇充, 菅裕司, 古舘和樹, 小栗瑛実, 小松彩友香, 細川夕菜, 藤岡茉生, 大橋隆宏, 米田大介, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 132 ( 12 ) 2697 - 2697 2022.11

Dermoscopy for Acral Melanocytic Lesions: Revision of the 3-step Algorithm and Refined Definition of the Regular and Irregular Fibrillar Pattern.

Toshiaki Saida, Hiroshi Koga, Hisashi Uhara

Dermatology practical & conceptual 12 ( 3 ) e2022123 2022.07 [International journal]

Immunomodulation of Melanoma by Chemo-Thermo-Immunotherapy Using Conjugates of Melanogenesis Substrate NPrCAP and Magnetite Nanoparticles: A Review

Yasuaki Tamura, Akira Ito, Kazumasa Wakamatsu, Takafumi Kamiya, Toshihiko Torigoe, Hiroyuki Honda, Toshiharu Yamashita, Hisashi Uhara, Shosuke Ito, Kowichi Jimbow

International Journal of Molecular Sciences 23 ( 12 ) 2022.06 [International journal]

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

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 2022.06 [Domestic journal]

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.

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 ( Springer Science and Business Media LLC ) 2022.06

クロタミトンによる肛囲・会陰皮膚潰瘍の2例

半田稔也, 神谷崇文, 箕輪智幸, 菅裕司, 肥田時征, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 132 ( 5 ) 1303 - 1303 2022.05

Delayed-onset abscopal effect after palliative radiotherapy for acral melanoma treated with anti-PD-1 therapy.

Hiroshi Sasaki, Junji Kato, Kohei Horimoto, Sayuri Sato, Yuna Hosokawa, Toshiya Handa, Eri Kobayashi, Kazuki Furudate, Haruka Sigyo, Takaaki Tsuchiya, Masanori Someya, Hisashi Uhara

The Journal of dermatology 49 ( 8 ) e255-e256 2022.03 [International journal]

Prognoses of patients with melanoma who continue/discontinue anti-programmed death-1 therapy after achieving a complete response in a real-world setting: a multicentre retrospective study.

Junji Kato, Kenjiro Namikawa, Jiro Uehara, Motoo Nomura, Yasuhiro Nakamura, Hisashi Uhara, Hiroshi Uchi, Shusuke Yoshikawa, Yukiko Kiniwa, Yoshiyuki Nakamura, Takuya Miyagawa, Shigeto Matsushita, Tatsuya Takenouchi, Naohito Hatta, Fumitaka Ohno, Taku Maeda, Satoshi Fukushima, Naoya Yamazaki

The British journal of dermatology 187 ( 4 ) 594 - 596 2022.03 [International journal]

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 ( Wiley ) 2022.03

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 2022.03 [International journal]

【遺伝性疾患と遺伝カウンセリング】Cowden症候群/PTEN過誤腫症候群

塩野谷愛香, 肥田時征, 水上都, 菅原太郎, 長谷川匡, 菅野康吉, 宇原久

皮膚病診療 ( (株)協和企画 ) 44 ( 3 ) 210 - 214 2022.03

【診断に苦慮した症例】初診時の主訴が上肢の片側性皮膚硬化であったWerner症候群

古舘和樹, 肥田時征, 黄倉真恵, 宇原久

皮膚病診療 ( (株)協和企画 ) 44 ( 1 ) 52 - 55 2022.01

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 2021.12 [International journal]

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 2021.08 [International journal]

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.

Expression of programmed cell death ligand 1 (PD-L1) at in situ and invasive extramammary Paget's disease and literature review.

Junji Kato, Shintaro Sugita, Kohei Horimoto, Sayuri Sato, Daisuke Yoneta, Masahide Sawada, Mao Fujioka, Tadashi Hasegawa, Hisashi Uhara

The Australasian journal of dermatology 62 ( 3 ) 412 - 414 2021.08 [International journal]

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

Five-year survival with nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma.

Hisashi Uhara, Yoshio Kiyohara, Jiro Uehara, Yasuhiro Fujisawa, Tatsuya Takenouchi, Masaki Otsuka, Hiroshi Uchi, Satoshi Fukushima, Hironobu Minami, Masahiro Hatsumichi, Naoya Yamazaki

The Journal of dermatology 48 ( 5 ) 592 - 599 2021.05 [International journal]

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

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

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 2021.04 [International journal]

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 2021.04 [International journal]

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.

メラノーマに特化したシーケンスパネルの開発

肥田時征, 堀本浩平, 加藤潤史, 佐藤さゆり, 藤岡茉生, 宇原久, 井戸川雅史, 丹下正一朗, 時野隆至

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 131 ( 3 ) 541 - 542 2021.03

工業用セメントによる全身性接触皮膚炎の1例

菅裕司, 半田稔也, 箕輪智幸, 神谷崇文, 宇原久, 澄川靖之

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 131 ( 1 ) 131 - 131 2021.01

肺扁平上皮癌に合併したBazex症候群の1例

塩野谷愛香, 肥田時征, 西坂尚大, 汐谷心, 宇原久

臨床皮膚科 ( (株)医学書院 ) 74 ( 13 ) 1101 - 1106 2020.12

＜文献概要＞70歳代,男性.初診の4ヵ月前から掌蹠,臀部,膝に角化性紅斑局面と爪甲の変形が出現した.Bazex症候群を疑い全身精査を行ったが異常はなかった.乾癬型薬疹も考え,被疑薬を中止したが皮疹は増悪したため,初診の4ヵ月後にCTを撮像したところ,右下肺野に結節が発見された.肺扁平上皮癌(pT3N0M0)であった.根治術後に皮疹と爪症状が著明に軽快した.Bazex症候群の本邦報告例(26例)を解析した結果,84%が皮疹先行例,11%が悪性腫瘍先行例であった.皮疹先行例のうち,腫瘍診断のタイミングは1年以内が73%,3年以内が95%であった.四肢末端に治療抵抗性の角化性紅斑と爪変形が出現した場合は本症候群を疑い,初診時に悪性腫瘍が発見されなくても2〜3年程度は,画像検査や内視鏡検査を含めた定期的な内臓癌の検査をする必要があると考えた.

工業用セメントによる全身性接触皮膚炎の一例

菅裕司, 澄川靖之, 半田稔也, 箕輪智幸, 神谷崇文, 宇原久

日本皮膚免疫アレルギー学会総会学術大会プログラム・抄録集 ( (一社)日本皮膚免疫アレルギー学会 ) 50回 209 - 209 2020.12

Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A-Induced Production of IL-36γ in Tonsillar Epithelial Cells.

Keiju Kobayashi, Ryuta Kamekura, Junji Kato, Shiori Kamiya, Takafumi Kamiya, Kenichi Takano, Shingo Ichimiya, Hisashi Uhara

The Journal of investigative dermatology 141 ( 6 ) 1533 - 1541 2020.11 [International journal]

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

Case of pneumatosis cystoides intestinalis with pemphigus vulgaris.

Eri Kobayashi, Yuji Kan, Takafumi Kamiya, Ayako Kumagai, Hisashi Uhara

The Journal of dermatology 47 ( 11 ) e412-e413 2020.11 [International journal]

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 2020.10 [International journal]

Two cases of angioedema without wheals induced by exercising or bathing.

Tomoyuki Minowa, Yasuyuki Sumikawa, Ayako Kumagai, Takafumi Kamiya, Hisashi Uhara

Allergology international : official journal of the Japanese Society of Allergology 69 ( 4 ) 648 - 649 2020.10 [International journal]

Cold urticaria comorbid with heat urticaria: A case report.

Takahiro Ohashi, Yuji Kan, Hiroyuki Takahashi, Daisuke Yoneta, Kimi Kase, Yasuyuki Sumikawa, Hisashi Uhara

The Journal of dermatology 47 ( 9 ) e325-e326 2020.09 [International journal]

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 ) 2020.08 [International journal]

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.

Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma.

Kenjiro Namikawa, Yoshio Kiyohara, Tatsuya Takenouchi, Hisashi Uhara, Hiroshi Uchi, Shusuke Yoshikawa, Sumiko Takatsuka, Hiroshi Koga, Naoko Wada, Hironobu Minami, Masahiro Hatsumichi, Yoshinobu Namba, Naoya Yamazaki

The Journal of dermatology 47 ( 11 ) 1257 - 1266 2020.08 [Refereed] [International journal]

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

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 2020.07 [International journal]

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.

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

Tokimasa Hida, Katsuhiko Tsukamoto, Masae Okura, Hisashi Uhara

The Journal of dermatology 2020.07 [International journal]

Regular sweating activities for the treatment of cholinergic urticaria with or without acquired idiopathic generalized anhidrosis.

Tomoyuki Minowa, Yasuyuki Sumikawa, Yuji Kan, Takafumi Kamiya, Hisashi Uhara

Dermatologic therapy 33 ( 4 ) e13647 2020.07 [International journal]

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

Real-world safety and efficacy data of ipilimumab in Japanese radically unresectable malignant melanoma patients: A postmarketing surveillance.

Naoya Yamazaki, Yoshio Kiyohara, Hisashi Uhara, Tetsuya Tsuchida, Keiko Maruyama, Naoki Shakunaga, Eijun Itakura, Akira Komoto

The Journal of dermatology 2020.06 [Refereed] [International journal]

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

Anti-PD1 checkpoint inhibitor therapy in acral melanoma: A multicentre study of 193 Japanese patients.

Y Nakamura, K Namikawa, K Yoshino, S Yoshikawa, H Uchi, K Goto, Y Nakamura, S Fukushima, Y Kiniwa, T Takenouchi, H Uhara, T Kawai, N Hatta, T Funakoshi, Y Teramoto, A Otsuka, H Doi, D Ogata, S Matsushita, T Isei, T Hayashi, Y Shibayama, N Yamazaki

Annals of oncology : official journal of the European Society for Medical Oncology 2020.06 [Refereed] [International journal]

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

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 2020.06 [International journal]

【まるわかり皮膚科生体検査診断ツールを完全マスター】(Part.2)皮膚の機能を評価しよう遺伝子検査皮膚悪性腫瘍

肥田時征, 宇原久

Visual Dermatology ( (株)学研メディカル秀潤社 ) 19 ( 臨時増刊号 ) 139 - 143 2020.06

進行期悪性黒色腫のバイオマーカーとしての血清NSEの有用性

佐藤さゆり, 加藤潤史, 堀本浩平, 黄倉真恵, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 5 ) 1248 - 1248 2020.05

コリン性蕁麻疹における定期的な発汗刺激の有効性に関する後方視的検討

箕輪智幸, 澄川靖之, 菅裕司, 神谷崇文, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 5 ) 1217 - 1217 2020.05

悪性黒色腫における各種PD-L1抗体による染色性の差異についての検証

米田大介, 加藤潤史, 箕輪智幸, 澤田匡秀, 神谷崇文, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 5 ) 1248 - 1248 2020.05

コリン性蕁麻疹における定期的な発汗刺激の有効性に関する後方視的検討

箕輪智幸, 澄川靖之, 菅裕司, 神谷崇文, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 5 ) 1217 - 1217 2020.05

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 2020.04 [Refereed] [International journal]

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.

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)の2例

執行延明, 西田彩華, 菅野莉英, 藤岡茉生, 大橋隆宏, 堀本浩平, 加藤潤史, 肥田時征, 宇原久, 村瀬和幸, 井山諭, 須釜佑介, 前田和男

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 3 ) 418 - 418 2020.03

腹部に生じた巨大な尖圭コンジローマ

石田倫子, 三苫千景, 中原真希子, 内博史, 肥田時征, 黄倉真恵, 宇原久, 古江増隆

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 82 ( 1 ) 3 - 4 2020.02

Successful therapy for diffuse cutaneous systemic sclerosis-induced digital ulcer treated with hyperbaric oxygen therapy.

Yuji Kan, Takafumi Kamiya, Ayako Kumagai, Yuna Hosokawa, Hisashi Uhara

The Journal of dermatology 47 ( 2 ) e62-e64 2020.02 [International journal]

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 2020.02 [Refereed] [International journal]

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.

神経線維腫を伴わない神経線維腫症1型2家系の遺伝子解析

肥田時征, 井戸川雅史, 石川亜貴, 水上都, 加藤潤史, 澄川靖之, 時野隆至, 宇原久

日本レックリングハウゼン病学会学術大会プログラム・抄録集 ( 日本レックリングハウゼン病学会 ) 11回 15 - 15 2020.02

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 ) 2020.01 [Refereed] [International journal]

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.

カルシフィラキシスにガス壊疽を合併した1例

小林英理, 堀本浩平, 西田彩華, 執行延明, 菅野莉英, 箕輪智幸, 藤岡茉生, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 1 ) 39 - 39 2020.01

発汗指導を行ったコリン性蕁麻疹12症例の検討

箕輪智幸, 澄川靖之, 菅裕司, 兼古理恵, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 1 ) 80 - 80 2020.01

メルケル細胞癌に対してアベルマブ投与を行った2例

執行延明, 細川夕菜, 箕輪智幸, 藤岡茉生, 佐藤さゆり, 堀本浩平, 加藤潤史, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 1 ) 40 - 40 2020.01

中毒疹様皮疹を契機に診断に至った全身性エリテマトーデス(SLE)の1例

西田彩華, 小林英理, 細川夕菜, 箕輪智幸, 熊谷綾子, 菅裕司, 神谷崇文, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 1 ) 39 - 39 2020.01

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 1 - 5 2019.12 [Refereed] [International journal]

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.

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 2019.12 [Refereed] [Domestic journal]

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.

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 2019.12 [Refereed] [International journal]

Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Japanese subgroup analysis from the phase 3 CheckMate 238 study.

Kenji Yokota, Hiroshi Uchi, Hisashi Uhara, Shusuke Yoshikawa, Tatsuya Takenouchi, Takashi Inozume, Kentaro Ozawa, Hironobu Ihn, Yasuhiro Fujisawa, Anila Qureshi, Veerle de Pril, Yasushi Otsuka, Jeffrey Weber, Naoya Yamazaki

The Journal of dermatology 46 ( 12 ) 1197 - 1201 2019.12 [Refereed] [International journal]

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

Eosinophilic fasciitis in a 2-year-old child treated with a combination of methotrexate and corticosteroids.

Yuji Kan, Hisashi Uhara, Shiori Kamiya, Ayako Kumagai, Toshiya Handa

The Journal of dermatology 46 ( 12 ) e474-e475 2019.12 [International journal]

Japanese real-world study of sequential nivolumab and ipilimumab treament in melanoma.

Arata Tsutsumida, Satoshi Fukushima, Kenji Yokota, Shusuke Yoshikawa, Osamu Yamasaki, Atsushi Tanemura, Ryuhei Okuyama, Hisashi Uhara, Yusuke Muto, Azusa Miyashita, Masashi Akiyama, Tatsuya Kaji, Hiroshi Koga, Junji Kato, Teruaki Katayama, Eijun Itakura, Naoya Yamazaki, Yoshio Kiyohara

The Journal of dermatology 46 ( 11 ) 947 - 955 2019.11 [Refereed] [International journal]

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

肘に全周性に発症した熱傷瘢痕癌の1例

西田彩華, 堀本浩平, 執行延明, 半田稔也, 菅野莉英, 松井馨之, 藤岡茉生, 大橋隆宏, 加藤潤史, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 11 ) 2336 - 2336 2019.10

ニボルマブによってリウマチ性多発筋痛症様症状を呈した1例

執行延明, 西田彩華, 菅野莉英, 箕輪智幸, 藤岡茉生, 堀本浩平, 加藤潤史, 肥田時征, 宇原久, 津田玲子, 高橋裕樹

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 11 ) 2336 - 2336 2019.10

体温上昇により誘発された血管浮腫の2例

箕輪智幸, 澄川靖之, 宇原久

アレルギーの臨床 ( (株)北隆館 ) 39 ( 11 ) 915 - 918 2019.10

[症例1]は18歳女性。アトピー性皮膚炎。体温上昇によって眼瞼腫脹が出現した。[症例2]は20歳女性。アトピー性皮膚炎。体温上昇によって眼瞼腫脹、アナフィラキシーが出現した。2症例とも補体は正常で、血管浮腫の家族歴はなく、蕁麻疹の合併もなかったため、体温上昇によって誘発された血管浮腫と考えた。入浴や運動による血管浮腫、アナフィラキシー、コリン性蕁麻疹はアトピー性皮膚炎を有する若年女性に好発するとされている。我々の症例はコリン性蕁麻疹の合併がなかったが経過を追いたい。(著者抄録)

自己免疫性水疱症例における免疫グロブリン大量療法後の血小板減少についての検討

小林英理, 菅裕司, 細川夕菜, 箕輪智幸, 米田大介, 熊谷綾子, 神谷崇文, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 11 ) 2335 - 2335 2019.10

メラノーマにおける抗PD-1抗体治療中止後の効果持続について

加藤潤史, 半田稔也, 松井馨之, 箕輪智幸, 藤岡茉生, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 澄川靖之, 宇原久

日本癌治療学会学術集会抄録集 ( (一社)日本癌治療学会 ) 57回 P160 - 2 2019.10

腹部に生じた巨大尖圭コンジローマの1例

石田倫子, 中原真希子, 内博史, 和田尚子, 宮崎玲子, 辻学, 中原剛士, 三苫千景, 肥田時征, 黄倉真恵, 宇原久, 古江増隆

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 81 ( 5 ) 438 - 438 2019.10

放射線治療を行った基底細胞癌症例の検討

西田彩華, 堀本浩平, 加藤潤史, 執行延明, 菅野莉英, 藤岡茉生, 大橋隆宏, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 9 ) 1909 - 1909 2019.08

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)の1例

執行延明, 西田彩華, 菅野莉英, 藤岡茉生, 大橋隆宏, 堀本浩平, 加藤潤史, 肥田時征, 宇原久, 井山諭, 前田和男, 須釜佑介

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 9 ) 1910 - 1910 2019.08

尋常性天疱瘡の治療中に腸管気腫症をきたした1例

小林英理, 菅裕司, 半田稔也, 松井馨之, 細川夕菜, 箕輪智幸, 熊谷綾子, 神谷崇文, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 9 ) 1909 - 1909 2019.08

末梢血中の腫瘍由来DNAを用いた悪性黒色腫に対するニボルマブの治療効果の評価

芦田敦子, 境澤香里, 奥山隆平, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 8 ) 1647 - 1647 2019.07

転移性悪性黒色腫のNivolumab治療における血清5-S-CDの有用性

面高俊和, 皆川茜, 古賀弘志, 奥山隆平, 若松一雅, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 8 ) 1648 - 1648 2019.07

局所麻酔薬アレルギー疑い患者の皮膚テスト陽性率と発作時の症状の検討

澄川靖之, 江畑加奈子, 神谷崇文, 菅裕司, 石井泰江, 肥田時征, 加藤潤史, 堀本浩平, 宇原久

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 81 ( 3 ) 253 - 253 2019.06

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 2019.06 [Refereed] [International journal]

Long-term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma.

Naoya Yamazaki, Yoshio Kiyohara, Hisashi Uhara, Jiro Uehara, Yasuhiro Fujisawa, Tatsuya Takenouchi, Masaki Otsuka, Hiroshi Uchi, Hironobu Ihn, Masahiro Hatsumichi, Hironobu Minami

Cancer science 110 ( 6 ) 1995 - 2003 2019.06 [Refereed] [International journal]

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

Clinical and Histopathologic Characteristics of Melanocytic Lesions on the Volar Skin Without Typical Dermoscopic Patterns.

