Recurrent, Tumor Mutation Burden-High, Cutaneous Angiosarcoma of the Scalp Treated with Pembrolizumab

Introduction: Chemoradiotherapy with taxanes is well-recognized as a first-line therapy for cutaneous angiosarcoma (CAS), but second-line therapy for CAS is still controversial. Case Presentation: In this report, we described a 75-year-old Japanese case of recurrent, tumor mutation burden-high CAS on the scalp treated with pembrolizumab. Our present case survived for 1 year despite of taxane refractory CAS with mediastinal lymph node metastasis, though the administration of anti-PD-1 Abs alone could not fully suppress the tumor progression of CAS. Conclusion: Since various factors such as pro-angiogenic molecules are correlated with the tumor progression in CAS, the administration of anti-PD-1 Abs alone could not fully suppress the tumor progression of CAS. Further novel anticancer drugs are needed in the future for the treatment of CAS

Keratoacanthoma Centrifugum Marginatum with Spontaneous Regression and Its Possible Differential Diagnosis

Keratoacanthoma centrifugum marignatum (KCM) is a rare variant of keratoacanthoma, which is characterized by the dense infiltration of inflammatory cells throughout the dermis, especially around the keratinocytic islands. Therefore, it is sometimes difficult to differentiate between KCM and cutaneous T-cell lymphomas. In this report, we describe a case of KCM with spontaneous regression that showed dense infiltration of CD3+CD8+ T cells. Our present case suggested the importance of investigating tumor-infiltrating lymphocytes to avoid the misdiagnosis of KCM as cutaneous T-cell lymphoma

Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma

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

Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice

We have recently shown that wild type mice are highly tolerant, whereas thyrotropin receptor (TSHR) knockout (KO) mice are susceptible to immunization with the mouse TSHR, the autoantigen in Graves\u27 disease. However, because TSHR KO mice lack the endogenous TSHR, Graves-like hyperthyroidism cannot be expected to occur in these mice. We therefore performed adoptive transfer of splenocytes from TSHR KO mice into nude mice expressing the endogenous TSHR. Anti-TSHR autoantibodies were detected in approximately 50% recipient mice 4 wk after adoptive transfer of splenocytes (5 × 10 7/mouse) from TSHR KO mice immunized with adenovirus expressing mTSHR A subunit and persisted for 24 wk. Depletion of regulatory T cells by anti-CD25 antibody in the donor mice increased successful transfer rates without increasing antibody levels. Some recipient mice showed transient increases in thyroid-stimulating antibodies and T4 levels 4-8 wk after transfer, but many became thyroid-blocking antibody positive and hypothyroid 24 wk later. Adoptive transfer of splenocytes from naïve TSHR KO mice transiently induced very low antibody titers when the recipient mice were treated with anticytotoxic lymphocyte antigen 4 and antiprogrammed cell death 1 ligand 1 antibodies for 8 wk after transfer. Histologically, macrophages infiltrated the retrobulbar adipose tissues and extraocular muscles in a small fraction of the recipients. Our findings demonstrate successful adoptive transfer of anti-TSHR immune response from TSHR KO mice to nude mice. Although the recipient mice developed only transient and infrequent hyperthyroidism, followed by eventual hypothyroidism, induction of orbital inflammation suggests the possible role of anti-TSHR immune response for Graves\u27 orbitopathy

Topical and Systemic Formulation Options for Cutaneous T Cell Lymphomas

Although various anti-cutaneous T-cell lymphoma (CTCL) therapies are available for clinical use, appropriate chemotherapy lines for the treatment of CTCLs have yet to be established. Therefore, to date, various clinical trials for the treatment of advanced CTCLs are ongoing. In this review, we evaluate the therapeutic options that are available in clinical practice for treatment of early- and advanced-stage CTCLs (targeted therapies, histone deacetylase (HDAC) inhibitors, retinoids, interferons, cytotoxic drugs, etc.). We also examine clinical trials of novel regimens for the treatment of CTCLs

Serum CCL22 Increased in Advanced Melanoma Patients with Liver Metastases: Report of 5 Cases

Advanced melanoma patients with liver metastases show a limited response to immunotherapy by the induction of regulatory T cells and depletion of effector cells, which leads to a poor prognosis. Tumor-associated macrophages (TAMs) induce apoptosis of activated antigen-specific CD8+ T cells in melanomas, leading to induction of tolerance to immune checkpoint inhibitors. In addition, TAMs produce various chemokines, and several serum pro-inflammatory chemokines measured at baseline are useful for the prediction of the efficacy of immunomodulatory drugs. In this study, serum levels of CCL22, CXCL5, and CXCL10 were evaluated by ELISA at baseline in 10 melanoma patients, 5 with liver metastases and 5 with lung metastases, treated with anti-PD1 Abs. Serum levels of CCL22, but not CXCL5 and CXCL10, were increased in patients with liver metastases compared to those with lung metastases or historical controls. The present data suggest that elevated serum CCL22 levels might be a biomarker for liver metastases in melanoma patients

The Antimicrobial Peptide Cathelicidin Exerts Immunomodulatory Effects via Scavenger Receptors

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents