Publications by authors named "Jun Asai"

91 Publications

Case of Rapidly Expanding Conjunctival Malignant Melanoma Initially from Primary Acquired Melanosis Diagnosed 14 Years Earlier.

Int Med Case Rep J 2021 28;14:361-364. Epub 2021 May 28.

Department of Ophthalmology, Nara Medical University, Nara, Japan.

Primary acquired melanosis (PAM) of the conjunctiva is a potentially serious melanocytic lesion that can lead to the development of a melanoma. A 60-year-old woman noticed pigmentation of the conjunctiva of her left eye for more than 10 years. She underwent excisional biopsy combined with cryotherapy and was diagnosed with PAM without atypia by intraoperative consultation. She was followed for 7 years, and no changes were observed. Fourteen years after the initial biopsy, she noted a growing conjunctival tumor, and a melanoma was suspected. She underwent orbital exenteration and skin grafting procedures. Histopathological examination of the specimen led to a diagnosis of conjunctival malignant melanoma. Re-examination of the initial biopsy specimen revealed that there was a proliferation of melanocytes that partially expanded over the basal layer of the conjunctiva which had been diagnosed as PAM with moderate atypia. We conclude that this case of conjunctival PAM had progressed to a conjunctival malignant melanoma after 14 years. Pathological evaluation of intraepithelial lesions has its limitations; thus, cases of PAM, even in the absence of obvious atypia, require careful follow-up.
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http://dx.doi.org/10.2147/IMCRJ.S310702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168958PMC
May 2021

Outcome of combination therapy using BRAF and MEK inhibitors among Asian patients with advanced melanoma: An analysis of 112 cases.

Eur J Cancer 2021 Mar 24;145:210-220. Epub 2021 Jan 24.

Department of Dermatologic Oncology, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Japan.

Background: As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Minh) have been conducted in Western countries, little is known about the effect of B + Minh among East Asian populations.

Material And Methods: Data from patients with advanced melanoma treated using B + Minh (either dabrafenib + trametinib or encorafenib + binimetinib) were retrospectively collected from 16 institutes in Japan. Response rates, adverse events, patterns of failure and survival were analysed.

Results: We analysed 112 of 144 collected patient records and, of these, 14 had acral/mucosal melanoma. The response rate for the entire cohort was 75.0%. There were no statistical differences in response rates between acral/mucosal and cutaneous melanomas (64.3% versus 76.5%), whereas previous treatment using immune checkpoint inhibitors (ICIs) did not affect response (72.7% versus 73.9%) to B + Minh, response to ICI after B + Minh was only 20%. Patients who achieved complete response had the best overall survival rates at 24 months (94.7%). Elevated serum lactate dehydrogenase levels and 3 or more metastatic sites were independently associated with survival. The most common relapse site was the brain (17.9%). More than half of the patients (58.8%) experienced grade III/IV pyrexia.

Conclusion: B + Minh was effective among Japanese patients with melanoma, including those with acral/mucosal melanoma. Factors associated with survival were similar to previous Western studies. B + Minh response was not affected by the previous use of ICI; however, vigilance against brain metastasis during B + Minh therapy is required as the brain was our most commonly encountered relapse site.
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http://dx.doi.org/10.1016/j.ejca.2020.12.021DOI Listing
March 2021

Extensive gas gangrene secondary to an infected epidermal cyst on the back.

Australas J Dermatol 2020 Dec 5. Epub 2020 Dec 5.

Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1111/ajd.13519DOI Listing
December 2020

Mycosis fungoides in a patient with ulcerative colitis on anti-tumor necrosis factor-alpha therapy.

Clin J Gastroenterol 2021 Feb 21;14(1):170-175. Epub 2020 Nov 21.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

A 46-year-old man with a history of ulcerative colitis (UC) for over 25 years was treated with infliximab for 7 years. He noticed gradually spreading erythema on his right lower abdomen, femur, and buttocks. Skin biopsy from the right lower abdomen revealed massive invasion of lymphocytes in the papillary dermis and epidermal layer. In conjunction with the findings of immunohistochemistry, the skin lesion was diagnosed as mycosis fungoides (MF) at infiltration stage. Infliximab was discontinued, and narrow-band ultraviolet light B therapy was initiated to treat the skin lesion. The patient achieved remission for MF following treatment and UC has not relapsed for more than 1 year with 5-aminosalicylic acid treatment alone. This is the first case of MF in a UC patient treated with anti-tumor necrosis factor-alpha (anti-TNFα). Lymphoma occurrence is a complication of treatment with anti-TNFα agent or thiopurine. However, there is no evidence regarding the relationship between MF and UC. Hence, these immunomodulatory agents may have triggered the occurrence of MF in this case. When treating UC patients with immunomodulatory agents, the possibility of MF or other types of lymphoma as rare complications must be considered.
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http://dx.doi.org/10.1007/s12328-020-01277-3DOI Listing
February 2021