Yasutomo Mikoshiba, Akane Minagawa, Hiroshi Koga, Yoshiharu Yokokawa, Hisashi Uhara, Ryuhei Okuyama

JAMA dermatology 155 ( 5 ) 578 - 584 2019.05 [International journal]

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

悪性黒色腫における抗PD-1抗体と放射線治療

加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 澤田匡秀, 藤岡茉生, 箕輪智幸, 松井馨之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 5 ) 1177 - 1177 2019.05

ペムブロリズマブの投与にて完全奏功を維持している陰部悪性黒色腫の1例

堀本浩平, 加藤潤史, 松井馨之, 佐々木洋, 細川夕菜, 澤田秀匡, 佐藤さゆり, 肥田時征, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 35回 116 - 116 2019.04

小児期発症の病歴を持つメラノーマの病理組織学的検討

皆川茜, 宇原久, 芦田敦子, 境澤香里, 古賀弘志, 奥山隆平

日本皮膚病理組織学会抄録集 ( 日本皮膚病理組織学会 ) 35回 50,31 - 50,31 2019.04

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 2019.04 [Refereed] [International journal]

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.

Bowen病に合併したMerkel細胞癌の1例

辻あすか, 大橋敦子, 三宅知美, 上條史尚, 古賀弘志, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 4 ) 560 - 560 2019.04

根治切除不能な化学療法未治療の悪性黒色腫に対するニボルマブとイピリムマブ併用第II相試験(最終報告)

内博史, 清原祥夫, 竹之内辰也, 宇原久, 古賀弘志, 山崎直也

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 35回 114 - 114 2019.04

ダーモスコピーで診断困難であった脂漏性角化症の臨床的特徴

皆川茜, 古賀弘志, 高沢裕子, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 4 ) 560 - 560 2019.04

Decrease of Anti-DSG3, but Not Anti-DSG1 Antibody, After Cessation of Sitagliptin Treatment in a Patient With Pemphigus Vulgaris.

Toshiya Handa, Takafumi Kamiya, Yasuyuki Sumikawa, Tomoyuki Minowa, Ayako Kumagai, Masahide Sawada, Hisashi Uhara

JAMA dermatology 155 ( 3 ) 391 - 393 2019.03 [International journal]

抗PD-1抗体治療で著効し、治療中断後も再発のない悪性黒色腫の4例

半田稔也, 加藤潤史, 松井馨之, 箕輪智幸, 藤岡茉生, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 3 ) 353 - 353 2019.03

結節性硬化症の皮膚病変に対するシロリムス外用療法の効果

肥田時征, 神谷崇文, 宇原久, 石川亜貴

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 3 ) 356 - 356 2019.03

アザチオプリンを投与中に汎発性帯状疱疹と汎血球減少を発症した1例

松井馨之, 澄川靖之, 箕輪智幸, 熊谷綾子, 神谷崇文, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 3 ) 356 - 356 2019.03

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 2019.02 [Refereed]

リツキシマブが原因と考えられたTEN型薬疹の1例

松井馨之, 澄川靖之, 箕輪智幸, 熊谷綾子, 神谷崇文, 宇原久, 村瀬和幸

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 1 ) 45 - 45 2019.01

クローン型脂漏性角化症(clonal seborrheic keratosis)のダーモスコピー所見

半田稔也, 加藤潤史, 藤岡茉生, 堀本浩平, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 1 ) 47 - 47 2019.01

Dermoscopy of Melanoma and Non-melanoma Skin Cancers.

Junji Kato, Kohei Horimoto, Sayuri Sato, Tomoyuki Minowa, Hisashi Uhara

Frontiers in medicine 6 180 - 180 2019 [International journal]

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

【皮膚科で使うMTXの完全マニュアル】(Part4)乾癬以外の皮膚疾患へのMTXの応用(case (16)) リンパ腫様丘疹症

神谷崇文, 宇原久

Visual Dermatology ( (株)学研メディカル秀潤社 ) 18 ( 1 ) 96 - 97 2018.12

Efficacy and safety of nivolumab in combination with ipilimumab in Japanese patients with advanced melanoma: An open-label, single-arm, multicentre phase II study.

Kenjiro Namikawa, Yoshio Kiyohara, Tatsuya Takenouchi, Hisashi Uhara, Hiroshi Uchi, Shusuke Yoshikawa, Sumiko Takatsuka, Hiroshi Koga, Naoko Wada, Hironobu Minami, Masahiro Hatsumichi, Suguru Asada, Yoshinobu Namba, Naoya Yamazaki

European journal of cancer (Oxford, England : 1990) 105 114 - 126 2018.12 [Refereed] [International journal]

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

血清CYFRA21-1値が病勢を反映した汗孔癌の1例

松井馨之, 加藤潤史, 藤岡茉生, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 12 ) 2666 - 2666 2018.11

DPP-4阻害薬内服中に発症した尋常性天疱瘡の1例

半田稔也, 神谷崇文, 丸尾亜紀, 箕輪智幸, 大橋隆宏, 江畑加奈子, 熊谷綾子, 澄川靖之, 宇原久, 澤田匡秀, 兼古理恵

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 12 ) 2665 - 2665 2018.11

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 2018.11 [Refereed] [International journal]

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 2018.11 [Refereed]

Topline results from phase II of combination treatment with canerpaturev (HF10), an oncolytic viral immunotherapy, and ipilimumab in patients with unresectable or metastatic melanoma after anti-PD-1 therapy

T. Isei, K. Yokota, H. Uhara, Y. Fujisawa, T. Takenouchi, Y. Kiyohara, H. Uchi, H. Saruta, H. Ihn, T. Inozume, D. Watanabe, A. Takahashi, S. Fukushima, M. Tanaka, N. Yamazaki

Annals of oncology : official journal of the European Society for Medical Oncology 29 viii452 - viii453 2018.10 [Refereed]

体温上昇により誘発された血管浮腫の2例

箕輪智幸, 澄川靖之, 半田稔也, 熊谷綾子, 神谷崇文, 宇原久

日本皮膚免疫アレルギー学会雑誌 ( (一社)日本皮膚免疫アレルギー学会 ) 2 ( 1 ) 164 - 164 2018.10

痔核硬化剤に添加された亜硫酸塩の過敏症と考えられた1例

半田稔也, 箕輪智幸, 大橋隆宏, 江畑加奈子, 熊谷綾子, 神谷崇文, 澄川靖之, 宇原久

日本皮膚免疫アレルギー学会雑誌 ( (一社)日本皮膚免疫アレルギー学会 ) 2 ( 1 ) 184 - 184 2018.10

小児毛孔性紅色粃糠疹にビタミンA製剤が奏効した1例

菅裕司, 澄川靖之, 宇原久

日本皮膚免疫アレルギー学会雑誌 ( (一社)日本皮膚免疫アレルギー学会 ) 2 ( 1 ) 181 - 181 2018.10

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 - 251 2018.09 [Refereed] [International journal]

【皮膚科専門医が教える! がん治療に伴う"危険な"皮膚障害の診かたと考えかた】

宇原久

Cancer Board Square 4 ( 2 ) 204 - 231 2018.07 [Refereed]

ニボルマブ投与中に発症した扁平苔癬の1例

松井馨之, 加藤潤史, 藤岡茉生, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 8 ) 1665 - 1665 2018.07

ピロ亜硫酸ナトリウムによる過敏症と診断した1例

半田稔也, 箕輪智幸, 大橋隆宏, 江畑加奈子, 熊谷綾子, 神谷崇文, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 8 ) 1664 - 1664 2018.07

温熱負荷によって誘発されたangioedemaの1例

箕輪智幸, 澄川靖之, 半田稔也, 熊谷綾子, 神谷崇文, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 8 ) 1665 - 1665 2018.07

抗PD-1抗体で治療した悪性黒色腫における好中球リンパ球比、血小板リンパ球比、リンパ球単球比の意義

箕輪智幸, 加藤潤史, 松井馨之, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 34回 127 - 127 2018.06

BRAF/MEK阻害薬が奏効したG-CSF産生悪性黒色腫の1例

箕輪智幸, 加藤潤史, 江畑可奈子, 高橋仁美, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 宇原久, 佐藤勉

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 80 ( 3 ) 290 - 290 2018.06

直腸癌の多発皮膚転移

加瀬貴美, 加藤潤史, 澄川靖之, 肥田時征, 杉田真太朗, 宇原久

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 80 ( 3 ) 181 - 182 2018.06

膝窩にセンチネルリンパ節を同定した足原発の悪性黒色腫の当科におけるまとめ

堀本浩平, 加藤潤史, 肥田時征, 佐藤さゆり, 澤田匡秀, 佐々木洋, 井上夕菜, 松井馨之, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 34回 163 - 163 2018.06

ニボルマブ投与後にイピリムマブを使用した進行期悪性黒色腫の9例

佐藤美聡, 宇原久, 古賀弘志, 奥山隆平

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 80 ( 3 ) 301 - 301 2018.06

根治切除不能な化学療法未治療の悪性黒色腫に対するニボルマブ(NIV)とイピリムマブ(IPI)併用第II相試験

竹之内辰也, 清原祥夫, 宇原久, 古賀弘志, 内博史, 山崎直也

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 34回 149 - 149 2018.06

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 ) 2018.05 [Refereed]

乳房外Paget病に対するセカンドラインとしてのTS-1療法

加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 澤田匡秀, 藤岡茉生, 松井馨之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 5 ) 1221 - 1221 2018.05

悪性黒色腫における好中球・リンパ球比,血小板・リンパ球比,リンパ球・単球比と病期との関連

松井馨之, 加藤潤史, 箕輪智幸, 澤田匡秀, 佐藤さゆり, 堀本浩平, 神谷崇文, 肥田時征, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 5 ) 1235 - 1235 2018.05

Safety and efficacy of nivolumab in Japanese patients with malignant melanoma: An interim analysis of a postmarketing surveillance

Yoshio Kiyohara, Hisashi Uhara, Yoshihiko Ito, Noritake Matsumoto, Tetsuya Tsuchida, Naoya Yamazaki

Journal of Dermatology ( Blackwell Publishing Ltd ) 45 ( 4 ) 408 - 415 2018.04 [Refereed]

A postmarketing surveillance study is ongoing to evaluate nivolumab treatment for Japanese patients with malignant melanoma and accumulate data on all adverse events (AE) and efficacy. In this interim analysis, we evaluated data from approximately 100 Japanese medical institutions obtained from the nivolumab approval date in Japan (4 July 2014) through 3 July 2016. Patients were monitored during the first 12 months of treatment. Nivolumab was administrated by i.v. infusion (2 mg/kg every 3 weeks). A total of 680 and 610 patients were evaluated for safety and efficacy, respectively. The incidences of adverse drug reactions (ADR) and grade 3 or higher ADR were 53.53% and 12.35%, respectively. Predominant ADR included hypothyroidism (11.32%) and abnormal enzyme activity, such as increase of aspartate aminotransferase (7.79%), alanine aminotransferase (6.76%), alkaline phosphatase (6.18%) and γ-glutamyltransferase (5.44%). Grade 3 or higher ADR of special interest with an incidence of 1% or higher were hepatic function disorder (2.50%), colitis/diarrhea (2.06%) and infusion reaction (1.32%). No cases of encephalitis or venous thromboembolism, other AE of special interest, were observed. The estimated median overall survival was 379 days (95% confidence interval [CI], 290–not reached [NR]) in the overall population, NR (95% CI, 305–NR) for cutaneous melanoma and 340 days (95% CI, 275–NR) for mucosal melanoma. The improvement rate based on the antitumor response at the last evaluation was 22.2% (131/590 patients). No new safety concerns were raised, and serious ADR of special interest were infrequent. Nivolumab showed equivalent efficacy in patients with mucosal melanoma and those with cutaneous melanoma.

右示指の黒色斑を伴った紅色結節

箕輪智幸, 神谷崇文, 亀倉南穂, 加藤潤史, 肥田時征, 宇原久

日本皮膚病理組織学会抄録集 ( 日本皮膚病理組織学会 ) 34回 52,19 - 52,19 2018.04

膝窩センチネルリンパ節を同定した右母趾悪性黒色腫の1例

佐々木洋, 堀本浩平, 加藤潤史, 肥田時征, 佐藤さゆり, 澤田匡秀, 井上夕菜, 松井馨之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 4 ) 608 - 608 2018.04

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 2018.04 [Refereed] [International journal]

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.

乳児臀部肉芽腫の1例

丸尾亜紀, 箕輪智幸, 江畑加奈子, 大橋隆宏, 神谷崇文, 澄川靖之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 4 ) 608 - 608 2018.04

ドセタキセル療法が奏効した古典型カポジ肉腫の1例

井上夕菜, 加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 澤田匡秀, 佐々木洋, 松井馨之, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 4 ) 609 - 609 2018.04

アトピー性皮膚炎を合併したtransient hypogammaglobulinemia of infancyの1例

箕輪智幸, 澄川靖之, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 4 ) 607 - 607 2018.04

寒冷蕁麻疹の2例

大橋隆宏, 澄川靖之, 高橋宏征, 米田大介, 山口華央, 加瀬貴美, 菅裕司, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 4 ) 607 - 607 2018.04

Recent advances in therapeutic strategies for unresectable or metastatic melanoma and real-world data in Japan

Hisashi Uhara

International Journal of Clinical Oncology ( Springer Tokyo ) 1437-7772 (Electronic) 1 - 7 2018.02 [Refereed]

New therapeutic strategies including immunotherapy and selective molecular target inhibitors have brought about a new era in the treatment of patients with advanced melanoma. In Japan, the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab, the BRAF inhibitor (BRAFi) vemurafenib, dabrafenib and MEK inhibitor (MEKi) trametinib have been available for the treatment of unresectable and metastatic melanoma. The BRAFi + MEKi combination shows high response rates (60–70%) and rapid response induction associated with symptom control, with a progression-free survival of 12 months. Nivolumab and pembrolizumab offer moderate response rates (30–40%) and long survival (3- to 5-year survival: 30–50%). In Japan, treatment options for the first-line setting frequently include nivolumab or pembrolizumab monotherapy and BRAFi + MEKi combinations (for patients with BRAF-mutant melanoma). Ipilimumab is included in the second-line setting, and the nivolumab + ipilimumab combination has not been approved yet in Japan. Although these medications have demonstrated impressive efficacy, the clinical trials and real-world data have shown that the clinical benefit is not fully satisfactory. We have to carefully manage a new class of adverse events due to these medicines. Moreover, biomarkers are emerging with which we can identify a population that would experience more benefits without severe adverse events.

巨大な褐色斑と多発性色素性母斑を伴ったびまん性神経線維腫

肥田時征, 杉田真太朗, 菅原太郎, 山下利春, 宇原久

日本レックリングハウゼン病学会学術大会プログラム・抄録集 ( 日本レックリングハウゼン病学会 ) 9回 30 - 30 2018.02

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 2018.02 [Refereed] [International journal]

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.

乳房Paget病のダーモスコピー所見の検討

江畑加奈子, 肥田時征, 澄川靖之, 宇原久, 久冨五郎, 前田和男, 疋田政博, 松本光博

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 1 ) 59 - 59 2018.01

悪性黒色腫患者における好中球・リンパ球比の有用性

松井馨之, 加藤潤史, 箕輪智幸, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 1 ) 62 - 62 2018.01

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 2018.01 [Refereed] [International journal]

局所麻酔薬による即時型アレルギーが疑われた38例についての検討

江畑加奈子, 澄川靖之, 肥田時征, 神谷崇文, 石井泰江, 菅裕司, 加藤潤史, 堀本浩平, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 1 ) 62 - 62 2018.01

肺扁平上皮癌を合併したBazex症候群の1例

塩野谷愛香, 肥田時征, 宇原久, 西坂尚大, 汐谷心

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 128 ( 1 ) 63 - 63 2018.01

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

Hida, T. Sato, S. Okura, M. Uhara, H

Eur J Dermatol 1952-4013 (Electronic) 2018 [Refereed]

Multiple Melanonychia Striata as a Sign of Connective Tissue Disorders

Edamitsu, T. Uhara, H. Minagawa, A. Okuyama, R

J Am Acad Dermatol 1097-6787 (Electronic) 2018 [Refereed]

Efficacy and toxicity of ipilimumab used after nivolumab in patients with melanoma

Sato, M. Uhara, H. Koga, H. Okuyama, R

J Dermatol 45 ( 10 ) 287 - 289 2018 [Refereed]

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

Hida, T. Okura, M. Kobayashi, K. Yamashita, T. Nishigori, C. Uhara, H

J Dermatol 1346-8138 (Electronic) 2018 [Refereed]

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

Kamiya, S. Kato, J. Kamiya, T. Yamashita, T. Sumikawa, Y. Hida, T. Horimoto, K. Sato, S. Takahashi, H. Sawada, M. Kubo, T. Torigoe, T. Uhara, H

Asia Pac J Clin Oncol 1743-7563 (Electronic) 2018 [Refereed]

Serum 5-S-cysteinyldopa behavior in the early phase of nivolumab treatment of 12 melanoma patients

Omodaka, T. Minagawa, A. Uhara, H. Wakamatsu, K. Koizumi, T. Yokokawa, Y. Koga, H. Okuyama, R

J Dermatol 1346-8138 (Electronic) 2018 [Refereed]

Successful rechallenge with nivolumab therapy after radiotherapy in mucosal melanoma

Kato, J. Hida, T. Horimoto, K. Sato, S. Kobayashi, K. Sawada, M. Fujioka, M. Tsuchiya, T. Someya, M. Uhara, H

J Dermatol 1346-8138 (Electronic) 2018 [Refereed]

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

Kato, J. Hida, T. Kamiya, T. Sato, S. Takahashi, H. Torigoe, T. Uhara, H

JAMA Dermatol 154 ( 5 ) 621 - 622 2018 [Refereed]

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

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

J Eur Acad Dermatol Venereol 32 ( 7 ) 299 - 301 2018 [Refereed]

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

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

Int J Dermatol 57 ( 7 ) 31 - 33 2018 [Refereed]

Unique dermoscopic feature of a long-standing pencil core granuloma on the head

Yoshikawa, M. Kamiya, T. Sumikawa, Y. Uhara, H

J Dermatol 1346-8138 (Electronic) 2018 [Refereed]

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

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

Eur J Dermatol 1952-4013 (Electronic) 2018 [Refereed]

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

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

J Eur Acad Dermatol Venereol 1468-3083 (Electronic) 2018 [Refereed]

Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan

Uhara, H. Kiyohara, Y. Tsuda, A. Takata, M. Yamazaki, N

Clin Transl Oncol 20 ( 2 ) 169 - 175 2018 [Refereed]

Circulating tumour DNA for monitoring treatment response to anti-PD-1 immunotherapy in melanoma patients

Atsuko Ashida, Kaori Sakaizawa, Hisashi Uhara, Ryuhei Okuyama

Acta Dermato-Venereologica ( Medical Journals/Acta D-V ) 97 ( 10 ) 1212 - 1218 2017.11 [Refereed]

Anti-programmed cell death-1 (anti-PD-1) antibody shows high therapeutic efficacy in patients with advanced melanoma. However, assessment of its therapeutic activity can be challenging because of tumour enlargement associated with intratumoural inflammation. Because circulating tumour DNA (ctDNA) correlates with tumour burden, we assessed the value of ctDNA levels as an indicator of tumour changes. Quantification of ctDNA (BRAFmutant or NRASmutant) levels by droplet digital PCR in 5 patients with BRAF or NRAS mutant melanoma during the treatment course showed dynamic changes corresponding to radiological and clinical alterations. In 3 cases in which the anti- PD-1 antibody was effective, ctDNA levels decreased within 2–4 weeks after treatment initiation. In 2 cases in which the anti-PD-1 antibody was ineffective, ctDNA levels did not decrease after treatment initiation. ct- DNA could be a useful biomarker to predict early response to treatment in patients with advanced melanoma treated with anti-PD-1 immunotherapy.

