Details of a Researcher - Funakoshi, Takeru

Papers - Funakoshi, Takeru

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Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors

Hirai I., Funakoshi T., Kamijuku H., Fukuda K., Mori M., Sakurai M., Koda Y., Kato J., Mori T., Watanabe N., Noji S., Yaguchi T., Iwata T., Ohta S., Fujita T., Tanosaki R., Handa M., Okamoto S., Amagai M., Kawakami Y.

Cancer Science (Cancer Science) 2021

ISSN 13479032

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).

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Anti-PD-1 antibody therapy for epithelial skin malignancies: An investigator-initiated, open-label, single-arm, multicenter, phase II clinical trial (NMSC-PD1 Study)

Ishii M., Hirai I., Tanese K., Fusumae T., Nakamura Y., Fukuda K., Uchi H., Kabashima K., Otsuka A., Yokota K., Yamazaki N., Namikawa K., Fujimura T., Takenouchi T., Yamamoto Y., Nishiguchi M., Sato Y., Amagai M., Funakoshi T.

Medicine (Medicine) 99 ( 44 ) 2020.10

INTRODUCTION: Malignant cutaneous epithelial tumors comprise various skin malignancies originating from the cutaneous epithelium, including cutaneous squamous cell carcinoma, basal cell carcinoma, and malignant cutaneous adnexal tumors. Treatment options are limited, as the rarity of these tumors, especially among Asians, renders well-controlled clinical trials extremely challenging to conduct. Thus, we designed a clinical trial to evaluate the efficacy and safety of the anti-programmed cell death-1 (PD-1) monoclonal antibody nivolumab in patients with metastatic cutaneous squamous cell carcinomas and other rare metastatic cutaneous epithelial tumors. METHODS AND ANALYSIS: This is an open-label, single-arm, multicenter, phase 2 clinical trial involving patients with metastatic malignant cutaneous epithelial tumors. Nivolumab (480 mg) will be administered intravenously every 4 weeks for a maximum of 26 doses. The primary outcome of the study will be the response rate based on response evaluation criteria in solid tumors, version 1.1. Assuming a null hypothesis of a response rate ≤5% and an alternative hypothesis of a 25% response rate, a minimum of 26 patients are required to achieve a 5% two-sided type I error and 80% power based on the exact binomial distribution. Finally, a target cohort size of 30 patients was determined as some patient dropout will be expected. DISCUSSION: This is the first phase 2 clinical trial evaluating the efficacy and safety of the PD-1 inhibitor nivolumab in Asian patients with metastatic malignant cutaneous epithelial tumors. The findings of the study will contribute to the development of novel treatment approaches for patients with rare cutaneous malignancies, which remains an unmet clinical need. TRIAL REGISTRATION: Registry number: jRCT 2031190048.

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Acute onset olfactory/taste disorders are associated with a high viral burden in mild or asymptomatic SARS-CoV-2 infections

Nakagawara K., Masaki K., Uwamino Y., Kabata H., Uchida S., Uno S., Asakura T., Funakoshi T., Kanzaki S., Ishii M., Hasegawa N., Fukunaga K.

International Journal of Infectious Diseases (International Journal of Infectious Diseases) 99 19 - 22 2020.10

ISSN 12019712

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Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients

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

Annals of Oncology (Annals of Oncology) 31 ( 9 ) 1198 - 1206 2020.09

ISSN 09237534

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

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Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results

Kamata A., Kurihara Y., Funakoshi T., Takahashi H., Kuroda K., Hachiya T., Amagai M., Yamagami J.

British Journal of Dermatology (British Journal of Dermatology) 182 ( 5 ) 1221 - 1227 2020.05

Joint Work, Accepted, ISSN 00070963

© 2019 British Association of Dermatologists Background: A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. Objectives: To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. Methods: We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme-linked immunosorbent assay. Results: Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE− patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180-IgE levels were significantly higher among IgE+ patients than IgE± or IgE− patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE− patients. A significant correlation was detected between BP180-IgG and BP180-IgE, but not between BPDAI scores and any of BP180-IgG, BP180-IgE or blood eosinophil count. Conclusions: IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic?. BP180-IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add?. Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180-specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.

