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Colágeno Tipo VII , Epidermólisis Ampollosa Distrófica , Humanos , Epidermólisis Ampollosa Distrófica/genética , Epidermólisis Ampollosa Distrófica/patología , Epidermólisis Ampollosa Distrófica/diagnóstico , Colágeno Tipo VII/genética , Mutación , Masculino , Piel/patología , Análisis Mutacional de ADN , Femenino , Genes RecesivosRESUMEN
Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.
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Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Ictiosis , Pitiriasis Rubra Pilaris , Humanos , Pitiriasis Rubra Pilaris/genética , Ictiosis Lamelar/genética , Eritrodermia Ictiosiforme Congénita/genética , Eritrodermia Ictiosiforme Congénita/patología , Fenotipo , Mutación , Transportadoras de Casetes de Unión a ATP/genéticaRESUMEN
Therapeutic advantages of immune checkpoint inhibitors, anti-programmed death-1 (PD-1), and anticytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in melanoma have been reported recently. In this study, we conducted a retrospective study to evaluate the clinical efficacy and safety of the combined use of nivolumab and ipilimumab as a first-line therapy for Japanese patients with advanced melanoma. Moreover, we examined the effects of second-line treatment. Seven patients were enrolled in this study. The median progression-free survival (PFS) and median overall survival (OS) were 7 months (95%CI, 1.868-12.132) and 12 months (95%CI, 0.000- 27.397), respectively. The objective response rate (ORR) and the disease control rate (DCR) were 42.9 % and 85.7 %. Three patients chose pembrolizumab monotherapy as second-line therapy after the combination therapy due to their BRAF wild-type status, which resulted in progressive disease. ORR and DCR were 0% and 33.3%, respectively, with pembrolizumab. Grade 3 or 4 immune-related adverse events occurred in 71.4% of the patients treated with the combined-therapy. All irAEs were treated with corticosteroid or hormone replacement therapy. Although this single center retrospective study had some limitations, it demonstrated good efficacy for the combined use of nivolumab and ipilimumab as a first-line therapy for Japanese patients with advanced melanoma. Moreover, poor efficacy was observed for the second-line therapy after the combined therapy. These findings suggest that a novel second-line therapy is required for patients with advanced melanoma in Japan, particularly for patients with wildtype BRAF.
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Melanoma , Nivolumab , Humanos , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Estudios Retrospectivos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/uso terapéutico , Japón , Melanoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease (sAIBD). In addition to disease causing autoantibodies, several leukocyte subsets, including mast cells and eosinophils, play key roles in mediating skin inflammation. Detailed immunophenotyping and, more recently, the therapeutic effects of interleukin-4 (IL-4) receptor alpha inhibition in BP pointed to a prominent role of T helper 2 (Th2) cells. Among other cell types, IL-9 is expressed by Th2 and mast cells and potentially drives allergic, Th2-dominated inflammation. Although cytokines in BP have been relatively well investigated, the role of IL-9 has remained enigmatic. This study aimed to evaluate the effect of IL-9 in BP. Serum IL-9 levels were significantly elevated in patients with BP and decreased upon induction of remission. Serum IL-9 levels were not elevated in epidermolysis bullosa acquisita, another sAIBD. The time-course analysis using serum sets from four patients with BP revealed that serum IL-9 was a sensitive biomarker of BP. IL-9-positive cells infiltrated dominantly in BP lesions, especially in the blister fluid, and Th9 cells were abundant. Therefore, IL-9 was elevated in the serum and lesions of BP, which could be a biomarker of BP.
