Language：English   Publishing type：Research paper (scientific journal)  

Immune checkpoint inhibitors (ICIs) bring prognostic benefits to patients with malignancies. However, there is a substantial number of patients whose lesions are not improved by ICIs. In addition, ICIs may cause immune-related adverse events (irAEs), which could lead to an unfavorable prognosis with fatal consequences. Therefore, we conducted a retrospective study to evaluate the utility of circulating sPD-L1 (soluble programmed cell death 1 ligand 1) as a biomarker in patients with advanced melanoma treated with anti-PD-1 (programmed cell death 1 protein) antibodies. Sera from 31 consecutive patients were prospectively collected before and after anti-PD-1 antibody treatment and the serum level of sPD-L1 was evaluated. We found that high sPD-L1 levels before treatment were associated with better prognosis, and this association was observed only in patients with a low tumor burden. We also found that sPD-L1 levels were elevated in patients who developed severe irAEs after treatment, and the patients with severe irAEs had significantly higher fluctuations in sPD-L1 (delta sPD-L1) than those without severe irAEs. Our study suggests that serum sPD-L1 level is a useful biomarker to predict tumor response and irAE development in patients with advanced melanoma treated with anti-PD-1 antibodies.

DOI： 10.1111/1346-8138.17183

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1346-8138.17019

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/1346-8138.17063

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Cutaneous angiosarcoma (CAS) is an endothelial cell-derived, highly aggressive type of vascular tumour. Although chemoradiotherapy with paclitaxel (PTX) is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial, and there is no standard therapy for taxane-resistant CAS. Plasminogen activator inhibitor-1 (PAI-1) is associated with poor clinical outcomes, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancers. Since PAI-1 protects endothelial cells from Fas ligand-mediated apoptosis, PAI-1 inhibition might induce apoptosis of endothelial cell-derived tumours such as CAS. This is a single-arm, open-label, multi-institutional, Phase 2 clinical trial to assess the efficacy and safety of PTX in combination with TM5614 (PAI-1 inhibitor) in patients with PTX-resistant CAS. PTX will be administered for 28 weeks, with oral administration of TM5614. The primary endpoint of this study will be the overall response rate (ORR) at 28 weeks after starting treatment (central image evaluation). The secondary endpoint will include the ORR at 28 weeks after starting treatment (investigator evaluation), ORR at 8 weeks and 16 weeks after initiation of treatment (central and investigator evaluation), progression-free survival, overall survival, disease control rate and safety profiles. Assuming the null hypothesis of a response rate of 13.6% and an alternative hypothesis of 45%, a minimum of 15 patients are required to achieve a two-sided, Type I error of 5% and power of 70% based on the exact binomial distribution. Data quality control will be conducted by a combination of centralized (remote) and on-site monitoring. This study will contribute to the development of novel combination therapy for PTX-resistant CAS patients, which remains an unmet clinical need.

DOI： 10.1111/exd.14976

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. METHODS: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. RESULTS: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. CONCLUSIONS: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

DOI： 10.1002/cam4.6438

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Since anti-PD-1 Abs can cause irreversible immune-related adverse events (irAEs), the associations between their efficacies and the incidence of irAEs are important to evaluate the use of anti-PD-1Abs for the treatment of melanoma, especially in the adjuvant setting. The purpose of this post hoc analysis study was to retrospectively analyze the associations between recurrence-free survival (RFS) at 12 months and the onset of any irAEs in 31 non-acral cutaneous and 30 acral melanoma cases treated with anti-PD-1 Abs therapy at the adjuvant setting in Asians. There were 20 cases with greater than grade 1 AEs in both the acral and non-acral cutaneous groups. Of the acral melanoma, 10 cases were nails or toes, and 20 cases were soles and heels. The log-rank test showed that RFS was better in cases with AEs than in cases without AEs. The present study suggested that the different profiles of irAEs between non-acral cutaneous and acral melanoma might correlate with the different response to anti-PD1 Abs of melanoma in the adjuvant setting.

DOI： 10.1111/1346-8138.16912

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/bjd/ljad183

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/bjd/ljad114

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Efficacy of anti-PD-1 antibody monotherapy (PD1) or anti-PD-1 plus anti-CTLA-4 combination therapy (PD1 +CTLA4) for melanoma is affected by its clinical subtype. The amount of tumor mutation burden (TMB) caused by cumulative sun damage (CSD) is occasionally used to explain this; however, their relationship in Japanese nonacral cutaneous melanoma (NACM) is still unclear. OBJECTIVE: To analyze the ICI efficacy and its relationship with CSD of the primary lesion in Japanese patients with NACM. METHODS: Japanese patients with advanced BRAF wild-type NACM who received first-line ICIs were recruited. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), and the degree of solar elastosis (SE) were evaluated. RESULTS: A total of 146 patients (PD1 group 113 and PD1 +CTLA4 group 33) were included. No significant differences in ORR were observed between the PD1 and PD1 +CTLA4 groups (35 % vs. 36 %; P = 0.67) or PFS and OS (median PFS 6.1 months vs. 8.5 months; P = 0.46, median OS 28.1 months vs. not reached; P = 0.59). Multivariate survival analysis revealed that PD1 +CTLA4 did not prolong the PFS and OS. The SE score had no effect on either PFS or OS. CONCLUSIONS: ICI efficacy was not as high as those reported in Western countries, and PD1 +CTLA4 did not present better clinical efficacy compared to PD1. Indicators of CSD did not serve as a predictor for clinical advantage. These findings may partially support the theory that ICI efficacy is affected by CSD; however, other unrecognized factors may also exist.

DOI： 10.1016/j.jdermsci.2023.03.008

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial. From the above findings, the efficacy and safety profiles of taxane-switch (change paclitaxel to docetaxel or vise), eribulin methylate, and pazopanib regimens in second-line chemotherapy were evaluated retrospectively in 50 Japanese taxane-resistant CAS patients. Although there was no significant difference in progression-free survival (P = 0.3528) among the regimens, the incidence of all adverse events (AEs) (P = 0.0386), as well as severe G3 or more AEs (P = 0.0477) was significantly higher in the eribulin methylate group and pazopanib group than in the taxane-switch group. The present data suggest that switching to another taxane should be considered for the treatment of taxane-resistant CAS in second-line therapy based on the safety profiles.

DOI： 10.1111/1346-8138.16786

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Eribulin mesylate (ERB) is a synthetic analog of halichondrin B, inhibiting tumor cell growth by disrupting microtubule function. Recently, anticancer drugs have been shown to not only act directly on tumor cells but also to exert antitumor effects by modifying the tumor environment. Although ERB has also been speculated to modify the tumor microenvironment including the immune response to tumors, the precise mechanism remains unclear. In our study, ERB suppressed the tumor growth of MC38 colon cancer in wildtype mice, whereas ERB failed to inhibit the tumor growth in Rag1-deficient mice which lack both B and T cells. Moreover, depletion of either CD4+ or CD8+ T cells abrogated the antitumor effect of ERB, indicating that both CD4+ and CD8+ T cells play an important role in ERB-induced antitumor effects. Furthermore, ERB treatment increased the number of tumor infiltrating lymphocytes (TILs) as well as the expression of activation markers (CD38 and CD69), immune checkpoint molecules (LAG3, TIGIT and Tim3) and cytotoxic molecules (granzyme B and perforin) in TILs. ERB upregulated E-cadherin expression in MC38. CD103 is a ligand of E-cadherin and induces T-cell activation. ERB increased the proportion of CD103+ cells in both CD4+ and CD8+ TILs. The ERB-induced antitumor effect with the increased TIL number and the increased expression of activation markers, inhibitory checkpoint molecules and cytotoxic molecules in TILs was abrogated in CD103-deficient mice. Collectively, these results suggest that ERB exerts antitumor effects by upregulation of E-cadherin expression in tumor cells and subsequent activation of CD103+ TILs.

DOI： 10.1080/2162402X.2023.2218782

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Anti-PD-1 antibodies (Abs) are among the optimal adjuvant therapies for melanoma at high risk of recurrence, especially BRAF wild-type melanoma, but the anti-tumour effects of anti-PD-1 Abs in the adjuvant setting for acral melanoma have not been evaluated previously. The aim of this study was to analyse the efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting in an Asian population including a high ratio of acral melanoma. The efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting were retrospectively analysed in 78 Japanese patients with advanced melanoma, including 31 cases (40%) of acral melanoma. Overall relapse-free survival was 60.3% (47 of 78 cases, 95% confidence interval (CI) 49.2-70.4%), and 39.7% of patients (31 of 78 patients, 95% CI 29.6-50.8%) relapsed during the adjuvant PD-1 Ab treatment. Six cases (7.9%) discontinued the protocol due to serious adverse events. One case (1.3%) discontinued the protocol due to trauma. The relapse-free survival of acral melanoma was 25.8%, whereas that of high cumulative sun damage was 60.0%, and that of low cumulative sun damage was 57.1%. The acral type had a significantly lower 12-month relapse-free survival than other cutaneous types (p = 0.029). The acral type appeared to be an independent prognostic factor on multivariate analysis (p = 0.015). Adverse events due to anti-PD-1 antibody were observed in 37.1% overall. The results of this study suggest that anti-PD-1 Ab therapy in the adjuvant setting is less effective for acral melanoma than for other cutaneous types.

DOI： 10.2340/actadv.v102.678

PubMed

researchmap

Language：English  

DOI： 10.1111/bjd.21230

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jid.2021.12.015

PubMed

researchmap

Language：English  

DOI： 10.1016/j.ejca.2022.02.020

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

IMPORTANCE: Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE: To develop recommendations for the care of adults with EMPD. EVIDENCE REVIEW: A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGS: The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years. CONCLUSIONS AND RELEVANCE: Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

DOI： 10.1001/jamaoncol.2021.7148

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.16263

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction (cADR). Distinguishing SJS/TEN from nonsevere cADRs is difficult, especially in the early stages of the disease. OBJECTIVE: To overcome this limitation, we developed a computer-aided diagnosis system for the early diagnosis of SJS/TEN, powered by a deep convolutional neural network (DCNN). METHODS: We trained a DCNN using a dataset of 26,661 individual lesion images obtained from 123 patients with a diagnosis of SJS/TEN or nonsevere cADRs. The DCNN's accuracy of classification was compared with that of 10 board-certified dermatologists and 24 trainee dermatologists. RESULTS: The DCNN achieved 84.6% sensitivity (95% confidence interval [CI], 80.6-88.6), whereas the sensitivities of the board-certified dermatologists and trainee dermatologists were 31.3 % (95% CI, 20.9-41.8; P < .0001) and 27.8% (95% CI, 22.6-32.5; P < .0001), respectively. The negative predictive value was 94.6% (95% CI, 93.2-96.0) for the DCNN, 68.1% (95% CI, 66.1-70.0; P < .0001) for the board-certified dermatologists, and 67.4% (95% CI, 66.1-68.7; P < .0001) for the trainee dermatologists. The area under the receiver operating characteristic curve of the DCNN for a SJS/TEN diagnosis was 0.873, which was significantly higher than that for all board-certified dermatologists and trainee dermatologists. CONCLUSIONS: We developed a DCNN to classify SJS/TEN and nonsevere cADRs based on individual lesion images of erythema. The DCNN performed significantly better than did dermatologists in classifying SJS/TEN from skin images.

DOI： 10.1016/j.jaip.2021.09.014

PubMed

researchmap

Language：Japanese   Publisher：(一社)茨城県医師会  

researchmap

Language：Japanese   Publisher：(一社)茨城県医師会  

researchmap

Language：Japanese   Publisher：(一社)茨城県医師会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Cornification involves cytoskeletal cross-linkages in corneocytes (the brick) and the secretion of lipids/adhesion structures to the interstitial space (the mortar). Because the assembly of lipid envelopes precedes corneocyte maturation, loricrin is supposed to be dispensable for the protection against desiccation. Although the phenotypes of Lor knockout (LKO) mice are obscure, the antioxidative response on the KEAP1/NRF2 signaling pathway compensates for the structural defect in utero. In this study, we asked how the compensatory response is evoked after the defects are repaired. To this end, the postnatal phenotypes of LKO mice were analyzed with particular attention to the permeability barrier function primarily maintained by the mortar. Ultrastructural analysis revealed substantially thinner cornified cell envelopes and increased numbers of lamellar granules in LKO mice. Superficial epidermal damages triggered the adaptive repairing responses that evoke the NRF2-dependent upregulation of genes associated with lamellar granule secretion in LKO mice. We also found that corneodesmosomes are less degraded in LKO mice. The observation suggests that loricrin and NRF2 are important effectors of cornification, in which proteins need to be secreted, cross-linked, and degraded in a coordinated manner.

DOI： 10.1016/j.xjidi.2021.100065

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γ‒mediated T helper type (Th)1-, IL-4‒mediated Th2-, and IL-17A‒mediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1‒deficient mice than in wild-type or Pd-l2‒deficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2‒deficient mice were more severe than that in wild-type or Pd-l1‒deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity.

DOI： 10.1016/j.jid.2021.06.026

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

Cutaneous angiosarcoma (CAS) is rare and most previous studies of CAS have been small case series, and randomized, phase II studies of CAS are limited. Since treatment options for CAS are controversial, and because only paclitaxel should be recommended based on high-level evidence, it is important to evaluate the efficacy of another taxane-derived agents, docetaxel, in real-world practice. The efficacy and safety profiles of chemoradiotherapy using taxane-based agents, docetaxel and paclitaxel, were retrospectively examined in the maintenance setting in 90 Japanese CAS patients, including 35 docetaxel-treated cases and 55 paclitaxel-treated cases. Overall survival and dose duration time of the patient group treated with docetaxel was equivalent to that with paclitaxel, even in the cohorts with metastasis. Adverse events due to docetaxel and paclitaxel were observed in 77.1% and 69.1% of cases, respectively. The incidence ratio of total severe adverse events tended to be higher in the docetaxel-treated group (40.0%) than in the paclitaxel-treated group (23.6%). Peripheral neuropathy occurred only in the paclitaxel-treated group, whereas high-grade interstitial pneumonia developed only in the docetaxel-treated group. In addition, we also evaluate 19 patients selected other taxanes, 17 patients selected eribulin methylate, 11 patients pazopanib, and 2 patients selected nivolumab as second-line chemotherapy. The efficacy of a monthly docetaxel regimen is equivalent to a three-weekly paclitaxel regimen evaluated by Overall survival and DDT, even in the cohorts with metastasis, and it is a tolerable protocol for CAS as a maintenance therapy in the Japanese population.

DOI： 10.1002/ski2.180

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Patients with resected stage IIIB, IIIC and IIID melanomas have a high risk of recurrence. Therefore, an appropriate protocol for stage III melanoma is needed. Since adjuvant dabrafenib plus trametinib (D+T) combined therapy and anti-PD1 antibody (Ab) therapy reduce the risk of recurrence in patients with resected stage III BRAF-mutated melanoma, selecting the adjuvant therapy for BRAF-mutated melanoma is controversial. The efficacy and safety profiles of D+T combined therapy in the adjuvant setting were retrospectively analyzed in 36 Japanese. BRAF-mutated advanced melanoma patients. The relapse-free rate (RFR) at 12 months was 82.1% (95% confidential interval (CI), 63.9-92.6%). In the 21 patients who completed the protocol, the RFR at 12 months was 85.7% (95% CI, 64.5-95.9%). In the seven patients whose protocol was interrupted by adverse events, the RFR was 71.4% (95% CI, 35.2-92.4%). The incidence rate of any AEs for all patients was 69.7% (95% CI, 52.5-82.8%), including 13 cases of pyrexia, five cases of skin rash and four cases of liver dysfunction. The present study suggested that D+T therapy in the adjuvant setting is a useful and very tolerable protocol for BRAF-mutated melanoma in the Japanese population.