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Case of metastatic cutaneous myoepithelial carcinoma lacking severe cytological atypia

Hirai I, Tanese K, Nakamura Y, Amagai M, Mikami S, Funakoshi T

J Dermatol 47 ( 3 ) e97 - e98 2020.03

Joint Work, Accepted, ISSN 0385-2407

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Metastatic Cutaneous Squamous Cell Carcinoma in Liver Successfully Treated With Partial Hepatectomy and Adjuvant Irinotecan Chemotherapy

Asahina Y, Nakamura Y, Tanese K, Hirai I, Fukuda K, Amagai M, Funakoshi T

In Vivo 34 ( 2 ) 825 - 828 2020.03

Joint Work, Accepted, ISSN 0258-851X

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Primary malignant melanoma of the uterine cervix or vagina which were successfully treated with nivolumab

Anko M., Nakamura M., Kobayashi Y., Tsuji K., Nakada S., Nakamura Y., Funakoshi T., Banno K., Aoki D.

Journal of Obstetrics and Gynaecology Research (Journal of Obstetrics and Gynaecology Research) 46 ( 1 ) 190 - 195 2020.01

Joint Work, Accepted, ISSN 13418076

© 2019 Japan Society of Obstetrics and Gynecology Primary malignant melanomas (MM) originating from the gynecological tract are rare. They respond poorly to immunotherapy when compared with cutaneous MM. This study reports two cases. The first is of a 54-year-old woman with a cervical amelanotic polypoid mass who was diagnosed as having stage IB1 cervical melanoma according to the International Federation of Gynecology and Obstetrics system. At 17 months post-surgery, a computed tomography examination revealed recurrence of a 68 mm pelvic tumor. The second case is of a 37-year-old woman with a 7 cm hemorrhagic mass on the vaginal wall. The patient was diagnosed as having stage IV vaginal melanoma according to the American Joint Committee on Cancer definition. Both patients received nivolumab therapy, programmed cell death receptor 1 monoclonal antibodies, and the tumors almost disappeared. These cases may add the possibility of using colposcopy with narrow-band imaging and positron-emission tomography to diagnose and evaluate primary MM.

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Variable indoleamine 2,3-dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy

Iga N., Otsuka A., Hirata M., Kataoka T., Irie H., Nakashima C., Matsushita S., Uchi H., Yamamoto Y., Funakoshi T., Fujisawa Y., Yoshino K., Fujimura T., Hata H., Ishida Y., Kabashima K.

Cancer Science (Cancer Science) 110 ( 11 ) 3434 - 3441 2019.11

Joint Work, Accepted, ISSN 13479032

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti–programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti–programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti–CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti–PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti–PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti–PD-1 antibody from the perspective of IDO and PD-L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression-free survival (HR = 0.33, 95% CI = 0.13-0.81, P = 0.016), whereas PD-L1 expression on tumors was not associated with progression-free survival. Significantly lower expression of IDO in tumors was found in non–responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti–PD-1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.

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Serum cytokeratin 19 fragment 21-1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget's disease

