start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=28 end-page=36 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Local Control of Conjunctival Malignant Melanoma by Proton Beam Therapy in a Patient With No Metastasis in Six Years From in Situ to Nodular Lesions en-subtitle= kn-subtitle= en-abstract= kn-abstract=Conjunctival malignant melanoma is extremely rare, with no standard of care established at moment. Here we report a 65-year-old woman, as a hepatitis B virus (HBV) carrier, who presented concurrently a liver mass and lower bulbar conjunctival pigmented lesions in the right eye. Needle liver biopsy and excisional conjunctival biopsy showed hepatocellular carcinoma and conjunctival malignant melanoma in situ, respectively. The priority was given to segmental liver resection for hepatocellular carcinoma after transcatheter arterial chemoembolization. In 1 year, she underwent second and third resection of bulbar conjunctival pigmented lesions, and the pathological examinations constantly showed melanoma in situ. In the course, she showed gradual widening of pigmented lesions to upper bulbar conjunctiva and lower palpebral conjunctiva and lower eyelid. About 2.5 years from the initial visit, the lower eyelid lesion was resected for a genomic DNA-based test of BRAF mutations which turned out to be absent, and then, she began to have intravenous anti-programmed cell death-1 (PD-1), nivolumab every 3 or 4 weeks. She developed iritis in the right eye with conjunctival melanoma as an immune-related adverse event, 3 months after the beginning of nivolumab, and so she used daily topical 0.1% betamethasone eye drops to control the intraocular inflammation. She showed no metastasis in 6 years of follow-up, but later in the course, 5 years from the initial visit, she developed abruptly a non-pigmented nodular lesion on the temporal side of the bulbar conjunctiva along the corneal limbus, accompanied by two pigmented nodular lesions in the upper and lower eyelids in a few months. She thus, underwent proton beam therapy toward the conjunctival melanoma and achieved the successful local control. Proton beam therapy is a treatment option in place of orbital exenteration, and multidisciplinary team collaboration is desirable to achieve better cosmetic and functional outcomes in conjunctival malignant melanoma. en-copyright= kn-copyright= en-aut-name=MatsuoToshihiko en-aut-sei=Matsuo en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OgataTakeshi en-aut-sei=Ogata en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WakiTakahiro en-aut-sei=Waki en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TachibanaKota en-aut-sei=Tachibana en-aut-mei=Kota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujiTomokazu en-aut-sei=Fuji en-aut-mei=Tomokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AdachiTakuya en-aut-sei=Adachi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Regenerative and Reconstructive Medicine (Ophthalmology), Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Radiology, Proton Beam Center, Tsuyama Chuo Hospital kn-affil= affil-num=3 en-affil=Department of Radiology, Proton Beam Center, Tsuyama Chuo Hospital kn-affil= affil-num=4 en-affil=Department of Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Dermatology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Dermatology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Ocular surface kn-keyword=Ocular surface en-keyword=Conjunctiva kn-keyword=Conjunctiva en-keyword=Malignant melanoma kn-keyword=Malignant melanoma en-keyword=Proton beam therapy kn-keyword=Proton beam therapy en-keyword=Nivolumab kn-keyword=Nivolumab en-keyword=PD-1 inhibitor kn-keyword=PD-1 inhibitor en-keyword=Immune checkpoint inhibitor kn-keyword=Immune checkpoint inhibitor END start-ver=1.4 cd-journal=joma no-vol=115 cd-vols= no-issue=10 article-no= start-page=3231 end-page=3247 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240809 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8(+) T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44(+) effector memory T cells and CD69(+) early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers. en-copyright= kn-copyright= en-aut-name=FujimotoTakuya en-aut-sei=Fujimoto en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KanehiraNoriyuki en-aut-sei=Kanehira en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsushitaHirokazu en-aut-sei=Matsushita en-aut-mei=Hirokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SakuraiYoshinori en-aut-sei=Sakurai