Subcutaneous nodule showing loss of BAP1 in large plaque-type blue nevus: Melanoma or not?

J Dermatol 2020 Dec 3;47(12):e437-e438. Epub 2020 Sep 3.

Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15591DOI Listing
December 2020

Novel ex vivo disease model for extramammary Paget's disease using the cancer tissue-originated spheroid method.

J Dermatol Sci 2020 Sep 5;99(3):185-192. Epub 2020 Aug 5.

Department of Dermatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan. Electronic address:

Background: Extramammary Paget's disease (EMPD) is a rare skin cancer that frequently occurs in the anogenital region in the elderly. Prognosis in patients with metastatic EMPD is poor as EMPD treatment has advanced little in recent years, primarily because no EMPD cell line has been established.

Objective: We aimed to establish an ex vivo EMPD disease model using the cancer tissue-originated spheroid (CTOS) method, which is used to prepare and culture primary cancer cells while maintaining cell-cell contact.

Methods: Thirteen samples from 12 EMPD patients were obtained. CTOSs were prepared and cultured using CTOS method. Histopathological examination of the CTOSs was performed. We investigated optimum medium conditions and effects of growth factors for CTOS growth. Chemo-sensitivity assays were conducted.

Results: CTOSs were successfully prepared from 3 primary lesions and 2 metastatic lymph nodes. Of these, 2 CTOSs (EMPD-3 and EMPD-4) could be maintained and passaged long term ex vivo. Following transplantation of CTOSs to NOD/Scid mice, CTOS-derived xenotumors exhibited ductal formation, indicating that CTOSs retained the original tumor characteristics. Chemo-sensitivity assays revealed that docetaxel significantly inhibited EMPD-3 growth in a dose-dependent manner, whereas EMPD-4 was not clearly inhibited. These findings indicate the heterogeneity of EMPD and potential use of chemosensitivity assays with patient-derived CTOS to select the most effective drugs for each patient.

Conclusion: To our knowledge, this study represents the first establishment of an ex vivo-EMPD disease model involving conventional cell lines. EMPD CTOSs might be useful for developing new therapeutic strategies.
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http://dx.doi.org/10.1016/j.jdermsci.2020.07.006DOI Listing
September 2020

Safety and tolerability of PD-1/PD-L1 inhibitors in elderly and frail patients with advanced malignancies.

Oncol Lett 2020 Oct 15;20(4):14. Epub 2020 Jul 15.

Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan.

The number of elderly patients with cancer has increased due to aging of the population. However, safety of programmed cell death-1 (PD-1) or programed cell death ligand 1 (PD-L1) inhibitors in elderly patients remains controversial, and limited information exists in frail patients. The present study retrospectively identified 197 patients treated with nivolumab, pembrolizumab or atezolizumab for unresectable advanced cancer between September 2014 and December 2018. Patients were divided into the elderly (age, ≥75 years) and non-elderly (age, <75 years) groups. The detailed immune-related adverse events (irAE) profile and development of critical complications were evaluated. To assess tolerability, the proportion of patients who continued PD-1/PD-L1 inhibitor for >6 months was analyzed. In the two groups, a three-element frailty score, including performance status, Charlson Comorbidity Index and neutrophil-lymphocyte ratio, was estimated, and patients were divided into the low-, intermediate- and high-frailty subgroups. Safety and tolerability were evaluated using the aforementioned items. A total of 58 patients (29.4%) were aged ≥75 years. No significant difference was found in the development of irAEs, hospitalization and treatment discontinuation due to irAEs between the two groups. However, the occurrence of unexpected critical complications was significantly higher in the elderly group (P=0.03). Among the elderly patients with high frailty, more critical complications and fatal irAE (hepatitis) were observed. In this population, 33.3% were able to continue treatment for >6 months without disease progression. The present analysis based on real world data showed similar safety and tolerability of PD-1/PD-L1 inhibitors in elderly patients with advanced malignancies. However, the impact of irAE in elderly patients, especially those with frailty, was occasionally greater compared with that in younger and fit patients.
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http://dx.doi.org/10.3892/ol.2020.11875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406883PMC
October 2020

Unusual presentation of extramammary Paget's disease with multiple lymph node metastases showing scant uptake of F-fluorodeoxyglucose in positron emission tomography/computed tomography.