Phase 2 study to evaluate efficacy and safety of combination therapy with nivolumab (NIVO) and ipilimumab(IPI) in patients with previously untreated melanoma

Y. Kiyohara, T. Takenouchi, H. Uhara, H. Koga, H. Uchi, N. Yamazaki

Annals of Oncology ( Elsevier {BV} ) 28 x113 - x114 2017.11

Circulating tumor DNA for monitoring treatment response to anti-PD-1 immunotherapy in melanoma patients

A. Ashida, K. Sakaizawa, H. Uhara, R. Okuyama

JOURNAL OF INVESTIGATIVE DERMATOLOGY ( ELSEVIER SCIENCE INC ) 137 ( 10 ) S291 - S291 2017.10 [Refereed]

【がん分子標的薬の効果と副作用-期待される効果と評価-】抗体薬抗PD-1抗体薬、抗CTLA-4抗体薬

宇原久

日本臨床 75 ( 9 ) 1359 - 1364 2017.09 [Refereed]

Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan

Shigeaki Suzuki, Nobuhisa Ishikawa, Fumie Konoeda, Nobuhiko Seki, Satoshi Fukushima, Kikuko Takahashi, Hisashi Uhara, Yoshikazu Hasegawa, Shinichiro Inomata, Yasushi Otani, Kenji Yokota, Takashi Hirose, Ryo Tanaka, Norihiro Suzuki, Makoto Matsui

NEUROLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 89 ( 11 ) 1127 - 1134 2017.09 [Refereed]

Objective: To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan. Methods: We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used. Results: There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 6 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity. Conclusions: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.

Nail apparatus melanoma thickness is associated with side and age

A. Minagawa, T. Omodaka, H. Koga, Y. Yokokawa, H. Uhara, R. Okuyama

BRITISH JOURNAL OF DERMATOLOGY ( WILEY ) 177 ( 3 ) E65 - E66 2017.09 [Refereed]

【免疫チェックポイント阻害薬がん薬物療法の新時代】各腫瘍における免疫チェックポイント阻害薬の現状悪性黒色腫

宇原久

薬事 59 ( 12 ) 2403 - 2407 2017.09 [Refereed]

抗PD-1抗体をベースとした各種併用療法

宇原久

がん免疫療法 1 ( 2 ) 90 - 91 2017.09 [Refereed]

BRAF/MEK阻害薬が奏効した悪性黒色腫の2例

箕輪智幸, 加藤潤史, 江畑加奈子, 高橋仁美, 澤田匡秀, 佐藤さゆり, 堀本浩平, 肥田時征, 宇原久, 西川武志

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 127 ( 9 ) 2121 - 2121 2017.08

複数の自己抗体を検出した自己免疫性表皮下水疱症の1例

澤田匡秀, 肥田時征, 氏家英之, 泉健太郎, 西江渉, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 127 ( 9 ) 2117 - 2117 2017.08

強皮症に合併した指尖部潰瘍に対し高圧酸素療法が奏功した1例

安食さえ子, 菅裕司, 高橋宏征, 米田大介, 山口華央, 神谷詩織, 加瀬貴美, 澄川靖之, 米田明弘, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 127 ( 9 ) 2118 - 2118 2017.08

眼瞼外脂腺癌のダーモスコピー所見と対応する皮膚病理所見の検討

堀本浩平, 加藤潤史, 澤田匡秀, 高橋仁美, 佐藤さゆり, 石井泰江, 神谷崇文, 肥田時征, 澄川靖之, 宇原久

日本皮膚病理組織学会抄録集 ( 日本皮膚病理組織学会 ) 33回 59,36 - 59,36 2017.06

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study

Naoya Yamazaki, Yoshio Kiyohara, Hisashi Uhara, Jiro Uehara, Manabu Fujimoto, Tatsuya Takenouchi, Masaki Otsuka, Hiroshi Uchi, Hironobu Ihn, Hironobu Minami

CANCER SCIENCE ( WILEY ) 108 ( 6 ) 1223 - 1230 2017.06 [Refereed]

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

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study.

Naoya Yamazaki, Yoshio Kiyohara, Hisashi Uhara, Jiro Uehara, Manabu Fujimoto, Tatsuya Takenouchi, Masaki Otsuka, Hiroshi Uchi, Hironobu Ihn, Hironobu Minami

Cancer science 108 ( 6 ) 1223 - 1230 2017.06 [Refereed] [International journal]

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

脂腺母斑に生じた基底細胞癌のダーモスコピー所見

皆川茜, 古賀弘志, 宇原久, 奥山隆平

西日本皮膚科 ( 日本皮膚科学会-西部支部 ) 79 ( 3 ) 313 - 314 2017.06

Blue gray ovoid nestとarborizing vesselsを示した上眼瞼の紅色結節

皆川茜, 代田志保, 古賀弘志, 宇原久, 安齋眞一, 奥山隆平

日本皮膚病理組織学会抄録集 ( 日本皮膚病理組織学会 ) 33回 55,32 - 55,32 2017.06

ベムラフェニブ投与後にPD-L1の発現が増加した悪性黒色腫の1例

加藤潤史, 高橋仁美, 澤田匡秀, 佐藤さゆり, 堀本浩平, 神谷崇文, 肥田時征, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 33回 147 - 147 2017.05

乳房外Paget病に対するイミキモドの有効性に関する検討

澤田匡秀, 加藤潤史, 高橋仁美, 佐藤さゆり, 堀本浩平, 石井泰江, 肥田時征, 米田明弘, 山下利春, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 33回 169 - 169 2017.05

Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma.

Naoya Yamazaki, Yoshio Kiyohara, Hisashi Uhara, Hajime Iizuka, Jiro Uehara, Fujio Otsuka, Yasuhiro Fujisawa, Tatsuya Takenouchi, Taiki Isei, Keiji Iwatsuki, Hiroshi Uchi, Hironobu Ihn, Hironobu Minami, Hideaki Tahara

Cancer science 108 ( 5 ) 1022 - 1031 2017.05 [Refereed] [International journal]

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

有棘細胞癌におけるサイトケラチン19の発現の検討

加藤潤史, 澤田匡秀, 高橋仁美, 佐藤さゆり, 神谷詩織, 堀本浩平, 肥田時征, 山下利春, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 127 ( 5 ) 1138 - 1138 2017.05

小児期発症の病歴を持つメラノーマの特徴

皆川茜, 宇原久, 芦田敦子, 境澤香里, 古賀弘志, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 127 ( 5 ) 1140 - 1140 2017.05

Detection of BRAF(V600K) mutant tumor-derived DNA in the pleural effusion from a patient with metastatic melanoma

Kaori Sakaizawa, Atsuko Ashida, Hisashi Uhara, Ryuhei Okuyama

CLINICAL CHEMISTRY AND LABORATORY MEDICINE ( WALTER DE GRUYTER GMBH ) 55 ( 4 ) E92 - E95 2017.04 [Refereed]

Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041).

Naoya Yamazaki, Tatsuya Takenouchi, Manabu Fujimoto, Hironobu Ihn, Hiroshi Uchi, Takashi Inozume, Yoshio Kiyohara, Hisashi Uhara, Kazuhiko Nakagawa, Hiroshi Furukawa, Hidefumi Wada, Kazuo Noguchi, Takashi Shimamoto, Kenji Yokota

Cancer chemotherapy and pharmacology 79 ( 4 ) 651 - 660 2017.04 [Refereed] [International journal]

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

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

Masayuki Amagai, Shigaku Ikeda, Takashi Hashimoto, Masato Mizuashi, Akihiro Fujisawa, Hironobu Ihn, Yasushi Matsuzaki, Mikio Ohtsuka, Hiroshi Fujiwara, Junichi Furuta, Osamu Tago, Jun Yamagami, Akiko Tanikawa, Hisashi Uhara, Akimichi Morita, Gen Nakanishi, Mamori Tani, Yumi Aoyama, Eiichi Makino, Masahiko Muto, Motomu Manabe, Takayuki Konno, Satoru Murata, Seiichi Izaki, Hideaki Watanabe, Yukie Yamaguchi, Setsuko Matsukura, Mariko Seishima, Koji Habe, Yuichi Yoshida, Sakae Kaneko, Hajime Shindo, Kimiko Nakajima, Takuro Kanekura, Kenzo Takahashi, Yasuo Kitajima, Koji Hashimoto

Journal of dermatological science 85 ( 2 ) 77 - 84 2017.02 [Refereed] [International journal]

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

【がん免疫療法-がん完治に向けての新たな治療法の探索-】免疫チェックポイント阻害薬悪性黒色腫に対する治療

宇原久

日本臨床 75 ( 2 ) 216 - 220 2017.02 [Refereed]

Nail apparatus melanoma in a Japanese population: a comparative study of surgical procedures and prognoses in a large series of 151 cases

Ogata, D. Uhara, H. Tsutsumida, A. Yamazaki, N. Mochida, K. Amano, M. Yoshikawa, S. Kiyohara, Y. Tsuchida, T

Eur J Dermatol 27 ( 6 ) 620 - 626 2017 [Refereed]

Quantitative analysis of the BRAF V600E mutation in circulating tumor-derived DNA in melanoma patients using competitive allele-specific TaqMan PCR

Atsuko Ashida, Kaori Sakaizawa, Asuka Mikoshiba, Hisashi Uhara, Ryuhei Okuyama

International Journal of Clinical Oncology ( Springer Tokyo ) 21 ( 5 ) 981 - 988 2016.10 [Refereed]

Background: BRAFV600E is a common mutation in melanoma, and BRAF inhibitors are effective in treating of BRAF mutation-positive melanoma. DNA carrying this mutation is released from melanoma cells into the circulation. As such, circulating tumor-derived DNA (ctDNA) in peripheral blood represents a novel biomarker for evaluating tumor features in cancer patients. However, ctDNA is present in the peripheral blood at very low levels, which makes the detection of specific mutations in this DNA a challenge. Competitive allele-specific TaqMan PCR (castPCR), a straightforward commercially available assay, is a sensitive technique for quantitating a small amount of DNA. Methods: The level of BRAFV600E ctDNA was quantified by castPCR in 26 consecutive plasma samples from six melanoma patients. Results: The castPCR assay was performed using a mixture of BRAFV600E DNA and BRAFwild DNA and found to be able to detect BRAFV600E at a fractional abundance of ≥0.5 % in 2- to 10-ng samples of genomic DNA. Cell-free DNA was then extracted from peripheral blood samples collected from six patients with melanoma harboring the BRAFV600E mutation. BRAFV600E ctDNA was detected in three patients, at a fractional abundance of between 1.28 and 58.0 % of total BRAF cell-free DNA. The abundance of BRAFV600E ctDNA correlated with tumor burden, as determined by computed tomography imaging. In two cases, an increase in the level of BRAFV600E ctDNA preceded exacerbation of clinical symptoms. Conclusion: The castPCR assay can detect and quantitate small amounts of BRAFV600E ctDNA in samples containing large amounts of BRAFwild cell-free DNA. Thus, we suggest that the castPCR assay is suitable for monitoring ctDNA in the plasma of melanoma patients.

Phase I study of pegylated interferon-alpha-2b as an adjuvant therapy in Japanese patients with malignant melanoma

Naoya Yamazaki, Hisashi Uhara, Hidefumi Wada, Kenji Matsuda, Keiko Yamamoto, Takashi Shimamoto, Yoshio Kiyohara

JOURNAL OF DERMATOLOGY ( WILEY-BLACKWELL ) 43 ( 10 ) 1146 - 1153 2016.10 [Refereed]

In the adjuvant setting for malignant melanoma, interferon (IFN)--2b and pegylated (PEG) IFN--2b were approved in several countries including the USA before these were approved in Japan. To resolve the drug-lag issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN--2b. As with a previously reported phase III study, patients were to receive PEG IFN--2b 6 g/kg per week s.c. during an 8-week induction phase, followed by a maintenance phase at a dose of 3 g/kg per week up to 5 years. Dose-limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose-limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug-related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration-time curve and maximum observed serum concentration were observed between Japanese and historical non-Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN--2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.

肢端黒子型悪性黒色腫の解剖学的分布

面高俊和, 皆川茜, 古賀弘志, 芦田敦子, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 126 ( 11 ) 2131 - 2131 2016.10

パクリタキセルにより強皮症様皮膚硬化を呈した1例

大橋敦子, 芦田敦子, 古賀弘志, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 126 ( 11 ) 2128 - 2128 2016.10

メラノーマ患者におけるcirculating tumor DNAによるニボルマブ治療の評価

芦田敦子, 境澤香里, 宇原久, 奥山隆平

日本癌学会総会記事 ( (一社)日本癌学会 ) 75回 P - 2322 2016.10

Late onset of acute urticaria after bee stings

Yuko Asai, Hisashi Uhara, Atsushi Miyazaki, Minoru Saiki, Ryuhei Okuyama

Case Reports in Dermatology ( S. Karger AG ) 8 ( 3 ) 341 - 343 2016.09 [Refereed]

Here we report the cases of five patients with a late onset of acute urticaria after a bee sting. The ages of the five Japanese patients ranged from 33 to 86 years (median: 61). All patients had no history of an allergic reaction to bee stings. The onset of urticaria was 6-14 days (median: 10) after a bee sting. Although four of the patients did not describe experiencing a bee sting at their presentation, the subsequent examination detected anti-bee-specific IgE antibodies. So, we think a history of a bee sting should thus be part of the medical interview sheet for patients with acute urticaria, and an examination of IgE for bees may help prevent a severe bee-related anaphylactic reaction in the future.

A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis of 301 patients with invasive primary tumors

Kuniaki Ohara, Yasuhiro Fujisawa, Koji Yoshino, Yoshio Kiyohara, Takafumi Kadono, Yozo Murata, Hisashi Uhara, Naohito Hatta, Hiroshi Uchi, Shigeto Matsushita, Tatsuya Takenouchi, Toshihiko Hayashi, Kenichi Yoshimura, Manabu Fujimoto

JOURNAL OF DERMATOLOGICAL SCIENCE ( ELSEVIER IRELAND LTD ) 83 ( 3 ) 234 - 239 2016.09 [Refereed]

Background: Although extramammary Paget disease (EMPD) usually appears as carcinoma in situ, it sometimes becomes invasive (iEMPD) and fatal. However, a TNM staging system for iEMPD has yet to be established. Objective: The aim of this study was to establish a TNM staging system for iEMPD. Methods: We retrospectively collected iEMPD patients treated at 12 institutes in Japan. Factors reported to be associated with survival such as distant metastasis, lymph node (LN) metastasis, and primary tumor status were evaluated using the log-rank test. Results: We enrolled 301 iEMPD patients, of whom 114 had remote metastases (49 had both distant and LN metastasis; 2, distant metastasis only; and 63, LN metastasis only) and the remaining 187 patients had no remote metastasis. Distant metastasis (M1) showed worse survival (P < 0.00001). In the analysis of the 250 patients without distant metastasis, LN metastasis also showed worse survival (P < 0.00001). Among the patients with LN metastasis, 2 or more LN metastases (N2) showed worse survival than did single LN metastasis (N1, P = 0.02). Lastly, in the analysis of the 187 patients without metastasis, tumor thickness of over 4 mm or lymphovascular invasion showed worse survival (T2, P < 0.05 and P < 0.001, respectively). Patients with neither of these features were defined as T1. From these results, we propose this TNM staging system: stage I, T1NOMO; stage II, T2NOMO; stage Ma, any TN1M0; stage IIIb, anyTN2M0; stage IV, anyTanyNM1. Other than stages II and IIIa, each stage had a statistically distinct survival curve. Conclusion: We propose a TNM staging system for EMPD using simple factors for classification that could provide important prognostic information in managing EMPD. However, accumulation of more patient data and further revision of the system are required. (C) 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Frequency of level II and III axillary nodes metastases in patients with positive sentinel lymph nodes in melanoma: a multi-institutional study in Japan.

Arata Tsutsumida, Akira Takahashi, Kenjiro Namikawa, Naoya Yamazaki, Hisashi Uhara, Yukiko Teramoto, Tatsuya Takenouchi, Satoshi Fukushima, Kenji Yokota, Jiro Uehara, Shigeto Matsushita, Yoshitsugu Shibayama, Naohito Hatta, Yuri Masui, Hiroshi Uchi, Yasuhiro Fujisawa, Dai Ogata

International journal of clinical oncology 21 ( 4 ) 796 - 800 2016.08 [Refereed] [Domestic journal]

BACKGROUND: Axillary lymph node dissection (ALND) has been recommended to include levels I-III for melanoma patients who have evidence of metastasis in the axillary sentinel lymph node (SLN). The extent of the subsequent axillary dissection is in debate. The objective of this study was to determine the frequency of metastasis of level III nodes in addition to that of level II nodes in this setting. METHODS: A multi-institutional retrospective study was undertaken in 14 melanoma treatment centers in Japan. RESULTS: Between 2007 and 2012, 69 patients with involved axillary SLNs underwent a subsequent ALND and 55 underwent level I and II dissections. Level III metastatic nodes, which is our primary endpoint, were seen in only 1 patient (1.5 %). The level II metastatic rate was 4.4 %. CONCLUSIONS: Our study sample size was small, but melanoma patients with positive SLN rarely had level III disease, suggesting that level III dissection may be unnecessary. We also found that level II metastasis was not so frequent. More evidence is needed to standardize the extent of ALND and to identify the patients who would have the most benefit with undergoing level II dissection for positive axillary SLNs.

DOI PubMed J-GLOBAL

BRAF変異を有する悪性黒色腫における免疫応答と予後解析

中村謙太, 芦田敦子, 木庭幸子, 宇原久, 奥山隆平

日本臨床免疫学会会誌 ( (一社)日本臨床免疫学会 ) 39 ( 4 ) 423 - 423 2016.08

Water-based correction fluid is a useful skin marker for determination of the tumor margin of basal cell carcinoma under high-frequency ultrasound

Koichi Hayashi, Ryuhei Okuyama, Hisashi Uhara

Journal of Dermatology ( Blackwell Publishing Ltd ) 43 ( 7 ) 823 - 825 2016.07 [Refereed]

We propose a new method to determine the appropriate preoperative surgical margin of basal cell carcinoma (BCC) by using water-based correction fluid as a skin marker showing the tumor position on the skin under high-frequency ultrasound (HFUS). After a provisional evaluation by dermoscopy, an approximately 2-mm dot of water-based correction fluid is applied to the tumor margin. The ultrasound waves are blocked by the dot of correction fluid, and a low-signal column is observed under the dot of correction fluid. The dots of correction fluid are moved and located as near as possible to the tumor margin, which is shown as a solid hypoechoic area by the HFUS. After confirming that the dots of correction fluid are applied to the circumferential margin, we draw a line in the gaps between the dots. Before the operation, the dots of correction fluid are removed by forceps, and a line for the tumor margin is drawn where the dots were. The surgical margin is set just outside of this line with the use of a measuring device. Water-based correction fluid is thus a useful skin marker under HFUS to determine the circumferential surgical margin of BCC.