en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KenmotsuNaoya en-aut-sei=Kenmotsu en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MizutaRyo en-aut-sei=Mizuta en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KondoNatsuko en-aut-sei=Kondo en-aut-mei=Natsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TakataTakushi en-aut-sei=Takata en-aut-mei=Takushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KitamatsuMizuki en-aut-sei=Kitamatsu en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=IgawaKazuyo en-aut-sei=Igawa en-aut-mei=Kazuyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FujimuraAtsushi en-aut-sei=Fujimura en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OtaniYoshihiro en-aut-sei=Otani en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=ShirakawaMakoto en-aut-sei=Shirakawa en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TeraishiFuminori en-aut-sei=Teraishi en-aut-mei=Fuminori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SuzukiMinoru en-aut-sei=Suzuki en-aut-mei=Minoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MichiueHiroyuki en-aut-sei=Michiue en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute kn-affil= affil-num=5 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=6 en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=9 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=10 en-affil=Faculty of Science and Engineering, Kindai University kn-affil= affil-num=11 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=12 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=13 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=18 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=19 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=20 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= en-keyword=abscopal effect kn-keyword=abscopal effect en-keyword=advanced melanoma kn-keyword=advanced melanoma en-keyword=boron neutron capture therapy kn-keyword=boron neutron capture therapy en-keyword=boron-neutron immunotherapy kn-keyword=boron-neutron immunotherapy en-keyword=immune combination therapy kn-keyword=immune combination therapy END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=12 article-no= start-page=1433 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20211219 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Bilateral Optic Disc Swelling as a Plausible Common Ocular Sign of Autoinflammatory Diseases: Report of Three Patients with Blau Syndrome or Cryopyrin-Associated Periodic Syndrome en-subtitle= kn-subtitle= en-abstract= kn-abstract=The aim of this study is to describe bilateral optic disc swelling in three consecutive patients with Blau syndrome or cryopyrin-associated periodic syndrome at a single institution. Case 1 was a 30-year-old woman receiving 25 mg etanercept twice weekly who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 5 months old and genetically diagnosed with Blau syndrome with CARD15/NOD2 mutation (N670K) at 13 years old. At 10 years old, she began to have uveitis with optic disc swelling in both eyes, resulting in macular degeneration and optic disc atrophy at 17 years old only when etanercept was introduced. Case 2 was a 21-year-old man receiving adalimumab every 2 weeks who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 1.5 years old and genetically diagnosed as Blau syndrome with CARD15/NOD2 mutation (C495Y) at 5 years old. At 8 years old, around the time of adalimumab introduction, he began to show bilateral optic disc swelling which continued until the age of 16 years when the dose of adalimumab was increased. Case 3 was a 20-year-old woman receiving canakinumab every 8 weeks for systemic symptoms such as fever, headache, vomiting, and abdominal pain and later for sensorineural hearing disturbance on both sides. She had been diagnosed genetically with cryopyrin-associated periodic syndrome with NLRP3 mutation (Y859C) at 7 years old. At 5 years old, she was found to have bilateral optic disc swelling, which continued until the age of 10 years when she began receiving canakinumab (IL-1β inhibitor). Bilateral optic disc swelling might be tentatively designated as a plausible common ocular feature, if it occurred, in autoinflammatory diseases to pay more attention to ophthalmic complications in rare diseases. en-copyright= kn-copyright= en-aut-name=MatsuoToshihiko en-aut-sei=Matsuo en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YashiroMasato en-aut-sei=Yashiro en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MankiAkira