J Dermatol 2020 Oct 23;47(10):e378-e380. Epub 2020 Jul 23.

Departments of, Department of, Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15519DOI Listing
October 2020

Wound, pressure ulcer and burn guidelines - 1: Guidelines for wounds in general, second edition.

J Dermatol 2020 Aug 2;47(8):807-833. Epub 2020 Jul 2.

Department of Dermatology, JCHO Chukyo Hospital, Nagoya, Japan.

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition.
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http://dx.doi.org/10.1111/1346-8138.15401DOI Listing
August 2020

Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review.

J Dermatol 2020 Jul 4;47(7):770-773. Epub 2020 May 4.

Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Japan.

Agminated nevus refers to a clustered group of melanocytic nevi confined to a localized area of the body. It rarely involves acral skin, but recognition of acquired agminated nevus (AAN) in the acral area is clinically important because it may mimic acral lentiginous melanoma (ALM). However, acral AAN has only been described in a few case reports and its clinical characteristics remain unclear. We report three additional cases of acral AAN to further analyze the differential points between ALM. Clinical images, including those of dermoscopy, of three cases of acral AAN were reviewed. The lesions were located on the sole or lateral border of the foot. All acral AAN were flat and large in size (>20 mm in greatest dimension), and associated with asymmetry and irregular border. However, no parallel ridge pattern suggesting ALM was observed on dermoscopy. In two patients, the lesions on the sole were totally resected; microscopic evaluation of these two lesions confirmed junctional nests of banal melanocytes. AAN lesions on the sole with chronic mechanical pressure are slightly larger and more diffuse; thus, they may be more likely to be overdiagnosed as malignancy upon inspection than those in the non-acral area. Understanding the concept of the disease and careful dermoscopic evaluation leads to an accurate diagnosis.
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http://dx.doi.org/10.1111/1346-8138.15353DOI Listing
July 2020

Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition.

J Dermatol 2020 Nov 28;47(11):1207-1235. Epub 2020 Apr 28.

Department of Geriatric and Environmental Dermatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created.
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http://dx.doi.org/10.1111/1346-8138.15335DOI Listing
November 2020

High dose rate interstitial brachytherapy for early stage lip cancer using customized dental spacer.

J Radiat Res 2020 May;61(3):506-510

Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kyoto, Japan.

The present study aimed to report the efficacy and toxicity of our high-dose-rate (HDR) brachytherapy for early stage lip cancer (LC) using customized dental spacers. A retrospective analysis was performed among six patients with early stage LC treated with HDR interstitial brachytherapy between April 2015 and August 2019 using customized dental spacers. The total treatment dose was 49 Gy/7 fractions or 54 Gy/9 fractions. The median follow-up duration for the patients was 13 (range: 2-52) months. All patients completed the entire brachytherapy protocol safely and have experienced no local recurrence thus far. The CTV D100 and D90 values per fraction were median 100 (range: 98.3-100) % prescribed dose (PD) and median 133.4 (range: 129.3-138.9) % PD, respectively. The D2cc and D0.1cc values per fraction for the mandible were median 1.07 (range, 0.79-1.88) Gy and median 1.65 (range: 1.21-2.83) Gy, D2cc and D0.1cc values per fraction for oral cavity were median 1.48 (range, 1.31-1.72) Gy and median 2.73 (range: 1.79-2.88) Gy, respectively. Acute toxicities encountered were mucositis and lip edema limited to the irradiated area; none of them was beyond grade 2 and all were resolved within 1-2 months after treatment. We did not observe any late grade 2 adverse events or worse. This study shows that the adverse effects of HDR brachytherapy for early stage LC can be minimized using a dental spacer. Cooperation with the dentistry department is essential to make spacers that are individually customized for each patient.
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http://dx.doi.org/10.1093/jrr/rraa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299259PMC
May 2020

Dupilumab therapy rapidly improved alopecia areata associated with trichotillomania in an atopic dermatitis patient.