Usefulness of docetaxel as first-line chemotherapy for metastatic extramammary Paget's disease

Koji Yoshino, Yasuhiro Fujisawa, Yoshio Kiyohara, Takafumi Kadono, Yozo Murata, Hisashi Uhara, Naohito Hatta, Hiroshi Uchi, Shigeto Matsushita, Tatsuya Takenouchi, Toshihiko Hayashi, Kuniaki Ohara

JOURNAL OF DERMATOLOGY ( WILEY-BLACKWELL ) 43 ( 6 ) 633 - 637 2016.06 [Refereed]

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first-line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1-year overall survival rate determined by the Kaplan-Meier method was 75.0%. All adverse effects were manageable and no treatment-related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first-line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.

Fish collagen is an important panallergen in the Japanese population

Y. Kobayashi, H. Akiyama, J. Huge, H. Kubota, S. Chikazawa, T. Satoh, T. Miyake, H. Uhara, R. Okuyama, R. Nakagawara, M. Aihara, N. Hamada-Sato

Allergy: European Journal of Allergy and Clinical Immunology ( Blackwell Publishing Ltd ) 71 ( 5 ) 720 - 723 2016.05 [Refereed]

Collagen was identified as a fish allergen in early 2000s. Although its allergenic potential has been suggested to be low, risks associated with collagen as a fish allergen have not been evaluated to a greater extent. In this study, we aimed to clarify the importance of collagen as a fish allergen. Our results showed that 50% of Japanese patients with fish allergy had immunoglobulin E (IgE) against mackerel collagen, whereas 44% had IgE against mackerel parvalbumin. IgE inhibition assay revealed high cross-reactivity of mackerel collagen to 22 fish species (inhibition rates: 87-98%). Furthermore, a recently developed allergy test demonstrated that collagen triggered IgE cross-linking on mast cells. These data indicate that fish collagen is an important and very common panallergen in fish consumed in Japan. The high rate of individuals' collagen allergy may be attributable to the traditional Japanese custom of raw fish consumption.

血液循環腫瘍DNAよりBRAF変異が検出できた進行期悪性黒色腫症例

芦田敦子, 御子柴飛鳥, 熊谷尚美, 境澤香里, 古賀弘志, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 126 ( 5 ) 975 - 975 2016.05

足底のメラノーマは物理的荷重部位に好発する

皆川茜, 古賀弘志, 面高俊和, 宇原久, 奥山隆平

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 32回 124 - 124 2016.05

Melanoma

Hisashi Uhara

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 43 ( 4 ) 404 - 407 2016.04 [Refereed]

Since 2011, several effective drugs for patients with metastatic melanoma, including BRAF inhibitors, MEK inhibitors, and immune checkpoint inhibitors, have been approved. The combination of BRAF and MEK inhibitors achieve response rates of 70% and a median progression-free survival of > 11 months in patients. The combination of ipilimumab and nivolumab has shown response rates of up to 60-70% and a median progression-free survival of 11-14 months, despite increased toxicities. Moreover, many clinical trials for new combination therapies are still ongoing.

【メラノーマ-基礎から最新薬物療法まで】分子異常

芦田敦子, 木庭幸子, 宇原久

カレントテラピー ( (株)ライフメディコム ) 34 ( 4 ) 344 - 349 2016.04

爪部メラノーマの好発部位と腫瘍厚の関連

皆川茜, 古賀弘志, 面高俊和, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 126 ( 4 ) 436 - 436 2016.04

Eccrine porocarcinoma shares dermoscopic characteristics with eccrine poroma: A report of three cases and review of the published work

Tomohiro Edamitsu, Akane Minagawa, Hiroshi Koga, Hisashi Uhara, Ryuhei Okuyama

Journal of Dermatology ( Blackwell Publishing Ltd ) 43 ( 3 ) 332 - 335 2016.03 [Refereed]

Eccrine porocarcinoma (EPC) is a rare malignant skin tumor presumably arising from the intraepidermal ductal portion of the sweat gland. EPC occasionally mimics eccrine poroma (EP), seborrhea keratosis (SK), basal cell carcinoma (BCC), pyogenic granuloma (PG) and amelanotic melanoma with its clinical appearance as a pink nodule. Dermoscopy is an invaluable technique in diagnosing skin tumors. However, few cases of EPC have been reported using dermoscopic images, and their details were not well examined. Here, we present three histopathologically proven cases of EPC and summarize their dermoscopic findings together with five previously reported cases. None of the eight cases showed dermoscopic evidence indicative of SK (comedo-like openings, milia-like cysts, fissures and ridges, and hairpin vessels with white halo), BCC (blue-gray ovoid nests, multiple blue-gray globules, wheel-like structures, shiny white areas, leaf-like areas and arborizing vessels) or PG (reddish homogeneous area with collarette and white rail lines). A milky red area, which was suggestive of amelanotic melanoma, was not detectable in any cases. Seven cases exhibited a polymorphous vascular pattern mainly consisting of hairpin, linear-irregular and dotted vessels. A combination of round-to-oval pink-white structureless areas and white-to-pink halo was observed in five of eight cases, with one case showing the white-to-pink halo alone. Our investigation revealed that the dermoscopic characteristic of EP was also observed in discrete areas of EPC lesions. Thus, it is possible that the histopathological architecture of EPC contains portions of benign EP-like components. Awareness of this dermoscopic aspect of EPC may be helpful when diagnosing pink nodules.

Nivolumab-induced organizing pneumonia in a melanoma patient

Tasuku Sano, Hisashi Uhara, Yasutomo Mikoshiba, Aya Kobayashi, Ryuhei Uchiyama, Kazunari Tateishi, Hiroshi Yamamoto, Ryuhei Okuyama

Japanese Journal of Clinical Oncology ( Oxford University Press ) 46 ( 3 ) 270 - 272 2016.03 [Refereed]

We report the case of a 70-year-old woman with vaginal melanoma and multiple metastases in the lung. After the third dose of nivolumab, decreased room-air resting arterial oxygen saturation with bilateral basal fine crackles on auscultation developed despite the absence of respiratory symptoms. Computed tomography showed ground-glass opacities with airspace consolidations scattered with a peculiar distribution, and most were observed around the existing metastatic tumors in the lung. From the 42nd day to the 56th day after the last administration of nivolumab, she received dexamethasone 1-2 mg/body for the prevention of adverse events after stereotactic radiation for brain metastasis. At 3 months after the last administration of nivolumab, a computed tomography scan revealed improvement of the pneumonia and a decreased size and number of metastatic lesions in the lung, although some lesions showed enlargement. Further examination is needed to clarify the relationship between the pattern of pneumonia after Nivo therapy and clinical effects.

Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma

Takushi Shirai, Tasuku Sano, Fuminao Kamijo, Nana Saito, Tomomi Miyake, Minori Kodaira, Nagaaki Katoh, Kenichi Nishie, Ryuhei Okuyama, Hisashi Uhara

Japanese Journal of Clinical Oncology ( Oxford University Press ) 46 ( 1 ) 86 - 88 2016.01 [Refereed]

We reported an 81-year-old woman with metastatic melanoma, in whom myasthenia gravis and rhabdomyolysis developed after nivolumab monotherapy. The first symptom of myasthenia gravis was dyspnea. Ultrasonography detected hypokinesis of the bilateral diaphragm suggesting myasthenia gravis, although there was no abnormal finding of the lungs in computed tomography images. Acetylcholine receptor binding antibodies were low-titer positive in the preserved serum before administration of nivolumab, strongly suggesting that the myasthenia gravis was a nivolumab-related immune adverse event. Despite the remarkable clinical benefits of immune checkpoint inhibitors for patients with advanced melanoma, it is important to recognize unexpected immune-related adverse events.

Melanoma with BRAF Mutation in Circulating Cell-free DNA despite no Mutation in the Primary Lesion: A Case Report

Atsuko Ashida, Hisashi Uhara, Asuka Mikoshiba, Kaori Sakaizawa, Naomi Kumagai, Hiroshi Koga, Ryuhei Okuyama

ACTA DERMATO-VENEREOLOGICA ( ACTA DERMATO-VENEREOLOGICA ) 96 ( 1 ) 128 - 129 2016 [Refereed]

Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients.

Kaori Sakaizawa, Atsuko Ashida, Aya Uchiyama, Takamichi Ito, Yasuhiro Fujisawa, Dai Ogata, Shigeto Matsushita, Kazuyasu Fujii, Satoshi Fukushima, Yoshitsugu Shibayama, Naohito Hatta, Tatsuya Takenouchi, Jiro Uehara, Ryuhei Okuyama, Naoya Yamazaki, Hisashi Uhara

Journal of dermatological science 80 ( 1 ) 33 - 7 2015.10 [Refereed] [International journal]

BACKGROUND: The importance of the genetic background of melanoma cells to the individual susceptibility to treatment has become apparent. In Caucasians, BRAF mutations are frequently detected in lesions on the skin of younger patients compared to NRAS and KIT mutations. However, clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations have not been fully evaluated in East Asians. OBJECTIVE: To clarify clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. METHODS: Clinical data were retrospectively collected from 11 hospitals in Japan. BRAF, NRAS and KIT mutations were evaluated with polymerase chain reaction and Sanger sequencing. The relationships between these gene mutations and pathological and clinical findings were analyzed. RESULTS: The number of cases examined was 171 (primary: 135, metastases: 11, paired: 25), and all were Japanese patients. The detection rates of BRAF, NRAS and KIT mutations were 30.4%, 12.3% and 12.9%, respectively. Compared with the wild type, the presence of BRAF mutations was significantly associated with younger age (median, 50.0 years vs. 70.0 years, p<0.001). BRAF mutation was frequently detected in the lesions of the scalp (80%; 4/5), trunk (72.0%; 18/25), extremities (56.7%; 17/30) and neck (44.4%; 4/9), and the least prevalent were the face (22.2%; 2/9), nail (12.5%; 3/24), palm or sole (8.9%; 4/45) and mucosa (0%). NRAS mutations were prevalent in the face (33.3%) and palm or sole (20.0%), and the median age of these patients was 70.5 years. A KIT mutation was observed in the nail apparatus (25%), palm or sole (15.6%) and mucosa (18.2%). The median age of the patients with a KIT mutation was 63.0 years. Heterogeneity of mutations between primary and metastatic lesions was detected in six of 25 cases (24%). Solar elastosis was identified in 12 of 71 cases (15.3%), among which four cases harbored BRAF(V600E) (2 cases), BRAF(V600K), NRAS(Q61K) or NRAS(Q61L), respectively. CONCLUSION: Some clinical characteristics associated with BRAF, NRAS and KIT mutations were observed in Japanese patients, and we observed both similarities to and differences from those of Caucasians. Our findings could provide useful information in efforts to clarify the tumor genesis of malignant melanomas.

DOI PubMed J-GLOBAL

進行期メラノーマ患者におけるcastPCR法を用いたBRAFV600E血液循環腫瘍DNAの検出

芦田敦子, 境澤香里, 宇原久, 奥山隆平

日本癌学会総会記事 ( (一社)日本癌学会 ) 74回 P - 3303 2015.10

【家族性腫瘍学-家族性腫瘍の最新研究動向-】症候群 Familial atypical multiple mole melanoma syndrome(家族性多発性メラノーマ症候群、家族性異型多発母斑黒色腫症候群)

芦田敦子, 宇原久

日本臨床 ( (株)日本臨床社 ) 73 ( 増刊6 家族性腫瘍学 ) 99 - 102 2015.08

Notch down-regulation in regenerated epidermis contributes to enhanced expression of interleukin-36α and suppression of keratinocyte differentiation during wound healing

Yuko Takazawa, Eisaku Ogawa, Rumiko Saito, Ryuhei Uchiyama, Shuntaro Ikawa, Hisashi Uhara, Ryuhei Okuyama

Journal of Dermatological Science ( Elsevier Ireland Ltd ) 79 ( 1 ) 10 - 19 2015.07 [Refereed]

Background: Notch signaling controls a number of cellular processes, including cell fate decisions, proliferation, differentiation, and survival/apoptosis, in multiple tissues. In the epidermis, Notch1 functions as a molecular switch that controls the transition of cells from an undifferentiated state into a differentiated state. Objective: To clarify the functions of Notch in the regenerated epidermis during wound healing. Methods: Wounds on mouse skin were immunostained. To investigate the functions of Notch, Notch was inhibited in primary keratinocytes by treatment with a γ-secretase inhibitor and by small interfering RNA-mediated knockdown, and was activated by a recombinant adenovirus approach. Results: Notch1 and Notch2 were down-regulated in the regenerated epidermis during wound healing. To clarify the significance of this down-regulation, we examined its effect on expression of the interleukin (IL)-1 family of proinflammatory cytokines because wounds are exposed to pathogens from the outside world. Among the IL-1 family, IL-36α expression was induced by Notch inhibition. This was consistent with the decreased IL-36α expression in Notch-overexpressing keratinocytes. Notch down-regulation in the regenerated epidermis may reinforce defense against stress from the outside world by inducing IL-36α expression. Next, we examined the effects of Notch down-regulation on keratinocyte growth and differentiation. Notch down-regulation did not alter keratinocyte proliferation. On the other hand, Notch1 down-regulation suppressed induction of spinous layer-specific keratins (keratin1 and keratin10) in keratinocytes, which was consistent with the decreased expression of these keratins in the regenerated epidermis. The reduced levels of these keratins would increase cellular flexibility. Conclusion: Notch down-regulation in the epidermis appears to contribute to tissue regeneration during wound healing.

Phase I/II study of vemurafenib in patients with unresectable or recurrent melanoma with BRAF(V600) mutations

Naoya Yamazaki, Yoshio Kiyohara, Naofumi Sugaya, Hisashi Uhara

JOURNAL OF DERMATOLOGY ( WILEY-BLACKWELL ) 42 ( 7 ) 661 - 666 2015.07 [Refereed]

We investigated the efficacy and safety of vemurafenib in Japanese patients with unresectable or recurrent melanoma with BRAF(V600) mutations. This was a two-step open-label multicenter phase I/II study. Step 1 evaluated the initial safety of vemurafenib 960mg administrated p.o. twice daily in three patients. In step 2, eight patients received vemurafenib 960mg administrated p.o. twice daily for 28-day treatment cycles; the primary outcome measure was response rate, as determined by independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events (AE) experienced by five or more patients were arthralgia (n=10), myalgia (n=8), alopecia (n=7), and rash, maculopapular rash and decreased appetite (n=5 each). Three patients had grade 3 AE. One serious AE occurred in one patient (abnormal hepatic function). Six patients required dose reduction because of AE. One patient died within 28days after the last dose, but death was caused by disease progression and not associated with the study drug. In the eight patients in step 2, overall response rate was 75.0%, none had a complete response and six had a partial response (75.0%). Median response duration was 240.0days, disease control rate 87.5%, median progression-free survival 416.0days and median overall survival 443.0days. In conclusion, vemurafenib treatment resulted in an overall response rate of 75% in Japanese patients with metastatic melanoma with BRAF(V600) mutations. All toxicities were manageable.

信州大学における悪性黒色腫245例(2000〜2009年)の臨床統計

中村謙太, 皆川茜, 芦田敦子, 古賀弘志, 木庭幸子, 奥山隆平, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 125 ( 8 ) 1587 - 1592 2015.07

2000年から2009年に信州大学を受診した245症例の悪性黒色腫を解析した。疾患特異的5年生存率は、0期100%、I期98%、II期82%、III期59%、IV期18%だった。51例が初回根治術後に転移を起こし、初回転移臓器種の比率(該当臓器転移の症例数/全転移症例数)は、肺55%、皮膚・皮下35%、リンパ節24%、脳12%だった。肺転移の89%とリンパ節転移の50%が予定の画像検査で、皮膚・皮下転移の94%とリンパ節転移の36%が理学所見での発見であり、丁寧な診察と定期的な画像検査が悪性黒色腫の遠隔転移の早期発見に有用と思われた。(著者抄録)

A Case of Vulval Extramammary Paget Disease With Dermal Invasion Showing Mucinous Carcinoma

Shiho Asaka, Akihiko Yoshizawa, Kenji Sano, Hisashi Uhara, Takayuki Honda, Hiroyoshi Ota

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 34 ( 4 ) 396 - 400 2015.07 [Refereed]

We report a case of vulval extramammary Paget disease (EMPD) with dermal invasion showing mucinous carcinoma (MC). An 80-year-old woman presented with vulvar itching and pain. A physical examination showed a pigmented vulvar, perianal erythematous plague, and a subcutaneous nodule in the left major labia. No internal malignancy, such as colorectal or genitourinary carcinoma, was identified in any of the clinical examinations. A histological examination of the resected specimen revealed Pagetoid tumor cells that had spread widely through the epidermis and invaded the dermis forming a solid nest with mucous lake-like MC. Immunohistochemical examination revealed that the tumor cells in the epidermis and dermis were positive for CK7, CEA, GCDFP-15, MUC5AC, and MUC2, but negative for CK20, MUC6, and CDX2. Only the invasive component showed overexpression of p53. A diagnosis of primary EMPD with dermal invasion showing MC of the vulva was made. This is an extremely rare diagnosis, and we suggest that immunohistochemical evaluations in addition to systemic work-ups are helpful in distinguishing between these cases and those involving vulvar or perianal skin invasion of underlying colorectal or genitourinary carcinomas, which are referred to as secondary EMPD.