Nakamura Y, Tanese K, Hirai I, Amagai M, Kawakami Y, Funakoshi T

Br J Dermatol (British Journal of Dermatology) 181 ( 3 ) 535 - 543 2019.09

Joint Work, Accepted, ISSN 0007-0963

© 2019 British Association of Dermatologists Background: Extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma affecting the genitals and axillary regions. As metastasis of these tumours is itself rare, solid disease management strategies have not been established. Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21-1 (CYFRA 21-1) levels have been identified as candidate biomarkers for tumour progression in EMPD. Objectives: To determine the accuracy of and the correlation between these markers in patients with EMPD. Methods: Serum CEA and CYFRA 21-1 levels were examined in 30 patients with EMPD treated at Keio University Hospital, and compared against clinical information. Both assays were performed at the time of diagnosis, during the postoperative observation period, and following systemic treatment in those with confirmed metastasis. Serum levels were then correlated with tumour progression status and treatment responses. Results: Normal levels for both assays were observed in all 11 patients with primary localized disease (100%). In patients with metastatic disease the CEA positivity rate was 79% (15 of 19 patients), with a rate of 63% (12 of 19 patients) for CYFRA 21-1. Changes in CEA and CYFRA 21-1 levels were statistically independent; however, using a combined view, elevated levels of either marker improved the positivity rate to 95% (18 of 19 patients). Use of both markers also correlated well with treatment responses. Conclusions: The combination of CEA and CYFRA 21-1 is useful for predicting metastasis and treatment response in patients with EMPD, especially in those who only have elevation of a single marker. What's already known about this topic?. Serum levels of carcinoembryonic antigen (CEA) and cytokine 19 fragment 21-1 (CYFRA 21-1) have been shown to be elevated in patients with extramammary Paget disease (EMPD). Elevation of serum CEA levels is associated with tumour progression of EMPD. A single small study reported that serum CYFRA 21-1 levels are elevated in patients with EMPD with lymph node metastasis. What does this study add?. Serum CEA and CYFRA 21-1 were present in 79% and 63% of 19 cases of metastatic EMPD, respectively. Elevations of CEA and CYFRA 21-1 were statistically independent. CEA and CYFRA 21-1 combination assays were positive in 95% of cases of metastatic EMPD. What is the translational message?. Combination assays with CEA and CYFRA 21-1 are useful for monitoring treatment response in patients with metastatic EMPD, particularly in those with elevation of either marker.

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Successful control of adrenal metastasis with transcatheter arterial chemoembolization in metastatic melanoma patient undergoing treatment with immune checkpoint inhibitor

Tahara U, Tanese K, Nakamura Y, Hirai I, Amagai M, Oguro S, Funakoshi T

J Dermatol 46 ( 8 ) e276 - e278 2019.08

Joint Work, Accepted, ISSN 0385-2407

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Updates on the systemic treatment of advanced non-melanoma skin cancer

Tanese K., Nakamura Y., Hirai I., Funakoshi T.

Frontiers in Medicine (Frontiers in Medicine) 6 160 2019.07

Joint Work, Accepted, ISSN 2296-858X

© 2019 Tanese, Nakamura, Hirai and Funakoshi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Non-melanoma skin cancers (NMSCs), which represent a diverse group of cutaneous malignancies, are the most common forms of human neoplasia. The incidence of these diseases is increasing due to a number of factors, including that of increasing human lifespans. The majority of NMSCs are basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC), with the remainder being various rare skin cancers, including extramammary Paget's disease (EMPD), Merkel cell carcinoma (MCC), and several skin adnexal carcinomas. Of these, MCC usually shows aggressive behavior with a high mortality rate. On the other hand, BCC, cSCC, EMPD, and skin adnexal tumors usually show an indolent clinical course and metastasize only rarely. Nevertheless, the metastatic forms of these tumors commonly lead to poor patient outcome. A definitive management strategy for the treatment of advanced NMSC has not been established, mainly due to their rarity and lack of reliable information based on well-controlled randomized trials. Chemotherapeutic regimens for treatment of these diseases have been mainly based on the observations of isolated, small case series or clinical trials with a limited numbers of patients. However, accumulating evidence regarding their pathobiological backgrounds as well as recent advances in molecular biotechnology have facilitated the development of novel drugs for treatment of these diseases. Over the past decade, the U.S. Food and Drug Administration has approved several molecular targeting therapies, including Hedgehog inhibitors for BCC, monoclonal antibodies targeting anti-programmed death ligand-1 and anti- programmed cell death 1 (PD-1) for MCC, and anti-PD-1 for cSCC. Here, we review their clinical utility and discuss updated systemic treatment strategies for advanced NMSC.