Allergol Int 2020 Jul 28;69(3):480-482. Epub 2020 Mar 28.

Department of Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

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http://dx.doi.org/10.1016/j.alit.2020.02.009DOI Listing
July 2020

Squamous cell carcinoma arising from plasma cell cheilitis successfully treated with brachytherapy.

J Dermatol 2020 Jun 18;47(6):e239-e240. Epub 2020 Mar 18.

Departments of, Department of, Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15318DOI Listing
June 2020

CD163-positive macrophage infiltration predicts systemic involvement in sarcoidosis.

J Cutan Pathol 2020 Jul 17;47(7):584-591. Epub 2020 Mar 17.

Department of Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

Background: Sarcoidosis is a chronic and systemic inflammatory disease, in which patients present with noncaseating epithelioid granulomas. Cutaneous lesions of sarcoidosis develop in 9% to 35% of all sarcoidosis patients and comprise various clinical subtypes. It usually affects multiple organs and has a variable clinical course; this is called systemic sarcoidosis (SS). However, occasionally, it only affects the skin and is then called cutaneous sarcoidosis (CS). Recent observations suggest that serum levels of soluble CD163 correlate with immune cell activity in sarcoidosis patients; however, the contribution of M1 and M2 macrophages toward disease progression remains unclear.

Methods: We evaluated macrophage phenotypes histopathologically using skin biopsy samples obtained from patients with CS (n = 8) and SS (n = 31) and performed immunostaining with CD68, iNOS (M1 macrophages), PD-L1, and CD163 (M2 macrophages).

Results: The density of CD163-positive cells in the SS group was significantly higher than that in the CS group. There was no significant correlation between the CD163 (+) cell density and serum angiotensin-converting enzyme level, serum calcium, or tuberculin reaction.

Conclusions: Immunostaining for CD163 may be a novel and useful marker to predict systemic involvement in patients with cutaneous lesions of epithelioid granulomas.
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http://dx.doi.org/10.1111/cup.13675DOI Listing
July 2020

Cutaneous lymphoma in Japan, 2012-2017: A nationwide study.

J Dermatol Sci 2020 Mar 25;97(3):187-193. Epub 2020 Jan 25.

Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: The types of cutaneous lymphoma (CL) and their incidences can vary among geographic areas or ethnic groups.

Objective: This study aimed to investigate the incidence of various CL types in Japan using epidemiological data from a nationwide registration system for CL.

Methods: A questionnaire was sent to participating hospitals, all of which had been approved to conduct residency programs for board-certified dermatologists by the Japanese Dermatological Association. Data from patients newly diagnosed with CL were collected electronically.

Results: Between 2012 and 2017, 2547 new patients with CL from the dermatological institutes were registered. In total, 2090 patients had primary CL and 453 had secondary CL. Those with primary CL included 1609 (77.0 %) patients with mature T- and natural killer (NK)-cell neoplasms, 442 (21.1 %) with B-cell neoplasms, and 39 (1.9 %) with blastic plasmacytoid dendritic cell neoplasms. Mycosis fungoides (MF) was the most common CL subtype in the present study (1003 patients, 48.0 %), and 72.4 % of MF patients had early-stage disease, similar to observations in previous studies on other cohorts. Primary cutaneous CD30+ T-cell lymphoproliferative disorders and adult T-cell leukemia/lymphoma were the second and third most common subtypes, respectively.

Conclusion: Compared to that in our previous cohort (2007-2011), the number of registered T- and NK-cell CL cases decreased, whereas that of B-cell CL cases increased from 44.8-73.7 patients/year. These results provide insight into CL trends within the Japanese population, which might contribute to a better understanding of the disease.
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http://dx.doi.org/10.1016/j.jdermsci.2020.01.010DOI Listing
March 2020

Systemic treatment of patients with advanced cutaneous squamous cell carcinoma: response rates and outcomes of the regimes used.

Eur J Cancer 2020 03 28;127:108-117. Epub 2020 Jan 28.

Department of Dermatology, Saitama Medical University, 38, Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Few patients with cSCC experience metastases, but the prognosis of advanced cSCC (acSCC) is dismal. Evidence regarding systemic therapy for acSCC is limited. Therefore, we aimed to determine the most effective systemic treatment for acSCC.