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Penfigoide Ampolloso , Humanos , Interleucina-9 , Virulencia , Vesícula/etiología , Inflamación/complicaciones , BiomarcadoresRESUMEN
Japanese patients with very high-risk cutaneous squamous cell carcinomas (cSCCs), based on the National Comprehensive Cancer Network guidelines, have been reported to display a higher cumulative incidence of relapse and disease-specific death (DSD) than those with high-risk cSCC. Therefore, prognosis prediction is crucial for Japanese patients with very high-risk cSCCs. Herein, we aimed to evaluate the prognostic prediction ability of our novel Japanese Risk Factor Scoring Systems (JARF scoring) in a Japanese cohort of cSSC patients. Data of 424 Japanese patients with resectable very high-risk cSCCs were analysed. We compared the prognostic ability of the following three staging systems: Brigham and Women's Hospital (BWH) tumour staging, number of NCCN very high-risk factors, and JARF scoring, including recurrent tumour, high-risk histological features, deep tumour invasion and lymphatic or vascular involvement as risk factors. The prognostic ability of these staging systems was evaluated according to the cumulative incidence of local recurrence (LR), regional lymph node metastasis (RLNM), DSD, and overall survival (OS). When BWH staging was used, high T stage led to significantly poor outcomes only in the cumulative incidence of RLNM (p = 0.01). The presence of very high-risk NCCN factors led to significantly poor outcomes in terms of RLNM (p = 0.03) and OS (p = 0.02). Meanwhile, a high number of risk factors in the JARF scoring system clearly led to poor outcomes in terms of LR (p = 0.01), RLNM (p < 0.01), DSD (p = 0.03), and OS (p < 0.01). The JARF scoring system may accurately predict the risk of recurrence and death in very high-risk cSCC patients in Japan.
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Carcinoma de Células Escamosas , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Estudios Transversales , Pueblos del Este de Asia , Japón , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
Autoimmune bullous diseases (AIBDs), which are a group of tissue-specific autoimmune diseases of the skin, present with various blistering lesions on the skin and mucous membranes, and show autoantibodies of IgG, IgA and IgM against epidermal cell surfaces and basement membrane zone. To date, AIBDs have been classified into a number of distinct subtypes by clinical and histopathological findings, and immunological characteristics. In addition, various biochemical and molecular biological studies have identified various novel autoantigens in AIBDs, which has resulted in proposals of new subtypes of AIBDs. In this article, we summarized various distinct AIBDs, and proposed the latest and most comprehensive classification of AIBDs with their autoantigen molecules.
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Autoantígenos , Enfermedades Autoinmunes , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Autoanticuerpos , Autoantígenos/inmunología , Enfermedades Autoinmunes/clasificación , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Piel/patología , Enfermedades Cutáneas Vesiculoampollosas/clasificación , Enfermedades Cutáneas Vesiculoampollosas/inmunología , Enfermedades Cutáneas Vesiculoampollosas/patologíaRESUMEN
BACKGROUND: Extramammary Paget's disease (EMPD) is a slowly advancing malignancy that sometimes progresses to the invasion of the dermis, systemic metastases, and death. Although there have been reports that dermal invasion is associated with poor prognosis, no molecular markers of this invasion have been identified thus far. The aim of this study was to identify key molecules for predicting the risk of EMPD dermis invasion. METHOD: We performed microarray screening for three cases of in-situ EMPDs, three cases of invasive EMPDs, and three cases of normal epidermis. We identified a molecule that exhibited a stepwise increase in expression. Further, we analyzed 47 cases of EMPD using immunohistochemical staining (IHC) and examined the correlated clinicopathological findings, including prognosis. RESULT: We examined molecules that showed stepwise differences with invasion. We focused on transcription factor activating enhancer-binding protein 2 B (TFAP2B). Of the 47 EMPD patients, 38 (80.9 %) and 9 (19.1 %) had low and high TFAP2B expression, respectively. TFAP2B expression was significantly correlated with invasion into the dermis, mass formation, and preoperative lymph node metastasis (p = 0.001, 0.042, and 0.033, respectively). The cumulative postoperative recurrence-free rate in the TFAP2B-high expression group was significantly lower than that in the TFAP2B-low expression group (P < 0.001). In univariate analysis of recurrence-free survival, TFAP2B expression was found to be a significant factor (p = 0.006). CONCLUSION: The expression of TFAP2B, which was comprehensively found by microarray screening, may correlate with the invasiveness of EMPD and may be an unfavorable prognostic factor.