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好酸球増多症と多発性単神経炎,紫斑を伴った末梢性T細胞リンパ腫非特定型の1例

柳澤絵里加, 栗原佑一, 舩越建, 高橋勇人, 加野美希, 深井達夫, 戸澤圭一, 清水隆之, 天谷雅行, 海老原全

臨床皮膚科 ((株)医学書院) 73 ( 6 ) 457 - 464 2019.05

Joint Work, Accepted, ISSN 0021-4973

＜文献概要＞61歳,男性.初診3ヵ月前より発熱,咽頭痛を自覚し,四肢に紅斑が生じた.前医で好酸球数増加を指摘され,持続する発熱と紅斑を主訴に当科を紹介され受診した.紅斑からの病理組織では真皮から脂肪織の血管周囲に好酸球とリンパ球が浸潤していた.経過中,多発性単神経炎と紫斑が生じ,好酸球性多発血管炎性肉芽腫症が疑われた.その後,項部に丘疹が新生し,同部位からの病理組織で真皮全層に異型なCD4陽性T細胞が増生しており,T細胞受容体β鎖の遺伝子再構成を認めた.FDG-PETでは全身のリンパ節,肝実質,両側肺野への集積亢進を認めた.末梢性T細胞リンパ腫,非特定型と診断した.好酸球数増加をきたす疾患としてリンパ増殖性疾患は鑑別に挙がるが,多彩な臨床症状を呈し,診断が困難なことがあり,異なる皮疹が出現した場合は繰り返し生検を施行する必要がある.

妊娠中に急激に増大した隆起性皮膚線維肉腫の1例

豊島進, 栗原佑一, 持丸奈央子, 平井郁子, 中村善雄, 久保亮治, 天谷雅行, 舩越建

臨床皮膚科 ((株)医学書院) 73 ( 6 ) 451 - 456 2019.05

Joint Work, Accepted, ISSN 0021-4973

＜文献概要＞41歳,女性.初診1年前から左季肋部に結節を自覚した.妊娠15週頃から急速に増大し,妊娠17週時に当科を受診した.初診時,表面に紫斑を伴う4cm大の弾性軟の腫瘤を認めた.超音波検査で血管に富む境界明瞭な腫瘤であり,血管腫を疑い局所麻酔下で全摘術を行った.病理組織学的に,真皮から皮下に境界明瞭で血管に富む腫瘍を認めた.構成する細胞は紡錘形の細胞で,花むしろ状配列をなしてびまん性に増殖していた.核の大小不同や分裂像は目立たなかった.免疫組織化学染色ではCD34陽性,FISH法で第17染色体COL1A1遺伝子座と第22染色体PDGFB遺伝子座の転座が示唆された.隆起性皮膚線維肉腫と診断し,妊娠24週時に全身麻酔で筋膜を含め追加切除した.この腫瘍は以前にも妊娠中に急激に増大する腫瘍として報告されている.経過観察中に増大すると手術の侵襲が大きくなることや,転移の可能性もあるため,妊婦に生じた腫瘤における重要な鑑別疾患と考えられた.

Rituximab therapy for refractory autoimmune bullous diseases: A multicenter, open-label, single-arm, phase 1/2 study on 10 Japanese patients

Kurihara Y., Yamagami J., Funakoshi T., Ishii M., Miyamoto J., Fujio Y., Kakuta R., Tanikawa A., Aoyama Y., Iwatsuki K., Ishii N., Hashimoto T., Nishie W., Shimizu H., Kouyama K., Amagai M.

Journal of Dermatology (Journal of Dermatology) 46 ( 2 ) 124 - 130 2019.02

Joint Work, Accepted, ISSN 03852407

© 2018 Japanese Dermatological Association This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m 2 of body surface area). The primary end-points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD1

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Accumulation of exhausted CD8+ T cells in extramammary Paget's disease

Iga N., Otsuka A., Yamamoto Y., Nakashima C., Honda T., Kitoh A., Nakajima S., Egawa G., Nomura T., Dainichi T., Matsushita S., Tanizaki H., Yamamoto Y., Funakoshi T., Fujisawa Y., Fujimura T., Hata H., Ishida Y., Kabashima K.