Patients And Methods: This retrospective study involved 16 Japanese institutions. We documented patient and tumour characteristics and disease course of patients with acSCC who received systemic therapy between 1st January 2006 and 31st December 2015. We compared the overall survival (OS) and progression-free survival (PFS) for (1) platinum versus non-platinum groups, (2) radiation plus chemotherapy first-line therapy (RCT) versus non-RCT groups and (3) platinum-based RCT versus non-platinum-based RCT groups.

Results: Although the use of platinum-based systemic therapy was not associated with statistically significant improvements in PFS and OS, there were significant differences between the RCT and non-RCT groups (PFS: p < 0.001, OS: p = 0.003). In the subgroup analysis, RCT significantly prolonged PFS and OS in the nodal SCC (nSCC) group. For the RCT and non-RCT groups, the median OS was 110 and 14 months, respectively, and the 5-year OS rate was 54% and 21%, respectively.

Conclusion: RCT could improve OS in patients with nSCC. However, further multicenter prospective studies are needed to establish evidence for superiority of RCT.
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http://dx.doi.org/10.1016/j.ejca.2019.12.018DOI Listing
March 2020

Wound, pressure ulcer and burn guidelines - 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers.

J Dermatol 2020 Oct 21;47(10):1071-1109. Epub 2020 Jan 21.

Tanioka Dermatology Clinic, Kyoto, Japan.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.
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http://dx.doi.org/10.1111/1346-8138.15186DOI Listing
October 2020

Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication.

J Dermatol 2020 Mar 6;47(3):223-235. Epub 2020 Jan 6.

Institute of Dermato-Immunology and Allergy, Southern Tohoku General Hospital, Koriyama, Japan.

In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behçet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behçet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long-term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behçet's disease.
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http://dx.doi.org/10.1111/1346-8138.15207DOI Listing
March 2020

Acral malignant melanoma exhibiting cartilaginous differentiation in a metastatic lymph node.

J Dermatol 2020 Feb 10;47(2):e39-e41. Epub 2019 Dec 10.

Departments of, Department of, Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15188DOI Listing
February 2020

Japanese Dermatological Association Guidelines: Outlines of guidelines for cutaneous melanoma 2019.

J Dermatol 2020 Feb 28;47(2):89-103. Epub 2019 Nov 28.

Department of Dermatology, International University of Health and Welfare, Narita, Japan.

With consideration of the ongoing developments in treatment options for cutaneous melanoma, the Japanese Skin Cancer Society published the first guidelines for cutaneous melanoma in 2007 and later revised them in 2015. Here, we report on an English version of the 2019 Japanese Melanoma Guidelines. In this latest edition, all processes were carried out according to the Grading of Recommendations, Assessment, Development and Evaluation system. A comprehensive published work search, systematic review and determination of recommendations in each clinical question were performed by a multidisciplinary expert panel consisting of dermatologists, a plastic and reconstructive surgeon, and a radiation oncologist. The advent of novel agents, such as immune checkpoint inhibitors and molecular-targeted agents, has drastically changed the nature of treatment for adjuvant and advanced-stage diseases among melanoma patients worldwide. Additionally, recent reports of clinical trials regarding surgical procedures and a better understanding of molecular biology and tumor immunology in clinical types of melanoma have had an impact on clinical practise. Based on these viewpoints, eight relevant clinical questions were raised in this report that aim to help clinicians select the appropriate therapeutic approach.
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http://dx.doi.org/10.1111/1346-8138.15151DOI Listing
February 2020

Radiation-induced osteosarcoma of the skull mimicking cutaneous tumor after treatment for frontal glioma.

J Dermatol 2020 Jan 22;47(1):69-71. Epub 2019 Oct 22.

Department of Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

Radiation-induced sarcomas are recognized complications of radiation therapy and are associated with poor prognosis. Radiation-induced osteosarcoma is one of the rare types of radiation-induced sarcomas, with the risk of radiation-induced osteosarcomas being only 0.01%-0.03% among all patients treated with radiotherapy. There have been only four reported cases of radiation-induced osteosarcomas after radiotherapy for gliomas. Here, we report a unique case of radiation-induced osteosarcomas arising on the skull and extending to the skin, with a short latent period. We also review the clinical features of the previously reported cases.
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http://dx.doi.org/10.1111/1346-8138.15125DOI Listing
January 2020

Potassium iodide in successful treatment of erythema nodosum-like lesions induced by combination therapy with dabrafenib and trametinib.