DOI： 10.1097/CMR.0000000000000770

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc  

Although the development of autoimmune disorders is recognized in drug-induced hypersensitivity syndrome (DIHS), the serial change of B-cell activity has not been well-addressed. Herein, the serum levels of IL-6, IL-10, B-cell activating factor of the tumor necrosis factor family (BAFF), and a proliferation-inducing ligand (APRIL) in three DIHS patients were tracked over time. While IL-6 and IL-10 tended to be elevated according to the disease activity, BAFF and APRIL increased during the improved phase. Our results imply that the continuous activation of B cells may be involved in the prolonged disease activity of DIHS and the development of autoimmune disorders.

DOI： 10.1002/cia2.12191

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The purpose of this study was to develop a deep learning-based computer-aided diagnosis system for skin disease classification using photographic images of patients. The targets are 59 skin diseases, including localized and diffuse diseases captured by photographic cameras, resulting in highly diverse images in terms of the appearance of the diseases or photographic conditions. METHODS: ResNet-18 is used as a baseline model for classification and is reinforced by metric learning to boost generalization in classification by avoiding the overfitting of the training data and increasing the reliability of CADx for dermatologists. Patient-wise classification is performed by aggregating the inference vectors of all the input patient images. RESULTS: The experiment using 70,196 images of 13,038 patients demonstrated that classification accuracy was significantly improved by both metric learning and aggregation, resulting in patient accuracies of 0.579 for Top-1, 0.793 for Top-3, and 0.863 for Top-5. The McNemar test showed that the improvements achieved by the proposed method were statistically significant. CONCLUSION: This study presents a deep learning-based classification of 59 skin diseases using multiple photographic images of a patient. The experimental results demonstrated that the proposed classification reinforced by metric learning and aggregation of multiple input images was effective in the classification of patients with diverse skin diseases and imaging conditions.

DOI： 10.1007/s11548-021-02440-y

PubMed

researchmap

Language：English  

DOI： 10.1093/rheumatology/keab370

PubMed

researchmap

Language：English  

DOI： 10.1016/j.bbrc.2021.07.009

PubMed

researchmap

Language：English  

DOI： 10.1097/DAD.0000000000001962

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4168/aair.2021.13.5.819

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy. METHODS: Wild-type, β2-microglobulin-null, perforin-null, Igμ-null and interferon α/β receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8+ or CD4+ T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib. RESULTS: Immunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in β₂-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igμ-null mice developed myositis normally. Adoptive transfer of CD8+ T cells induced myositis in recipients, while transfer of CD4+ T cells or IgG did not. Treatment with tofacitinib inhibited TIF1γ-induced myositis. CONCLUSIONS: Here we show that TIF1γ is immunogenic enough to cause experimental myositis, in which CD8+ T cells and type I interferons, but not CD4+ T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.

DOI： 10.1136/annrheumdis-2020-218661

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.

DOI： 10.1007/s00262-021-02870-2

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Several studies have demonstrated the usefulness of negative pressure closure (NPC) for the stabilization of skin grafts because it provides a uniform pressure to the graft. The results of our previous retrospective study also suggested the superiority of NPC over tie-over methods for the stabilization of split-thickness skin graft (STSG) in large or muscle-exposing defects. However, the usefulness of NPC for graft stabilization is yet to be fully established. This prospective, phase II clinical study was conducted to investigate the safety and efficacy of NPC for the stabilization of STSG in large or muscle-exposing defects. Patients who would require STSG for reconstruction of defects in the trunk and extremities other than hands and feet measuring >10 cm in the longest diameter or with muscle exposure were enrolled. NPC was applied for skin graft stabilization. Seven patients who had received wide excision of malignant tumors and resulted in muscle-exposed skin defects were included. All patients underwent meshed STSG. The mean size of the defect was 94.5 cm2 (range 63.6-164.9). The mean time from the skin graft harvesting to the NPC stabilization was 15.6 min (range 10.7-19.5). The mean survival rate of the skin graft at postoperative day 7 and 10 was 98.7% (range 97-100) and 96.5% (range 89.4-98.4), respectively. No adverse events associated with the procedure were observed. This prospective study provided further evidence of the safety and efficacy of NPC for STSG stabilization in patients with large or muscle-exposing skin defects.

DOI： 10.1111/1346-8138.15970

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.16005

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

DOI： 10.3390/cancers13163948

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/hyab067

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The efficacy of small molecule inhibitors for intracellular signal mediators varies among the individuals, and their mechanism of action is broad. A phosphodiesterase 4 inhibitor apremilast shows a dramatic effect on a certain proportion of psoriatic patients by modulating the cellular metabolism and regulating the production of pro-inflammatory molecules. However, it is unclear to which disease subtype this drug benefits. While psoriasis is a Th17-mediated disease, how immune cells are affected by the modulation of cellular metabolism is not fully evaluated, either. OBJECTIVE: This study aims to identify the indices which predict the efficacy of apremilast in psoriasis, and to investigate the impact of metabolic activity in immune cells on the psoriatic pathogenesis. METHODS: The association of treatment efficacy with clinical and laboratory data of the 58 psoriatic patients was evaluated. The reflector of the associated index was also sought among the indices of cellular metabolic pathways by use of an extracellular flux analyzer. RESULTS: There was a correlation between clinical improvement and the serum lactate dehydrogenase (LDH) level in the patients treated with apremilast but not in those with biologics. Serum LDH level did not correlate with the cutaneous disease severity but correlated with the oxygen consumption rate of blood T cells. CONCLUSION: Psoriatic patients with high serum LDH level can be benefitted by apremilast. The serum LDH level reflects the augmented respiratory activity of T cells in psoriasis. Our results would highlight the importance of regarding metabolic skew in immune cells as a treatment target in psoriasis.

DOI： 10.1016/j.jdermsci.2021.07.007

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Mast cells (MCs) are present in various organs including the skin, peritoneal cavity, lung, and intestine and involved in the development of allergic diseases and host defense against infection. However, the regulatory mechanism of mast cell activation remains incompletely understood. We found in a database that Clec12b encoding a C-type lectin receptor Clec12b is preferentially expressed in skin MCs in mice. However, neither MCs in other tissues such as trachea, tongue, esophagus, or peritoneal cavity nor most lymphocytes and myeloid cells express Clec12b. To analyze the protein expression of Clec12b, we newly generated a monoclonal antibody (named TX109), which recognizes both mouse and human Clec12b. Consistent with the gene expression profile, flow cytometry analysis demonstrated that Clec12b is expressed only on MCs in the skin, but not on any other immune cell types in various tissues, in mice. Similarly, Clec12b is also expressed on skin MCs, but not on circulating lymphocytes and myeloid cells, in humans. Our results suggest that Clec12b plays an important role in the regulation of MCs activation in the skin.

DOI： 10.1016/j.bbrc.2021.04.097

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Patients with graft-versus-host disease (GVHD) develop characteristic mucocutaneous phenomena consisting of erosive erythema with histopathological findings including interface dermatitis and keratinocyte (KC) death, resulting in widespread sclerodermatous changes. We found that KCs exhibit marked production of TGFβ1 in skin lesions of chronic GVHD but not in those of acute GVHD. To further investigate the roles of KCs, the main targets of donor T cells, in sclerodermatous changes followed by interface dermatitis, we established a murine model of chronic GVHD-like sclerodermatous changes followed by acute GVHD-like mucocutaneous injury in genetically modified mice transferred with KC-specific CD8 T cells. Although transfer of granzyme B-deficient CD8 T cells did not result in either mucocutaneous injury or sclerodermatous changes in recipients, IFN-γ-deficient CD8 T-cell recipients developed severe acute mucocutaneous injury but milder sclerodermatous changes than wild-type CD8 T-cell recipients. Moreover, IFN-γ-deficient CD8 T-cell recipients had a lower expression of TGFβ1 in the epidermis than the control. Murine primary KCs undergoing FasL-induced apoptosis and incubated with IFN-γ produced TGFβ1, the production of which was inhibited by a pan-caspase inhibitor. Our results indicate that IFN-γ promotes TGFβ1 production by apoptotic KCs, which mediates the development of widespread sclerodermatous changes in KC-targeting GVHD.

DOI： 10.1016/j.jid.2020.09.033

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/hyab021

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Acute graft-versus-host disease (aGVHD) induced by allogenic hematopoietic stem cell transplantation is an immunological disorder in which donor lymphocytes attack recipient organs. It has been proven that recipient nonhematopoietic tissue cells, such as keratinocytes, are sufficient as immunological targets for allogenic donor T cells, whereas Langerhans cells (LCs) are potent professional hematopoietic antigen-presenting cells existing in the target epidermis and eliminated during the early phase of mucocutaneous aGVHD. Moreover, LCs have been reported to negatively regulate various types of immune responses. Here, we present data showing that initial depletion of recipient LCs exacerbates mucocutaneous lesions in a murine model of allogenic bone marrow transplantation-induced aGVHD. Furthermore, another murine model of mucocutaneous aGVHD induced in mice with keratinocytes genetically expressing chicken ovalbumin by transfer of ovalbumin-specific CD8+ OT-I cells also showed that LC-depleted recipient mice develop aggravated mucocutaneous disease owing to decreased apoptosis of skin-infiltrating OT-I cells. Moreover, coexisting LCs directly induce apoptosis and inhibit the proliferation of OT-I cells in vitro partially via B7 family proteins. Collectively, our results indicate that LCs negatively regulate mucocutaneous aGVHD-like lesions in situ by inhibiting the number of infiltrating CD8+ T cells.

DOI： 10.1016/j.jid.2020.09.018

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

We report the 5-year follow-up results from a single-arm, open-label, multicenter phase II study (ONO-4538-08) conducted in Japan. Twenty-four patients with treatment-naïve, recurrent, or unresectable stage III/IV malignant melanoma received 3 mg/kg nivolumab every 2 weeks until progressive disease or unacceptable toxicity occurred. The 5-year overall survival (OS) rate was 26.1%. Five years after the start of nivolumab treatment, there were six survivors. The 5-year OS rate was 66.7% for patients with a superficial spreading type, 14.3% for acral lentiginous type, and 16.7% for mucosal type. The 5-year progression-free survival rate was 17.2%. No new cases of partial response or complete response were observed after 3 years, and overall response and disease control rates were similar to those reported at 3 years. The treatment-related adverse events reported between the 3- and 5-year follow-up periods were anemia (grade 2), white blood cell count decrease (grade 2), and psoriasiform dermatitis (grade 2) in one patient each. No new grade 3 or higher treatment-related adverse events occurred in this period. In conclusion, first-line treatment with nivolumab in Japanese patients with unresectable or metastatic melanoma resulted in confirmed long-term survival. No new safety signals were reported in the studied population.

DOI： 10.1111/1346-8138.15804

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Surgical-site infection (SSI) is one of the major postoperative complications in surgery, which can cause significant morbidity. However, factors associated with SSI in dermatological surgery are not well understood. Here, we retrospectively investigated 512 patients who underwent outpatient surgery for skin tumors at the University of Tsukuba Hospital to analyze factors associated with postoperative SSI. The overall incidence of SSI was 28 (5.5%). Univariate logistic regression analysis revealed that SSI was significantly associated with invasive squamous cell carcinoma (iSCC), Bowen's disease (BD), actinic keratosis (AK), longer diameter of defects, presence of ulcer, reconstruction with full-thickness skin graft and local skin flaps, medical history of diabetes mellitus, and use of immunosuppressive agents. However, in the multivariate analysis only iSCC, BD, and AK retained significance. The frequencies of SSI in iSCC, BD, and AK were 22% (13/58 patients), 15.6% (5/32), and 25% (2/8), respectively; however, the frequency of other non-SCC tumors was only 1.9% (8/414). χ2 -Tests revealed that the frequency of SSI in iSCC, BD, and AK were all significantly higher than in non-SCC tumors, with the frequencies being more than eight times higher. These results suggest that invasive and in situ lesions of SCC are independent risk factors of SSI development after outpatient skin surgery.

DOI： 10.1111/1346-8138.15782

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing. EXPERIMENTAL DESIGN: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization. RESULTS: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases. CONCLUSIONS: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.

DOI： 10.1158/1078-0432.CCR-20-3205

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.ejca.2020.12.021

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The efficacy of encorafenib plus binimetinib (E + B) combination therapy for BRAF-mutated advanced melanoma as second-line therapy and beyond is still unknown. In this report, we investigated 22 cases of BRAF-mutated advanced melanoma treated with E + B combination therapy. The objective response rate (ORR) for the total cohort was 68.4%. Notably, the ORR for the second-line and beyond cohort was 73.3%, suggesting that the therapeutic effect of E + B combination therapy is comparable with that of first-line targeted therapy. In contrast, overall survival and progress-free survival in our present cohort was worse than that in a previous clinical trial. Notably, although the incidence rate of severe adverse events was higher than that in a previous report, our present study suggested that E + B combination therapy is a well-tolerated antimelanoma regimen. Our present study suggested that the efficacy and safety profile of E + B combination therapy as a second-line therapy and beyond is comparable with that of first-line targeted therapy.

DOI： 10.1111/1346-8138.15688

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15715

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15700

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15704

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jid.2020.06.013

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15681

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15723

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Recent studies have highlighted that human resident memory T cells (TRM) are functionally distinct from circulating T cells. Thus, it can be postulated that skin T cells age differently from blood-circulating T cells. We assessed T-cell density, diversity, and function in individuals of various ages to study the immunologic effects of aging on human skin from two different countries. No decline in the density of T cells was noted with advancing age, and the frequency of epidermal CD49a+ CD8 TRM was increased in elderly individuals regardless of ethnicity. T-cell diversity and antipathogen responses were maintained in the skin of elderly individuals but declined in the blood. Our findings demonstrate that in elderly individuals, skin T cells maintain their density, diversity, and protective cytokine production despite the reduced T-cell diversity and function in blood. Skin resident T cells may represent a long-lived, highly protective reservoir of immunity in elderly people.

DOI： 10.1038/s42003-020-01551-7

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

We herein report three patients with cardiac angiosarcoma who were directly admitted to the intensive-care unit for hemodynamic instability with circulatory collapse. Using a multidisciplinary cardio-oncologic approach, we diagnosed their condition as angiosarcoma by an invasive biopsy and urgently started weekly paclitaxel administration despite their poor performance status. Their vital signs were soon stabilized, leading to the patients' discharge from the hospital. Although no treatment guidelines for cardiac angiosarcoma have been established, chemotherapy with paclitaxel can be an option for cases presenting with hemodynamic instability.

DOI： 10.2169/internalmedicine.5420-20

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jdermsci.2020.10.012

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4103/ijd.IJD_584_18

PubMed

researchmap

Language：English  

Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.