en-aut-sei=Manki en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Ophthalmology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Melanoma Center, Department of Dermatology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pediatrics, Okayama City Hospital kn-affil= en-keyword=autoinflammatory diseases kn-keyword=autoinflammatory diseases en-keyword=Blau syndrome kn-keyword=Blau syndrome en-keyword=Muckle-Wells syndrome kn-keyword=Muckle-Wells syndrome en-keyword=CINCA/NOMID syndrome kn-keyword=CINCA/NOMID syndrome en-keyword=cryopyrin-associated periodic syndromes kn-keyword=cryopyrin-associated periodic syndromes en-keyword=optic disc swelling (optic papillitis) kn-keyword=optic disc swelling (optic papillitis) END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=12 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20211118 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Proton beam therapy followed by pembrolizumab for giant ocular surface conjunctival malignant melanoma: A case report en-subtitle= kn-subtitle= en-abstract= kn-abstract=The present study describes proton beam therapy as a clinical option to achieve local control of giant conjunctival melanoma in an aged person, instead of orbital exenteration. An 80?year?old woman with one?year history of left?eye injection and hemorrhage experienced rapid growth of the ocular surface black mass. At the initial visit, a black, elastic hard, hemorrhage?prone, thickened mass in the size of 30x40 mm with a presumed wide stalk covered the total area of the lid fissure on the left side. Biopsy of the mass demonstrated anomalous melanin?containing cells in fibrin and hemorrhage, which were positive for cocktail?mix antibodies against tyrosinase, melanoma antigen recognized by T cells?1 and human melanoma black?45, indicative of malignant melanoma. One month after the initial visit, the patient underwent proton beam therapy at the total dose of 70.4 Gy (relative biological effectiveness) in 32 fractions (~10 min each) in one and a half months. One month after the end of proton beam therapy, 3.5 months from the initial visit, the patient was found by computed tomographic scan to have multiple metastatic lesions in bilateral lung fields. With the evidence of absent BRAF mutation, the patient underwent intravenous administration of pembrolizumab 77.2 mg every three weeks five times in total. Then, three months after proton beam therapy, ocular surface melanoma almost subsided and the clear cornea allowed visualization of the intraocular lens inside the eye. In three weeks, spontaneous corneal perforation was plugged with iris incarceration. The patient died suddenly of unknown cause 7.5 months from the initial visit. The local control of giant conjunctival melanoma was achieved by proton beam therapy, leading to patient's satisfaction and better quality of life. Proton beam therapy, followed by immune checkpoint inhibitors, would become the future standard of care for unresectable giant conjunctival melanoma. en-copyright= kn-copyright= en-aut-name=MatsuoToshihiko en-aut-sei=Matsuo en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatsuiKuniaki en-aut-sei=Katsui en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WakiTakahiro en-aut-sei=Waki en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Regenerative and Reconstructive Medicine (Ophthalmology), Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=2 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Radiation Oncology, Department of Radiology, Kawasaki Medical School kn-affil= affil-num=5 en-affil=Department of Radiology, Tsuyama Chuo Hospital kn-affil= en-keyword=ocular surface kn-keyword=ocular surface en-keyword=conjunctiva kn-keyword=conjunctiva en-keyword=malignant melanoma kn-keyword=malignant melanoma en-keyword=proton beam therapy kn-keyword=proton beam therapy en-keyword=pembrolizumab kn-keyword=pembrolizumab en-keyword=PD?1 inhibitor kn-keyword=PD?1 inhibitor en-keyword=immune checkpoint inhibitor kn-keyword=immune checkpoint inhibitor en-keyword=corneal perforation kn-keyword=corneal perforation END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=11 article-no= start-page=e003134 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=202111 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background
Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples.

Methods
We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort.

Results
Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance.