PLoS ONE (PLoS ONE) 14 ( 1 ) e0211135 2019.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 1932-6203

Copyright: © 2019 Iga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03-24.4). On the other hand, the number of PD-1+ cells was

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PET-CTで患側膝部に滑膜炎による異常集積を認めた病期IIIC第2趾悪性黒色腫の1例

雪野祐莉子, 栗原佑一, 八代聖, 久保亮治, 安西秀美, 菊田一貴, 森岡秀夫, 川井田みほ, 舩越建

臨床皮膚科 ((株)医学書院) 73 ( 1 ) 65 - 70 2019.01

Joint Work, Accepted, ISSN 0021-4973

＜文献概要＞76歳,女性.左第2趾原発の悪性黒色腫に対し,転移検索目的にFDG-PET/CTを施行したところ原発巣の他同側の左膝と左鼠径部にFDGの集積を認めた.足趾離断,膝病変切除および鼠径リンパ節郭清を行った.病理組織像で原発巣と左鼠径リンパ節は悪性黒色腫であったが,膝病変はCD68陽性泡沫状細胞が増生しており,悪性黒色腫の転移ではなく,色素性絨毛結節性滑膜炎であった.術後は悪性黒色腫に対しインターフェロンβ維持療法を行っていたが,肺転移を認めたためニボルマブ投与へ変更した.下垂体性副腎不全および認知症を発症したため治療を中止したが,3年3ヵ月時点で生存中である.FDG-PET/CTは悪性腫瘍の転移巣検索として広く使用されているが,FDG集積を認める病変として悪性腫瘍以外にも炎症疾患や感染症,良性腫瘍があり注意を要する.本症では術前の画像検査のみでは色素性絨毛結節性滑膜炎と診断できなかった.非典型的なFDG集積を認めた場合は組織診を含め追加検査が必要と考えた.

Combination Cisplatin-Epirubicin-Paclitaxel Therapy for Metastatic Extramammary Paget's Disease

Hirai I., Tanese K., Nakamura Y., Ishii M., Kawakami Y., Funakoshi T.

Oncologist (Oncologist) 24 ( 6 ) e394 - e396 2019

Joint Work, Accepted, ISSN 10837159

© AlphaMed Press 2019 Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required. In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane- and/or platinum-based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability. This is the first regimen to combine taxane and anthracycline. When treating breast cancer, anthracycline is regarded as the key cytotoxic agent, and anthracycline in combination with taxane constitutes a key chemotherapeutic regimen. Given our results, we speculate both drugs are critical chemotherapeutic agents for the treatment of metastatic EMPD.

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Association of baseline serum levels of CXCL5 with the efficacy of nivolumab in advanced melanoma

Fujimura T, Sato Y, Tanita K, Lyu C, Kambayashi Y, Amagai R, Otsuka A, Fujisawa Y, Yoshino K, Matsushita S, Uchi H, Yamamoto Y, Hata H, Funakoshi T, Nonomura Y, Tanaka R, Okuhira H, Wada N, Hashimoto A, Aiba S

Frontiers in Medicine (Frontiers in Medicine) 6 ( APR ) 2019

Joint Work

© 2019 Fujimura, Sato, Tanita, Lyu, Kambayashi, Amagai, Otsuka, Fujisawa, Yoshino, Matsushita, Uchi, Yamamoto, Hata, Funakoshi, Nonomura, Tanaka, Okuhira, Wada, Hashimoto and Aiba. Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly increased in responders compared to non-responders. In contrast, there were no significant differences of baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for screening patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

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

Fujisawa Y., Funakoshi T., Nakamura Y., Ishii M., Asai J., Shimauchi T., Fujii K., Fujimoto M., Katoh N., Ihn H.

Journal of Dermatological Science (Journal of Dermatological Science) 92 ( 3 ) 230 - 236 2018.12

Joint Work, Accepted, ISSN 09231811

© 2018 Japanese Society for Investigative Dermatology 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 check

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