The role of sentinel lymph node biopsy in the management of invasive extramammary Paget's disease: Multi-center, retrospective study of 151 patients

Yasuhiro Fujisawa, Koji Yoshino, Yoshio Kiyohara, Takafumi Kadono, Yozo Murata, Hisashi Uhara, Naohito Hatta, Hiroshi Uchi, Shigeto Matsushita, Tatsuya Takenouchi, Toshihiko Hayashi, Manabu Fujimoto, Kuniaki Ohara

JOURNAL OF DERMATOLOGICAL SCIENCE ( ELSEVIER IRELAND LTD ) 79 ( 1 ) 38 - 42 2015.07 [Refereed]

Background: Although extramammary Paget's disease (EMPD) mostly presents as intraepithelial carcinoma, we sometimes encounter patients with invasive EMPD (iEMPD) who have lymph node metastasis and may develop distant metastasis. Although sentinel lymph node biopsy (SLNB) is widely accepted for various cancers, there is no large study that has assessed its role in iEMPD. Objective: The main objective of this study is to assess the role of SLNB in patients with iEMPD. Materials and methods: We retrospectively collected data on 151 iEMPD patients treated from 1998 to 2012 in 11 institutes in Japan. All 151 patients received curative surgery for their primary tumor and none of them had distant metastasis. SLNB was performed on the 107 patients without lymphadenopathy to determine their LN status. The 44 other patients with lymphadenopathy underwent one of the following procedures to determine their LN status: SLNB in 22 cases, immediate LN dissection in 21, and LN biopsy in 1. Results: Compared to those without lymphadenopathy, patients with lymphadenopathy had advanced primary tumors (nodule in the primary tumor, thicker tumor, deeper invasion level, and lymphovascular invasion). The rate of LN metastasis in patients with lymphadenopathy was 80%, compared to 15% in patients without lymphadenopathy who underwent SLNB. Compared to those with negative SLN, patients with positive SLN had advanced primary tumors (nodule in the primary tumor, deeper invasion level, and lymphovascular invasion). Multivariate analysis revealed that dermal invasion (odds ratio 5.8, p = 0.04) and lymphovascular invasion (odds ratio 18.0, p = 0.0023) were independent factors associated with SLN positivity. Notably, there was no difference in survival between patients with or without SLN metastasis (p = 0.71). On the other hand, patients with lymphadenopathy showed worse survival than those with positive SLN (p = 0.045). Conclusion: Clinical lymphadenopathy was strongly correlated with pathological LN metastasis and also associated with worse survival than absence of lymphadenopathy. The rate of occult LN metastasis detected by SLNB was 15%. Survival was not affected by SLN status even when an advanced primary tumor was present in patients with positive SLN. Our results raise the possibility that SLNB and subsequent LN dissection improved the survival of patients with early stage lymphatic spread. Our study indicates that SLNB should be considered for iEMPD if lymphadenopathy is not apparent. (C) 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

全身性サルコイドーシスに伴い黒色刺青部のみが隆起した刺青サルコイドーシスの1例

中村謙太, 河内繁雄, 大橋敦子, 古賀弘志, 宇原久, 江石義信, 奥山隆平

臨床皮膚科 ( (株)医学書院 ) 69 ( 7 ) 469 - 473 2015.06

41歳,男性.約20年前に上腕,体幹,大腿に,黒,緑,青,赤色,黄色の刺青を施した.1年前から両眼ぶどう膜炎を発症した.両側の肺門リンパ節腫脹,血清ACE値上昇,気管支肺胞洗浄液でリンパ球増加とCD4/8比上昇を認めた.半年前から黒色刺青部に一致した隆起性浸潤局面を認め,生検病理組織像で黒色色素を取り込んだマクロファージを含む類上皮肉芽腫を認めた.全身性サルコイドーシスに伴った刺青サルコイドーシスと診断した.刺青部位に皮疹がみられた場合は,サルコイドーシスを鑑別疾患の1つとして診断を進めることが重要である.(著者抄録)

II. BRAF inhibitor and MEK inhibitor

Hisashi Uhara

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 42 ( 4 ) 428 - 433 2015.04 [Refereed]

【メラノーマ最新情報】日本人におけるMAPK系の遺伝子変異率と遺伝子検査の実際

芦田敦子, 宇原久

Derma. ( (株)全日本病院出版会 ) ( 230 ) 63 - 68 2015.04

分子標的治療の発展により、腫瘍組織の遺伝子情報が薬剤の選択に大きく影響を及ぼす時代を迎えている。日本人のメラノーマ患者の変異率は、BRAF変異:約30%、NRAS変異:7〜10%、KIT変異:4〜5%であり、白人の変異率に比べ低い。また、それぞれの変異ごとに異なった臨床的特徴(好発部位、年齢など)が存在する。遺伝子変異の検査に用いる検体は、ホルマリン固定パラフィン包埋(FFPE)組織からの切り出し標本である。従って、将来の転移に備え、ヘマトキシリン・エオジン(HE)標本を作製する時点(初回切除時以後)から、遺伝子変異の検索に適したDNAを抽出することを前提に手術検体の適切な固定や保管を行うことが極めて重要である。(著者抄録)

皮膚癌の術後出血が診断の契機となった後天性13因子欠乏症の1例

三宅知美, 芦田敦子, 宇原久, 奥山隆平, 福澤正男, 一瀬白帝

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 125 ( 4 ) 955 - 955 2015.04

地中海沿岸地域以外で認められた、CYP4F22遺伝子変異による葉状魚鱗癬症例

杉浦一充, 武市拓也, 棚橋華奈, 秋山真志, 古庄知己, 宇原久, 奥山隆平, 才田謙

角化症研究会記録集 ( 角化症研究会事務局 ) 29 24 - 27 2015.03

Combination chemotherapy of low-dose 5-fluorouracil and cisplatin for advanced extramammary Paget's disease

Yasutaka Tokuda, Fuyuko Arakura, Hisashi Uhara

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER JAPAN KK ) 20 ( 1 ) 194 - 197 2015.02 [Refereed]

Background Extramammary Paget's disease (EPD) is a cutaneous adenocarcinoma. It is usually curable by wide local excision. However, the prognosis for EPD patients with metastases is extremely poor because effective chemotherapy for advanced EPD has not been established. Methods We retrospectively analyzed the efficacy of combination chemotherapy consisting of infusions of 5-fluorouracil (5-FU, 600 mg/m(2)/body, 5 days/week) and cisplatin (5-10 mg/body, 5-7 days/week) administered intravenously for 8-24 h (low-dose FP). Results The patients were 15 males and 7 females and the ages ranged from 54 to 91 years old (median 71). The toxicities of low-dose FP were as follows: hematopoietic dysfunction (n = 4), gastrointestinal dysfunction (4), nephropathy (1), and phlebitis (1). Almost all toxicities were grade 1 or 2 except for 2 cases with grade 3 leukopenia or pancytopenia. Seventeen patients were treated with low-dose FP only, and the clinical results included 10 partial responses (PR), 4 stable disease (SD), and 3 progressive disease (PD). The overall survival ranges (medians) were 5-51 months (12) in all 22 patients, 6-51 months (13) in the 13 patients showing complete response or PR, and 5-12 months (11) in the 6 SD patients. The reported palliative effects of low-dose FP include control of pain and improvement of lymphedema. Conclusion Although the number of cases is limited and there is a bias because cases without clinical effects are less likely to be reported, this regimen might be considered a relatively effective option for advanced EPD.

Melanocytic Naevus Shows Parallel Ridge Pattern due to the Melanin Columns Under the Ridges

Tasuku Sano, Akane Minagawa, Hiroshi Koga, Hisashi Uhara, Ryuhei Okuyama

Acta Dermato-Venereologica ( Medical Journals/Acta D-V ) 95 ( 1 ) 95 - 96 2015 [Refereed]

A melanocyte-melanoma precursor niche in sweat glands of volar skin

Natsuko Okamoto, Takahiro Aoto, Hisashi Uhara, Satoshi Yamazaki, Hidenori Akutsu, Akihiro Umezawa, Hiromitsu Nakauchi, Yoshiki Miyachi, Toshiaki Saida, Emi K. Nishimura

Pigment Cell and Melanoma Research ( Blackwell Publishing Ltd ) 27 ( 6 ) 1039 - 1050 2014.11 [Refereed]

Determination of the niche for early-stage cancer remains a challenging issue. Melanoma is an aggressive cancer of the melanocyte lineage. Early melanoma cells are often found in the epidermis around sweat ducts of human volar skin, and the skin pigmentation pattern is an early diagnostic sign of acral melanoma. However, the niche for melanoma precursors has not been determined yet. Here, we report that the secretory portion (SP) of eccrine sweat glands provide an anatomical niche for melanocyte-melanoma precursor cells. Using lineage-tagged H2B-GFP reporter mice, we found that melanoblasts that colonize sweat glands during development are maintained in an immature, slow-cycling state but renew themselves in response to genomic stress and provide their differentiating progeny to the epidermis. FISH analysis of human acral melanoma expanding in the epidermis revealed that unpigmented melanoblasts with significant cyclin D1 gene amplification reside deep in the SP of particular sweat gland(s). These findings indicate that sweat glands maintain melanocyte-melanoma precursors in an immature state in the niche and explain the preferential distribution of early melanoma cells around sweat glands in human volar skin.

BRAF変異をともなう日本人黒色腫患者の臨床的特徴

宇原久, 境澤香里, 芦田敦子, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 124 ( 10 ) 1943 - 1943 2014.09

Toll-Like receptor 4 signaling promotes the migration of human melanoma cells

Yuko Takazawa, Yukiko Kiniwa, Eisaku Ogawa, Aya Uchiyama, Atsuko Ashida, Hisashi Uhara, Yasufumi Goto, Ryuhei Okuyama

Tohoku Journal of Experimental Medicine ( Tohoku University Medical Press ) 234 ( 1 ) 57 - 65 2014.08 [Refereed]

Immune cell Toll-like receptors (TLRs) recognize conserved microbial components, leading to immune and inflammatory responses. However, TLRs are also expressed in cancer cells, including melanoma cells, which express TLR2-4. TLR4 ligands have received attention as immunotherapies therefore, we assessed the expression of TLR4 in human melanoma specimens (29 primary lesions and 28 metastatic lesions) representing different types of melanoma. A high percentage (≥ 90%) of melanoma lesions expressed TLR4, as judged by immunohistochemistry. Next, the role of TLR4 in cell proliferation and migration was assessed using the TLR4-positive (TLR4+) melanoma cell lines 501mel and 888mel, and TLR4-negative (TLR4‒) 928mel melanoma cells. Lipopolysaccharide (LPS), a TLR4 agonist, increased the proliferation of TLR4+ melanoma cells but not of TLR4‒ 928mel cells. The proliferation-inducing effect of LPS in 888mel cells was abolished by blockade of TLR4 signaling via treatment with short interfering RNA (siRNA) targeting TLR4 or myeloid differentiation primary response gene 88 (MyD88), a molecule downstream of TLR4. However, knockdown of TLR4 or MyD88 expression did not affect the LPS-induced proliferation of 501mel cells, suggesting that residual TLR4 signaling is sufficient to maintain cell proliferation. By contrast, LPS increased the migration of TLR4+ melanoma cells, and this effect was substantially inhibited by TLR4 or MyD88 knockdown. Furthermore, TLR4 knockdown decreased cell migration even in the absence of LPS, suggesting the presence of an endogenous TLR4 ligand(s) in melanoma cells. TLR4 signaling may contribute to melanoma progression, and caution should be exercised when using TLR4 ligands as adjuvant therapy for cancer.

肢端黒子型悪性黒色腫の解剖学的分布

面高俊和, 皆川茜, 古賀弘志, 芦田敦子, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 124 ( 4 ) 829 - 829 2014.04

メラノサイト系腫瘍での良性悪性の鑑別における5-Hydroxymethylcytocineの有用性

内山龍平, 宇原久, 小川英作, 古賀弘志, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 124 ( 4 ) 828 - 828 2014.04

(ス)長期間症状が遷延している薬剤過敏症症候群(DIHS)の1例

上條史尚, 芦田敦子, 葭矢裕之, 佐藤勇樹, 小林彩, 村田浩, 宇原久, 奥山隆平, 福澤正男

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 124 ( 3 ) 355 - 355 2014.03

(ス)膵転移をきたした隆起性皮膚線維肉腫/線維肉腫(DFSP/FS)の1例

大橋敦子, 芦田敦子, 村田浩, 宇原久, 奥山隆平, 吉田香奈子

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 124 ( 3 ) 355 - 355 2014.03

汗孔角化症のダーモスコピー所見

宇原久, 古賀弘志, 奥山隆平, 斎田俊明

茨城県臨床医学雑誌 ( (一社)茨城県医師会 ) ( 49 ) 88 - 88 2014.02

NRAS mutations in primary and metastatic melanomas of Japanese patients

Hisashi Uhara, Atsuko Ashida, Hiroshi Koga, Eisaku Ogawa, Aya Uchiyama, Ryuhei Uchiyama, Koichi Hayashi, Yukiko Kiniwa, Ryuhei Okuyama

International Journal of Clinical Oncology ( Springer-Verlag Tokyo ) 19 ( 3 ) 544 - 548 2014 [Refereed]

Background: Characterization of the MAPK signaling pathway in melanoma has led to the development of MEK inhibitors for the treatment of NRAS-mutated melanoma. The success of molecular-targeted therapies underscores the need to identify mutations in target genes. Most of the current data on genetic mutations have been obtained from Caucasian melanoma patients, and screenings of Asian populations are limited. Objective: The aim of the present study was to examine NRAS mutations in primary and metastatic lesions of Japanese melanoma patients. Methods: Clinical melanoma specimens were collected from 127 Japanese patients, including primary (n = 67), metastatic (n = 25) and paired primary and metastatic lesions (n = 35). NRAS mutations in exons 1 and 2 were assessed by polymerase chain reaction and Sanger sequencing. Results: The incidence of NRAS mutations was 7.1 %. NRASQ61 was the predominant genetic alteration (77.8 %). NRAS mutations were most frequently detected in acral melanomas (9.3 %), followed by melanomas without chronic sun-induced damage (7.0 %) and mucosal melanomas (4.8 %), and were not detected in melanomas with chronic sun-induced damage. In addition, NRAS mutations were more prevalent in the extremities than in other sites. The NRAS sequence in metastatic lesions did not match that of the primary tumor in one case. Conclusion: The frequency of NRAS mutations is lower in the Asian population than in Caucasian patients. The observed heterogeneity of melanoma suggests that genotyping of both primary and metastatic lesions is important to identify candidate patients for molecular-targeted therapies. © 2013 Japan Society of Clinical Oncology.

IgA/IgG pemphigus with infiltration of neutrophils and eosinophils in an ulcerative colitis patient

Ryuhei Uchiyama, Norito Ishii, Fuyuko Arakura, Yukiko Kiniwa, Koh Nakazawa, Hisashi Uhara, Takashi Hashimoto, Ryuhei Okuyama

Acta Dermato-Venereologica ( Medical Journals/Acta D-V ) 94 ( 6 ) 737 - 738 2014 [Refereed]

A case of anti-BP180-type mucous membrane pemphigoid with esophageal, genital and ophthalmic lesions

Toshikazu Omodaka, Hisashi Uhara, Ryuhei Uchiyama, Tasuku Sano, Hitomi Kubo, Norito Ishii, Takashi Hashimoto, Ryuhei Okuyama

Nishinihon Journal of Dermatology ( Western Division of Japanese Dermatological Association ) 76 ( 4 ) 345 - 348 2014 [Refereed]

A 66-year-old Japanese male presented with a three-year history of nasal bleeding and sore throat, followed by erosion in the oral cavity, conjunctiva, genital area and esophagus. Direct immunofluorescence revealed deposition of complement 3, IgG and IgA to the epidermal basement membrane zone. Indirect immunofluorescence revealed only IgA reactivity with the epidermal side of the split. Enzyme-linked immunosorbent assays revealed negative results for anti-desmoglein 1, antidesmoglein 3 and anti-BP180 (NC16a) antibodies. Immunoblotting analyses were performed using EDTA-separated normal human epidermal and dermal extracts, concentrated HaCaT cell culture supernatant, recombinant proteins of the BP180 NC16a and C-terminal domains, and purified human laminin-332. The patient serum showed positive reactivity only with the BP180 C-terminal domain. Based on the clinical, histopathological and immunological findings, we made a diagnosis of anti- BP180-type mucous membrane pemphigoid. Treatment with oral prednisolone 25 mg/day and azathioprine 100 mg/day was started. Subsequently, the prednisolone dose was increased to 60 mg/day. However, the mucosal erosions did not improve. The administration of methyl-prednisolone at 1 g/day for 3 days resulted in gradual clearance of the mucosal lesions. Anti- BP180-type mucous membrane pemphigoid is usually indolent. When lesions are limited to the oral cavity, they respond well to low-dose prednisolone. Our patient had extensive lesions outside the oral cavity and required more intensive therapy.

日本人の悪性黒色腫患者におけるNRAS遺伝子変異の解析(Assessment of NRAS mutation in Japanese melanoma patients)

芦田敦子, 宇原久, 奥山隆平

日本癌学会総会記事 ( (一社)日本癌学会 ) 72回 518 - 518 2013.10

Clinical effects of stereotactic radiation surgery in patients with metastatic melanoma

Asuka Mikoshiba, Hisashi Uhara, Hiroshi Murata, Ryuhei Okuyama

Journal of Dermatology 40 ( 8 ) 626 - 628 2013.08 [Refereed]

We examined the effectiveness of stereotactic radiation surgery (SRS) in 14 patients with brain metastasis in our hospital. The age of the patients ranged 45-85 years old (mean, 65). Brain metastasis was detected by neurological symptoms in seven patients and by regular imaging examination in the remaining patients. The number of metastatic lesions in the brain before SRS ranged 1-11 (median, 2). The treatment number of SRS was 1-4 times (median, 2). Six of 14 patients had neurological symptoms before SRS. Overall survival (OS) after SRS was 1.7-21.2 months (median, 8.2). The progression-free survival (PFS) after SRS was 0.9-10.5 months (median, 2.2). The result of univariate analysis showed that the application of two or more courses of SRS was significantly related to OS (P = 0.005). Single metastatic lesion (P = 0.051) and no extracranial lesion (P = 0.055) showed a slight tendency to be related to disease-free survival (DFS). Neither lactate dehydrogenase nor neurological symptoms were significantly related to OS or DFS. Although OS and DFS after SRS were not very long, the treatment of brain metastases has the potential to prevent neurological events. Repeating SRS may be accepted as a local therapy in the multimodal approach including new molecular targeting drugs for metastatic melanoma. © 2013 Japanese Dermatological Association.

【皮膚悪性腫瘍-基礎と臨床の最新研究動向-】悪性黒色腫悪性黒色腫の分子生物学分子生物学 MAPキナーゼ経路 NRAS、BRAF、MEK

芦田敦子, 木庭幸子, 宇原久, 奥山隆平

日本臨床 ( (株)日本臨床社 ) 71 ( 増刊4 皮膚悪性腫瘍 ) 126 - 129 2013.08

パクリタキセルにより強皮症様皮膚硬化を呈した1例

大橋敦子, 芦田敦子, 古賀弘志, 宇原久, 奥山隆平

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 29回 140 - 140 2013.08

日本人のメラノーマのおけるBRAF、NRAS、KITの遺伝子変異の解析

芦田敦子, 宇原久, 奥山隆平

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 29回 137 - 137 2013.08

【皮膚悪性腫瘍-基礎と臨床の最新研究動向-】悪性黒色腫悪性黒色腫の分子生物学分子生物学チロシンキナーゼ KIT

芦田敦子, 木庭幸子, 宇原久, 奥山隆平

日本臨床 ( (株)日本臨床社 ) 71 ( 増刊4 皮膚悪性腫瘍 ) 134 - 138 2013.08

A case of hypocomplementaemic urticarial vasculitis with a high serum level of rheumatoid factor

Atsuko Ashida, Hiroshi Murata, Atsuko Ohashi, Eisaku Ogawa, Hisashi Uhara, Ryuhei Okuyama

Australasian Journal of Dermatology 54 ( 3 ) e62 - e63 2013.08 [Refereed]

We report a case of hypocomplementaemic urticarial vasculitis with an elevated serum rheumatoid factor level. Hypocomplementaemic urticarial vasculitis is an immune complex-mediated disease characterised by urticarial eruptions. High levels of rheumatoid factor may be associated with hypocomplementaemia due to the consumption of complement, because the rheumatoid factor can form immune complexes with immunoglobulin. It is necessary to pay attention to the amounts of complement in cases of urticarial eruptions with elevated rheumatoid factor level. The eruptions were relieved with a combination of prednisolone and colchicine. © 2012 The Australasian College of Dermatologists.