Conclusions
The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer. en-copyright= kn-copyright= en-aut-name=KawashimaShusuke en-aut-sei=Kawashima en-aut-mei=Shusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InozumeTakashi en-aut-sei=Inozume en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawazuMasahito en-aut-sei=Kawazu en-aut-mei=Masahito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UenoToshihide en-aut-sei=Ueno en-aut-mei=Toshihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagasakiJoji en-aut-sei=Nagasaki en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TanjiEtsuko en-aut-sei=Tanji en-aut-mei=Etsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HonobeAkiko en-aut-sei=Honobe en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OhnumaTakehiro en-aut-sei=Ohnuma en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KawamuraTatsuyoshi en-aut-sei=Kawamura en-aut-mei=Tatsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=UmedaYoshiyasu en-aut-sei=Umeda en-aut-mei=Yoshiyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NakamuraYasuhiro en-aut-sei=Nakamura en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KawasakiTomonori en-aut-sei=Kawasaki en-aut-mei=Tomonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KiniwaYukiko en-aut-sei=Kiniwa en-aut-mei=Yukiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FukushimaSatoshi en-aut-sei=Fukushima en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=IkeharaYuzuru en-aut-sei=Ikehara en-aut-mei=Yuzuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=ManoHiroyuki en-aut-sei=Mano en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SuzukiYutaka en-aut-sei=Suzuki en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=NishikawaHiroyoshi en-aut-sei=Nishikawa en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MatsueHiroyuki en-aut-sei=Matsue en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=2 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=3 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=4 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=5 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=6 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=7 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=8 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=9 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=10 en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center kn-affil= affil-num=11 en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center kn-affil= affil-num=12 en-affil=Department of Pathology, Saitama Medical University International Medical Center kn-affil= affil-num=13 en-affil=Department of Dermatology, Shinshu University School of Medicine kn-affil= affil-num=14 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University kn-affil= affil-num=16 en-affil=Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=18 en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo kn-affil= affil-num=19 en-affil=Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center kn-affil= affil-num=20 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=21 en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=3 article-no= start-page=913 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200130 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis en-subtitle= kn-subtitle= en-abstract= kn-abstract=The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin- and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC's serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD. en-copyright= kn-copyright= en-aut-name=NomuraHayato en-aut-sei=Nomura en-aut-mei=Hayato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SuganumaMutsumi en-aut-sei=Suganuma en-aut-mei=Mutsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakeichiTakuya en-aut-sei=Takeichi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KonoMichihiro en-aut-sei=Kono en-aut-mei=Michihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IsokaneYuki en-aut-sei=Isokane en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SunagawaKo en-aut-sei=Sunagawa en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KobashiMina en-aut-sei=Kobashi en-aut-mei=Mina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SugiharaSatoru en-aut-sei=Sugihara en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KajitaAi en-aut-sei=Kajita en-aut-mei=Ai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MiyakeTomoko en-aut-sei=Miyake en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HiraiYoji en-aut-sei=Hirai en-aut-mei=Yoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=AkiyamaMasashi en-aut-sei=Akiyama en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MorizaneShin en-aut-sei=Morizane en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=2 en-affil=Department of Dermatology, Nagoya University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Dermatology, Nagoya University Graduate School of Medicine kn-affil= affil-num=4 en-affil=Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine kn-affil= affil-num=5 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=6 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=7 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=8 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=9 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=10 