J Dermatol 2020 Jan 6;47(1):e7-e8. Epub 2019 Oct 6.

Department of Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15108DOI Listing
January 2020

Clinical features of immune-related thyroid dysfunction and its association with outcomes in patients with advanced malignancies treated by PD-1 blockade.

Oncol Lett 2019 Aug 12;18(2):2140-2147. Epub 2019 Jun 12.

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Programmed cell death protein-1 (PD-1) blockade therapy has improved outcomes in the treatment of advanced cancers. The therapy is well-tolerated, although it occasionally causes immune-related adverse events (irAEs). Thyroid dysfunction is one of the most common irAEs seen. Our aim was to clarify the clinical characteristics of thyroid dysfunction induced by PD-1 blockade and its association with the therapeutic effect of the treatment in advanced cancers. A total of 174 patients who received nivolumab or pembrolizumab for metastatic or unresectable advanced cancers were included in this retrospective study. The patients were divided into two groups: The thyroid dysfunction group and the euthyroid group. In the present study, the clinical characteristics, the association with anti-thyroid antibodies, as well as the progression-free survival (PFS) and overall survival (OS) were estimated. An adjusted Cox proportional hazard regression model was used to evaluate prognostic factors for OS and PFS. This study showed that 25 out of 150 patients (16.7%) developed immune-related thyroid dysfunction. Hypothyroidism occurred in the early stage of the clinical course (median: 12 weeks); subsequently, 9 of the 25 patients underwent a transient period of hyperthyroidism, all with mild symptoms. The presence of positive anti-thyroid antibodies at baseline was significantly higher in the thyroid dysfunction group (13/22) than in the euthyroid group (18/100, P=0.0002). Moreover, PFS (median: 66 vs. 27 weeks, hazard ratio (HR): 0.50, 95% CI: 0.26-0.89, P=0.02) and OS (median 156 vs. 59 weeks, HR: 0.34, 95% CI: 0.13-0.75, P=0.01) were significantly longer in the thyroid dysfunction group than in the euthyroid group. Multivariable analysis also revealed that thyroid dysfunction was an independent prognostic factor for OS (HR: 0.42, 95% CI: 0.16-0.97, P=0.04). These findings may enable the early recognition and appropriate management of thyroid dysfunction, and help in maximizing the therapeutic effect of PD-1 blockade.
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http://dx.doi.org/10.3892/ol.2019.10466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607381PMC
August 2019

Treatment rationale and design of a phase II study of narrow-band ultraviolet B phototherapy for cutaneous steroid-refractory acute graft-vs-host disease following allogenic stem-cell transplantation.

Medicine (Baltimore) 2019 Jul;98(28):e16372

Division of Hematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

Background: Acute graft-vs-host disease (aGVHD) is a common complication of allogenic hematopoietic stem-cell transplantation (allo-HSCT) and skin is the most common and often the 1st site at which aGVHD develops. Cutaneous aGVHD is usually treated with oral and/or topical corticosteroids as the 1st-line treatment; however, steroid-refractory aGVHD not only impairs patients' quality of life but also causes significant morbidity and mortality after allo-HSCT. Narrow-band ultraviolet B (NB-UVB) phototherapy has been utilized for a wide range of immunologic inflammatory skin diseases, but there is limited information on the efficacy, safety, and biomarkers for response prediction of NB-UVB for cutaneous aGVHD.

Aims: The purpose of this study is to investigate the efficacy and safety of NB-UVB phototherapy for steroid-refractory cutaneous aGVHD.

Patients And Methods: A total of 40 subjects aged from 16 to 70 years with steroid-refractory cutaneous aGVHD after allo-HSCT will be included in the trial. Patients with worse than stage 2 intestine/liver aGVHD will be excluded. Eligible patients will undergo NB-UVB phototherapy until resolution or further worsening of rash or occurrence of an unmanageable adverse event. The primary endpoint is the overall response rate. The secondary outcomes include rates for complete response, partial response, stable disease, progressive disease, duration of response, sparing effect on calcineurin inhibitors and/or corticosteroids, safety, and predictive biomarkers for treatment response.

Ethics And Dissemination: The protocol has been approved by the institutional Clinical Research Review Board of Kyoto Prefectural University of Medicine. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals.

