RESUMEN
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.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Antígeno CTLA-4/genética , Pueblos del Este de Asia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Melanoma Cutáneo MalignoRESUMEN
Three-dimensional (3D) epidermal models reconstructed from human skin-derived keratinocytes have been utilized as an alternative to animal testing and models, not only in toxicology, but also in skin biology. Although there are currently several reconstructed human epidermis (RHE) models commercially available, the donors of the keratinocytes are not identified in these models. A tailor-made system is needed to investigate the individual differences in RHE derived from each donor.It is possible to make an individual RHE using each donor's keratinocytes, which are usually obtained by invasive procedures such as skin excision or biopsy. To overcome this drawback, we established an RHE model using keratinocytes derived from plucked hair follicles as a less invasive procedure under conditions without feeder cells, serum, or matrix proteins. In this chapter, we provide a method of isolation and two-dimensional (2D) culture of keratinocytes derived from adult human plucked hair follicles including the outer root sheath (ORS). We also provide a detailed protocol for establishing an RHE model by culturing the keratinocytes under a 3D culture condition. We believe that our less invasive technique will provide a useful tool for investigating individual RHE in both normal and disease settings.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Epidermis , Queratinocitos , Ingeniería de Tejidos/métodos , Separación Celular/métodos , Células Cultivadas , Folículo Piloso/citología , Humanos , Modelos BiológicosAsunto(s)
Albinismo Oculocutáneo , Dermoscopía , Melanoma Amelanótico , Neoplasias Cutáneas , Humanos , Albinismo Oculocutáneo/complicaciones , Albinismo Oculocutáneo/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/complicaciones , Melanoma Amelanótico/patología , Melanoma Amelanótico/diagnóstico , Melanoma Amelanótico/diagnóstico por imagen , Melanoma Amelanótico/complicaciones , Masculino , FemeninoAsunto(s)
Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/patología , Granuloma/complicaciones , Paniculitis/complicaciones , Adulto , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Eritema Nudoso/complicaciones , Femenino , Humanos , Inmunohistoquímica , Infliximab , Neutrófilos , Paniculitis/patología , Grasa Subcutánea/patologíaRESUMEN
BACKGROUND: Langerhans cells (LCs) are one of the initial target cells for HIV following sexual exposure and they are productively infected by HIV. HIV-infected LCs migrate to the draining lymph nodes (dLNs) and transmit the virus to CD4+ T cells, leading to the dissemination of HIV. In contrast with the role of LCs in initial HIV acquisition, little is known about the modulation of immune responses by HIV-infected LCs. OBJECTIVE: We aimed to elucidate the induction of HIV-specific CD8+ T cells and regulatory T cells (Tregs), both of which play important roles in regulating the progression of HIV infection. METHODS: We examined the inducibility of HLA-A*0201 restricted HIV-specific CD8+ T cells and Tregs by HIV-primed LCs or HIV-primed dendritic cells (DCs) as a control. RESULTS: The number of HIV-specific CD8+ T cells induced by HIV-primed monocyte-derived LCs (mLCs) was significantly higher than that by HIV-primed monocyte-derived DCs (mDCs). Additionally, HIV-specific CD8+ T cells induced by HIV-primed mLCs produced more IFN-γ than HIV-nonspecific CD8+ T cells. HIV-primed human epidermal LCs also induced IFN-γ-producing HIV-specific CD8+ T cells. As for the induction of Tregs, HIV-primed mLCs and human epidermal LCs significantly impaired the induction of FoxP3hiCD45RA- effector Tregs than HIV-unprimed mLCs and human epidermal LCs. CONCLUSIONS: HIV-primed LCs trigger beneficial immune responses against HIV infection through the increased induction of HIV-specific CD8+ T cells and the decreased induction of effector Tregs in the initial phase of HIV infection, thereby contributing to the prolonged onset of AIDS.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Linfocitos T CD8-positivos/inmunología , VIH-1/inmunología , Células de Langerhans/inmunología , Linfocitos T Reguladores/inmunología , Síndrome de Inmunodeficiencia Adquirida/patología , Síndrome de Inmunodeficiencia Adquirida/virología , Recuento de Células , Células Cultivadas , Progresión de la Enfermedad , Células Epidérmicas , Epidermis/patología , VIH-1/aislamiento & purificación , Antígeno HLA-A2/análisis , Antígeno HLA-A2/inmunología , Humanos , Células de Langerhans/virología , Activación de Linfocitos/inmunología , Linfocitos T Reguladores/virología , Técnicas de Cultivo de TejidosAsunto(s)
Enfermedades de la Uña , Neoplasias Cutáneas , Dermoscopía , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Uña/diagnóstico por imagen , Enfermedades de la Uña/cirugía , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
We report a case of an 88-year-old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium-to-large-sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death-1 (PD-1), Bcl-6 and CXCL13. Flow cytometry analysis showed that CD4(+) PD-1(hi) T cells also expressed CD10, inducible T-cell co-stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T-cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)-cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH-cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.