【皮膚悪性腫瘍-基礎と臨床の最新研究動向-】有棘細胞癌(日光角化症・Bowen病) 有棘細胞癌の治療化学療法化学療法(最新の分子標的薬を含む)

古賀弘志, 宇原久, 奥山隆平

日本臨床 ( (株)日本臨床社 ) 71 ( 増刊4 皮膚悪性腫瘍 ) 507 - 511 2013.08

【皮膚悪性腫瘍-基礎と臨床の最新研究動向-】悪性黒色腫悪性黒色腫の治療分子標的薬その他のMAPK系阻害剤

古賀弘志, 宇原久, 奥山隆平

日本臨床 ( (株)日本臨床社 ) 71 ( 増刊4 皮膚悪性腫瘍 ) 392 - 396 2013.08

汗孔角化症のダーモスコピー所見

宇原久, 古賀弘志, 奥山隆平, 斎田俊明

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 8 ) 1559 - 1559 2013.07

Clinical course of drug-induced hypersensitivity syndrome treated without systemic corticosteroids

H. Uhara, M. Saiki, S. Kawachi, A. Ashida, S. Oguchi, R. Okuyama

Journal of the European Academy of Dermatology and Venereology 27 ( 6 ) 722 - 726 2013.06 [Refereed]

Background/aim Drug-induced hypersensitivity syndrome (DIHS) is a severe reaction to drugs which characteristically occurs after a long latency period. In addition, human herpes virus 6 (HHV-6) reactivation is a characteristic finding in DIHS, which has been known to be related to disease severity. Because DIHS has generally been treated by systemic corticosteroids, the natural clinical course is not clear. Methods Data for patients with both DIHS and HHV-6 reactivation were retrospectively collected from four hospitals. Results Data were collected on 12 patients ranging in age from 21 to 76 years (median, 65.5). All cases had been suspected of DIHS at their initial visit, and the elevation of serum anti-HHV-6 antibody had been confirmed (4-256 times: median 32). The culprit drugs were carbamazepine (6), salazosulfapyridine (4), mexiletine (1) and zonisamide (1). The period of latency from the first administration of the drug ranged from 15 to 50 days (median, 30). All patients were treated conservatively for DIHS without systemic corticosteroids. The peaks of the patients' symptoms and laboratory findings were as follows (days from the onset of skin lesions): fever, 4-16 (median, 10.5) liver abnormality, 3-22 (median, 7.5) leukocytosis, 7-20 (median, 9). All patients recovered without pneumonia, myocarditis, nephritis or other systemic disease, from 7 to 37 days (median, 18) after withdrawal of the drug and from 11 to 44 days (median, 21) after the onset of skin lesions. Conclusion It might be unnecessary to give systemic corticosteroids immediately to all patients suspected of having DIHS. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

Platinum and anthracycline therapy for advanced cutaneous squamous cell carcinoma

Kenta Nakamura, Ryuhei Okuyama, Toshiaki Saida, Hisashi Uhara

International Journal of Clinical Oncology 18 ( 3 ) 506 - 509 2013.06 [Refereed]

Background: Because metastatic cutaneous squamous cell carcinoma (CSCC) is rare, standard chemotherapy has not been fully established. In Japan, combination platinum and anthracycline chemotherapy has been used for elderly patients with advanced CSCC because of its low toxicity. However, the clinical benefit of this therapy has not been fully examined. Methods: We retrospectively examined the response rate of combination platinum and anthracycline chemotherapy for metastatic CSCC. Results: Eight patients received combination chemotherapy for metastatic lesions there were lymph node lesions in 6 patients and skin and lung lesions in one patient each. The combination regimens were as follows: cisplatin (CDDP) (60-90 mg/m2/day, day 1) and adriamycin (ADM) (20-40 mg/m2/day, day 1 or 2) was administered in 5 patients CDDP (10-15 mg/m2/day, days 1-5) and epirubicin (epi-ADM) (10-15 mg/m2/day, days 1-5) was administered in 2 patients and carboplatin (CBDCA) (200-400 mg/m2/day, day 1) and ADM (20-40 mg/m 2/day, day 1 or 2) was administered in one patient. The responses were as follows: complete response in 2 patients (CDDP + ADM for lung metastasis, CDDP + epi-ADM for lymph node metastasis), partial response in 1 (CDDP + ADM for lymph node metastasis), stable disease in 2, and progressive disease in 3. A durable response was observed in 2 patients showing complete responses (58 and 112 months). Conclusions: The clinical effect of the combination of platinum and anthracycline for metastatic CSCC was limited despite the findings of two patients showing durable complete responses. © 2012 Japan Society of Clinical Oncology.

マイコプラズマ感染により発症したStevens Johnson症候群(SJS)の1例

御子柴育朋, 大橋敦子, 芦田敦子, 村田浩, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 2 ) 171 - 171 2013.02

腹部に生じた隆起性皮膚線維肉腫(DFSP)病変を伴う線維肉腫の1例

大橋敦子, 芦田敦子, 村田浩, 宇原久, 奥山隆平, 吉田香奈子

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 2 ) 172 - 172 2013.02

喉頭狭窄をきたした後天性表皮水疱症の1例

木庭幸子, 大橋敦子, 芦田敦子, 宇原久, 奥山隆平, 小口真司

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 2 ) 171 - 171 2013.02

魚介による口腔アレルギー症候群の1例

御子柴育朋, 斉藤奈那, 大橋敦子, 芦田敦子, 村田浩, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 2 ) 173 - 173 2013.02

小児膿疱性乾癬の1例

御子柴育朋, 村田浩, 赤羽聡子, 佐藤勇樹, 芦田敦子, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 2 ) 174 - 174 2013.02

全身性サルコイドーシスに伴った刺青サルコイドーシスの1例

中村謙太, 大橋敦子, 古賀弘志, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 123 ( 2 ) 174 - 174 2013.02

Dermoscopic characteristics of acquired melanocytic naevus in childhood affecting the acral region

Akane Minagawa, Hiroshi Koga, Hisashi Uhara, Ryuhei Okuyama

Acta Dermato-Venereologica 93 ( 6 ) 751 - 752 2013 [Refereed]

Dermoscopic findings in melanocytic naevus show characteristic patterns depending on age of onset and location (1, 2). On the trunk and extremities, a globular pattern is characteristic in both acquired melanocytic naevus (AMN) of childhood and in small-sized congenital melanocytic naevus (CMN), whereas a reticular pattern is common in melanocytic naevus in adulthood. Individual AMN on the back rarely change their dermoscopic patterns during adolescence (3) but the situation for AMN of the acral region has not been fully explored. We report here the results of dermoscopic analysis of acral AMN in children. © 2013 Acta Dermato-Venereologica.

Epidermal-type FABP is a predictive marker of clinical response to systemic treatment and ultraviolet therapy in psoriatic skin lesions.

Miyake T, Ogawa E, Mikoshiba A, Kobayashi A, Hosoe H, Kashiwabara S, Uhara H, Owada Y, Okuyama R

Journal of dermatological science 68 ( 3 ) 199 - 202 2012.12 [Refereed]

Cutaneous angiosarcoma of the leg showing radiation sensitivity

Atsuko Ohashi, Hitomi Kubo, Maiko Iwade, Junko Shiohara, Minoru Takata, Hisashi Uhara, Ryuhei Okuyama

Australasian Journal of Dermatology 53 ( 3 ) e51 - e53 2012.08 [Refereed]

We report a case of cutaneous angiosarcoma occurring on the leg of a 97-year-old Japanese woman. Considering the patient's age and general condition, she was treated with electron beam irradiation, which led to the almost complete disappearance of the tumour. Because cutaneous angiosarcoma is an aggressive tumour with a high propensity for local recurrence and distant metastases, therapy preferably involves a multimodal approach. However, monotherapy with radiation may be effective in some cases of cutaneous angiosarcoma. © 2011 The Australasian College of Dermatologists.

日本人の悪性黒色腫患者におけるBRAF、KIT遺伝子変異の解析(Assessment of BRAF and KIT mutations in Japanese melanoma patients)

芦田敦子, 宇原久, 村田浩, 後藤康文, 奥山隆平

日本癌学会総会記事 ( (一社)日本癌学会 ) 71回 359 - 359 2012.08

シクロスポリンが著効した小児膿疱性乾癬の1例

御子柴育朋, 村田浩, 赤羽聡子, 佐藤勇樹, 芦田敦子, 宇原久, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 122 ( 9 ) 2336 - 2336 2012.08

【膿疱を伴う皮膚疾患(2)】<臨床例>治療に難渋した小児膿疱性乾癬

御子柴育朋, 芦田敦子, 村田浩, 宇原久, 奥山隆平

皮膚病診療 ( (株)協和企画 ) 34 ( 7 ) 683 - 686 2012.07

＜症例のポイント＞・膿疱性乾癬は乾癬全体の1%程度といわれ、比較的少数である。しかし、膿疱性乾癬は小児例が11.7%を占めることから、小児期に発症することが少なくないと思われる。・自験例ではステロイド薬、活性型ビタミンD3製剤の外用に反応せず、シクロスポリンの内服を行った。・シクロスポリン投与後、全身状態は安定し皮疹の改善は図られた。しかし、寛解には至らずときどき再燃がみられる。・乾癬は慢性的に継続するため、継続した治療が必要である。一方、小児の場合、治療の選択肢が限られ、治療に難渋する症例も少なくない。(著者抄録)

頭部血管肉腫の5例

葭矢裕之, 芦田敦子, 村田浩, 宇原久, 奥山隆平

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 28回 132 - 132 2012.06

ダーモスコピー、サージカルテープ、高周波エコーの併用による基底細胞癌の境界の推測

林宏一, 宇原久, 古賀弘志, 奥山隆平

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 28回 126 - 126 2012.06

Applicability of radiocolloids, blue dyes and fluorescent indocyanine green to sentinel node biopsy in melanoma

Hisashi Uhara, Naoya Yamazaki, Minoru Takata, Yuji Inoue, Akihiro Sakakibara, Yasuhiro Nakamura, Keisuke Suehiro, Akifumi Yamamoto, Riei Kamo, Kosuke Mochida, Hideya Takenaka, Toshiharu Yamashita, Tatsuya Takenouchi, Shusuke Yoshikawa, Akira Takahashi, Jiro Uehara, Mikio Kawai, Hiroaki Iwata, Takafumi Kadono, Yoshitaka Kai, Shoichi Watanabe, Satoru Murata, Tetsuya Ikeda, Hidekazu Fukamizu, Toshihiro Tanaka, Naohito Hatta, Toshiaki Saida

JOURNAL OF DERMATOLOGY ( WILEY-BLACKWELL ) 39 ( 4 ) 336 - 338 2012.04 [Refereed]

Patients with primary cutaneous melanoma underwent sentinel node (SN) mapping and biopsy at 25 facilities in Japan by the combination of radiocolloid with gamma probe and dye. Technetium-99m (99mTc)-tin colloid, 99mTc-phytate, 2% patent blue violet (PBV) and 0.4% indigo carmine were used as tracers. In some hospitals, 0.5% fluorescent indocyanine green, which allows visualization of the SN with an infrared camera, was concomitantly used and examined. A total of 673 patients were enrolled, and 562 cases were eligible. The detection rates of SN were 95.5% (147/154) with the combination of tin colloid and PBV, 98.9% (368/372) with the combination of phytate and PBV, and 97.2% (35/36) with the combination of tin colloid or phytate and indigo carmine. SN was not detected in 12 cases by the combination method, and the primary tumor was in the head and neck in six of those 12 cases. In eight of 526 cases (1.5%), SN was detected by PBV but not by radiocolloid. There were 13 cases (2.5%) in which SN was detected by radiocolloid but not by PBV. In 18 of 36 cases (50%), SN was detected by radiocolloid but not by indigo carmine. Concomitantly used fluorescent indocyanine green detected SN in all of 67 cases. Interference with transcutaneous oximetry by PVB was observed in some cases, although it caused no clinical trouble. Allergic reactions were not reported with any of the tracers. 99mTc-tin colloid, 99mTc-phytate, PBV and indocyanine green are useful tracers for SN mapping.

Surgical treatment of nail apparatus melanoma in situ: The use of artificial dermis in reconstruction

Koichi Hayashi, Hisashi Uhara, Hiroshi Koga, Ryuhei Okuyama, Toshiaki Saida

Dermatologic Surgery 38 ( 4 ) 692 - 694 2012.04 [Refereed]

Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level

K. Sakaizawa, Y. Goto, Y. Kiniwa, A. Uchiyama, K. Harada, S. Shimada, T. Saida, S. Ferrone, M. Takata, H. Uhara, R. Okuyama

British Journal of Cancer 106 ( 5 ) 939 - 946 2012.02 [Refereed]

Background: The availability of molecular-targeted therapies for the treatment of melanoma has emphasised the need to identify mutations in target genes such as BRAF and KIT. Circulating tumour cells (CTC) are present in the peripheral blood of a significant proportion of cancer patients.Methods:High molecular weight melanoma-associated antigen (HMW-MAA) was used to isolate melanoma cells from peripheral blood as it is selectively expressed at high levels on melanomas. The HMW-MAA-positive cells were isolated using immunomagnetic beads. After removing CD45 + cells, CTC were identified by staining with MART-1-and gp100-specific antibodies (HMW-MAA , CD45 + , MART-1/gp100 + ). Single, isolated CTC were then subjected to BRAF and KIT mutational analysis.Results:CTC (HMW-MAA , CD45 - , MART-1/gp100 + ) were isolated from the blood of 11 patients and BRAF and KIT were sequenced in nine and four patients, respectively. The BRAF sequences identified in the CTC were inconsistent with those identified in autologous melanoma tumours in three patients and the KIT sequences were inconsistent in three patients. In addition, polyclonal BRAF mutations were identified in one patient and concomitant mutations in BRAF and KIT were identified in another patient.Conclusion:Melanoma cells show clonal heterogeneity. Therefore, CTC genotyping may be crucial for successful molecular-targeted therapy. © 2012 Cancer Research UK All rights reserved.

Prediction of additional lymph node positivity and clinical outcome of micrometastases in sentinel lymph nodes in cutaneous melanoma: a multi-institutional study of 450 patients in Japan.

Kenjiro Namikawa, Naoya Yamazaki, Yasuo Nakai, Hironobu Ihn, Yasushi Tomita, Hisashi Uhara, Tatsuya Takenouchi, Yoshio Kiyohara, Yoichi Moroi, Yuhei Yamamoto, Fujio Otsuka, Hideki Kamiya, Hajime Iizuka, Naohito Hatta, Takafumi Kadono

The Journal of dermatology 39 ( 2 ) 130 - 7 2012.02 [Refereed] [International journal]

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

温熱負荷試験で誘発できた血管浮腫の1例

小林彩, 芦田敦子, 木庭幸子, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 122 ( 2 ) 418 - 418 2012.02

温熱負荷試験で誘発できた血管浮腫の1例

小林彩, 芦田敦子, 木庭幸子, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 122 ( 1 ) 106 - 107 2012.01

A case of advanced malignant melanoma responding to single-dose dacarbazine

UCHIYAMA Ryuhei, IDE Yoko, MINAGAWA Akane, KOGA Hiroshi, KINIWA Yukiko, UHARA Hisashi, TAKATA Minoru, SAIDA Toshiaki, KURAI Makoto

Skin Cancer ( The Japanese Skin Cancer Society ) 26 ( 2 ) 139 - 142 2011.09

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

Characteristic distribution of melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic differentiation from early acral melanoma

Toshiaki Saida, Hiroshi Koga, Yasufumi Goto, Hisashi Uhara

American Journal of Dermatopathology 33 ( 5 ) 468 - 473 2011.07 [Refereed]

Clinical and histopathologic differentiation between early acral melanoma and acral nevus is often difficult. Dermoscopy is helpful in this differentiation. On dermoscopy, early acral melanoma shows the parallel ridge pattern showing band-like pigmentation on the ridges of the surface skin markings, whereas a representative dermoscopic pattern in acquired acral nevus is the parallel furrow pattern showing parallel linear pigmentation along the surface furrows. The parallel furrow pattern suggests that melanocytes of acral nevus preferentially proliferate in the crista profunda limitans, an epidermal rete ridge underlying the surface furrow. In the present study, however, we found that in 13 of 18 acquired acral nevi, proliferation of melanocytes were detected not only in the crista profunda limitans but also in the crista profunda intermedia (CPI), an epidermal rete ridge underlying the surface ridge. Very interestingly, Fontana-Masson staining of these acral nevi revealed that even when proliferation of melanocytes was prominent in the CPI, melanin granules in the cornified layer were observed as regular melanin columns situated under the surface furrows and were hardly detected under the surface ridges. These findings indicate that in acral nevus, melanin granules produced by melanocytes in the CPI are not transferred to the upper epidermis. Hence, we must be careful not to overdiagnose an acral melanocytic lesion in which an increased number of melanocytes are detected in the CPI. Even in such a case, if melanin granules in the cornified layer are detected as melanin columns regularly distributed under the surface furrows, the lesion is strongly suggested to be a benign acral nevus. Copyright © 2011 by Lippincott Williams & Wilkins.

Thermal angiooedema induced by hot water

Aya Kobayashi, Hisashi Uhara, Atsuko Ashida, Yukiko Kiniwa, Ryuhei Okuyama

Acta Dermato-Venereologica 91 ( 3 ) 343 - 344 2011.05 [Refereed]

喉頭狭窄をきたした後天性表皮水疱症の1例

木庭幸子, 大橋敦子, 芦田敦子, 宇原久, 鬼頭良輔, 福田俊平, 橋本隆, 奥山隆平

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 121 ( 3 ) 585 - 585 2011.03

Key points in dermoscopic differentiation between early acral melanoma and acral nevus

Toshiaki Saida, Hiroshi Koga, Hisashi Uhara

Journal of Dermatology 38 ( 1 ) 25 - 34 2011.01 [Refereed]

Acral skin is the most prevalent site of malignant melanoma in non-Caucasian populations. On acral skin, other various kinds of pigmented lesions are also detected. Particularly, melanocytic nevus is commonly seen on acral volar skin approximately 10% of Japanese have a nevus on their soles. Prognosis of acral melanoma is still generally poor because of delayed detection in the advanced stages. To improve the prognosis, early detection is essential. Early acral melanoma is seen as a brownish macule, which is clinically quite similar to acral nevus. Therefore, clinicians often face a dilemma when they see a pigmented macule on acral volar skin. Introduction of dermoscopy was a great epoch in this field. Pigmentation pattern on dermoscopy is completely opposite between early acral melanoma and acral nevus pigmentation on the ridges of the surface skin markings is detected in early acral melanoma, whereas pigmentation along the furrows of the skin markings is seen in acral nevus. We termed these dermoscopic patterns the parallel ridge pattern and the parallel furrow pattern, respectively. These features are highly helpful in the differentiation between the two biologically distinct entities. The sensitivity and specificity of the parallel ridge pattern in diagnosing early acral melanoma is 86% and 99%, respectively. However, we must be aware that dermoscopic features in acral nevus sometimes mimic the parallel ridge pattern and that other conditions also could show dermoscopic features similar to the parallel ridge pattern. In this review article, we summarize key points of the dermoscopic diagnosis of early acral melanoma and then describe the three-step algorithm for the management of acral melanocytic lesions, which surely aids us in effectively detecting early acral melanoma and in reducing unnecessary resection of benign nevus. © 2011 Japanese Dermatological Association.