DOI： 10.3389/fonc.2021.618201

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Nivolumab plus ipilimumab combined therapy is among the most effective therapies for advanced melanoma. However, this therapy is also associated with a high frequency of immune-related adverse events (irAEs). To avoid such severe irAEs caused by additional administration of anti-CTLA4 antibodies, biomarkers to distinguish responders from non-responders among patients treated with anti-PD1 antibodies are important. The purpose of this study is to evaluate the increased serum levels of CCL11, CCL24, and CCL26 as a predictive biomarker for the efficacy of anti-PD1 antibodies in advanced cutaneous melanoma patients. This study analyzed increased serum levels of CCL11, CCL24, and CCL26 in 46 cases of advanced cutaneous melanoma treated with anti-PD1 antibodies. Serum levels on day 42 were compared to baseline (day 0) and analyzed statistically. Receiver operating characteristic curves were established to evaluate the correlation between serum levels of CCL11, CCL24, and CCL26 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 correlated significantly with the efficacy of anti-PD1 antibodies. In contrast, no significant correlations were seen between increased serum levels of CCL11 and CCL24 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 may be a useful biomarker for identifying those patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

DOI： 10.1097/CMR.0000000000000685

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis.

DOI： 10.1038/s42003-020-01308-2

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Immunoglobulin A vasculitis (IgAV) is a type of vasculitis affecting small vessels with deposition of immune complexes consisting of IgA and complement component 3. IgAV involves the skin, gastrointestinal (GI) tract, joints, and kidneys. Adult patients have higher risks of gastrointestinal tract involvement than children. To investigate the risk factors of the GI tract involvements in adult IgAV patients, we enrolled 29 adult (aged ≥ 20 years) Japanese patients recently (from 2013 to 2019) histopathologically diagnosed with IgAV and classified them into the GI lesion (+) group and the GI lesion (−) group. All patients presented with purpura on the lower extremities
moreover, GI lesion (+) patients presented significantly more with extensive purpura on the upper extremities, and low levels of factor XIII activity (≤70%) than gastrointestinal lesion (−) patients (87.5% vs 28.6% [P =.004]
odds ratio [OR], 17.5
95% confidence interval [CI], 2.4 to 366], and 57.1% vs 14.3% [P =.04]
OR, 8
95% CI, 1.06 to 83.9, respectively). There was no significant difference between the two groups in the populations with extensive purpura on the trunk, arthralgia, hematuria, proteinuria, or elevated serum levels of C-reactive protein or IgA. Widespread purpura on the upper extremities accompanied by a low factor XIII activity is a suggestive factor for severe GI lesions in adult IgAV patients.

DOI： 10.1002/cia2.12136

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Recent clinical trials revealed that both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors significantly prolonged survival in melanoma patients when used for both advanced stage disease and postoperative adjuvant therapy. Although BRAF/MEK inhibitors are associated with a higher objective response rate than ICI, most patients relapse during treatment. However, progression patterns during treatment with BRAF/MEK inhibitors have not been extensively investigated. Here, we retrospectively collected the data of melanoma patients initially treated with BRAF/MEK inhibitors or anti-programmed death 1 (PD-1) antibody monotherapy at the University of Tsukuba Hospital and compared their results. The χ2 -test revealed that frequency of brain metastasis (BM) development was significantly higher in cases treated with BRAF/MEK inhibitors compared with those with anti-PD-1 antibody monotherapy. In addition, BM-free survival in cases treated with BRAF/MEK inhibitors was significantly shorter than those treated with anti-PD-1 antibody monotherapy. Our results indicate that BM development during treatment with BRAF/MEK inhibitors may be more frequent than anti-PD-1 antibody monotherapy, even though the extracranial metastases are well controlled. Therefore, we recommend frequent brain examinations during treatment with BRAF/MEK inhibitors to detect BM at an early stage and to promptly administrate ICI with local radiation therapy.

DOI： 10.1111/1346-8138.15479

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer. While Mohs micrographic surgery is commonly accepted for BCC treatment, surgical excision with free margins is widely considered the best treatment modality for BCCs in Japan. However, little is known about the predictors of the invasion levels of BCCs. OBJECTIVE: To investigate the optimization of deep surgical margins by identifying factors significantly influencing the invasion levels of facial BCCs. METHODS: The tumor invasion level was defined as the deepest part of a tumor. Tumor thickness was measured from the top of the granular layer to the deepest extension of the tumor or from the ulcer base overlying the deepest point of invasion in ulcerated lesions. Factors independently associated with tumor thickness and invasion level were identified by multivariate analysis. Six variables were tested: age, sex, anatomical region (nose, orbit, others), histologic pattern (aggressive, non-aggressive), presence of pigmentation, and diameter. RESULTS: We included 718 cases of facial BCCs involving 705 Japanese patients. The most frequent anatomical region and histologic pattern were the nose and nodular pattern, respectively. Only tumor diameter showed a correlation with tumor thickness (β = 0.377, P < 0.001). Tumor diameter (AOR = 71.189, 95 % CI: 11.420-430.931, P = 0.01) and the following anatomical regions showed correlations with the invasion level: nose/others: AOR=2.769, 95 % CI: 1.235-6.493, P = 0.01; orbit/others: AOR=6.369, 95 % CI: 2.728-15.429, P < 0.001; orbit/nose: AOR=2.300, 95 % CI: 1.056-4.984, P = 0.04. CONCLUSIONS: This study serves as a guide for optimizing deep surgical margins and planning surgery for facial BCCs considering independently associated factors.

DOI： 10.1016/j.jdermsci.2020.07.001

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2-related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.

DOI： 10.4049/jimmunol.2000274

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15421

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15406

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jdermsci.2020.05.003

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/hyz201

PubMed

researchmap

Language：English  

DOI： 10.1093/rheumatology/kez527

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2020.3779

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Bexarotene is useful for both early and advanced cutaneous T-cell lymphoma (CTCL), and is sometimes applied to ultraviolet-tolerant early CTCL patients as one of the first-line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m2 cohort (conventional dose) was 76.2%, while that of the 150-300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional-dose cohort and 19.1 months for the low-dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional-dose cohort and 12.5% for the low-dose with NBUVB cohort. Our present study suggests that low-dose bexarotene plus NBUVB therapy is well-tolerated and could be one of the optimal therapies for advanced CTCL.

DOI： 10.1111/1346-8138.15322

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15341

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression-free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.

DOI： 10.1111/1346-8138.15345

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15331

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15298

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Angiomatoid Spitz nevus (ASN) is a rare histological variant of Spitz nevus (SN) that is characterized by prominent blood vessel proliferation around the intradermal melanocytes of SN. In contrast, SN may have pagetoid components, which are characterized by epidermal proliferation of single melanocytes. However, cases of ASN with predominant pagetoid melanocytic proliferation in the epidermis have not been reported. Here, we report a case of ASN with surrounding pagetoid melanocytic proliferation without formation of tumor nests in the epidermis in the plantar region. A 12-year-old girl presented with a bright red nodule surrounded by a brown macule on the sole of her right foot. Histologically, the nodule showed tumor nests in the dermis, composed of spindle or epithelioid melanocytes containing abundant cytoplasm and large nuclei. Around the nests, numerous blood vessels were seen. In the overlying epidermis of the nodule, numerous eosinophilic Kamino bodies were found along the dermal-epidermal interface. In the macule, proliferation of oval melanocytes was present as single-cell units in the epidermis. Theses melanocytes had abundant cytoplasm with large nuclei, which were larger than those of the surrounding keratinocytes. From these findings, a diagnosis of ASN with surrounding pagetoid melanocytic proliferation was made. Vascular endothelial growth factor and fibroblast growth factor 2 were strongly expressed in the melanocytes as well as in the endothelial cells in our case. Therefore, angiogenic factors produced by the melanocytes of SN might have played important roles in the surrounding angiogenesis of this case.

DOI： 10.1111/1346-8138.15275

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15279

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15253

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15258

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15205

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Psoriasis is an autoinflammatory/autoimmune skin disease and the epitome of an exaggerated primary inflammatory response in the surface barrier tissue. Despite the efficacy of dimethyl fumarate, an electrophilic drug for psoriasis management, there is a paucity of mechanistic evidence in vivo. In response to electrophiles, the Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) system mediates a myriad of cytoprotective mechanisms, including the regulation of excessive inflammatory response and epidermal differentiation. Because the psoriasiform tissue reaction comprises neutrophil infiltration and parakeratotic scaling, it is hypothesized that Nrf2 not only regulates inflammatory responses but also maintains epidermal differentiation, a hallmark of epidermal homeostasis. By using the imiquimod-induced cutaneous inflammation model, an exaggerated inflammatory response and impaired epidermal differentiation in Nrf2-/- mice was detected. Dimethyl fumarate treatment in Nrf2+/+ mice attenuated a psoriasiform tissue reaction and rescued epidermal differentiation, which was not observed in Nrf2-/- mice. In accordance with the fact that psoriasis plaques form well-demarcated parakeratotic lesions in association with the psoriasiform tissue reaction, the lesional skin showed reduced expression levels of NRF2 and its downstream target genes compared with nonlesional skin. In conclusion, Nrf2 attenuates the psoriasiform tissue reaction and underscores the mechanistic legitimacy of the electrophile-based approach for the management of psoriasis.

DOI： 10.1016/j.ajpath.2019.10.022

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.jdermsci.2020.01.010

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15163

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: The stratum corneum protects against the entry of pathogens, allergens, and irritants while preventing dehydration. The Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) system maintains skin barrier homeostasis. Aggregated evidence suggests that NRF2-mediated antioxidative response is hardwired into the stratified squamous epithelia. Honey and chamomile have long been regarded as natural antioxidants. Nonetheless, it is still unclear whether they activate the KEAP1/NRF2 system in the epidermis and could promote epidermal barrier recovery. METHODS: To address the abovementioned issue, we explored the antioxidative property of honey/chamomile extract by using non-cell-based KEAP1-inhibition assay and cultured human epidermal keratinocytes. RESULTS: Herein we report that the extract inhibited KEAP1-NRF2 interaction and induced keratinocyte production of antioxidant small proline-rich protein. CONCLUSION: Our results may offer an opportunity to develop cosmetic products that boost NRF2-mediated antioxidative/antiaging, epidermis-intrinsic bio-responses.

DOI： 10.2147/CCID.S270602

PubMed

researchmap

Language：English  

Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors (ICIs) for treating melanoma. However, these previous studies comprised mainly Caucasian populations, in which cutaneous melanoma (CM) is the major clinical type. In contrast, Asian populations have a distinct profile of melanoma and show much higher frequencies of acral lentiginous melanoma (ALM) and mucosal melanoma (MCM). Compared with CM, ALM and MCM show poorer response to ICIs, but the mechanisms have not been fully understood. To evaluate the immune status in each melanoma subtype, we examined the number of total tumor-infiltrating lymphocytes (TILs), CD4+ TILs, CD8+ TILs, and tumor-infiltrating FoxP3+ regulatory T cells (Tregs) to evaluate the immune status in each melanoma subtype using data from 137 patients with melanoma. Total TIL numbers in ALM and MCM were significantly lower than that in CM. CD4+ TIL number in MCM was also lower than CM although CD4+ TIL number in ALM was comparable with CM. In contrast, CD8+ TIL numbers in both ALM and MCM were significantly lower than that in CM. Although number of tumor-infiltrating Tregs was comparable among the 3 subtypes, the proportion of tumor-infiltrating Tregs in CD4+ T cells in MCM was significantly higher than in CM and ALM. Multivariate regression analysis revealed that ALM and MCM were significantly associated with a lower total TIL number, but only MCM was significantly associated with a lower CD4+ TIL number. Multivariate regression analysis also revealed that both ALM and MCM were significantly associated with a lower CD8+ TIL number. Our results suggest that both ALM and MCM are independent factors of lower total TIL number, which may be associated with poorer responses to ICIs in ALM and MCM.

DOI： 10.3389/fonc.2020.524700

PubMed

researchmap

Language：English  

DOI： 10.3389/fmed.2020.613152

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

House dust mite (HDM) is a major allergen that causes allergic diseases such as atopic dermatitis. However, the regulatory mechanisms of HDM-induced immune responses are incompletely understood. NC/Nga mice are an inbred strain that is more susceptible to HDM and develops more severe dermatitis than other strains. Using whole-exome sequencing, we found that NC/Nga mice carry a stop-gain mutation in Clec10a, which encodes a C-type lectin receptor, Clec10a (MGL1/CD301a). The repair of this gene mutation using the CRISPR-Cas9 system ameliorated HDM-induced dermatitis, indicating that the Clec10a mutation is responsible for hypersensitivity to HDM in NC/Nga mice. Similarly, Clec10a -/- mice on the C57BL/6J background showed exacerbated HDM-induced dermatitis. Clec10a expressed on skin macrophages inhibits HDM-induced Toll-like receptor 4 (TLR4)-mediated inflammatory cytokine production through the inhibitory immunoreceptor tyrosine activating motif in its cytoplasmic portion. We identified asialoglycoprotein receptor 1 (Asgr1) as a functional homolog of mouse Clec10a in humans. Moreover, we found that a mucin-like molecule in HDM is a ligand for mouse Clec10a and human Asgr1. Skin application of the ligand ameliorated a TLR4 ligand-induced dermatitis in mice. Our findings suggest that Clec10a in mice and Asgr1 in humans play an important role in skin homeostasis against inflammation associated with HDM-induced dermatitis.

DOI： 10.1126/sciimmunol.aax6908

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2019.3659

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2019.3658

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The multinational phase 3 CheckMate 238 trial compared adjuvant therapy with nivolumab versus ipilimumab among patients with resected stage III or IV melanoma (N = 906). In this Japanese subgroup analysis of CheckMate 238 (n = 28; nivolumab, n = 18; ipilimumab, n = 10), both the 12- and 18-month recurrence-free survival rates were 56% for nivolumab and 30% for ipilimumab (hazard ratio, 0.66; 97.56% confidence interval, 0.19-2.24; P = 0.4390). No new safety signals were reported for Japanese patients. Results were consistent with those from the CheckMate 238 global population, indicating that nivolumab has the potential to be a treatment option for Japanese patients with resected melanoma who are at high risk of recurrence.

DOI： 10.1111/1346-8138.15103

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.15084

PubMed

researchmap

Language：English  

Some bone lesions are reported to mimic bone metastasis on imaging tests. Herein, we report a case of a 55-year-old Japanese man who presented with a skin tumor on the left lower extremity. He also had a history of recurrent generalized cutaneous blister and erosion formation since childhood. His skin lesions were diagnosed as cutaneous squamous cell carcinoma complicated by recessive dystrophic epidermolysis bullosa. Magnetic resonance imaging of the left lower extremity detected multiple focal bone lesions mimicking bone metastases in the left femur and tibia. However, bone biopsy revealed that the bone lesions were osteonecrosis without tumor cells. We suggest that cancer-induced osteonecrosis should be included in the differential diagnosis of bone lesions suspected of being metastases on magnetic resonance imaging.

DOI： 10.2340/00015555-3303

PubMed

researchmap

Language：English  

DOI： 10.1111/all.13853

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/cas.14195

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1684/ejd.2019.3624

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population. In addition, drug resistance sometimes abrogates the persistent efficacy of combined therapy with BRAF and MEK inhibitors. Therefore, recent pre-clinical study-based clinical trials have attempted to identify optimal drugs (e.g., immune checkpoint inhibitors or histone deacetylase (HDAC) inhibitors) that improve the anti-melanoma effects of BRAF and MEK inhibitors. In addition, the development of novel protocols to avoid resistance of BRAF inhibitors is another purpose of recent pre-clinical and early clinical trials. This review focuses on pre-clinical studies and early to phase III clinical trials to discuss the development of combined therapy based on BRAF inhibitors for BRAF-mutant advanced melanoma, as well as mechanisms of resistance to BRAF inhibitors.