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Enfermedad de Paget Extramamaria , Neoplasias Cutáneas , Factor de Transcripción AP-2 , Humanos , Metástasis Linfática , Enfermedad de Paget Extramamaria/metabolismo , Enfermedad de Paget Extramamaria/patología , Enfermedad de Paget Extramamaria/secundario , Pronóstico , Neoplasias Cutáneas/patología , Coloración y Etiquetado , Factor de Transcripción AP-2/metabolismoRESUMEN
Immunoglobulin A (IgA) pemphigus, also known as intercellular IgA dermatosis, is a rare autoimmune bullous disease presenting with IgA anti-keratinocyte cell surface autoantibodies. Concomitant lymphoproliferative disorders have been reported in IgA pemphigus, including IgA monoclonal gammopathy of undetermined significance and IgA type multiple myeloma (MM). A 35-year-old Japanese woman with a 3-year history of pruritic papulovesicles on her lower legs and trunk was referred to our department. Histopathological examination revealed acantholytic blisters, and results of both direct and indirect immunofluorescence were negative. Direct and indirect immunofluorescence were still negative 3 years and 7 months later. Approximately 7 years after her first visit, the patient was re-referred to us because of disease exacerbation. Histopathological findings revealed subcorneal blistering with acantholysis, in which neutrophil-dominant inflammatory cells were present. Indirect immunofluorescence was positive for IgA on the epidermal cell surface and both desmoglein (Dsg) 1/3 and (Dsc) desmocollin 1-3 enzyme-linked immunosorbent assays (ELISAs) for IgA were positive. The histological findings and positive Dsc1 IgA ELISA led to the diagnosis of subcorneal pustular dermatosis (SPD)-type IgA pemphigus. Further examination revealed hyper-IgA globulinemia, increased serum IgA-κ protein, and increased plasma cells in the bone marrow, enabling the diagnosis of IgA type MM. Daratumumab, lenalidomide, and dexamethasone (DLd) therapy was effective for both the MM and the skin lesions, resulting in negative results on Dsg1/3 and Dsc1-3 IgA ELISAs. The association between IgA pemphigus and IgA type multiple myeloma remains unclear, and only seven cases including the present case have been reported. Literature review revealed associations between SPD-type and IgA κ chain in IgA pemphigus and MM, and that in most cases the onset or diagnosis of MM was simultaneous or occurred after the diagnosis of IgA pemphigus. Therefore, clinicians should be aware of the development of multiple myeloma during the clinical course of patients with SPD-type IgA pemphigus.
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Enfermedades Autoinmunes , Mieloma Múltiple , Pénfigo , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Femenino , Adulto , Pénfigo/complicaciones , Pénfigo/diagnóstico , Pénfigo/tratamiento farmacológico , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Autoanticuerpos , Inmunoglobulina ARESUMEN
Eruptive xanthomas are skin manifestations associated with hypertriglyceridemia. Accordingly, the improvement of hypertriglyceridemia can ameliorate this condition. We report a case of a patient with type 2 diabetes mellitus who was diagnosed with this skin lesion. Clinicians should be aware that eruptive xanthomas could indicate metabolic disorders associated with atherosclerosis.
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Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization disorders that gradually progress during childhood, resulting in difficulties to establish a diagnosis and to identify a candidate gene for sequencing. Dermoscopic examination with staining of palmoplantar skin using a whiteboard marker, so-called "furrow ink test", could be a useful tool for differentiation between furrow and ridge in understanding the morphological characteristics of PPK. One of the striking features in autosomal dominant loricrin keratoderma (LK) is diffuse PPK with honeycomb pattern. In this study, we performed dermoscopic furrow ink test in a Japanese family of LK with the most frequent mutation c.684dup, p.Ser229Valfs*107 in the loricrin gene. The severe lesion revealed that irregular circular hyperkeratoses were aggregated and normal structures of furrows and ridges were disrupted. To accurately describe the nature of this dermoscopic patterned skin surface, we suggest that the condition could be termed as "irregular cobblestone appearance" rather than "honeycomb pattern". Regular cobblestone appearance to maintain parallel furrow structure was observed in early or mild hyperkeratotic lesions. Eccrine sweat glands that open on the surface of ridges nearly disappeared, resulting in hypohidrosis.