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=11 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=12 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=13 en-affil=Department of Dermatology, Nagoya University Graduate School of Medicine kn-affil= affil-num=14 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= en-keyword=atopic dermatitis kn-keyword=atopic dermatitis en-keyword=serine proteases kn-keyword=serine proteases en-keyword=kallikrein-related peptidases kn-keyword=kallikrein-related peptidases en-keyword=epidermal barrier dysfunction kn-keyword=epidermal barrier dysfunction en-keyword=lympho-epithelial Kazal-type-related inhibitor (LEKTI) kn-keyword=lympho-epithelial Kazal-type-related inhibitor (LEKTI) en-keyword=SPINK5 kn-keyword=SPINK5 en-keyword=filaggrin kn-keyword=filaggrin END start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue= article-no= start-page=1 end-page=6 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20191120 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Lacrimal Sac Malignant Melanoma in 15 Japanese Patients: Case Report and Literature Review en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background. Primary malignant melanoma of the lacrimal sac is rare. A patient with lacrimal sac melanoma was presented, and 14 Japanese patients with lacrimal sac melanoma in the literature were reviewed. Case Presentation. A 78-year-old Japanese man was presented with painless swelling of the lacrimal sac on the left side. Dacryocystectomy revealed diffuse infiltration with large epithelioid cells, sometimes with pigments, which were positive for cocktail mix of antibodies to tyrosinase, melan A (MART-1), and HMB45, leading to pathological diagnosis of melanoma. One month later, positron emission tomography (PET) revealed 2 high-uptake sites (SUVmax = 10.29 and 15.38) at the levels of medial canthus and nasolacrimal duct, but no abnormal uptake in the other site of the body. The lesion had the BRAF V600E mutation. He began to take daily oral dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), leading to no abnormal uptake on PET in half a year. He had stable disease in good physical status with small and weak uptake sites of lymph nodes on PET 1 year later. Results. In the review of 15 Japanese patients, including this patient, local recurrence was noted in 4 patients, regional lymph node metastasis only in 3, distant metastasis in 6, and no metastasis in 6. Five patients died within 2 years and the others were alive in short follow-up periods. Conclusions. Chemotherapy was the standard for local recurrence or metastasis. Emerging molecular target drugs, as shown in the present patient, would change the strategy for management of lacrimal sac melanoma. en-copyright= kn-copyright= en-aut-name=MatsuoToshihiko en-aut-sei=Matsuo en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Okayama University Graduate School of Interdisciplinary Science and Engineeing in Health Systems kn-affil= affil-num=2 en-affil=Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=BRAF inhibitor kn-keyword=BRAF inhibitor en-keyword=BRAF mutation kn-keyword=BRAF mutation en-keyword=MEK inhibitor kn-keyword=MEK inhibitor en-keyword=PET/CT kn-keyword=PET/CT en-keyword=dabrafenib kn-keyword=dabrafenib en-keyword=lacrimal sac kn-keyword=lacrimal sac en-keyword=malignant melanoma kn-keyword=malignant melanoma en-keyword=trametinib kn-keyword=trametinib END start-ver=1.4 cd-journal=joma no-vol=96 cd-vols= no-issue=1 article-no= start-page=26 end-page=32 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190821 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TNF-α and IL-17A induce the expression of lympho-epithelial Kazal-type inhibitor in epidermal keratinocytes en-subtitle= kn-subtitle= en-abstract= kn-abstract=BACKGROUND:
Serine proteases have important roles in skin barrier function and desquamation, and the aberrant expression or the dysfunction of serine proteases is associated with the pathogenesis of skin diseases. Serine protease activities are tightly regulated by serine proteases such as kallikrein-related peptidases (KLKs) and serine protease inhibitors such as lympho-epithelial Kazal-type related inhibitor (LEKTI). For a better understating of diseases' pathogenesis, the regulation mechanism of serine proteases and the inhibitors' expression in epidermal keratinocytes must be clarified.
OBJECTIVES:
To investigate the effects of the cytokines on the expression of LEKTI in epidermal keratinocytes.
METHODS:
Normal human epidermal keratinocytes (NHEKs) were stimulated with panels of inflammatory cytokines. The expression of serine protease inhibitors was analyzed using quantitative real-time PCR and ELISA. LEKTI expression in normal human skin and lesions from psoriasis or atopic dermatitis (AD) were analyzed by immunohistochemically and tape-stripping. Trypsin- and chymotrypsin-like serine protease activities in culture supernatants were measured by using specific substrates.
RESULTS:
TNF-α and IL-17A significantly induced the expression of LEKTI in NHEKs. The immunohistochemical and tape-stripping analysis revealed that psoriatic skin lesions had higher LEKTI expression compared to normal skin and AD lesions. Trypsin- and chymotrypsin-like protease activities in the culture media were upregulated 3-5 days later but attenuated 6-7 days later period by these cytokines.