DOI： 10.3390/cancers11091342

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2019.3573

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Pyrexia is the most common adverse event in patients with melanoma or other solid organ malignancies that are treated with the combination of dabrafenib and trametinib (combi-DT). Given the expanded indication for combi-DT, management of pyrexia is a high priority. No previous case series has revealed which blood markers reflect the course of pyrexia and there is no consensus on the management strategy for pyrexia. The current case series study describes the utility of neutrophil count (NC), neutrophil ratio (NR) and C-reactive protein (CRP) in 11 patients with metastatic melanoma and BRAF V600 mutations who experienced pyrexia during combi-DT in our department. We also described the clinical course of pyrexia episodes that were managed with the concomitant use of oral prednisolone and immediate withdrawal of combi-DT. Consequently, the analysis of 37 pyrexia episodes in 11 patients showed that the differences in NC, NR and CRP at the onset of pyrexia were significantly different from those at pyretolysis (P = 0.01, 0.006 and 0.03, respectively). Additionally, in the 24 pyrexia episodes treated with the concomitant use of oral prednisolone and the immediate withdrawal of combi-DT, the mean duration of pyrexia and the mean time to restart combi-DT were 3 and 6 days, respectively. Therefore, the blood markers that reflect the course of pyrexia during combi-DT may be helpful for the appropriate management of pyrexia; also, our management strategy for pyrexia successfully reduced the duration of pyrexia and did not require a long-term drug holiday. Further large-scale studies are required to verify our results.

DOI： 10.1111/1346-8138.14949

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17-producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs.

DOI： 10.1111/exd.13944

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2019.3586

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14747

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long-term follow up of a single-arm, open-label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post-hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment-related adverse events (TRAE), including select immune-related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the ORR was 66.7% (90% CI: 34.7, 88.3) for superficial spreading, 33.3% (90% CI: 11.7, 65.3) for mucosal, and 28.6% (90% CI: 10.0, 59.1) for acral lentiginous tumors. The median OS was 32.9 months, the 3-year OS rate was 43.5%, and the 3-year PFS rate was 17.2%. A long-term response was observed in all the tumor types. The most common TRAE included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long-term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type.

DOI： 10.1111/cas.14015

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Anti-programmed cell death protein 1 monoclonal antibodies (αPD-1mAbs) have been shown to be effective for advanced malignant melanoma. Treatment with αPD-1mAbs can also cause immune-related adverse events (irAEs). However, clinical predictive factors for treatment responses or irAE risk remain unclear. OBJECTIVE: To identify useful blood biomarkers for response and occurrence of irAEs with αPD-1mAbs treatment. METHODS: We retrospectively collected data from patients with melanoma treated with αPD-1mAbs at the University of Tsukuba Hospital. Clinical data including age, sex, clinical type, metastatic site, treatment course, blood laboratory tests, irAEs and treatment outcome were collected. RESULTS: Multivariate logistic regression analysis showed that increased baseline neutrophil-lymphocyte ratio (NLR) was significantly associated with poor response (odds ratio [OR]: 2.638, P = 0.0227, cutoff value = 2.8). Similarly, multivariate Cox regression analysis revealed that NLR at baseline were significantly associated with shorter progression survival (hazard ratio: 1.343, P = 0.0095). As for irAEs, logistic regression analysis revealed that baseline absolute eosinophil count was positively associated with occurrence of endocrine irAEs (OR: 1.601, P = 0.045, cutoff value = 240/μL). Additionally, a higher relative eosinophil count at 1 month was significantly correlated with occurrence of endocrine irAEs (OR: 1.229, P = 0.0296, cutoff value = 3.2%). CONCLUSION: Our results suggested that NLR > 2.8 could be a useful baseline biomarker for indicating poor response to αPD-1mAbs treatment and that absolute eosinophil count >240/μL at baseline and relative eosinophil count at 1 month >3.2% could be useful biomarkers to predict endocrine irAEs in patients receiving αPD-1mAbs.

DOI： 10.1093/jjco/hyy201

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1002/cam4.2110

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14680

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The American Joint Committee on Cancer (AJCC) 8th 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 7th and 8th 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 8th 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 7th and 8th 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 7th and 8th 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 7th and 8th Edition systems, we should be careful in managing Stage III disease since the survival curves of the 8th Edition staging were completely different from the 7th 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.

DOI： 10.1016/j.jdermsci.2019.04.003

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1684/ejd.2019.3497

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Morphea profunda refers to inflammatory and sclerotic lesions that start primarily from the deep dermis, subcutaneous fat and fascia. Its pediatric case published work is limited. Here, we report the case of an 8-year-old girl with a 5-year history of multiple subcutaneous nodules on her extremities and a right wrist joint contracture who had been previously diagnosed with juvenile idiopathic arthritis and treated with salazosulfapyridine, low-dose prednisolone (PSL) and methotrexate. We performed biopsies of two subcutaneous nodules, which revealed the typical morphology of morphea profunda. She was administrated a tapered course of oral PSL then cyclosporin A (CyA) for 20 weeks which completely resolved her joint contracture and subcutaneous nodules. We reviewed 11 previously reported cases of morphea profunda and found that some include circumscribed/linear morphea that develop into subcutaneous tissues, indicating that "classical" morphea profunda arising within the deep tissues has rarely been reported. Our report is the first to demonstrate the efficacy of CyA for treatment of morphea profunda, and the possibility of CyA as a treatment option to reduce oral steroid doses in juvenile cases.

DOI： 10.1111/1346-8138.14801

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14600

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14511

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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 higher in responders than in non-responders. In contrast, there were no significant differences in 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 identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

DOI： 10.3389/fmed.2019.00086

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background: There is no standard systemic therapy for unresectable cutaneous squamous cell carcinoma (ucSCC), although various chemotherapy regimens have been reported. In our department, concurrent chemoradiotherapy (CCRT) for ucSCC resulted in a 1-year survival rate similar to that of resectable cutaneous squamous cell carcinoma (cSCC). Treatment involves continued chemotherapy after CCRT. Here, we report the importance of continued chemotherapy after CCRT, based on treatment outcomes. Patients and Methods: We retrospectively evaluated 13 patients with ucSCC, assessing the overall survival, overall response rate (ORR), and disease control rate (DCR). Results: CCRT with continued chemotherapy resulted in an ORR of 84.6%, DCR of 92.3%, and 1-year survival rate of 75%. Of the 13 patients treated with CCRT with continued chemotherapy, 6 had no metastasis. The remaining 7 patients developed metastasis to other organs or lymph nodes beyond the regional lymph nodes, although most sites of metastasis were outside the irradiation area. Conclusion: We conclude that CCRT with continued chemotherapy was effective in treating the irradiation site (primary lesion and regional lymph nodes) and any organ metastasis, although, it is unclear for how long the treatment remains effective.

DOI： 10.3389/fmed.2019.00207

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The incidence of skin tumors has steadily increased. Although most are benign and do not affect survival, some of the more malignant skin tumors present a lethal threat if a delay in diagnosis permits them to become advanced. Ideally, an inspection by an expert dermatologist would accurately detect malignant skin tumors in the early stage; however, it is not practical for every single patient to receive intensive screening by dermatologists. To overcome this issue, many studies are ongoing to develop dermatologist-level, computer-aided diagnostics. Whereas, many systems that can classify dermoscopic images at this dermatologist-equivalent level have been reported, a much fewer number of systems that can classify conventional clinical images have been reported thus far. Recently, the introduction of deep-learning technology, a method that automatically extracts a set of representative features for further classification has dramatically improved classification efficacy. This new technology has the potential to improve the computer classification accuracy of conventional clinical images to the level of skilled dermatologists. In this review, this new technology and present development of computer-aided skin tumor classifiers will be summarized.

DOI： 10.3389/fmed.2019.00191

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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 not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.

DOI： 10.1371/journal.pone.0211135

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3416

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3411

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.jdermsci.2018.10.004

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Although recent clinical trials have revealed that immune checkpoint inhibitors significantly improved the overall survival (OS) of patients with advanced melanoma, these previous studies comprised mainly white populations, in which superficial spreading melanoma (SSM) and lentigo maligna melanoma are the major clinical types of melanoma. In contrast, Asians manifest a distinct clinicopathological type of melanoma from that of whites and show much higher frequencies of acral lentiginous melanoma (ALM) and mucosal melanoma, which have been shown to be less susceptible to immune checkpoint inhibitors. Because no comparative studies have been published showing improvement of OS by immune checkpoint inhibitors in Asian melanoma patients, we retrospectively collected the data for 45 melanoma patients treated with checkpoint inhibitors and 24 melanoma patients treated with chemotherapy alone before immune checkpoint inhibitors became available, and compared their OS. The results showed that the patients treated with immune checkpoint inhibitors had significantly better OS than did those treated with chemotherapy alone (P < 0.0001). Improved OS was observed in both the SSM and the ALM patients. In addition, multivariate Cox regression analyses revealed that use of immune checkpoint inhibitors was associated with favorable prognosis (P = 0.0001), indicating that use of immune checkpoint inhibitors is an independent factor for favorable survival. Our study showed that immune checkpoint inhibitors may also improve the prognosis of Asian melanoma patients.

DOI： 10.1111/1346-8138.14637

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Immune checkpoint blockade (ICB) induces a remarkable response in patients with certain cancers. However, the response rate is not yet satisfactory. Biomarkers that help physicians identify patients who would benefit from ICB need to be developed. Killer immunoglobulin-like receptors (KIRs) are a class of receptors that are mainly expressed by natural killer cells. KIR genotypes have been shown to influence the outcomes of patients with neuroblastoma and hematopoietic malignancies. KIRs may thus influence the clinical outcomes of melanoma patients receiving nivolumab. We aimed to identify the KIR genotype, or KIR/KIR-ligand combinations, which influence the outcomes of melanoma patients receiving nivolumab. We genotyped 112 melanoma patients who were treated with nivolumab for KIR and human leukocyte antigen. The clinical records of the patients were analyzed to determine if they showed a response to nivolumab, and whether or not they experienced adverse events. Our analysis showed that no KIR gene was associated with a response to nivolumab. The KIR/KIR-ligand combination did not correlate with a response to nivolumab. KIR genes were not predictive of experiencing adverse events of grade 2 or greater. We conclude that the KIR genotype or KIR/KIR-ligand genotype do not show predictive value in melanoma patients receiving nivolumab.

DOI： 10.1038/s41598-018-34044-z

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Skin grafts are frequently used for the reconstruction of skin defects, and optimal stabilization of the graft is essential for successful reconstruction. Although the tie-over technique has been widely used as a standard method in Japan, we sometimes encounter cases with significant graft loss due to suboptimal stabilization of the graft. Reported risk factors for increased graft loss include the following: defects of a large size, with muscle exposure, and located in the trunk and extremities. Recent studies have demonstrated the usefulness of negative-pressure closure (NPC) for the stabilization of skin grafts due to the uniform pressure it provides across the graft. Therefore, since March 2017, we have used NPC for skin graft stabilization in patients with defects in the trunk and extremities of more than 10 cm in size or with muscle exposure. We carried out a retrospective comparative study of the outcome of the conventional tie-over technique versus NPC. Mann-Whitney U-test revealed that NPC showed significantly higher graft survival rate than tie-over method (P = 0.0012). In addition, NPC showed a tendency toward shorter operative times (from skin graft harvest to the completion of the graft stabilization) than the tie-over method (P = 0.0931). These results suggest that NPC may be superior to the tie-over method for stabilization of skin grafts especially in large or muscle-exposing defects in the trunk or extremities.

DOI： 10.1111/1346-8138.14536

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14299

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jid.2018.03.1507

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3310

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3345

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14279

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.14275

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

OPINION STATEMENT: Melanoma is one of the most aggressive malignant skin tumors and its incidence has been increasing worldwide in recent decades. Among the four subtypes, acral lentiginous melanoma (ALM) shows the highest incidence in Asian countries, whereas ALM comprises only 1% of all melanomas in white populations. Early clinical diagnosis of ALM is essential, but early ALM lesions are often difficult to diagnose because the pigmentation of the lesions sometimes follows the skin marking of the palms and soles, resulting in an asymmetrical appearance and an irregular border in both ALM and benign melanocytic nevus. To overcome this difficulty, dermoscopy was introduced, and determination of the patterns by this method is essential for accurate clinical diagnosis of ALM. Although recent clinical trials have demonstrated that immune checkpoint inhibitors and BRAF/MEK inhibitors showed significantly improved overall survival of patients with advanced melanoma, ALM may be less susceptible to immune checkpoint inhibitors because of the poor immune response to the tumor. Therefore, strategies for enhancing the immune response to the tumor cells may be required when we apply immune checkpoint inhibitors in advanced ALM. In this context, imiquimod, dacarbazine, or interferon are possible therapies that may enhance the effectiveness of the immune checkpoint inhibitors. In addition to being known to have poor immunogenicity, ALM is also known to have infrequent BRAF mutation. Therefore, the majority of ALM patients may not benefit from therapy with BRAF/MEK inhibitors. However, some ALMs have mutations such as KIT and NRAS mutations, and therefore, targeted therapies may improve the survival of ALM patients in the future.

DOI： 10.1007/s11864-018-0560-y

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3267

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3292

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3285

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3278

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3293

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2018.3265

PubMed

researchmap

Language：English  

Our study suggested that surgical damage of the lymphatic system promotes tumor progression via impaired immune response. However, as pointed out by Valerio et al, lymph stasis is likely to induce immune stasis, resulting in not only enhanced tumor growth but also tumor generation. Although mechanisms of the tumor generation may not only include impaired immune response but also other factors induced by lymph stasis, we should avoid unnecessary lymphatic disruption in any surgeries and carefully consider the flap design to minimalize lymphatic disruption even in cases with benign tumors.

DOI： 10.1016/j.jdermsci.2018.02.011

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a therapeutic target in various cancers. Certain patients with advanced extramammary Paget's disease (EMPD) have also been reported to express HER2, which is therefore considered a therapeutic target for EMPD. However, an accurate methodology to determine HER2-positive EMPD has not been established. To assess the optimal methods for detection of HER2-positive EMPD, 73 EMPD samples were analyzed by immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), and the HER2 testing algorithm for breast cancer of the American Society of Clinical Oncology/College of American Pathologists, which combined the results of IHC staining and FISH. The results showed discordance in the rate of positive IHC staining and FISH results. While 68.6% (24/35) of the metastatic samples showed equivocal or positive IHC staining, only 37.1% (13/35) were positive by FISH. To assess the accuracy of these methods, the degree of HER2 expression detected by each method was correlated with the staining profiles of activated downstream signaling pathways involving phosphorylated p44/42 MAPK (Thr202/Tyr204) (p-ERK1/2) and phosphorylated AKT (Ser473) (p-AKT). Among 16 lymph node metastasis samples, all HER2-positive samples as determined by the testing algorithm stained positively for both p-ERK1/2 and p-AKT. On the other hand, 10-14.3% of the samples determined by FISH or IHC showed negative staining for p-ERK1/2 and p-AKT. The results showed that combining the results of IHC and FISH according to the HER2 testing algorithm is a useful method for accurately evaluating HER2-positive EMPD.

DOI： 10.1007/s12032-018-1154-z

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Both lymph nodes (LNs) and lymphatic channels from primary sites to regional LNs are critical for initiation of adaptive immunity. However, as LNs are common metastatic sites in skin cancers, LN biopsies or dissections are frequently performed. In addition, reconstructive skin flaps after tumor resection may damage lymphatic flow from primary sites to regional LNs. OBJECTIVE: This study was designed to investigate the effect on tumor progression by such surgeries. METHODS: We developed a mouse model that simulates LNs dissection or skin flap that blocks lymphatic flow from primary sites to regional LNs and monitored tumor progression. RESULTS: As a poor immunogenic tumor line, the growth of inoculated B16F10 melanoma into syngeneic C57BL/6 mice was not affected by these surgeries. However, the growth of the same cell line in allogenic Balb/c mice was accelerated while immune cell infiltration (CD4+ and CD8+ T cells) into the tumor was reduced by these surgeries. In addition, both cytotoxicity against B16F10 melanoma and numbers of apoptotic tumor cells were diminished by these surgeries. Similarly, tumor growth of the immunogenic MC38 cell line in syngeneic C57BL/6 mice was accelerated and immune cell infiltration and apoptotic tumor cells were reduced by these surgeries. CONCLUSION: These results strongly indicate that surgical damage of the lymphatic system may promote tumor progression via impaired adaptive immune response.

DOI： 10.1016/j.jdermsci.2017.12.016

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti-PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.

DOI： 10.18632/oncotarget.24509

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1684/ejd.2017.3192

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching. OBJECTIVE: Investigate the outcome of ipilimumab switching in Japanese patients. METHODS: We retrospectively collected 60 patients who were treated with ipilimumab after nivolumab from 9 institutes in Japan. Information of the primary tumor, treatment, response, irAE), and survival was collected. RESULTS: In our cohort, acral lentiginous and mucosal melanoma accounted for 53% of the cases. The most common reason for initiating ipilimumab was disease progression (93%). Median interval from the last nivolumab administration to first ipilimumab administration was 29days. Only 38% of patients completed 4 injections of ipilimumab. The best overall response was 3.6%. IrAE occurred in 78% of patients and 70% of those were of grade 3/4 (G3/4) and 31% of patients experienced 2 or more irAEs. An within interval of 28days or less between the last nivolumab administration and ipilimumab administration was correlated with the development of G3/4 pyrexia and 3 or more irAEs, but irAE occurrence did not affect survival. Multivariate analysis showed that endocrine irAE (relative risk=0.22, P=0.015) and skin irAE (relative risk=2.78, P=0.048) were significant factors associated with survival. CONCLUSION: In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated.

DOI： 10.1016/j.jdermsci.2017.10.009

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

DOI： 10.3389/fonc.2018.00530

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I). Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy.

DOI： 10.3389/fonc.2018.00003

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The most widely accepted treatment for cutaneous angiosarcoma (CAS) is wide local excision and postoperative radiation to decrease the risk of recurrence. Positive surgical margins and large tumors (T2, >5 cm) are known to be associated with poor prognosis. Moreover, T2 tumors are known to be associated with positive surgical margins. According to previous reports, the majority of CAS patients in Japan had T2 tumors, whereas less than half of the patients in the studies from western countries did so. Consequently, the reported 5-year overall survival of Japanese CAS patients without distant metastasis was only 9%, lower than that for stage-IV melanoma. For patients with T2 tumors, management of subclinical metastasis should be considered when planning the initial treatment. Several attempts to control subclinical metastasis have been reported, such as using adjuvant/neoadjuvant chemotherapy in addition to conventional surgery plus radiation. Unfortunately, those attempts did not show any clinical benefit. Besides surgery, new chemotherapeutic approaches for advanced CAS have been introduced in the past couple of decades, such as paclitaxel and docetaxel. We proposed the use of chemoradiotherapy (CRT) using taxanes instead of surgery plus radiation for patients with T2 tumors without distant metastasis and showed a high response ratio with prolonged survival. However, this prolonged survival was seen only in patients who received maintenance chemotherapy after CRT, indicating that continuous chemotherapy is mandatory to control subclinical residual tumors. With the recent development of targeted drugs for cancer, many potential drugs for CAS are now available. Given that CAS expresses a high level of vascular endothelial growth factor (VEGF) receptor, drugs that target VEGF signaling pathways such as anti-VEGF monoclonal antibody and tyrosine kinase inhibitors are also promising, and several successful treatments have been reported. Besides targeted drugs, several new cytotoxic anticancer drugs such as eribulin or trabectedin have also been shown to be effective for advanced sarcoma. However, most of the clinical trials did not include a sufficient number of CAS patients. Therefore, clinical trials focusing only on CAS should be performed to evaluate the effectiveness of these new drugs.

DOI： 10.3389/fonc.2018.00046

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Pyoderma gangrenosum (PG) is a chronic inflammatory disease of unknown cause that presents as an inflammatory and ulcerative disorder of the skin. PG is often associated with an underlying systemic disease. However, the frequencies of the underlying diseases are unclear in Japanese patients. In this retrospective, observational study, all patients diagnosed with PG who visited dermatology departments of nine regional hospitals in and around Ibaraki Prefecture were collected from 1982 to 2011 or 2014. The diagnoses of PG were based on the characteristic clinical and histological appearances and ruling out of infection. Sixty-two PG patients, including 29 males and 33 females, were identified. The ages of onset were 16-89 years, and the mean age was 50.2 years. Fifty (80%) of the 62 patients presented with an ulcerative PG, and the lower leg was the most common site (74%). Forty-six (74%) PG patients had underlying diseases. The most frequent was ulcerative colitis (32%), followed by myelodysplastic syndrome (11%), rheumatoid arthritis (6%) and aortitis syndrome (5%). For treatment, 54 cases (87%) received systemic corticosteroids and 10 received additional treatment with cyclosporin. There was no significant correlation between underlying diseases and response to the initial treatment. Multivariate analysis revealed that the number of affected sites negatively correlated with successful initial treatment. Fifteen (24%) of the 62 cases relapsed. In conclusion, ulcerative colitis and hematological disorders were frequently associated with PG while approximately a quarter of the cases were idiopathic.

DOI： 10.1111/1346-8138.13937

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.13979

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest. OBJECTIVE: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC). RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab.

DOI： 10.1016/j.jdermsci.2017.07.007

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jns.2017.08.014

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Most patients with head and neck skin tumors present with normal facial nerve function. A common treatment strategy for these patients is facial nerve preservation surgery, although the degree to which the nerve is successfully preserved is still unclear. Data on the incidence and recovery of facial nerve dysfunction are woefully lacking in the field of dermato-oncology. METHODS: In 23 patients with normal preoperative facial nerve function, we retrospectively reviewed twenty-six head and neck surgical interventions that included facial nerve exposure and protection, focusing particularly on the differences in outcome between intraparotid and extraparotid exposure of the facial nerve branches. RESULTS: Eleven of the 26 cases (42.4%) developed transient paresis, but only one (3.8%) developed permanent paresis. Of 41 dissected facial nerve branches, 14 developed transient paresis (34.1%) and one, a marginal mandibular branch, developed permanent paresis (2.4%). The branches most susceptible to developing paresis were the temporal (4/6 branches, 66.7%) and marginal mandibular branches (8/17 branches, 47.1%). Although the rate of paresis was higher, and ensuing recovery period slightly longer in the extraparotid dissection group compared to the intraparotid dissection group, there were no statistically significant differences between the two groups. The extraparotid and intraparotid rates of paresis were 48% (11/23 branches) and 21.1% (4/19 branches), respectively, P = 0.139; and the average recovery periods were 10.3 and 9.3 weeks, respectively, P = 0.64. CONCLUSIONS: The functional outcome, regardless of the different sites of facial nerve exposure, was almost always either complete facial nerve sparing or transient dysfunction that resolved within 6 months.

DOI： 10.1007/s10147-017-1148-4

PubMed

researchmap

Language：English  

DOI： 10.1111/ddg.12590_g

PubMed

researchmap

Language：English  

DOI： 10.1111/ddg.12590

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The number of very elderly patients who require surgery for cutaneous tumors is increasing. However, there is limited information on the safety of cutaneous surgery in such patients. METHODS: To evaluate the safety of cutaneous surgery in patients 90 years of age and older, we retrospectively reviewed the elderly patients who underwent surgery for cutaneous tumors under local anesthesia. Consecutive patients 90 years of age and older and 75-80 years old were included in the elderly group and the control group. RESULTS: The elderly and control groups included 104 and 106 patients, respectively. The mean age of the patients was 93.4 years (range, 90-101 years) in the elderly group and 77.4 years (range, 75-80 years) in the control group. The preoperative performance status was significantly worse in the elderly group than in the control group (P < 0.001). The surgical time was not significantly different between the two groups (P = 0.09). The occurrences of intraoperative and postoperative complications were not significantly different between the two groups (P = 0.19 and P = 0.07, respectively). CONCLUSIONS: The result of the present study indicates that cutaneous surgery for very elderly patients 90 years of age and older is as safe as for patients ranging in age from 75-80 years old.

DOI： 10.1111/ijd.13597

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.

DOI： 10.1111/cas.13226

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.13466

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Cutaneous squamous cell carcinoma is the second common cutaneous cancer, especially in the elderly. Sentinel lymph node biopsy is generally performed in breast cancers and cutaneous melanomas to detect occult nodal metastases. The benefit of sentinel lymph node biopsy in improving cutaneous squamous cell carcinoma prognosis is doubtful. One hundred and sixty-nine patients who underwent treatment for cutaneous squamous cell carcinoma between 2004 and 2015, and who were followed up for at least 6 months or developed metastases within the follow-up period were included. Forty-nine patients underwent sentinel lymph node biopsy, whereas 120 patients did not, including 13 who exhibited clinical lymph node metastases before treatment. Of these 49 patients, nine (18.4%) presented with sentinel lymph node metastasis, which occurred after treatment in three (6.1%) of them (false-negative). Among the 107 patients who did not undergo lymph node biopsy, 12 (11.2%) developed post-treatment metastases. The metastasis-free and disease-specific survival rates were not significantly different in those who did or did not undergo sentinel lymph node biopsy. Patients with clinical lymph node metastases had a higher risk compared with those without. Patients with T2-T4 tumors had a higher risk compared with those with T1 tumors. When selecting for those with T2 tumors or greater, the same lack of relationship was observed. In conclusion, in this small retrospective cohort, in patients with cutaneous squamous cell carcinoma, there were no significant differences in metastasis-free and disease-specific survival rates between those who did or did not undergo sentinel lymph node biopsy, regardless of T staging.

DOI： 10.1111/1346-8138.13577

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jdermsci.2016.12.019

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

After 4 weeks of the last dose of nivolumab, a 59-year-old man with stage IV melanoma was subject to treatment with ipilimumab. After 5 weeks, the patient developed severe hepatitis, showing markedly elevated levels of both aspartate aminotransferase and alanine aminotransferase (>2000 U/l). Using pulse steroid therapy with 1000 mg/d of methylprednisolone, liver function initially improved, but then deteriorated upon dosage reduction. Subsequently, mycophenolate mofetil (MMF) was administered at a dose of 2 g/d in addition to the corticosteroid, which resulted in aspartate aminotransferase and alanine aminotransferase levels gradually improving to grade 1, and the corticosteroid dose was successfully reduced to 0.5 mg/kg/d of oral prednisolone. Liver function then remained stable when MMF was tapered. In conclusion, the use of MMF improved liver function in this patient with steroid-refractory hepatitis induced by immune checkpoint inhibitor administration.

DOI： 10.1093/jjco/hyw167

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047, respectively). At the 20-week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.

DOI： 10.1111/1346-8138.13520

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n D 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNg stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p D 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) D 0.38, p D 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFN gamma expression. In vitro stimulation with IFN gamma increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with antiPD-1 antibodies could be a new therapeutic option for CAS.

DOI： 10.1080/2162402X.2016.1253657

Web of Science

Scopus

researchmap

Other Link： http://orcid.org/0000-0003-2196-7600

Language：English   Publishing type：Research paper (scientific journal)  

Recent studies have reported the overexpression of human epidermal growth factor receptor 2 (HER2) in primary extramammary Paget disease (EMPD). These results indicate that therapies that target HER2 may be useful in treating metastatic EMPD, for which the prognosis is poor. However, there is limited information on the expression and gene amplification of HER2 in metastatic EMPD. Twenty-six corresponding lymph node metastatic sites of primary EMPD underwent immunohistochemical evaluation of HER2 protein overexpression. In cases of HER2 protein overexpression, further analysis into the amplification of the HER2 gene was undertaken using dual colored in situ hybridization. In the corresponding lymph node metastasis of EMPD, HER2 protein overexpression and gene amplification were detected in 38 % and 19 % of cases, respectively. In 22 out of 26 cases (85 %), there were no differences in HER2 protein overexpression between the primary tumors and the corresponding lymph node metastasis (kappa coefficient 0.65). Likewise, HER2 gene amplification status was concordant in 92 % of cases (kappa coefficient 0.75). HER2 status is in good overall concordance between primary tumors and the corresponding metastatic sites. As there was a discrepancy in a minority of cases, HER2 status should be evaluated at both the primary and the metastatic sites, whenever possible.

DOI： 10.1007/s10585-016-9804-z

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although extramammary Paget disease (EMPD) usually appears as carcinoma in situ, it sometimes becomes invasive (iEMPD) and fatal. However, a TNM staging system for iEMPD has yet to be established. OBJECTIVE: The aim of this study was to establish a TNM staging system for iEMPD. METHODS: We retrospectively collected iEMPD patients treated at 12 institutes in Japan. Factors reported to be associated with survival such as distant metastasis, lymph node (LN) metastasis, and primary tumor status were evaluated using the log-rank test. RESULTS: We enrolled 301 iEMPD patients, of whom 114 had remote metastases (49 had both distant and LN metastasis; 2, distant metastasis only; and 63, LN metastasis only) and the remaining 187 patients had no remote metastasis. Distant metastasis (M1) showed worse survival (P<0.00001). In the analysis of the 250 patients without distant metastasis, LN metastasis also showed worse survival (P<0.00001). Among the patients with LN metastasis, 2 or more LN metastases (N2) showed worse survival than did single LN metastasis (N1, P=0.02). Lastly, in the analysis of the 187 patients without metastasis, tumor thickness of over 4mm or lymphovascular invasion showed worse survival (T2, P<0.05 and P<0.001, respectively). Patients with neither of these features were defined as T1. From these results, we propose this TNM staging system: stage I, T1N0M0; stage II, T2N0M0; stage IIIa, anyTN1M0; stage IIIb, anyTN2M0; stage IV, anyTanyNM1. Other than stages II and IIIa, each stage had a statistically distinct survival curve. CONCLUSION: We propose a TNM staging system for EMPD using simple factors for classification that could provide important prognostic information in managing EMPD. However, accumulation of more patient data and further revision of the system are required.

DOI： 10.1016/j.jdermsci.2016.06.004

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Axillary lymph node dissection (ALND) has been recommended to include levels I-III for melanoma patients who have evidence of metastasis in the axillary sentinel lymph node (SLN). The extent of the subsequent axillary dissection is in debate. The objective of this study was to determine the frequency of metastasis of level III nodes in addition to that of level II nodes in this setting. METHODS: A multi-institutional retrospective study was undertaken in 14 melanoma treatment centers in Japan. RESULTS: Between 2007 and 2012, 69 patients with involved axillary SLNs underwent a subsequent ALND and 55 underwent level I and II dissections. Level III metastatic nodes, which is our primary endpoint, were seen in only 1 patient (1.5 %). The level II metastatic rate was 4.4 %. CONCLUSIONS: Our study sample size was small, but melanoma patients with positive SLN rarely had level III disease, suggesting that level III dissection may be unnecessary. We also found that level II metastasis was not so frequent. More evidence is needed to standardize the extent of ALND and to identify the patients who would have the most benefit with undergoing level II dissection for positive axillary SLNs.