Asunto(s)
Neoplasias de Cabeza y Cuello/patología , Linfoma Cutáneo de Células T/patología , Linfocitos T Colaboradores-Inductores/patología , Anciano de 80 o más Años , Biomarcadores/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Linfoma Cutáneo de Células T/complicaciones , Úlcera Cutánea/etiología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
From a clinicopathological conference on nine elderly patients with Epstein-Barr virus (EBV)-associated T/natural killer (NK)-cell lymphoma, we have addressed the patients' backgrounds, clinical manifestations, histopathological findings, cytogenesis, complications and prognoses. Among these elderly patients (>65 years old), seven patients had extranodal NK/T-cell lymphoma, nasal type (ENKL) with an NK-cell phenotype, and two patients had EBV(+) T-cell lymphomas or lymphoproliferative disorders (LPD) with cutaneous lesions mimicking pityriasis lichenoides et varioliformis acuta (PLEVA) or hydroa vacciniforme (HV). No patients had a previous episode of EBV-related symptoms such as infectious mononucleosis, chronic active EBV infection, HV or hypersensitivity to mosquito bites. Elderly patients with ENKL may show the centroblastoid variant. EBV(+) CD8(+) CD56(+/-) lymphocytes may be responsible for the development of PLEVA or HV-like cutaneous lesions in the elderly.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Linfoma/virología , Anciano , Anciano de 80 o más Años , Infecciones por Virus de Epstein-Barr/patología , Humanos , Linfoma/patología , Piel/patologíaAsunto(s)
Relojes Circadianos/fisiología , Herpes Simple/fisiopatología , Herpesvirus Humano 2/patogenicidad , Interacciones Microbiota-Huesped/fisiología , Aciclovir/farmacología , Aciclovir/uso terapéutico , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Herpes Simple/mortalidad , Herpes Simple/prevención & control , Herpes Simple/virología , Herpesvirus Humano 2/aislamiento & purificación , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nectinas/metabolismo , Índice de Severidad de la Enfermedad , Piel/metabolismo , Piel/virología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Herpes simplex virus (HSV)-2 shedding is associated with increased risk for sexually acquiring HIV. Because Langerhans cells (LCs), the mucosal epithelium resident dendritic cells, are suspected to be one of the initial target cell types infected by HIV following sexual exposure, we examined whether and how HSV-2 affects HIV infection of LCs. Although relatively few HSV-2/HIV-coinfected LCs were detected, HSV-2 dramatically enhanced the HIV susceptibility of LCs within skin explants. HSV-2 stimulated epithelial cell production of antimicrobial peptides (AMPs), including human ß defensins and LL-37. LL-37 strongly upregulated the expression of HIV receptors in monocyte-derived LCs (mLCs), thereby enhancing their HIV susceptibility. Culture supernatants of epithelial cells infected with HSV-2 enhanced HIV susceptibility in mLCs, and this effect was abrogated by blocking LL-37 production. These data suggest that HSV-2 enhances sexual transmission of HIV by increasing HIV susceptibility of LCs via epithelial cell production of LL-37.