CONCLUSIONS:
In epidermal keratinocytes, the Th1&Th17 cytokines TNF-α and IL-17A induce the expression of serine protease inhibitor LEKTI, and it might occur to suppress the increase in the serine protease activities under inflammation. en-copyright= kn-copyright= en-aut-name=SugiharaSatoru en-aut-sei=Sugihara en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SugimotoSaeko en-aut-sei=Sugimoto en-aut-mei=Saeko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TachibanaKota en-aut-sei=Tachibana en-aut-mei=Kota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KobashiMina en-aut-sei=Kobashi en-aut-mei=Mina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NomuraHayato en-aut-sei=Nomura en-aut-mei=Hayato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MiyakeTomoko en-aut-sei=Miyake en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HiraiYoji en-aut-sei=Hirai en-aut-mei=Yoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MorizaneShin en-aut-sei=Morizane en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Departments of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Epidermal keratinocyte kn-keyword=Epidermal keratinocyte en-keyword=IL-17A kn-keyword=IL-17A en-keyword=Lympho-epithelial Kazal-type inhibitor kn-keyword=Lympho-epithelial Kazal-type inhibitor en-keyword=Serine protease inhibitor kn-keyword=Serine protease inhibitor en-keyword=TNF-α kn-keyword=TNF-α END start-ver=1.4 cd-journal=joma no-vol=24 cd-vols= no-issue=6 article-no= start-page=670 end-page=675 dt-received= dt-revised= dt-accepted= dt-pub-year=2014 dt-pub=201411 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Increase of DC-LAMP+ mature dendritic cell subsets in dermatopathic lymphadenitis of mycosis fungoides en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Little is known about the immunological milieu of the skin-draining lymph nodes (LNs) in mycosis fungoides (MF). Objectives: We studied dendritic cell (DC) subsets in the dermatopathic lymphadenitis of MF patients. Methods: We immunohistochemically examined DC subsets and their distribution in 16 LN samples from 14 patients with MF (N1 LN, eight patients; N2, four; and N3, four), and we compared them with non-metastatic sentinel LNs from eight patients with melanoma. Results: The number of S-100 protein+ DCs was markedly increased in the LNs from the MF patients and the major component was DC-LAMP+ mature DCs in the outer and paracortex areas, where DC-SIGN+ immature DCs were relatively decreased in proportion. In contrast, DC-SIGN+ cells were relatively increased in proportion compared to DC-LAMP+ cells in the medulla. Although no significant difference was observed in the proportions of CD1a+ or Langerin+ DCs among the N1, N2, and N3 nodes, CD163+ M2-type macrophages were increased in number in the N2 and N3 nodes. Conclusions: Our observations indicate that mature DCs accumulate in the outer and paracortex areas in dermatopathic lymphadenitis and M2-type macrophages might increase in number during disease progression. en-copyright= kn-copyright= en-aut-name=TadaKotaro en-aut-sei=Tada en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HamadaToshihisa en-aut-sei=Hamada en-aut-mei=Toshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AsagoeKenji en-aut-sei=Asagoe en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UmemuraHiroshi en-aut-sei=Umemura en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=Mizuno-IkedaKazuko en-aut-sei=Mizuno-Ikeda en-aut-mei=Kazuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AoyamaYumi en-aut-sei=Aoyama en-aut-mei=Yumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaMasaki en-aut-sei=Otsuka en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IwatsukiKeiji en-aut-sei=Iwatsuki en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Department of Dermatology, Okayama Medical Center affil-num=4 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=5 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=6 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=7 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=8 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences affil-num=9 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences en-keyword=Mycosis