DOI： 10.1007/s10147-015-0944-y

PubMed

researchmap

Language：English   Publisher：MEDKNOW PUBLICATIONS & MEDIA PVT LTD  

Seborrheic keratoses (SKs) are common epidermal tumors composed of benign keratinocytes. Malignant skin tumors including basal cell carcinoma (BCC) rarely arise within SKs. We report a rare case of an 82-year-old man with nodulocystic BCC that appeared at the center of a scaly hyperpigmented SK that had been presented for more than 10 years. It was histologically confirmed that CK19-positive BCC arose directly from the wall of the pseudohorn cyst, a part of the SK. Nodular and/or cystic BCC also rarely arise within SKs while the most common histologic type of BCC within SKs is the superficial type. Careful observation of SKs is important even though it is rarely a background condition for malignant transformation.

DOI： 10.4103/0019-5154.185720

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first-line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1-year overall survival rate determined by the Kaplan-Meier method was 75.0%. All adverse effects were manageable and no treatment-related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first-line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.

DOI： 10.1111/1346-8138.13200

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5°C after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible.

DOI： 10.1093/jjco/hyw036

PubMed

researchmap

Language：English  

Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment. We found that, in addition to the PD-L1 (p = 0.03), expression levels of PD-1 ligand-2 (PD-L2), granzyme A (GZMA) and human leukocyte antigen-A (HLA-A) in the pre-treatment tumors were significantly higher (p = 0.04, p = 0.01 and p = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of CD8, GZMA and perforin 1 (PRF1) expression levels as well as increased ratio of TBX21/GATA3, suggesting dominancy of helper T cell type 1 (Th1) response to type 2 (Th2) response. T cell receptor β (TCR-β) repertoire analysis revealed oligoclonal expansion of tumor-infiltrating T lymphocytes (TILs) in the tumor tissues of the responders. Our findings suggest that melanoma harboring high PD-1 ligands (PD-L1 and PD-L2), GZMA and HLA-A expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.

DOI： 10.1080/2162402X.2016.1204507

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Inc.  

Inguinal lymph node dissection (ILND) for skin cancer is associated with a high incidence of wound complications. The traditional skin approaches are associated with a high risk of wound/flap necrosis of the inguinal skin, which leads to wound dehiscence and wound infection. We report a novel approach for ILND without inguinal skin incision for patients with invasive extramammary Paget disease (EMPD) to minimize the wound complications inherent in conventional ILND. We totally performed this procedure in 3 patients with invasive EMPD with inguinal nodal metastases. No patient had complications, including flap necrosis, wound dehiscence, or wound infection. Our novel surgical approach would retain the vascular supply because there was no inguinal skin incision, preventing postoperative wound complications. In addition, ILND was easily performed with satisfactory exposure of the surgical field. However, the number of patients was small and the follow-up period was short. Further evaluation of a larger case series with longer follow-up is essential to investigate the effect, safety, and indications for this novel approach.

DOI： 10.1111/dth.12256

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1016/j.ajpath.2015.09.002

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The importance of the genetic background of melanoma cells to the individual susceptibility to treatment has become apparent. In Caucasians, BRAF mutations are frequently detected in lesions on the skin of younger patients compared to NRAS and KIT mutations. However, clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations have not been fully evaluated in East Asians. OBJECTIVE: To clarify clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. METHODS: Clinical data were retrospectively collected from 11 hospitals in Japan. BRAF, NRAS and KIT mutations were evaluated with polymerase chain reaction and Sanger sequencing. The relationships between these gene mutations and pathological and clinical findings were analyzed. RESULTS: The number of cases examined was 171 (primary: 135, metastases: 11, paired: 25), and all were Japanese patients. The detection rates of BRAF, NRAS and KIT mutations were 30.4%, 12.3% and 12.9%, respectively. Compared with the wild type, the presence of BRAF mutations was significantly associated with younger age (median, 50.0 years vs. 70.0 years, p<0.001). BRAF mutation was frequently detected in the lesions of the scalp (80%; 4/5), trunk (72.0%; 18/25), extremities (56.7%; 17/30) and neck (44.4%; 4/9), and the least prevalent were the face (22.2%; 2/9), nail (12.5%; 3/24), palm or sole (8.9%; 4/45) and mucosa (0%). NRAS mutations were prevalent in the face (33.3%) and palm or sole (20.0%), and the median age of these patients was 70.5 years. A KIT mutation was observed in the nail apparatus (25%), palm or sole (15.6%) and mucosa (18.2%). The median age of the patients with a KIT mutation was 63.0 years. Heterogeneity of mutations between primary and metastatic lesions was detected in six of 25 cases (24%). Solar elastosis was identified in 12 of 71 cases (15.3%), among which four cases harbored BRAF(V600E) (2 cases), BRAF(V600K), NRAS(Q61K) or NRAS(Q61L), respectively. CONCLUSION: Some clinical characteristics associated with BRAF, NRAS and KIT mutations were observed in Japanese patients, and we observed both similarities to and differences from those of Caucasians. Our findings could provide useful information in efforts to clarify the tumor genesis of malignant melanomas.

DOI： 10.1016/j.jdermsci.2015.07.012

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Subungual melanomas (SUM) are rare, and amputation is often required. Non-amputative wide local excision (WLE) of the nail unit with the periosteum of the distal phalanx, followed by skin graft, has been accepted for in situ or SUM of 0.5 mm or less thickness. However, previous reports have included a limited number of cases, and not all more than 0.5-mm thick SUM exhibit invasion or attachment to the distal phalanx. The aim of the present study was to investigate the local recurrence and prognosis for in situ, minimally invasive and invasive SUM that were treated using WLE. We retrospectively reviewed 50 patients with in situ (n = 48) or minimally invasive SUM (n = 2) (in situ or minimally invasive group) and 12 patients with more than 0.5-mm thick invasive SUM (invasive group) who were treated using WLE. All patients survived the follow-up period (24-207 months), although four patients with in situ SUM experienced local recurrence at the lateral margin and re-excision was required. In the invasive group, no patients experienced local recurrence, although one patient (8.3%) developed nodal metastasis at 86 months and regional lymph node dissection was required. WLE may provide acceptable local control for in situ and intermediate thickness SUM, without compromising the vital prognosis. However, a larger randomized prospective study with long-term follow up is required to evaluate adequately the risks associated with a non-amputative WLE for in situ and invasive SUM.

DOI： 10.1111/1346-8138.12923

PubMed

researchmap

Language：English  

DOI： 10.1111/ddg.12630

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although extramammary Paget's disease (EMPD) mostly presents as intraepithelial carcinoma, we sometimes encounter patients with invasive EMPD (iEMPD) who have lymph node metastasis and may develop distant metastasis. Although sentinel lymph node biopsy (SLNB) is widely accepted for various cancers, there is no large study that has assessed its role in iEMPD. OBJECTIVE: The main objective of this study is to assess the role of SLNB in patients with iEMPD. MATERIALS AND METHODS: We retrospectively collected data on 151 iEMPD patients treated from 1998 to 2012 in 11 institutes in Japan. All 151 patients received curative surgery for their primary tumor and none of them had distant metastasis. SLNB was performed on the 107 patients without lymphadenopathy to determine their LN status. The 44 other patients with lymphadenopathy underwent one of the following procedures to determine their LN status: SLNB in 22 cases, immediate LN dissection in 21, and LN biopsy in 1. RESULTS: Compared to those without lymphadenopathy, patients with lymphadenopathy had advanced primary tumors (nodule in the primary tumor, thicker tumor, deeper invasion level, and lymphovascular invasion). The rate of LN metastasis in patients with lymphadenopathy was 80%, compared to 15% in patients without lymphadenopathy who underwent SLNB. Compared to those with negative SLN, patients with positive SLN had advanced primary tumors (nodule in the primary tumor, deeper invasion level, and lymphovascular invasion). Multivariate analysis revealed that dermal invasion (odds ratio 5.8, p=0.04) and lymphovascular invasion (odds ratio 18.0, p=0.0023) were independent factors associated with SLN positivity. Notably, there was no difference in survival between patients with or without SLN metastasis (p=0.71). On the other hand, patients with lymphadenopathy showed worse survival than those with positive SLN (p=0.045). CONCLUSION: Clinical lymphadenopathy was strongly correlated with pathological LN metastasis and also associated with worse survival than absence of lymphadenopathy. The rate of occult LN metastasis detected by SLNB was 15%. Survival was not affected by SLN status even when an advanced primary tumor was present in patients with positive SLN. Our results raise the possibility that SLNB and subsequent LN dissection improved the survival of patients with early stage lymphatic spread. Our study indicates that SLNB should be considered for iEMPD if lymphadenopathy is not apparent.

DOI： 10.1016/j.jdermsci.2015.03.014

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.12705

PubMed

researchmap

Language：English  

DOI： 10.1111/ddg.12416

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Basal cell carcinoma (BCC) is a common malignant skin tumor. However, BCC that arise at the umbilicus is rare. We present three cases of umbilical BCC. Each BCC was excised at a different depth level, and all deep surgical margins were negative. All patients had no evidence of local recurrence or metastasis during the follow-up periods (12, 24, and 52 months). Reviewing the reported cases of umbilical BCC, the BCC cells did not seem to invade into the umbilical scar in most cases, and the deepest invasion levels of tumor cells were up to the middle layer of the subcutaneous tissue. However, the dermatological surgeons have to consider the possibility of surgical excision down to and including the umbilical attachment to the peritoneum, and intraoperative margin assessment should be necessary to avoid the risk of excessive or incomplete excision.

DOI： 10.1111/1346-8138.12640

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To show the efficacy of taxane-based chemotherapy for the treatment of cutaneous angiosarcoma. METHODS: A case-control study comparing patients who received taxanes without wide local excision (group A, n = 5) and patients who received conventional surgery-based therapy (group B, n = 8) in one university hospital in eastern Japan. Data were collected from a total of 13 patients with cutaneous angiosarcoma treated from November 1997 through July 2009. RESULTS: Group A received taxanes: four patients received docetaxel, and one patient received paclitaxel. Radiation was used concomitantly in two patients. Marginal local excision was performed in two patients. Group B received wide local excision followed by radiation (six patients), docetaxel (three patients), and interleukin-2 (two patients). No patients in group A had local recurrence, whereas five out of the eight patients in group B did (p < 0.05, chi-square test). Median overall survival was 31 months in group A and 10 months in group B. Estimated overall survival using the Kaplan-Meier method was significantly longer in group A (p < 0.05, log-rank test). CONCLUSION: In our series, taxane-based chemotherapy was superior to conventional surgery-based therapy. Our results indicated that taxane regimens without mutilating surgery offered both local control and prevention of metastasis, which led to prolonged survival.

DOI： 10.3109/09546634.2012.754839

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Subungual melanoma (SUM) is rare and represents approximately 2-3% and 20% of all cutaneous melanomas in Caucasians and Asians, respectively. Amputation has usually been performed for invasive SUM; however, not all invasive SUMs invade or attach to the distal phalanx. To investigate the possibility of non-amputative surgery for patients with invasive SUM, the distances between the deepest base of the melanoma cells and the bony surface in the surgical specimens of invasive SUM were measured. Thirty surgical specimens of invasive SUM were retrospectively reviewed. The contents of the specimens were as follows: 14 first toes, 10 thumbs, three second fingers, two third fingers, and one fifth finger. Four specimens showed bone invasion, and the tumor was attached to the bone in four specimens. The tumor-to-bone distance exceeded 0.9 mm in all the specimens with thicknesses <4 mm. In the non-ulcerated SUMs (nine specimens), only one SUM specimen showed bone attachment. There was a higher likelihood of bone attachment or invasion when tumor thickness (TT) exceeded 4 mm (Pearson chi-square test, P = 0.009; Fisher exact test, P = 0.004; student t test, 0.033). Univariate and multivariate analysis also revealed that thick TT had a statistically significant affect (odds ratio 1.807 and 1.865, 95% CI 1.11-3.01 and 1.11-3.13, P = 0.023 and 0.018). Non-amputative surgery may be possible for SUM tumors that are of intermediate-thickness. However, there has been little evidence demonstrating survival with non-amputative surgery for invasive SUM. A large, randomized, prospective clinical study is required to address this issue.

DOI： 10.1111/1346-8138.12622

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Lipomas are common, benign, small-sized, soft-tissue tumors. However, giant lipomas are uncommon and the tumor size can cause pain and nerve compression syndrome. The axilla is an extremely rare location for development of giant lipomas. We report two cases of axillary giant lipoma. A 47-year-old man (case 1) and a 42-year-old woman (case 2) presented with a large mass in the axillary region. Case 2 had tenderness in the shoulder and numbness in the upper arm. Magnetic resonance imaging of each tumor showed a homogenous soft-tissue mass in the axillary region, suggestive of lipoma. In case 2, the tumor extended from the axilla to the supraclavicular region and split and compressed the neurovascular bundle. Each lesion was successfully excised surgically without serious complications and recurrence. In case 2, the tenderness and numbness disappeared. Histologically, each lesion was composed of multilobulated, mature adipose cells, which led to a diagnosis of benign lipoma. Axillary giant lipoma is preferably excised surgically to avoid damage caused by tumor compression to the major vessels or nerves, to offer better local control and to establish a correct final diagnosis.

DOI： 10.1111/1346-8138.12598

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.12482

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

B-Myb (Mybl2) is a member of the Myb gene family of transcription factors involved in the control of cell growth, differentiation, and apoptosis. The effects of B-Myb on keratinocyte proliferation and differentiation have not yet been clarified. The present study was performed to examine the role of B-Myb in proliferation and differentiation of the spontaneously immortalized human skin keratinocyte cell line HaCaT and normal human keratinocytes with formation of a stratified epidermoid structure in air-liquid interface three-dimensional culture. B-Myb was expressed specifically in undifferentiated normal keratinocytes and downregulated during differentiation. The constitutive overexpression of B-Myb in HaCaT cells during air exposure-induced differentiation resulted in an undifferentiated phenotype, i.e., thickening of the stratified layers, suppression of differentiation marker expression, and retention of proliferative activity with activation of cell cycle regulatory proteins in the S and G2/M phases. In contrast, suppression of B-Myb caused their downregulation and constrained proliferation with retention of differentiation capacity. These findings suggested that B-Myb plays an important role in maintenance of the undifferentiated phenotype of keratinocytes in the basal epidermal layer.

