Details of a Researcher - UHARA Hisashi

Papers - UHARA Hisashi

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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.

DOI

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]

DOI PubMed

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.

DOI PubMed

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.

DOI PubMed

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.

DOI PubMed

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]

DOI PubMed

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.

DOI

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.

DOI PubMed

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

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Papers - UHARA Hisashi