fungoides kn-keyword=Mycosis fungoides en-keyword=dendritic cell kn-keyword=dendritic cell en-keyword=dermatopathic lymphadenitis kn-keyword=dermatopathic lymphadenitis en-keyword=DC-LAMP kn-keyword=DC-LAMP en-keyword=DC-SIGN kn-keyword=DC-SIGN en-keyword=M2-type macrophage kn-keyword=M2-type macrophage END start-ver=1.4 cd-journal=joma no-vol=69 cd-vols= no-issue=1 article-no= start-page=17 end-page=27 dt-received= dt-revised= dt-accepted= dt-pub-year=2015 dt-pub=201502 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Assessment of Melanoma-Initiating Cell Markers and Conventional Parameters in Sentinel Lymph Nodes of Malignant Melanoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sentinel lymph node (SLN) biopsies have widely been used for the detection of occult LN metastasis of malignant melanoma (MM). In addition to conventional biomarkers, we assessed the diagnostic and prognostic significance of melanoma-initiating cell (MIC) markers in SLNs of MM. We examined the expressions of gp100, MART-1 and tyrosinase mRNA for routine diagnosis and those of ABCB5, CD133, nestin, KDM5B, NGFR and RANK mRNA as MIC markers. The presence of micrometastasis was confirmed immunohistochemically using antibodies to S-100, HMB-45, MART-1, and tyrosinase. Discordance between immunohistochemical and molecular data was observed in 14 of 70 (20.0%) patients, among whom five (7.1%) were positive for only molecular markers;two of these five patients tested positive for micrometastasis by repeated immunohistochemical stainings. The quantitative expression levels of gp100, MART-1, and tyrosinase mRNA were significantly higher in the metastatic LNs;the cut-off values remain to be elucidated. ABCB5 mRNA expression was detected more frequently in the metastatic SLNs (p＜0.05) and in the group of patients with recurrence. To make a definite diagnosis of metastasis, we still need a combination of immunohistochemical and molecular probes. ABCB5 might be a suitable molecular marker for the detection of melanoma-initiating cells in SLNs. en-copyright= kn-copyright= en-aut-name=SuzukiNorihiro en-aut-sei=Suzuki en-aut-mei=Norihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakataMinoru en-aut-sei=Takata en-aut-mei=Minoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShirafujiYoshinori en-aut-sei=Shirafuji en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OtsukaMasaki en-aut-sei=Otsuka en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AsagoeKenji en-aut-sei=Asagoe en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HattaNaohito en-aut-sei=Hatta en-aut-mei=Naohito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IwatsukiKeiji en-aut-sei=Iwatsuki en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=4 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=5 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=6 en-affil= kn-affil=Department of Dermatology, Okayama Medical Center affil-num=7 en-affil= kn-affil=Department of Dermatology, Toyama Prefectural Central Hospital affil-num=8 en-affil= kn-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences en-keyword=melanoma kn-keyword=melanoma en-keyword=cancer-initiating cell kn-keyword=cancer-initiating cell en-keyword=sentinel lymph node kn-keyword=sentinel lymph node en-keyword=ABCB5 kn-keyword=ABCB5 END start-ver=1.4 cd-journal=joma no-vol=119 cd-vols= no-issue=1 article-no= start-page=87 end-page=89 dt-received= dt-revised= dt-accepted= dt-pub-year=2007 dt-pub=20070501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Panton-Valentine leukocidin (PVL) en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name=山崎修 kn-aut-sei=山崎 kn-aut-mei=修 aut-affil-num=1 ORCID= affil-num=1 en-affil= kn-affil=岡山大学医学部・歯学部附属病院 皮膚科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2002 dt-pub=20020325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=黄色ブドウ球菌によるバイオフｨルムに対する抗菌戦略としてのロキシスロマイシンとイミペネムの併用効果 kn-title=A combination of roxithromycin and imipenem as an antimicrobial strategy against biofilms formed by Staphylococcus aureus en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name= en-aut-sei= en-aut-mei= kn-aut-name=山ｱ修 kn-aut-sei=山ｱ kn-aut-mei=修 aut-affil-num=1 ORCID= affil-num=1 en-affil= kn-affil=岡山大学 END