Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs.

Background: The development and clinical success of KRAS inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with KRAS mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRAS inhibitors.

Methods: A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRAS drugs on NRF2.

Skin health survey on atopic dermatitis among Japanese children: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

Background: Precise skin phenotypic data are indispensable in accurately diagnosing atopic dermatitis (AD). Therefore, this study examined the interobserver concordance for AD and non-AD diagnoses between two dermatologists. AD prevalence determined by the self-reported physician diagnoses and the diagnoses determined from the United Kingdom (UK) diagnostic criteria were compared with the diagnoses made by the two dermatologists, using data from a skin health survey.

Plasminogen Activating Inhibitor-1 Might Predict the Efficacy of Anti-PD1 Antibody in Advanced Melanoma Patients.

Plasminogen activating inhibitor-1 (PAI-1) plays crucial roles in the development of various cancers, including melanomas. Indeed, various pro-tumorigenic functions of PAI-1 in cancer progression and metastasis have been widely reported. Among them, PAI-1 is also reported as a key regulator of PD-L1 expression on melanoma cells through endocytosis, leading to abrogating the efficacy of anti-PD1 antibodies (Abs).

Possible Roles of Proinflammatory Signaling in Keratinocytes Through Aryl Hydrocarbon Receptor Ligands for the Development of Squamous Cell Carcinoma.

Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including and -related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC.

Environmental pollutants and the immune response.

Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system.

Aryl Hydrocarbon Receptor Modulates Carcinogenesis and Maintenance of Skin Cancers.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a wide range of chemicals, including chemical carcinogens such as dioxins and carcinogenic polyaromatic hydrocarbons, and induces a battery of genes associated with detoxification, proliferation, and immune regulation. Recent reports suggest that AHR plays an important role in carcinogenesis and maintenance of various types of skin cancers. Indeed, AHR is a susceptibility gene for squamous cell carcinoma and a prognostic factor for melanoma and Merkel cell carcinoma.

Biomarkers for Predicting Efficacies of Anti-PD1 Antibodies.

Therapeutic options for treating advanced melanoma are progressing rapidly. Although anti-programmed cell death 1 (PD1) antibodies (e.g.

Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection.

Ipilimumab, in combination with nivolumab, is one of the promising drugs that enhance the anti-tumor immune response of patients with advanced melanoma. Since the co-administration of nivolumab with ipilimumab in the neoadjuvant setting expands melanoma-reactive T cells at the primary site of melanoma and has a high rate of histological complete response, the pre-surgical administration of this combination could be the optimal therapy for unresectable advanced melanoma. In this report, a case of unresectable advanced melanoma treated successfully with administration of nivolumab with ipilimumab before primary tumor resection is presented.

Malassezia-derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra-mammary Paget's disease.

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.

BRAF kinase inhibitors for treatment of melanoma: developments from early-stage animal studies to Phase II clinical trials.

Introduction: Approximately, 30.4-66.0% of cutaneous melanomas possess a mutation in the BRAF gene that activates downstream signaling through the mitogen-activated protein (MAP) kinase pathway; this provides an attractive target for the treatment of advanced melanoma.

Serum Level of Soluble CD163 May Be a Predictive Marker of the Effectiveness of Nivolumab in Patients With Advanced Cutaneous Melanoma.

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.

Serum levels of soluble CD163 and CXCL5 may be predictive markers for immune-related adverse events in patients with advanced melanoma treated with nivolumab: a pilot study.

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.

HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy.

Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis.

Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer.

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.

The Expression of Matrix Metalloproteinases in Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-expressing Cancer of Apocrine Origin.

Unlabelled: Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive tumor entity. Since there is no conventional therapy for advanced PCAC, exploratory treatments are sometimes used. As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD).

Phase I study of nivolumab combined with IFN-β for patients with advanced melanoma.

The efficacy of nivolumab is greater than that of other anti-melanoma drugs, so nivolumab-based combined therapies that enhance anti-tumor immune responses in patients with metastatic melanoma are of great interest to dermato-oncologists. As we have previously reported, IFN-β enhances the anti-tumor immune response of anti-PD-1 antibodies against B16F10 melanoma . To explore the potential of this property of IFN-β as part of a combination therapy for the treatment of metastatic melanoma patients, we performed a phase 1 trial, using a traditional rule-based 3 + 3 design, on patients with advanced melanoma.

Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas.

Background/aim: Tumor-associated macrophages (TAMs), together with splenic CD11b cells, help maintain the tumor microenvironment. The immunomodulatory compound imiquimod (IQM) stimulates innate immune cells, including macrophages, to induce antitumor effects. In order to elucidate the effects of IQM on the tumor microenvironment, we investigated the immunomodulatory effect of IQM during melanoma growth by using the B16F10 melanoma model.

Successful Treatment of Primary Cutaneous Peripheral T-Cell Lymphoma Presenting Acquired Ichthyosis with Oral Bexarotene Monotherapy.

Acquired ichthyosis (AI) is a reactive cutaneous manifestation that can be associated with malignant hematological disease, including cutaneous T-cell lymphoma (CTCL). Since it is difficult to distinguish AI from ichthyosiform mycosis fungoides, to select the treatment for CTCL with ichthyosis-like appearance and to evaluate its efficacy is sometimes challenging. In this report, we describe a case of primary cutaneous peripheral T-cell lymphoma not otherwise specified presenting AI successfully treated with oral bexarotene.

Retrospective Investigation of Cutaneous Squamous Cell Carcinoma on the Lip Treated with Peplomycin Administered Through a Superficial Temporal Artery.

Background: Continuous intra-arterial (IA) administration of peplomycin (PEP) through a tumor-feeding artery is one of the most effective treatments for cutaneous squamous cell carcinoma (cSCC) in cosmetic areas.

Patients And Methods: In order to determine the effective and safe dose of PEP and the curative rate of IA-PEP, we retrospectively investigated a case series of 24 patients with cSCC on the lips who were treated with IA-PEP.

Results: IA-PEP reduced the tumor mass in all 24 cases (100%).