DOI： 10.1007/s00403-014-1450-1

PubMed

researchmap

Language：English  

DOI： 10.1111/ijd.12103

PubMed

researchmap

Language：English  

DOI： 10.1111/1346-8138.12414

PubMed

researchmap

Language：English  

DOI： 10.1111/j.1365-4632.2012.05671.x

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Western Division of Japanese Dermatological Association  

Adult-onset anaphylactoid purpura (AP) is known to be associated with malignancy. However, few reports have described the clinical differences between adult-onset AP with malignancy and that without malignancy. We retrospectively reviewed data from 19 adult-onset cases of AP between 2004 and 2012 in our department and categorized them into two groups to compare their clinical features and managements: a malignancy group (group A: 6 cases) and a non-malignancy group (group B: 13 cases). In group A, all the patients had solid tumors and 3 cases (50%) were diagnosed as AP at the time of or prior to the discovery of malignancy. There were no significant differences between the two groups in the incident of precursory infections, arthralgia, gastrointestinal symptoms, or widespread purpura ranging beyond the lower limbs. The incident of renal dysfunction was significantly higher in group A than in group B (P&lt
0. 05). There were no significant differences between the two groups in the level of serum IgA and ASO. In group A, systemic steroid therapy mainly applied to renal dysfunction. We should be aware of the possibility of underlying malignancy when we encounter adult-onset AP. Because of the high rate of renal dysfunction, careful observation is recommend for adult-onset AP patients with malignancy.

DOI： 10.2336/nishinihonhifu.76.487

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Proliferation and differentiation in the epidermis must be tightly regulated. This regulation is known to involve a range of transcription factors, including pituitary tumor transforming gene 1 (PTTG1), a ubiquitously distributed transcription factor that regulates keratinocyte proliferation and differentiation. Psoriasis is a common but refractory skin disorder, the pathophysiology of which is characterized by hyperproliferation and impaired differentiation in the epidermis. The present study was conducted to clarify the less well-known roles of PTTG1 in the pathophysiology of psoriasis, focusing on its relationship with tumor necrosis factor-α (TNF-α), which is a critical mediator of the disease. The levels of PTTG1 expression were increased in the psoriatic epidermis. Overexpression of PTTG1 resulted in the overproduction of TNF-α, and TNF-α itself had an inductive effect on PTTG1 expression, suggesting that their expression may involve autoinduction. Moreover, overexpression of PTTG1 involved augmented the expression of cyclin A and B1 proteins in both cultured keratinocytes and the psoriatic epidermis. Therefore, enhanced expression of PTTG1 in the psoriatic epidermis may result in aberrant regulation of the cell cycle and impaired differentiation via the interplay between PTTG1 and TNF-α.

DOI： 10.1038/jid.2013.189

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Mucoepidermoid carcinoma (MEC) usually originates from the salivary glands. However, there has been no report on mucoepidermoid carcinoma of the columella. In this study, we report the case of a high-grade MEC of the columella that was successfully reconstructed after surgical resection with bilateral nasolabial flaps set up in a sandwich shape and an auricular cartilage graft. A 66-year-old man presented with a nodule on the columella. Histological findings were suggestive of a high-grade mucoepidermoid carcinoma. Wide excision was performed, and the defects of the columella and the nasal floor were reconstructed with bilateral nasolabial flaps set up in a sandwich shape and an auricular cartilage graft. The postoperative cosmetic result was good with excellent tissue texture. The reconstructed columella had an appropriate, not bulky, width as well as satisfactory height and depth. This reconstructive technique is particularly useful for correcting the large defect of the columella with nasal septum and/or nasal floor defects.

DOI： 10.1111/1346-8138.12274

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT) that can be classified as acute or chronic. Characteristic cutaneous manifestations of acute GVHD, which generally occurs within 3 months following BMT, include maculopapular exanthema and perifollicular papular lesions. Psoriasiform skin eruption as a manifestation of acute GVHD is rare. We report the case of a 4-year-old boy who developed a generalized psoriasiform eruption shortly after undergoing an allogeneic BMT. Histologic features of both psoriasis and acute GVHD were present.

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2013.2064

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific regulatory mechanisms for activation and suppression of loricrin gene transcription in differentiated keratinocytes. Here, we identified a regulatory element in the proximal promoter region of the loricrin gene involved in suppression of its expression in keratinocytes. A database search indicated that this sequence contained a POU transcription factor binding motif. Electrophoretic mobility shift assay revealed that Oct-1, Oct-6, and Oct-11 actually bind to the motif. Constructs with point mutations in the POU-binding motif showed increased reporter activity, indicating that the POU factors negatively regulate loricrin gene transcription. Cotransfection experiments suggested that Oct-6 and Oct-11 suppress loricrin gene transcription in a cooperative manner with AP-1 and Sp1. Furthermore, in vitro experiments indicated that the Oct-6 and Oct-11 can physically associate with both AP-1 factors and Sp1/Sp3. These findings indicate that Oct-6 and Oct-11 contribute to the regulation of loricrin gene transcription via interaction with AP-1 factors and Sp1/Sp3.

DOI： 10.1007/s00403-013-1317-x

PubMed

researchmap

Language：English   Publisher：JOHN LIBBEY EUROTEXT LTD  

DOI： 10.1684/ejd.2013.2068

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The standard technique using lymphoscintigraphy, blue dye and a gamma probe has established a reliable method for sentinel node biopsy for skin cancer. However, the detection rate of cervical sentinel lymph nodes (SLN) is generally lower than that of inguinal or axillary SLN because of the complexity of lymphatic drainage in the head and neck region and the "shine-through" phenomenon. Recently, indocyanine green fluorescence imaging has been reported as a new method to detect SLN. We hypothesized that fluorescence navigation with indocyanine green in combination with the standard technique would improve the detection rate of cervical sentinel nodes. We performed cervical sentinel node biopsies using the standard technique in 20 basins of 18 patients (group A) and using fluorescence navigation in combination with the standard technique in 12 basins of 16 patients (group B). The mean number of sentinel nodes was two per basin (range, 1-4) in group A and three per basin (range, 1-5) in group B. The detection rate of sentinel nodes was 83% (29/35) in group A and 95% (36/38) in group B. The false-negative rate was 6% (1/18 patients) in group A and 0% in group B. Fluorescence navigation with indocyanine green may improve the cervical sentinel node detection rate. However, greater collection of data regarding the usefulness of cervical sentinel node biopsy using indocyanine green is necessary.

DOI： 10.1111/1346-8138.12158

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Non-melanoma skin cancer is the most frequently occurring type of cancer worldwide and is caused by epidermal carcinogenesis and malignant progression that involve dysregulated expression of proto-oncogenes and tumor suppressor genes. The proto-oncogene pituitary tumor-transforming gene 1 (PTTG1) is a ubiquitously expressed transcription factor that can promote enhanced proliferation of cultured epidermal keratinocytes. To investigate the potential roles of PTTG1 in epidermal carcinogenesis and malignant progression, the expression of PTTG1 was analysed by immunohistochemistry along with Ki67, keratin 10 (K10) and p53 in tissue samples of cutaneous squamous cell carcinomas (SCC), actinic keratoses (AK) and Bowen's disease (BD). Expression levels of PTTG1 were compared among these disease groups to test for correlations with proliferation, differentiation capacity or the existence of mutated tumor suppressor genes in each disease group. In each disease group, the expression levels of PTTG1 correlated positively with those of Ki67, although the differentiation status, measured by K10 expression, did not show any correlation. In contrast, the existence of mutated p53 proteins showed a positive correlation only in the SCC group. Moreover, the expression levels of PTTG1 in SCC did not correlate with known prognostic factors such as TNM staging or tumor thickness. These results suggest that PTTG1 may represent a proliferation marker associated with mutated p53 proteins but is not an informative predictor of poor clinical outcomes in SCC.

DOI： 10.1111/exd.12118

PubMed

researchmap

Language：English  

DOI： 10.1684/ejd.2013.1963

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Neurofibromatosis type I (NF1) is associated with typical hypervascular tumors, including neurofibroma, glioma, malignant peripheral nerve sheath tumors (MPNST) and glomus tumors. Previously, we and other groups reported that neurofibromas showed high-level expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor involved in neovascularization. However, the molecular mechanism underlying the upregulation of VEGF in neurofibromas remains unclear. In this study, we examined the effects of Nf1 gene silencing on VEGF expression in Schwann cell and non-Schwann cell line and the upstream mTOR-HIF-1α - VEGF pathway in Schwann cell line. The results indicated that Nf1 gene silencing by lentiviral-mediated RNA interference resulted in elevated expression of VEGF, HIF-1α and phosphorylated mTOR at the protein level. The results obtained from Nf1 gene silencing in murine Schwann cell line analogously suggest that NF1 gene haploinsufficiency in human tumor Schwann cells may directly elicit upregulation of VEGF expression without the tumor microenvironment by activation of the mTOR-HIF-1α - VEGF pathway. We also showed that interleukin-6 is upregulated in Nf1 gene knock-down Schwann cells at the protein level.

DOI： 10.1111/exd.12115

PubMed

researchmap

Language：English   Publisher：MEDKNOW PUBLICATIONS & MEDIA PVT LTD  

DOI： 10.4103/0378-6323.107659

Web of Science

PubMed

researchmap

Language：English  

DOI： 10.2340/00015555-1295

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Loricrin is a major component of the epidermal cornified cell envelope and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific regulatory mechanisms for activation of loricrin gene transcription in differentiated keratinocytes. Here, we identified a positive regulatory element in the proximal promoter region of the loricrin gene involved in activation of its expression in differentiated keratinocytes. A database search indicated that this sequence contained a GATA-3 binding motif. Constructs with point mutations in the GATA-3 binding motif showed decreased reporter activity, indicating that GATA-3 positively regulates loricrin gene transcription. Western blotting analysis indicated that GATA-3 is more abundant in differentiated than in undifferentiated keratinocytes. Cotransfection experiments indicated that GATA-3 activates transcription of the loricrin gene in a cooperative manner with c-Fos and Sp1. These findings indicate that GATA-3 contributes to keratinocyte differentiation-specific activation of loricrin gene transcription via interaction with c-Fos and Sp1.

DOI： 10.1111/exd.12023

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The benefit of a sentinel lymph node (SLN) biopsy and adjuvant therapy for patients with thick (>4 mm) melanoma has not been well studied in the Asian population. We examined the benefit of an SLN biopsy and adjuvant therapy on prognosis in Japanese patients with thick melanoma. A review of the melanoma database collected from 26 institutions in Japan identified 291 patients with thick melanoma between 2005 and 2010. Univariate and multivariate analyses were performed to evaluate the factors predictive of the overall survival (OS) and the disease-free survival (DFS). Of the 242 patients with thick melanoma who underwent an SLN biopsy, the results for 96 (40%) were positive. On multivariate analysis, increased Breslow thickness (relative risk, 1.11; 95% confidence interval, 1.05-1.17; P=0.0002) and SLN metastasis (2.14; 1.04-4.43; P=0.040) were associated with a poor OS. Increased Breslow thickness (1.11; 1.04-1.18; P =0.0018), ulceration (3.11; 1.25-7.72; P=0.014), satellitosis (3.89; 1.62-9.31; P=0.0023), and SLN metastasis (2.24; 1.16-4.36; P=0.017) were associated with DFS. Adjuvant chemotherapy had no impact on either OS or DFS. Adjuvant use of a monthly dermal injection of interferon-β (IFN-β) was associated with a improvement in both OS (0.34; 0.17-0.67; P=0.0022) and DFS (0.42; 0.20-0.86; P=0.018). An SLN biopsy provided useful prognostic information and the adjuvant use of IFN-β improved both OS and DFS in Japanese patients with thick melanoma. These results were consistent with those of previous studies carried out on a white population. Therefore, we suggest that an SLN biopsy and adjuvant IFN should be considered for patients with thick melanoma irrespective of the Breslow thickness or ethnicity.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Giant congenital blue nevus (GCBN) is rare and usually occurs on the scalp. Malignant blue nevus (MBN) is also rare and has a poor prognosis. We report a case of MBN arising in a GCBN on the back. There have been three previous reports of MBN associated with GCBN on the trunk; our case had the earliest onset of MBN arising in a GCBN.

DOI： 10.1111/j.1525-1470.2011.01662.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

It is extremely rare that swelling of pelvic lymph nodes is found when inguinal lymph nodes contain only a microscopic amount of disease without enlargement. A 69-year-old woman with malignant melanoma of the heel was treated with a wide, local excision. About four years after the initial operation, a left common iliac node was enlarged although all lymph nodes in the obturator, external iliac and inguinal regions were not enlarged. Rapid pathological examination of the resected swollen lymph nodes revealed involvement of malignant melanoma, and left pelvic and groin dissection was undertaken. Histologically, multiple lymph node metastases were found in the common iliac, obturator, external iliac and inguinal regions. This case indicates that sentinel lymph node biopsy may be worth considering even for stage IA malignant melanoma of the lower extremity.

DOI： 10.1089/lrb.2012.0006

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Angiosarcoma is an uncommon malignancy, which spread out from the endothelial cells of vessels. Scalp angiosarcoma with cervical lymph node metastasis is particularly rare. This article describes a rare case of angiosarcoma of the scalp, presenting as neck inflammation. Imaging procedures such as computed tomography (CT), magnetic resonance image (MRI) and ultrasonography (US) were not sufficient to diagnose this case. A needle biopsy provided an effective and accurate diagnosis of cervical lymph node metastasis. Additional observation and physical examination was required to diagnose the origin of the primary cancerous lesion. Once the angiosarcoma diagnosis was confirmed histologically, sequential weekly and monthly docetaxel (DTX) treatment was effective in preventing reoccurrence. Nonetheless, the optimization of angiosarcoma treatment remains a future goal. Although patients generally describe pain and swelling at the primary lesion site, this patient complained only of painful neck inflammation, without any indication of pain or swelling of the scalp. A revised diagnostic protocol should note that cervical lymph node metastasis of unknown primary origin may result from angiosarcoma of the scalp.

DOI： 10.1038/ijos.2012.36

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND OBJECTIVES: Although sentinel lymph node (SLN) biopsy using radioisotope (RI) and blue dye (BD) achieved a high detection rate, approximately 5% of melanomas with negative SLNs develop nodal metastasis. We tested a new lymphatic navigation method using indocyanine green fluorescence imaging (ICG-FI) to detect such "occult" SLNs. METHODS: Thirty-four skin cancer patients received SLN biopsy with the following three methods: RI (99Tc-tin colloid), BD (2% patent blue), and ICG (0.5% indocyanine green). Lymph nodes detected by any of the three methods were counted as SLNs. RESULTS: ICG-FI detected more SLNs in 8 out of the 34 cases (24%). The average numbers of SLNs detected by ICG-FI, RI, and BD were 2.18, 1.76, and 1.73, respectively. Interestingly, ICG-FI not only detected more SLNs in one basin (ICG-FI: 1.64, RI: 1.50, and BD: 1.51 SLNs per basin), but also detected additional SLNs in other basins (ICG-FI: 1.32, RI: 1.18, and BD: 1.15 basins per case). CONCLUSION: ICG-FI detected SLNs more efficiently than did the conventional methods, and these "occult" SLNs may offer an explanation for some false-negative cases. We recommend using ICG-FI in addition to a conventional method to reduce the risk of overlooking these "occult" SLNs.

DOI： 10.1002/jso.23045

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The epidermis is a self-renewing tissue, the homeostasis of which is dependent upon the tight balance between proliferation and differentiation based on appropriate regulation of the cell cycle. The cell cycle regulation is dependent on the interactions among a number of cell cycle regulatory molecules, including the pituitary tumor-transforming gene 1 (PTTG1), also known as securin, a regulator of sister chromatid separation and transition from metaphase to anaphase. This study was conducted to clarify the less-known functions of PTTG1 in the epidermis by the use of keratinocytes cultured under two-dimensional (2D) or three-dimensional (3D) conditions. Forced overexpression of PTTG1 caused upregulation of cyclin B1, cyclin-dependent kinase 1 (CDK1), and c-Myc, resulting in enhanced proliferation and suppression of early differentiation without apparent alterations in terminal differentiation, and the exogenous PTTG1 was downregulated in association with cell cycle exit. In contrast, depletion of PTTG1 caused their downregulation and constrained proliferation with retention of differentiation capacity. These findings suggested that PTTG1 could alter the proliferation status by modulating the expression levels of the other cell cycle regulatory proteins, and excess PTTG1 primarily affects early differentiation of keratinocytes under the stability regulation associated with cell cycle exit.