Key point in dermoscopic differentiation between early nail apparatus melanoma and benign longitudinal melanonychia

Hiroshi Koga, Toshiaki Saida, Hisashi Uhara

Journal of Dermatology 38 ( 1 ) 45 - 52 2011.01 [Refereed]

Longitudinal melanonychia presents in various conditions including neoplastic and reactive disorders. It is much more frequently seen in non-Caucasians than Caucasians. While most cases of nail apparatus melanoma start as longitudinal melanonychia, melanocytic nevi of the nail apparatus also typically accompany longitudinal melanonychia. Identifying the suspicious longitudinal melanonychia is therefore an important task for dermatologists. Dermoscopy provides useful information for making this decision. The most suspicious dermoscopic feature of early nail apparatus melanoma is irregular lines on a brown background. Evaluation of the irregularity may be rather subjective, but through experience, dermatologists can improve their diagnostic skills of longitudinal melanonychia, including benign conditions showing regular lines. Other important dermoscopic features of early nail apparatus melanoma are micro-Hutchinson's sign, a wide pigmented band, and triangular pigmentation on the nail plate. Although there is as yet no solid evidence concerning the frequency of dermoscopic follow up, we recommend checking the suspicious longitudinal melanonychia every 6 months. Moreover, patients with longitudinal melanonychia should be asked to return to the clinic quickly if the lesion shows obvious changes. Diagnosis of amelanotic or hypomelanotic melanoma affecting the nail apparatus is also challenging, but melanoma should be highly suspected if remnants of melanin granules are detected dermoscopically. © 2011 Japanese Dermatological Association.

ホワイトボードマーカーによる皮野の染色はダーモスコピー診断に役立つ

宇原久, 古賀弘志, 高田実, 斎田俊明

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 120 ( 3 ) 747 - 747 2010.03

Tetracycline and niacinamide control bullous pemphigoid but not pemphigus foliaceus when these conditions coexist

Junko Shiohara, Kanako Yoshida, Junichi Hasegawa, Hisashi Uhara, Minoru Takata, Toshiaki Saida, Bungo Oyama, Takashi Hashimoto

Journal of Dermatology ( Blackwell Publishing Ltd ) 37 ( 7 ) 657 - 661 2010 [Refereed]

Pemphigus and pemphigoid are different types of autoimmune bullous disease and can occur in the same patient. We report a female patient with this condition. At first, we diagnosed her with bullous pemphigoid, and we treated her with tetracycline, niacinamide and a topical steroid. Tense bullas disappeared shortly after that, but crusted erythemas mainly on her head and trunk persisted. We examined BP180 and desmoglein 1 enzyme-linked immunosorbent assays, and also histological features, which showed coexistence of bullous pemphigoid and pemphigus foliaceus concurrently. Therefore, we tried prednisolone, which could control both conditions. This case showed that tetracycline and niacinamide could control bullous pemphigoid, but could not control pemphigus foliaceus, and that prednisolone was effective for both conditions. © 2010 Japanese Dermatological Association.

High-frequency 30-MHz sonography in preoperative assessment of tumor thickness of primary melanoma: Usefulness in determination of surgical margin and indication for sentinel lymph node biopsy

Koichi Hayashi, Hiroshi Koga, Hisashi Uhara, Toshiaki Saida

International Journal of Clinical Oncology 14 ( 5 ) 426 - 430 2009.10 [Refereed]

Background: High-frequency sonographic imaging has been used for the preoperative evaluation of primary malignant melanoma. In the present study, to identify the usefulness of 30-MHz sonography for determination of the surgical margin and indication for sentinel lymph node biopsy, the correlation between sonometric and histometric tumor thickness was investigated. Methods: A total of 74 primary melanomas, in patients seen at the dermatology clinic, Shinshu University Hospital, from 1998 to 2006, were evaluated using high-frequency sonographic equipment with two probes (15 MHz and 30 MHz), and tumor thickness was measured using electronic calipers before surgical treatment. All the primary lesions were surgically excised and Breslow's tumor thickness was measured histologically. Results: In 68 melanomas, excluding 2 lesions of melanoma in situ and 4 lesions with poor sonographic images, sonographic and histologic thickness showed good correlation (r = 0.887). Particularly, in 26 melanomas affecting the soles of the feet, sonographic and histologic thickness showed excellent correlation (r = 0.945). Regarding the T categorization, in which T1-T4 are divided at 1, 2, and 4 mm in thickness, the categories determined with sonometry corresponded very well to those determined with histometry. The correspondence was particularly excellent in thinner primary lesions with thickness around 1 mm. We excised almost all these primary melanomas with surgical margins based on the sonometric thickness. In 22 patients with sonometric thickness more than 1 mm, sentinel lymph node biopsy and/or radical lymphadenectomy was performed. Conclusion: High-frequency sonography (30-MHz) is very useful in the preoperative prediction of tumor thickness, particularly in thinner primary lesions, which allows us to determine surgical margins and indication for sentinel lymph node biopsy. © 2009 Japan Society of Clinical Oncology.

Transient myeloproliferative disorder with vesiculopustular eruption: Early smear is useful for quick diagnosis

Hisashi Uhara, Masaaki Shiohara, Atsushi Baba, Junko Shiohara, Toshiaki Saida

Journal of the American Academy of Dermatology 60 ( 5 ) 869 - 871 2009.05 [Refereed]

We report a male infant with Down syndrome who had a transient myeloproliferative disorder associated with skin lesions. He was transferred to a neonatal intensive care unit because of low body weight, fetal edema, disseminated intravascular coagulation, and 10% blast cells in the peripheral blood. On postnatal day (PD) 1, erythema with small papules, vesicles, and pustules appeared on the entire body. A smear preparation from the pustules on PD 2 showed 10% blast cells. A biopsy specimen taken on PD 5 revealed subcorneal pustules containing neutrophils and eosinophils. Genetic analyses detected a somatic mutation (197G> T, Glu295Stop) in exon 2 of GATA-1. On PD 10, the eruptions resolved spontaneously and the population of blast cells in peripheral blood decreased to 1%. The number of blast cells in pustules decreased markedly after three days. Therefore, we recommend that cytologic examination should be performed as early as possible. © 2008 American Academy of Dermatology, Inc.

Reversible extensive leukoencephalopathy in Sweet disease: A case report

Kazuhiro Fukushima, Akiyo Hineno, Minori Kodaira, Kazuko Machida, Wataru Ishii, Tomoki Kaneko, Hisashi Shimojo, Hisashi Uhara, Kanji Yamamoto, Hiroshi Morita, Kunihiro Yoshida, Shu-ich Ikeda

Journal of the Neurological Sciences 275 ( 1-2 ) 178 - 180 2008.12 [Refereed]

Sweet disease, also known as acute febrile neutrophilic dermatosis, is an idiopathic multisystem inflammatory disorder characterised by erythematous skin lesions and fever. "Neuro-Sweet disease" is a rare central nervous system involvement that coexists with the characteristic cutaneous lesions of Sweet disease. Here, we report a case of Sweet disease complicated with acute encephalopathy. This case showed extensive lesions in the cerebral white matter on magnetic resonance imaging (MRI) and high protein concentration in the cerebrospinal fluid (CSF) without pleocytosis. After steroid therapy, the patient's clinical syndrome recovered completely with no significant neurological deficits or abnormal findings on brain MRI, and normalization of the high CSF protein concentration. Both clinical and MRI findings suggested that the marked leukoencephalopathy in this case was mainly due to reversible oedema rather than destructive structural alterations in the cerebral parenchyma. © 2008 Elsevier B.V. All rights reserved.

Surgical treatment for anorectal malignant melanoma: report of five cases and review of 79 Japanese cases

Satoshi Ishizone, Naohiko Koide, Fumitoshi Karasawa, Noriyuki Akita, Futoshi Muranaka, Hisashi Uhara, Shinichi Miyagawa

INTERNATIONAL JOURNAL OF COLORECTAL DISEASE ( SPRINGER ) 23 ( 12 ) 1257 - 1262 2008.12 [Refereed]

Anorectal malignant melanoma (AMM) is a relatively rare disease. Because of its poor prognosis, the optimal surgical treatment for AMM is still controversial and difficult to determine. In this paper, we report five cases of AMM that have been treated by surgery and/or other methods at Shinshu University Hospital within the last decade. We also review the present five cases along with 74 other Japanese cases reported between 1997 and 2006 and discuss the role of surgery in the treatment of AMM. Among our AMM patients, two who underwent radical abdominoperineal resection had long survival, while the other three patients who underwent palliative surgery had a poor outcome. On the total of 79 AMM patients, those who underwent curative surgery had a better outcome than those who underwent palliative surgery (p < 0.0001). Furthermore, the outcome of AMM patients at stages 0 and I was better than that of AMM patients at stages II, III, and IV (p < 0.0001). There was no significant difference in survival between AMM patients with and without adjuvant chemotherapy. In conclusion, AMM patients treated by curative surgery can expect long-term survival, although the usefulness of adjuvant chemotherapy for AMM patients is controversial.

Neutrophilic dermatoses with acute myeloid leukemia associated with an increase of serum colony-stimulating factor

Hisashi Uhara, Toshiaki Saida, Hideyuki Nakazawa, Toshiro Ito

Journal of the American Academy of Dermatology 59 ( 2 ) S10 - S12 2008.08 [Refereed]

A case of primary Epstein-Barr virus-associated cutaneous diffuse large B-cell lymphoma unassociated with iatrogenic or endogenous immune dysregulation

Yasutaka Tokuda, Mana Fukushima, Koh Nakazawa, Shinji Oguchi, Yoko Koganehira, Maki Yamaura, Miwako Iijima, Hiroshi Murata, Hisashi Uhara, Minoru Takata, Toshiaki Saida, Tsutomu Katsuyama, Sigeo Nakamura

Journal of Cutaneous Pathology 35 ( 7 ) 666 - 671 2008.07 [Refereed]

Cutaneous Epstein-Barr virus (EBV)-associated B-cell lymphoma (EBVBL) in non-immunocompromised patients is very rare. Here, we report a case of cutaneous EBVBL in a 72-year-old Japanese woman without any signs of immunosuppression. She showed repeated high fever and skin eruptions on the face, limbs and palms. Histological diagnosis was diffuse large B-cell lymphoma. EBV infection was detected by in situ hybridization and Southern blotting. Immunostaining for viral proteins showed the patient to be positive for latent membrane protein 1 (LMP-1) and negative for Epstein-Barr virus nuclear antigen-1 (EBNA-2), indicating that a type II latency EBV infection pattern. © Blackwell Munksgaard 2008.

The Relationship between Tumor Thickness and the Metastatic Rate of Sentinel Lymph Nodes in Japanese Patients with Melanoma

Uhara Hisashi, Yamamoto Akifumi, Kiyohara Yoshio, Saida Toshiaki

The Japanese Journal of Dermatology ( Japanese Dermatological Association ) 118 ( 14 ) 3083 - 3088 2008

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

A pilot study of human interferon β gene therapy for patients with advanced melanoma by in vivo transduction using cationic liposomes

Kazuhiko Matsumoto, Hitomi Kubo, Hiroshi Murata, Hisashi Uhara, Minoru Takata, Shinichi Shibata, Satoshi Yasue, Akihiro Sakakibara, Yasushi Tomita, Toshiro Kageshita, Yutaka Kawakami, Masaaki Mizuno, Jun Yoshida, Toshiaki Saida

Japanese Journal of Clinical Oncology ( Oxford University Press ) 38 ( 12 ) 849 - 856 2008 [Refereed]

Background: Cationic liposomes containing the human interferon β (HuIFNβ) gene (IAB-1) was used for the clinical trial for glioma patients. HuIFNβ gene therapy showed much higher anti-tumor activity compared with the administration of HuIFNβ protein for melanoma. These results suggest that HuIFNβ gene therapy is an attractive strategy for the treatment of melanoma. Methods: Stage IV or III melanoma patients with cutaneous or subcutaneous metastatic lesions were enrolled in this pilot study. IAB-1 was dissolved by sterile PBS at a concentration of 30 μg DNA/ml and was injected into cutaneous or subcutaneous metastatic nodules three times a week for 2 weeks and the effect on the injected and non-injected metastatic lesions was evaluated. Results: Clinical responses were as follows (five patients): mixed response (MR) and no change in each one patient, and progressive disease in three patients. In the MR patient, the IAB-1 injected lesion disappeared clinically and histopathologically and one-half of IAB-1 non-injected skin metastases were transiently inflamed and mostly regressed. In the responded non-injected lesions of this patient, histopathologically, infiltration of CD4 positive T cells was observed around the melanoma cells in the dermis, which expressed the HLA-Class II antigen. Adverse events due to this gene therapy were not recognized in any of the patients. Conclusions: The efficacy of this gene therapy was generally insufficient however, some immunological responses were recognized in one patient. No adverse events were observed. HuIFNβ gene therapy could be an attractive strategy for treatment of a variety of malignancies, including melanoma, though some modifications should be required. © The Author (2008). Published by Oxford University Press. All rights reserved.

Multiple hypersonographic spots in basal cell carcinoma

Hisashi Uhara, Koichi Hayashi, Hiroshi Koga, Toshiaki Saida

Dermatologic Surgery 33 ( 10 ) 1215 - 1219 2007.10 [Refereed]

BACKGROUND: High-frequency ultrasound is a useful method to obtain preoperative information regarding extension of basal cell carcinoma. Its contribution to diagnosis is generally limited, however. Recently, we observed hypersonographic spots in some cases of basal cell carcinoma. OBJECTIVE: The present study was performed to determine the diagnostic value of this finding in this type of tumor. MATERIALS AND METHODS: We conducted a retrospective study of archived sonographic images with a 30- or 15-MHz scanner and histology specimens of a total of 85 lesions, consisting of 29 basal cell carcinomas and 56 melanomas. RESULTS: The findings were classified into four patterns as follows: Type A, multiple (more than five spots/lesion) hypersonographic spots (14 cases, 48%) Type B, sparse (3-5 spots/lesion) hypersonographic spots (7 cases, 24%) Type C, multiple moderate sonographic spots (3 cases, 10%) and Type D, sparse moderate sonographic spots (5 cases, 17%). Three of 56 melanoma lesions examined as controls showed the Type D pattern, but none showed Type A, B, or C patterns. Histopathologically, these hypersonographic spots in BCCs seemed to correspond to calcification, horn cysts, or clusters of apoptotic cells in the centers of nests of basal cell carcinoma. CONCLUSION: Multiple hypersonographic spots might become a useful finding for differential diagnosis between basal cell carcinoma and melanoma. © 2007 by the American Society for Dermatologic Surgery, Inc.

Eccrine porocarcinoma: Clinical and pathological studies of 12 cases

Junko Shiohara, Hiroshi Koga, Hisashi Uhara, Minoru Takata, Toshiaki Saida

Journal of Dermatology 34 ( 8 ) 516 - 522 2007.08 [Refereed]

Estrogen-receptor-alpha-positive extramammary Paget's disease treated with hormonal therapy

M. Iijima, H. Uhara, Y. Ide, S. Sakai, H. Onuma, M. Muto, K. Hayashi, F. Mitsura, S. Kobayashi, A. Yoshizawa, T. Saida

Dermatology 213 ( 2 ) 144 - 146 2006.08 [Refereed]

The patient was an 80-year-old man with scrotal and penile extramammary Paget's disease and prostate cancer. Both diseases were in advanced stages. Tumor cells of extramammary Paget's disease strongly expressed estrogen receptor α. The patient was concurrently treated with two kinds of hormonal therapy: the anti-estrogen tamoxifen (20 mg/day orally) for extramammary Paget's disease and the anti-androgen bicalutamide (80 mg/day orally) for prostate cancer. The toxicity of the therapy was mild. All of the metastatic lesions remained stable for 2 months after initiation of dual hormonal therapy. During a follow-up period of 22 months, performance status was well maintained for 17 months. Hormonal therapy may be an alternative for selected cases of advanced extramammary Paget's disease. Copyright © 2006 S. Karger AG.

【透析と皮膚】臨床例血栓性微小血管症を伴う高血圧性腎クリーゼを発症した全身性強皮症

古賀弘志, 宇原久, 斎田俊明

皮膚病診療 ( (株)協和企画 ) 25 ( 5 ) 533 - 536 2003.05

66歳男性.血栓性微小血管症を伴う高血圧性腎クリーゼを発症した全身性強皮症の1例を経験した.高血圧症でカルシウム拮抗剤内服中.両手足のむくみで受診した.両手首,両足首から末梢にび漫性の硬化性浮腫と舌小帯の短縮を認めた.病理組織所見は手背や前腕では汗腺分泌部以下にまで膠原線維が増生し,血管および付属器周囲にリンパ球主体の炎症性細胞浸潤認めた.自己抗体のプロフィールならびにKL-6値の上昇から全身性強皮症と診断し,D-ペニシラミン内服を開始したが,KL-6はさらに上昇し,胸部CTでは右下肺に間質性肺炎像が認められ,皮膚硬化も進行した.その後,クレアチニン値の上昇や腎生検より高血圧性腎クリーゼと診断され,あわせて種々検査から高血圧性腎クリーゼに合併した血栓性微小血管症と診断された.ACE阻害剤による降圧と血液透析,濃厚赤血球輸血とアルブミン,新鮮凍結血漿の輸注で症状は改善した

CD30陽性cutaneous large T cell lymphoma

吉澤さえ子, 太田桂子, 宮嵜敦, 芦田敦子, 六波羅詩穂, 宇原久, 斎田俊明

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 113 ( 5 ) 815 - 815 2003.04

Lymphangitis of the foot demonstrating lymphatic drainage pathways from the sole

Hisashi Uhara, Toshiaki Saida, Tomomi Watanabe, Yoshihiro Takizawa

Journal of the American Academy of Dermatology ( Mosby Inc. ) 47 ( 4 ) 502 - 504 2002.10 [Refereed]

Background: There are two main lymphatic routes from the lower extremity: the fibular route to the popliteal node and the tibial route to the distant groin node. However, little is known about lymphatics from the sole. Objective: We attempted to obtain detailed knowledge of the lymphatics from the sole. Methods: Eight patients with lymphangitis were examined and compared with the drainage patterns visualized by blue-dye injection in 7 cases of melanoma. Results: Six lymphangitic streaks started from the lateral edge of the plantar surface, 2 from the heel, and 1 each from the center of the sole and the little toe. All streaks ran to the tibial side and went up along the foot branch of the great saphenous vein. These findings were similar to those of the dye-injected melanoma cases. Conclusion: Lymphangitis makes visualization of lymphatic routes possible and may provide useful information about drainage.

