Details of a Researcher - UHARA Hisashi

Papers - UHARA Hisashi

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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.

DOI PubMed

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.

PubMed

【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.

DOI PubMed

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.

DOI PubMed

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.

DOI PubMed

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]

DOI

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

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.

DOI PubMed

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.

DOI

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.

DOI

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.

DOI

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]

PubMed

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Papers - UHARA Hisashi