DOI： 10.1038/jid.2012.74

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Subcutaneous panniculitis-like T-cell lymphoma is an uncommon form of CD8-positive cytotoxic T-cell lymphoma of the skin that predominantly affects the subcutaneous tissue and is extremely rare in early childhood (&lt
3 yrs). Here, we present an early pediatric case with an indolent form of subcutaneous panniculitis-like T-cell lymphoma occurring at 12 months old. The subcutaneous nodules gradually disappeared spontaneously, and the girl showed excellent prognosis with no aggressive treatment. © 2012 Wiley Periodicals, Inc.

DOI： 10.1111/j.1525-1470.2011.01658.x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1684/ejd.2011.1536

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Inguinal lymphocele is a well-known complication of inguinal lymph node dissection. Isosulfan blue has been used to identify and treat lymphoceles arising from lymphatics injured during surgery of the groin. However, the preventive use at the time of lymph node dissection has not been reported. OBJECTIVES: We evaluated the potential role of intraoperative injection of isosulfan blue during inguinal lymph node dissection for the prevention of postoperative lymphocele. METHODS: We performed 43 conventional inguinal lymph node dissections (group A) and 7 inguinal lymph node dissections using isosulfan blue injection around the dissected inguinal region (group B) to identify lymphatic leakage intraoperatively. RESULTS: Lymphoceles were observed in 13 of 43 dissections (30.23%) in group A and in 0 of 7 dissections (0%) in group B. The number of detected injured lymphatics ranged from 0 to 6 (mean 3.3) in group B. The mean postoperative lymphatic drainage output was less in group B than in group A. The mean number of days of suction catheter insertion was 4.43 days in group B, and 7.98 days in group A. CONCLUSIONS: The technique during inguinal lymph node dissection presented herein is useful for the prevention of postoperative lymphocele.

DOI： 10.1002/jso.21989

PubMed

researchmap

Language：English  

DOI： 10.1111/j.1346-8138.2010.01097.x

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The retinoic acid receptor-related orphan receptor gammat (ROR(gamma)t) is a key transcription factor involved in the generation of T-helper 17 (Th17) cells, which mediate tissue inflammation and autoimmunity. However, recent studies indicated that less than half of all ROR(gamma)t(+) Talphabeta cells express IL-17, while the others are Foxp3(+) Talphabeta cells expressing IL-10. These observations raise questions regarding the role of ROR(gamma)t in the early differentiation process of T cells from haematopoietic stem cells. METHODS: To examine the role of RORyt in T cell differentiation, mice were reconstituted with ROR(gamma)t cDNA-transduced haematopoietic stem cells and the role of ROR(gamma)t in T cell differentiation was studied in a mouse bone marrow transplantation model in vivo. RESULTS: While the number of Th17 cells increased with the reduction in Thl cell number in transplanted mice, peripheral blood Foxp3(+) Talphabeta cell number also increased, which attenuated the severity of contact hypersensitivity on skin exposed to 2,4-dinitrofluorobenzene. The number of non-transduced Foxp3(+) regulatory T cells (Treg cells) also increased in these mice. CONCLUSION: These observations suggest that the enforced expression of ROR(gamma)t in haematopoietic stem cells induces differentiation of Thl7 cells and results in an increase in Foxp3(+) Treg cell number to limit self-tissue damage.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The linear arrangement of discoid lupus erythematosus is uncommon. Here, we report a 6-year-old Japanese girl with linear discoid lupus erythematosus following the lines of Blaschko on her face and neck. Topical tacrolimus treatment improved the eruptions. The present case also indicated the important role of epidermal and dermal cells as well as immune cells in the pathogenesis of cutaneous lupus erythematodes. © 2010 Wiley Periodicals, Inc.

DOI： 10.1111/j.1525-1470.2010.01249.x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Yin-Yang-1 (YY1) is a member of the GLI-Krüppel family of transcription factors, and both YY1 mRNA and protein expression have been identified in a number of different tissues and cell types suggesting that it is expressed both constitutively and ubiquitously. In epidermal tissue, however, we reported previously that YY1 protein is expressed at high levels in undifferentiated basal keratinocytes and is downregulated during differentiation toward the suprabasal layers. This differential expression pattern during keratinocyte differentiation suggests that YY1 may have an important role in regulating keratinocyte differentiation. In this study, we examined the role of YY1 in differentiation of the human keratinocyte cell line HaCaT using air-liquid interface three-dimensional culture. The constitutive overexpression of YY1 in HaCaT cells during air exposure-induced differentiation resulted in an undifferentiated phenotype, thickening of the stratified layers, suppression of differentiation marker expression, and retention of proliferative activity. These findings suggested that YY1 may have an important role in maintenance of the undifferentiated phenotype of keratinocytes in the basal epidermal layer, and that reduction of YY1 expression in the suprabasal layers may allow keratinocytes to differentiate and move toward the upper layers of the epidermis.

DOI： 10.1038/jid.2010.229

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recently, indocyanine green (ICG) fluorescence imaging has been reported as new method to detect sentinel lymph nodes (SLNs). However, high introduction costs limit its use. OBJECTIVE: The purpose of this study was to test an ICG fluorescence detection system constructed with parts commonly available on the market and to compare the SLN detection rate with that of the conventional combined dye and RI methods. METHODS: We constructed this system using a charge-coupled device camera and light-emitting diodes. RESULTS: We could construct our system at a cost of less than USD 1,600. This system could trace lymphatic channels through the skin and detect SLNs in 16 patients with skin cancer. However, SLNs in the neck were difficult to detect through the skin. CONCLUSION: Our system could be assembled at a reasonable cost and allowed us to detect SLNs efficiently. It may be used as an alternative to radiotracer for detecting SLNs located in the groin and axillary regions.

DOI： 10.1159/000327080

PubMed

researchmap

Language：English  

DOI： 10.1001/archdermatol.2010.179

PubMed

researchmap

Language：English  

DOI： 10.1111/j.1346-8138.2009.00711.x

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Common acquired skin diseases with a polygenic background, such as lichen planus, may show linear or segmental manifestations of underlying systemic skin disease. The linear arrangement in such cases is usually consistent with the lines of Blaschko. Happle summarized the various types of segmental arrangement of common polygenic diseases and proposed a novel designation of superimposed segmental dermatosis. Here, we report a unilateral linear dermatitis distributed along the lines of Blaschko on the leg, which was not self-healing and persisted for at least 6 years without complete remission, and was accompanied by preceding chronic prurigo on the extremities. Histological examination showed subacute spongiotic dermatitis and epidermal infiltration of CD4-positive cells. This case report presents a superimposed segmental dermatitis that arose based on systemic eczematous conditions, such as chronic prurigo.

DOI： 10.1684/ejd.2009.0678

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1016/j.bjps.2008.06.023

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

We have demonstrated that dendritic cells (DCs) genetically modified to express tumor-associated antigens (TAAs) with retroviral vectors elicit more potential anti-tumor effect than those loaded with peptides because they can prime antigen-specific CD4+ T cells resulting in production of tumor-specific antibody. In this study, we showed the importance of antigen presentation via a major histocompatibility complex (MHC) class II molecule in cancer immunity against non-membrane bound TAAs such as the melanoma antigen gp100 by using DCs derived from MHC class II-deficient mice (C2KO). DCs were prepared by transduction of gp100 cDNA into haematopoietic progenitor cells obtained from C2KO followed by differentiation with cytokines (C2KO-gp/DCs). When C2KO-gp/DCs were inoculated into immunocompetent mice, the mice scarcely primed the antigen-specific Th1 cells and developed fewer CD8 T cells than did those inoculated with transduced DCs prepared from normal mice. The attenuated anti-tumor effect was also confirmed in a postimmunization setting where, while two of eight control mice eradicated the pre-existing melanoma cell line B16 (25%), no mice inoculated with C2KO-gp/DCs did. These results suggested not only the limitation of current protocols using MHC class I-restricted tumor peptides but also the usefulness of DCs expressing gp100 in vaccine therapy against melanoma.

DOI： 10.1111/j.1600-0625.2008.00802.x

PubMed

researchmap

Language：English  

DOI： 10.1016/j.jaad.2008.08.002

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with generation of reactive oxygen species. Cellular antioxidants prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. The transcription factor Nrf2 (NF-E2-related factor 2) and its negative regulator protein, Keap1 (Kelch-like-ECH-associated protein 1), are central regulators of cellular antioxidant responses. We used nrf2-null mice to investigate the roles of the Nrf2-Keap1 system in protection of skin from harmful effects of UVB irradiation. A single irradiation with UVB induced stronger and longer lasting sunburn reaction in nrf2-null mice. Histological changes, including epidermal necrosis, dermal edema, inflammatory cell infiltration, sunburn cell formation, TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2'-deoxyguanosine after UVB irradiation, were more prominent in nrf2-null mice. These findings indicate that the Nrf2-Keap1 pathway plays an important role in protection of the skin against acute UVB reactions, including cutaneous cell apoptosis and oxidative damage. However, there were no significant differences in skin carcinogenesis between nrf2-null and wild-type mice exposed to chronic UVB irradiation, suggesting that there is a complex and subtle balance between factors promoting and preventing photocarcinogenesis. Journal of Investigative Dermatology (2008) 128, 1773-1779; doi:10.1038/sj.jid.5701245; published online 17 January 2008.

DOI： 10.1038/sj.jid.5701245

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1524-4725.2008.34154.x

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Recently, low-dose 5-fluorouracil/cisplatin induction concurrent with radiation (chemoradiation) has been reported to be effective for locally advanced squamous cell carcinoma of the otorhinolaryngologic and gynecologic regions. However, to date, this therapeutic option has not been evaluated for squamous cell carcinoma of the skin. We evaluated chemoradiation therapy using cisplatin and 5-fluorouracil in two patients with locally advanced squamous cell carcinoma of the skin. Administration of cisplatin and 5-fluorouracil was conducted concurrently with conventionally fractionated radiation therapy. Cisplatin (patient 1: 4 mg/m(2)/d on days 1 to 5; patient 2: 15 mg/m(2)/d on days 1 to 5) and 5-fluorouracil (patient 1: 400 mg/m(2)/d for 7 days; patient 2: 850 mg/m(2)/d for 5 days) were administered intravenously for 1 hour and for 24 hours, respectively. Patient 1 underwent two courses of chemotherapy with a 3-week interval, and patient 2 underwent a single course of chemotherapy. The primary tumor of both patients showed complete regression, leaving ulceration. In patient 1, the ulceration completely resolved after 3 months. Patient 2 underwent surgical resection and full-thickness skin grafting. A histopathologic examination confirmed complete tumor regression. Neither patient suffered any serious side effects during this treatment. We conclude that chemoradiation using cisplatin and 5-fluorouracil was effective in these two patients with locally advanced squamous cell carcinoma of the skin. Several randomized studies have shown concurrent chemoradiation to be superior to radiation alone. This regimen is an option in managing patients who have unresectable primary tumors or who require preservation of local function.

PubMed

researchmap

Language：English  

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Pemphigus vulgaris and bullous pemphigoid are autoimmune blistering diseases of the skin and the mucosa characterized by circulating autoantibodies. Coexistence of these lesions is extremely uncommon. We report herein a case of both pemphigus vulgaris and bullous pemphigoid which occurred in the upper aerodigestive tract. The diagnosis was made based on the circulating autoantibodies and direct immunofluorescent studies. The literature on this subject is reviewed.

PubMed

researchmap

Language：English   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.jdermsci.2015.07.008

Web of Science

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1684/ejd.2012.1669

Scopus

PubMed

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1684/ejd.2010.1184

Scopus

PubMed

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1684/ejd.2010.1179

Scopus

PubMed

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1684/ejd.2008.0366

Scopus

PubMed

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

Scopus

PubMed

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：JOHN LIBBEY EUROTEXT LTD  

Web of Science

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

Scopus

PubMed

researchmap

Language：Japanese   Publisher：Japanese Dermatological Association  

Background: The sentinel lymph node (SN) is the first node or nodes to drain a cutaneous melanoma. Sentinel lymph node biopsy (SNB) is performed to determine whether regional metastases are present. The authors report our experience with the techniques of blue dye, lymphoscintigraphy, and a gamma probe of sentinel lymph node biopsy for malignant melanoma. SNB was attempted in 61 patients with clinical node metastasis negative cutaneous melanoma from October 1997 to September 2002 in the Dermatology Division, of National Cancer Center Hospital. Fifty-one patients were injected with blue dye alone. SNs were identified in 42 patients (82.3%). Ten patients underwent lymphoscintigraphy preoperatively. A gamma probe and blue dye helped in localizing the SN. The SNs were identified in 10 patients (100%) by the triple techniques. Collectively, we could identify the SNs in 52 patients (85%). SN metastasis was found to be negative in 39 (75%) of the 52 patients ; the other 13 patients (25%) had one or more positive SNs. Four (10.3%) of the 39 patients developed a recurrence despite having no evidence of metastatic SN. Continuously, we reexamined 57 SNs from the 39 patients reported as negative for malignant melanoma metastasis following routine HE (hematoxylin and eosin) stain. Metastases were apparent in 13 of these 52 patients, and 16 of the 73 SNs. Using the remaining 57 SNs from the 39 patients, we examined immunohistochemically stained deeper sections SNs with antibodies to Mitf (microphthalmia transcription factor), S-100, HMB-45, and Melan-A. These deeper serial sections and immunohistochemical stains detected microscopic metastases in 4 (10.3%) cases and 5 (8.7%) SNs that had been reported as negative for metastasis by routine pathological analysis.

DOI： 10.14924/dermatol.114.15

researchmap

Language：Japanese   Publisher：The Japanese Skin Cancer Society  

Various histopathological techniques have been developed in order to improve the detection of micrometastasis in the sentinel lymph nodes (SN) . In this study, we reexamined 55 SN from 42 patients reported as negative for malignant melanoma metastasis following routine HE (hematoxylin and eosin) stain. Metastases were apparent in 11 of the 42 patients, and 11 of the 55 SN. Of the remaining 44 SN from 31 patients we examined immunohistochemical stained deeper sections of the sentinel lymph nodes with antibodies to Mitf (microphthalmia transcription factor), S-100, HMB-45, Melan-A. 11 (35.5%) of 31 cases, 14 (31.8%) of 44 SN had immunoreactive cells for Mitf. 6 (19.4%) of 31 cases, 8 (18.2%) of 44 SN had immunoreactive cells for HMB-45.5 (16.1%) of 31 cases, 6 (13.6%) of 44 SN had immunoreactive cells for Melan-A. Deeper serial sections and immunohistochemical stains detected micrometastasis in 3 (9.7%) of 31 cases, 4 (9.1%) of 44 SN that had been reported as negative for metastasis by routine pathology analysis. Therefore, we evaluated immunohistochemical stains with deeper serial sections.[Skin Cancer (Japan) 2003; 18: 45-50]

DOI： 10.5227/skincancer.18.45

CiNii Books

researchmap