Evaluation of 5-S-cysteinyidopa as a marker of melanoma progression: 10 years' experience

K Wakamatsu, T Kageshita, M Furue, N Hatta, Y Kiyohara, J Nakayama, T Ono, T Saida, M Takata, T Tsuchida, H Uhara, A Yamamoto, N Yamazaki, A Naito, S Ito

MELANOMA RESEARCH ( LIPPINCOTT WILLIAMS & WILKINS ) 12 ( 3 ) 245 - 253 2002.06 [Refereed]

5-S-Cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression. In this study, we measured serum levels of 5-S-CD in 2648 samples taken from 218 patients in order to evaluate the usefulness of this parameter in following melanoma progression and prognosis. 5-S-CD levels were significantly elevated above the upper limit of the normal range (10 nmol/l) in stage IV melanoma patients. The sensitivity of elevated serum 5-S-CD levels in detecting distant metastasis was 73%, while the specificity was 98% and the positive predictive value 94%. The sensitivity was improved to 77% when cases of amelanotic melanoma were excluded. Patients without metastases had elevated 5-S-CD values in 5% of the 1480 serum samples. Changes in serum 5-S-CD levels were followed during disease progression until the end stage in 49 patients. In 33% of the patients, elevation of serum 5-S-CD levels preceded clinical detection of visceral metastases, and in 37% elevation of 5-S-CD levels occurred at the same time as visceral metastasis. Patients with elevated 5-S-CD levels before or after surgical treatment had significantly shorter survival times than those with normal levels. These results show that the level of 5-S-CD in the serum is a sensitive and specific marker in predicting distant metastases. Elevated serum levels of 5-S-CD, before or after surgical treatment, is associated with a poor prognosis. (C) 2002 Lippincott Williams Wilkins.

Docetaxel induced durable response in advanced extramammary Paget's disease: A case report

S Oguchi, M Kaneko, H Uhara, T Saida

JOURNAL OF DERMATOLOGY ( JAPANESE DERMATOLGICAL ASSOC ) 29 ( 1 ) 33 - 37 2002.01 [Refereed]

The patient was a 54-year-old Japanese man with a seven-month history of an eroded lesion on the scrotum. Skin biopsy confirmed the diagnosis of extramammary Paget's disease, and a CT scan revealed multiple metastases to the lymph nodes along the iliac artery and aorta. The patient underwent combination chemotherapy with mitomycin C, epirubicin, vincristine, cisplatin, and 5-fluorouracil. After two courses of the regimen, the primary lesions on the scrotum regressed, however, the lymph node metastases did not respond. A regimen of continuous administration of low-dose cisplatin and 5-fluorouracil was not effective for the metastases either. Hence, administration of docetaxel at a dose of 60 mg/m(2)/every four weeks was started. After two courses, the lymph node metastases decreased by 75% compared to the pre-treatment size, and the effect was judged a partial response. The major toxicities were neutropenia, alopecia, pitting edema, and facial erythema, but these were tolerable. Five courses of this regimen were followed by four courses of weekly administration of 25 mg/m(2) docetaxel. The partial response persisted for more than 12 months and the patient was able to enjoy daily life. Docetaxel may be an effective drug for patients with advanced extramammary Paget's disease.

Chemotherapy and chemoimmunotherapy for advanced malignant melanoma

Hisashi Uhara, Toshiaki Saida

Biotherapy 16 ( 3 ) 227 - 232 2002

Metastatic melanoma (MM) is resistant to chemotherapeutic agents. Only 10-20% of patients respond to single-drug chemotherapy. Although multi-drug combination chemotherapy increased the response rate to 30-40%, none of these regimens have improved survival compared with dacarbazine alone. Recently, two regimens, the combination of dacarbazine, carmustine, cisplatin and tamoxifen (Dartmouth regimen), and cisplatin/IL-2/interferon alfa-based chemoimmunotherapy, have shown evidence of activity against MM. The response rates were in the range of 40-50% with 10% complete responses. However, randomized studies of these regimens did not show improvement in survival. Recent evaluations of therapeutic regimens for MM are reviewed here.

Proposition of Guidelines for Chemotherapy of Malignant Melanoma Based on the Data Obtained from Relevant Literatures

SAIDA Toshiaki, UHARA Hisashi

Skin Cancer ( The Japanese Skin Cancer Society ) 16 ( 2 ) 158 - 169 2001.10

As members of the expert committee of the Japan Society of Clinical Oncology for the proposition of guidelines for cancer chemotherapy, we collected and evaluated relevant literatures of chemotherapy of malignant melanoma. Each literature was critically evaluated using an evaluation form and quality of evidence of each study was classified into 4 grades. Summing up all the available information, recommendation statements were described on several issues concerning chemotherapy of malignant melanoma, and strength of each recommendation was evaluated using standardized criteria. Critical response from readers to this paper is welcomed. [Skin Cancer (Japan) 2001; 16: 158-169]

Sequential biochemotherapy with cisplatin, interleukin-2 and interferon α or βin patients with metastatic melanoma

UHARA Hisashi, SAIDA Toshiaki

Skin Cancer ( The Japanese Skin Cancer Society ) 15 ( 3 ) 309 - 314 2000.12

We evaluated efficacy and toxicity of the combination of cisplatin, interleulin-2 (IL-2) and interferon (IFN) α or β in patients with metastatic melanoma. Ten patients received cisplatin, 50 or 80 mg/m² intravenously on day 1, IL-2, 70×10⁴ IU intravenously on days 4-7, 18-22 and IFN β, 300×10⁴ IU subcutaneously or intravenously on every second days (regimen A). Six patients received cisplatin 80 mg/m² intravenously on day 1, IL-2, 140×10⁴ IU subcutaneously on days 2-8 and IFNα, 500×10⁴ IU subcutaneously on days 2, 4, 6, 8 (regimen B). The induction cycle was repeated on day 29 in both regimens. There was no responder in 6 patients (A) and 4 patients (B) assessed for clinical response. Main toxisities were thrombocytopenia, neutropenia, anemia and nausea. Vitiligo-like depigmentation was seen in one patient, whose disease progressed during the therapy. There were no treatment-related death. These regimens had low activities in the treatment of advanced malignant melanoma. [Skin Cancer (Japan) 2000; 15: 309-314]

Solid facial edema in a patient with rosacea

Hisashi Uhara, Shigeo Kawachi, Toshiaki Saida

Journal of Dermatology ( Japanese Dermatological Association ) 27 ( 3 ) 214 - 216 2000 [Refereed]

We report a 53-year old man with symmetrical nonpitting edema, conjunctivitis, and acneiform eruptions on the face. Histopathological examination showed perifollicular lymphohistiocytic infiltration and telangiectasias in the upper dermis. Loosely aggregated non-caseating granulomas were scattered through the dermis some of them were seen in the perifollicular regions. The patient was treated with fleroxacin (100 mg/day, orally) for two weeks with a marked reduction of both solid facial edema and periorbital edema.

Newest knowledge of chemotherapy and chemoimmunotherapy for advanced malignant melanoma.

UHARA Hisashi, SAIDA Toshiaki

Skin Cancer ( The Japanese Skin Cancer Society ) 14 ( 1 ) 15 - 23 1999

Recently developed regimens for the treatment of patients with advanced malignant melanoma were reviewed. Combination chemotherapy of CDDP/BCNU/DTIC/tamoxifen (Dartmouth regimen) and sequential (concurrent) chemoimmunotherapy composed of CDDP based chemotherapy associated with IL-2 and IFN α have been reported to increase overall response rates and CR rates. However, they are still in the clinical trial setting. Temozolomide is an analogue of DTIC that has the advantage of being orally absorbed and crossing into the central nervous system (CNS). Fotemustine, a new nitrosourea, is also active in CNS metastasis. Results of the following two clinical trials of our study group were also described: DAC-Tam therapy using DTIC, ACNU, CDDP and tamoxifen, and sequential biochemotherapy using CDDP, IL-2 and IFN β.

Immunohistochemical detection of CDK4 and p16(INK4) proteins in cutaneous malignant melanoma

YL Wang, H Uhara, Y Yamazaki, T Nikaido, T Saida

BRITISH JOURNAL OF DERMATOLOGY ( BLACKWELL SCIENCE LTD ) 134 ( 2 ) 269 - 275 1996.02 [Refereed]

p16(INK4) gene, which encodes a specific inhibitor of cyclin-dependent kinase 4 (CDK4), has been recently reported as an important tumour suppressor gene. It is mapped to chromosome 9p21, which is frequently deleted or mutated in many tumour cell lines including malignant melanoma. Since the CDK4/cyclin D complex propels a cell to go through the G(1) check point of the cell cycle, a critical phase of cell division, alteration of the p16(INK4) gene could lead a cell to uncontrolled proliferation and malignant transformation. To clarify any role for p16(INK4) and CDK4 proteins in the development of human malignant melanoma, we have examined, immunohistochemically, the expression of these two proteins in melanocytic neoplasms including 19 primary lesions of nonfamilial melanoma. Intense nuclear and/or cytoplasmic expression of the CDK4 protein was observed in 11 of 19 cases (58%) of melanoma. In contrast, virtually no nuclear or cytoplasmic staining for CDK4 protein was detected in 28 benign melanocytic naevi, including six Spitz naevi. Expression of p16(INK4) protein was observed in three of 19 melanomas (16%) and in 17 of 28 benign naevi (61%). Inverse expression of CDK4 and p16(INK4), at individual cell level, was detected in one case of melanoma. The present study suggests that CDK4 overexpression is characteristic for malignant melanoma, and probably reflects its autonomous accelerated cell proliferation. The expression rate of p16(INK4) protein in malignant melanoma was lower than that in benign naevi, although the significance of p16(INK4) deletion in melanoma development has not been definitely confirmed.

Expression of α subunit of guanine nucleotide‐binding protein Go in Merkel cell carcinoma

Hisashi Uhara, Yu‐Lai Wang, Sachiyo Matsumoto, Shigeo Kawachi, Toshiaki Saida

Journal of Cutaneous Pathology 22 ( 2 ) 146 - 148 1995 [Refereed]

The α subunit of guanine nucleotide‐binding protein Go(Goα), which was initially isolated from bovine brain, interacts with muscarinic cholinergic receptors and regulates neuronal calcium channels. Goα is known to be localized in neural tissues, some endocrine cells, and neuroendocrine tumors. We have immunohistochemically investigated the expression of Goα in 4 cases of Merkel cell carcinoma using the method of microwave treatment. In all cases of Merkel cell carcinoma, Goα was consistently detected on the plasma membrane and cytoplasm of the tumor cells. Nerve fibers in the skin were also positive for Goα, but other epidermal or dermal components such as keratinocytes, melanocytes, fibroblasts, or lymphoid cells were negative. Tumor cells of squamous cell carcinoma, cutaneous lymphoma, sweat gland carcinoma, and malignant melanoma were negative for Go4aL. The present study indicates that Goα may be a useful immunohistochemical marker of Merkel cell carcinoma. Copyright © 1995, Wiley Blackwell. All rights reserved

Primary cutaneous plasmacytosis: Report of three cases and review of the literature

H. Uhara, T. Saida, S. Ikegawa, Y. Yamazaki, H. Mikoshiba, S. Nijoh, K. Kitano, C. S. Koh

Dermatology 189 ( 3 ) 251 - 255 1994 [Refereed]

Background: Cutaneous plasmacytosis is a rare disease characterized by peculiar multiple eruptions and hypergammaglobulinemia. More than 40 cases have been reported, mainly in Japan, although information concerning the disorder was limited to individual case reports. Objective and Methods: To clarify the clinicopathological and laboratory features, we reviewed 41 cases. Results: All patients were Japanese and the male-to-female ratio was 1:0.6. The onset ages ranged from 20 to 62 years, with a mean and median of 37 and 37 years. A superficial lymphadenopathy was detected in 58% (22/38), and polyclonal hypergammaglobulinemia was found in 93% (38/41). No cases were associated with any apparent underlying diseases. The course was chronic without spontaneous remission. Four patients died, 3 of whom succumbed to leukemia, respiratory failure or renal failure, respectively. Conclusion: The results suggest that the condition appears to be a variant of reactive plasmacytic disorders of unknown origin. © 1994 S. Karger AG, Basel.

Detection of Epstein‐Barr Virus DNA in a Japanese Case of Lymphoepithelioma‐like Thymic Carcinoma

Yoshihiro Matsuno, Kiyoshi Mukai, Hisashi Uhara, Ichiro Akao, Shuichiroh Furuya, Yuichi Sato, Setsuo Hirohashi, Yukio Shimosato

Japanese Journal of Cancer Research 83 ( 2 ) 127 - 130 1992 [Refereed]

Epstein‐Barr virus DNA was detected in a case of lymphoepithelioma‐like thymic carcinoma. A homogeneous terminal structure of the viral DNA was demonstrated in this case, indicating the presence of the viral genome in clonally expanded tumor cells. Since all of 26 other thymic epithelial tumors (eight non‐invasive, 13 invasive thymomas and four non‐lymphoepithelioma‐like thymic carcinomas) in Japanese were negative by polymerase chain reaction, it is suggested that lymphoepithelioma‐like thymic carcinoma may represent a unique pathological entity distinct from Epstein‐Barr virus‐negative thymic epithelial tumors, which are in the majority in Japan. Copyright © 1992, Wiley Blackwell. All rights reserved

Detection of epstein-barr virus dna in formalin-fixed paraffin-embedded tissue of nasopharyngeal carcinoma using polymerase chain reaction and in situ hybridization

Ichiro Akao, Yuichi Sato, Kiyoshi Muka, Hisashi Uhara, Shuichiro Furuya, Tomohide Hoshikawa, Yukio Shimosato, Isamu Takeyama

Laryngoscope 101 ( 3 ) 279 - 283 1991 [Refereed]

The polymerase chain reaction method for amplification of DNAin formalin-fixed, paraffin-embedded tissue sections was used to detect Epstein-Barr virus DNA in nasopharyngeal carcinomas from Japanese patients. Thirty-one cases of nasopharyngeal carcinoma and 8 cases of lymph node metastasis of nasopharyngeal carcinoma were studied. Detection rates of Epstein-Barr virus in various types of nasopharyngeal carcinoma according to the World Health Organization classification were as follows: 10 of 10 undifferentiated carcinomas, 8 of 13 nonkeratinizing carcinomas, and 5 of 7 keratinizing carcinomas. Eight lymph node metastases, for which the primary was positive for Epstein-Barr virus, also contained Epstein-Barr virus DNA. By in situ hybridization using a biotinylated Epstein-Barr virus probe, it was clearly demonstrated that Epstein-Barr virus DNA was localized in the nuclei of the neoplastic cells. The clinical features of nasopharyngeal carcinoma with or without Epstein-Barr virus were not different. These results demonstrate that nasopharyngeal carcinoma in Japanese patients is closely associated with Epstein-Barr virus infection, similar to nasopharyngeal carcinoma of other endemic and nonendemic areas. © The American Laryngological, Rhinological & Otological Society, Inc.

Detection of Epstein‐Barr Virus DNA in Reed‐Sternberg Cells of Hodgkin's Disease Using the Polymerase Chain Reaction and in situ Hybridization

Hisashi Uhara, Yuichi Sato, Kiyoshi Mukai, Ichiro Akao, Yoshihiro Matsuno, Shuichiroh Furuya, Tomohide Hoshikawa, Yukio Shimosato, Toshiaki Saida

Japanese Journal of Cancer Research 81 ( 3 ) 272 - 278 1990 [Refereed]

Thirty‐one cases of Hodgkin's disease were examined for the occurrence of Epstein‐Barr virus (EBV) genome by using the polymerase chain reaction (PCR) of DNA in formalin‐fixed paraffin‐embedded tissues and the in situ hybridization technique. The cases were subdivided into 17 cases of nodular sclerosis (NS), nine cases of mixed cellularity (MC), four cases of lymphocyte predominance (LP), and one case of lymphocyte depletion (LD). EBV DNA was detected in eight cases including four cases of NS, three cases of MC and one case of LP. The sensitivity of PCR was higher than that of Southern blot hybridization of DNA from fresh frozen tissue, because Southern blot hybridization using the BamHI‐W fragment of EBV detected virus DNA only in two of three cases which were positive by PCR. The results of in situ hybridization studies confirmed that EBV genome was localized within the nuclei of Reed‐Sternberg (RS) cells and their mononuclear variants. Furthermore, double‐labeling studies combining in situ hybridization and immunocytochemistry using CD30 (BerH2) and CD15 (LeuM1) as markers of RS cells, as well as pan B‐marker (L26) and pan T‐marker, CD45RO (UCHL1), were performed to demonstrate the phenotype of EBV DNA‐positive cells, confirming that EBV DNA was present in RS cells but not in lymphocytes. The results of this study indicate a significant association between EBV and some cases of Hodgkin's disease. Copyright © 1990, Wiley Blackwell. All rights reserved

Detection of human papillomavirus DNA in laryngeal squamous cell carcinomas by polymerase chain reaction

Tomohide Hoshikawa, Takashi Nakajima, Hisashi Uhara, Masahiro Gotoh, Yukio Shimosato, Kouichiro Tsutsumi, Isamu Ono, Satoshi Ebihara

Laryngoscope 100 ( 6 ) 647 - 650 1990 [Refereed]

The presence of human papillomavirus genomes-16 and -6b in metastatic cervical lymph nodes was examined in 34 cases of laryngeal carcinomas by means of polymerase chain reaction, which had been fixed in formalin and embedded in paraffin. Human papillomavirus DNAs extracted from paraffin-embedded tumor tissues were used for polymerase chain reaction with amplification of the E6 region of human papillomavirus genome-16 and the El region of human papillomavirus genome-6b. Human papillomavirus genome-16 sequences were positively amplified in six (17.6%) metastatic tumors -6b sequence was positively amplified in one (2.9%) metastatic tumor. Laryngeal carcinomas of glottic origin showed high human papillomavirus genome-16 DNA-positive rates (4 of 9 cases, 44.4%) compared to those of other sites. These results suggest that human papillomavirus genome-16 infection might be closely associated with the development of some laryngeal squamous cell carcinomas of glottic origin similar to uterine cervical carcinogenesis. © The American Laryngological, Rhinological & Otological Society, Inc.

BOWENS DISEASE WITH INVASIVE-CARCINOMA SHOWING SWEAT GLAND DIFFERENTIATION

T SAIDA, Y OKABE, H UHARA

JOURNAL OF CUTANEOUS PATHOLOGY ( MUNKSGAARD INT PUBL LTD ) 16 ( 4 ) 222 - 226 1989.08 [Refereed]

Phytohemagglutinin-binding sites in the skin: A useful histochemical marker of acrosyringium and distal portions of intradcrnial sweat ducts

Toshiaki Saida, Hisashi Uhara, Hajime Mikoshiba

Dermatology 179 ( 1 ) 25 - 28 1989 [Refereed]

Phytohemagglutinin (PHA)-binding sites were histochemically investigated in normal adult skin and various skin tumors using peroxidase-labeled lectin. In the normal skin, acrosyringium and distal portion of intradermal duct of eccrine and apocrine sweat glands were intensely stained with PHA. Other elements of the skin were virtually negative. Among various kinds of sweat gland tumors and other skin tumors, syringoma and eccrine porocar- cinoma were intensely stained with PHA. Small ductal structures of nodular hidradenoma and mixed tumor of the skin were also stained with PHA. No other skin tumors were positive with PHA staining. The present study clearly showed that PHA is a useful histochemical marker of distal portion of eccrine and apocrine sweat ducts. © 1989 Karger AG, Basel.

Heterophile hanganutziu-deicher antigen in ganglioside fractions of human melanoma tissues

Shigeo Kawachi, Toshiaki Saida, Hisashi Uhara, Uemura Kei-Ichi, Tamotsu Taketomi, Kyoichi Kano

International Archives of Allergy and Immunology 85 ( 3 ) 381 - 383 1988 [Refereed]

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