Details of a Researcher - UHARA Hisashi

Papers - UHARA Hisashi

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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.

DOI PubMed

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]

DOI

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.

DOI PubMed

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.

DOI PubMed

【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.

DOI PubMed

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.

DOI

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.

DOI

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.

DOI

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.

DOI PubMed

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.

DOI

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Papers - UHARA Hisashi