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Tinta , Queratodermia Palmoplantar , Humanos , Queratodermia Palmoplantar/diagnóstico , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Proteínas de la Membrana/genética , Enfermedades Cutáneas GenéticasAsunto(s)
Enfermedad del Hígado Graso no Alcohólico , Psoriasis , Humanos , Interleucina-17 , Hígado , Cirrosis Hepática/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Psoriasis/complicaciones , Psoriasis/tratamiento farmacológicoRESUMEN
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.
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Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Granulomatosis Linfomatoide/diagnóstico , Granulomatosis Linfomatoide/tratamiento farmacológico , Anciano , Biomarcadores , Biopsia , Neoplasias del Sistema Nervioso Central/etiología , Evolución Clonal , Femenino , Humanos , Inmunohistoquímica , Interferón-alfa/administración & dosificación , Granulomatosis Linfomatoide/etiología , Imagen por Resonancia Magnética , Evaluación de Síntomas , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Hiperqueratosis Epidermolítica , Queratodermia Palmoplantar , Humanos , Hiperqueratosis Epidermolítica/complicaciones , Hiperqueratosis Epidermolítica/diagnóstico , Hiperqueratosis Epidermolítica/genética , Queratina-1 , Queratodermia Palmoplantar/diagnóstico , Queratodermia Palmoplantar/genética , Mutación , LinajeRESUMEN
Pemphigus is a group of autoimmune bullous diseases characterized by the presence of autoantibodies against adhesion molecules, desmogleins, and desmocollins (DSCs). The pathogenicity of anti-DSC3 antibodies in pemphigus has been demonstrated; however, its characteristics have not yet been elucidated. We aimed to analyze the characteristics of anti-DSC3 antibodies using DSC3 domainâswapped desmoglein 2 molecules in which the prosequence and five extracellular (EC) domains of desmoglein 2 were replaced with the corresponding domains of human DSC3. Using these proteins, we established an ELISA and analyzed sera from 56 patients with pemphigus. In 34 pemphigus sera positive for DSC3 full-EC domains, 15 sera (44.1%) were positive for EC2 domain, whereas other domains were rarely positive. We assessed the reactivity to a calcium-dependent epitope in DSC3 by ELISA with EDTA. The reactivity with the EC2 domain was mostly compromised in the presence of EDTA. In the in vitro assay, IgG from patients with paraneoplastic pemphigus preadsorbed with EC2 prevented both reduction of DSC3 and keratinocyte dissociation as compared with that with EDTA-treated EC2. This study revealed a predominant recognition of calcium-dependent epitopes in EC2 domain by anti-DSC3 antibodies and its pathogenicity on keratinocyte adhesion through DSC3 depletion.
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Desmocolinas/metabolismo , Epítopos Inmunodominantes/metabolismo , Queratinocitos/metabolismo , Pénfigo/inmunología , Autoanticuerpos/metabolismo , Calcio/metabolismo , Adhesión Celular , Células Cultivadas , Desmocolinas/genética , Desmocolinas/inmunología , Ácido Edético , Espacio Extracelular/metabolismo , Humanos , Epítopos Inmunodominantes/genética , Epítopos Inmunodominantes/inmunología , Inmunoglobulina G/metabolismo , Síndromes Paraneoplásicos , Dominios Proteicos/genética , Dominios Proteicos/inmunología , Proteínas Recombinantes/genéticaRESUMEN
BACKGROUND: Extramammary Paget's disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8+ tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis. MATERIALS AND METHODS: We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections. RESULTS: PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8+ TIL count was significantly lower than that of the corresponding group with a high CD8+ TIL count and of the PD-L1- and PD-L2-negative group (p=0.026). CONCLUSION: The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.