Trial Registration: Trial registration numbers UMIN000032426 and jRCTs052180005.
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http://dx.doi.org/10.1097/MD.0000000000016372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641799PMC
July 2019

Classification of 3097 patients from the Japanese melanoma study database using the American joint committee on cancer eighth edition cancer staging system.

J Dermatol Sci 2019 May 17;94(2):284-289. Epub 2019 Apr 17.

Prognosis and Statistical Investigation Committee of the Japanese Skin Cancer Society, Japan; Department of Dermatology, Kagoshima University, Japan.

Background: The American Joint Committee on Cancer (AJCC) 8 Edition Cancer Staging System was implemented in 2018; however, it has not been validated in an Asian melanoma population.

Objective: The purpose of this study was to validate the new system using a cohort of Japanese melanoma patients.

Methods: The AJCC 7 and 8 Editions were used for TNM classification of patients in a database established by the Japanese Melanoma Study Group. Patient data with sufficient information to be applicable to the AJCC 8 staging were selected. The Kaplan-Meier method was used to estimate disease-specific survival and relapse-free survival.

Results: In total, data for 3097 patients were analyzed. The 5-year disease-specific survival according to the 7 and 8 Edition staging system were as follows: IA = 98.5%/97.9%; IB = 95.4%/96.2%; IIA = 94.2%/94.1%; IIB = 84.6%/84.4%; IIC = 72.2%/72.2%; IIIA = 76.2%/87.5%; IIIB = 60.7%/72.6%; IIIC = 42.0%/55.3% and IIID = none/26.0%. The 5-year relapse-free survival according to the 7 and 8 Edition staging was as follows: IA = 94.5%/92.7%; IB = 85.4%/85.3%; IIA = 80.1%/79.4%; IIB = 71.4%/70.6%; IIC = 56.8%/55.7%; IIIA = 56.8%/69.4%; IIIB = 42.6%/56.8%; IIIC = 20.0%/33.3% and IIID = none/6.5%.

Conclusion: The results show that new staging system could efficiently classify our Japanese melanoma cohort. Although there was no difference in Stage I and II disease between the 7 and 8 Edition systems, we should be careful in managing Stage III disease since the survival curves of the 8 Edition staging were completely different from the 7 Edition. Moreover, our results indicate that adjuvant therapies for Stage IIB and IIC should be developed, since the relapse-free survival for these stages were equivalent to Stage IIIA and IIIB, respectively.
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http://dx.doi.org/10.1016/j.jdermsci.2019.04.003DOI Listing
May 2019

Clinical and histopathological characteristics and survival analysis of 4594 Japanese patients with melanoma.

Cancer Med 2019 05 1;8(5):2146-2156. Epub 2019 Apr 1.

Prognosis and Statistical Investigation Committee of the Japanese Skin Cancer Society, Kumamoto, Japan.

Background: The incidence of melanoma among those of an Asian ethnicity is lower than in Caucasians; few large-scale Asian studies that include follow-up data have been reported.

Objectives: To investigate the clinical characteristics of Japanese patients with melanoma and to evaluate the prognostic factors.

Methods: Detailed patient information was collected from the database of Japanese Melanoma Study Group of the Japanese Skin Cancer Society. The American Joint Committee on Cancer seventh Edition system was used for TNM classification. The Kaplan-Meier method and Cox proportional hazards model were used to estimate the impact of clinical and histological parameters on disease-specific survival in patients with invasive melanoma.

Results: In total, 4594 patients were included in this analysis. The most common clinical type was acral lentiginous melanoma (40.4%) followed by superficial spreading melanoma (20.5%), nodular melanoma (10.0%), mucosal melanoma (9.5%), and lentigo maligna melanoma (8.1%). The 5-year disease-specific survival for each stage was as follows: IA = 98.0%, IB = 93.9%, IIA = 94.8%, IIB = 82.4%, IIC = 71.8%, IIIA = 75.0%, IIIB = 61.3%, IIIC = 41.7%, and IV = 17.7%. Although multivariate analysis showed that clinical classifications were not associated with survival across all stages, acral type was an independent poor prognostic factor in stage IIIA.

Conclusions: Our study revealed the characteristics of melanoma in the Japanese population. The 5-year disease-specific survival of each stage showed a similar trend to that of Caucasians. While clinical classification was not associated with survival in any stages, acral type was associated with poor survival in stage IIIA. Our result might indicate the aggressiveness of acral type in certain populations.
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http://dx.doi.org/10.1002/cam4.2110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536943PMC
May 2019

Nanoparticle-mediated local delivery of pioglitazone attenuates bleomycin-induced skin fibrosis.

J Dermatol Sci 2019 Jan 1;93(1):41-49. Epub 2018 Dec 1.

Department of Dermatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

Background: Nanoparticle-loaded delivery systems have attracted much attention recently. Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful biodegradable polymers for biomedical applications. There are only a few studies on the treatment of dermal fibrosis with sustained-release drugs. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in endogenous anti-fibrotic defense mechanisms. Recent studies have suggested that pioglitazone, a synthetic PPAR-γ activator, has effects beyond reducing blood sugar and it can reduce fibrosis and inflammation when used systemically.

Objective: We aimed to assess the effects of local injections of pioglitazone-loaded PLGA nanoparticles (PGN-NP) on an experimental sclerosis and to demonstrate the in vivo pharmacokinetics of subcutaneously administered PLGA nanoparticles.

Methods: Locally injectable PGN-NP were prepared and subcutaneously administered to bleomycin (BLM)-induced scleroderma model mice. The effect of pioglitazone was also evaluated with cultured fibroblasts. Coumarin-6-loaded fluorescent PLGA nanoparticles (FL-NP) and silicon naphthalocyanine-loaded near-infrared PLGA nanoparticles (NIR-NP) were used to demonstrate in vitro cellular uptake by cultured fibroblasts and the in vivo pharmacokinetics of subcutaneously administered nanoparticles.

Results: Weekly subcutaneous injections of PGN-NP attenuated skin fibrosis in BLM-induced scleroderma model mice. Pioglitazone significantly suppressed migration ability and TGF-β-mediated myofibroblast differentiation in cultured fibroblasts. FL-NP were internalized into cultured fibroblasts within 60 min, and PGN-NP-primed fibroblasts expressed anti-fibrotic phenotypes. Subcutaneously injected NIR-NP remained in the vicinity of the injection site more than non-particulate silicon naphthalocyanine.

Conclusion: These results provide a basis for the development of new treatments for dermal fibrosis and a better understanding of the potential of PLGA nanoparticles in dermatology.
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http://dx.doi.org/10.1016/j.jdermsci.2018.11.012DOI Listing
January 2019

Nation-wide survey of advanced non-melanoma skin cancers treated at dermatology departments in Japan.

J Dermatol Sci 2018 Dec 3;92(3):230-236. Epub 2018 Nov 3.

Prognosis and Statistical Investigation Committee, Japanese Skin Cancer Society, Japan; Department of Dermatology and Plastic Surgery, Kumamoto University, Japan.

Background: There are limited treatment options for advanced non-melanoma skin cancers (NMSCs). To overcome this issue, we need to conduct clinical studies, however, there is a lack of information on how many patients with advanced NMSCs are treated annually in Japan.

Objective: To investigate the actual number of advanced NMSC patients in Japan.

Methods: A questionnaire survey was sent to 668 institutes to educe information on: 1) the numbers of patients with squamous cell carcinoma (SCC), extramammary Paget disease (EMPD), other skin origin carcinomas, and cutaneous angiosarcoma (CAS) admitted in 2016 and 2017; 2) the preferred first- and second-line chemotherapies; and 3) the anticipated for future development.

Results: Questionnaires were returned from 383 (57.3%) institutes. They reported a total of 1765 patients over the 2 years. The annual number patients with SCC, EMPD, other skin carcinomas, and CAS was 323.5, 192.5, 126, and 240.5, respectively. We estimated the annual number of patients for all 668 institutes to be 1255.6. Current first- and second-line treatment for NMSCs were chemotherapy regimens, but immune checkpoint inhibitors were the most anticipated new drugs for SCC and CAS, while chemotherapy was still the most anticipated treatment for EMPD.

Conclusion: Considering that during 2017, the number of deaths in Japan due to NMSC was reported to be 948, our estimated annual number of patients with NMSCs, 1255.6 seems to be an accurate estimation. As most of the treatment options for advanced NMSCs are outdated, the results of this study should be used to propose clinical studies.
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http://dx.doi.org/10.1016/j.jdermsci.2018.10.004DOI Listing
December 2018