RESUMO
BACKGROUND: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. MATERIALS AND METHODS: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. RESULTS: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. CONCLUSION: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.
Assuntos
Células Dendríticas/transplante , Melanoma/terapia , Recidiva Local de Neoplasia/epidemiologia , RNA Mensageiro/imunologia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ligante CD27/genética , Ligante CD27/imunologia , Ligante de CD40/genética , Ligante de CD40/imunologia , Terapia Combinada/métodos , Células Dendríticas/metabolismo , Intervalo Livre de Doença , Eletroporação , Feminino , Seguimentos , Humanos , Imunoterapia/métodos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , RNA Mensageiro/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Procedimentos Cirúrgicos Operatórios , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Transplante Autólogo/métodos , Adulto JovemRESUMO
Head lice infestations are very common in children aged between 3 and 12 yr old. The eggs of the head louse are difficult to remove and remain firmly attached to the hair even after any head louse treatment. Solid in vitro and in vivo evidence to support the use of any of the proposed products to facilitate nit removal is scarce. The objective of the current study was to determine the efficacy of several products to remove eggshells from human hair using an objective measurement procedure. Water and ordinary hair conditioner significantly facilitated the removal of nits in vitro. We found no difference between ordinary conditioner and products specifically marketed for the purpose of nit removal. Other products such as formic acid solution and almond oil did not have a beneficial effect.
Assuntos
Preparações para Cabelo , Infestações por Piolhos/terapia , Óvulo , Pediculus , Dermatoses do Couro Cabeludo/terapia , Animais , Criança , Formiatos , Cabelo , Humanos , Derivados da Hipromelose , Metilcelulose/análogos & derivados , Óleos de Plantas , ÁguaRESUMO
In this study, we developed an in vivo vitiligo induction model to explore the underlying mechanisms leading to Koebner's phenomenon and to evaluate the efficacy of therapeutic strategies. The model consisted of 12 pigmented test regions on the back of generalized vitiligo patients that were exposed to three Koebner induction methods: cryotherapy, 755 nm laser therapy, and epidermal abrasion. In addition, four cream treatments (pimecrolimus, tacrolimus, steroid and placebo) were randomly applied. Koebnerization was efficiently induced by all three induction methods. In general, cryotherapy was the best method of Koebner induction, followed by 755 nm laser therapy and epidermal abrasion. Reproducible results were obtained, which showed enhanced depigmented surface areas and higher amounts of T lymphocytes in placebo-treated test zones compared to active treated areas. Tacrolimus and local steroids were better inhibitors of Koebner's process (P < 0.05) compared to pimecrolimus. Our in vivo vitiligo induction model is very informative to investigate vitiligo induction and to determine the efficacy of topical treatments in vitiligo. This proof of concept confirms the efficient comparison of head-to-head therapeutic strategies intra-individually in a standardized, specific and better timed way.
Assuntos
Crioterapia/efeitos adversos , Dermabrasão/efeitos adversos , Imunossupressores/uso terapêutico , Terapia com Luz de Baixa Intensidade/efeitos adversos , Vitiligo/tratamento farmacológico , Vitiligo/etiologia , Administração Cutânea , Adulto , Método Duplo-Cego , Feminino , Humanos , Imunossupressores/administração & dosagem , Células de Langerhans/patologia , Antígeno MART-1/análise , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Pomadas , Pregnadienodiois/administração & dosagem , Pregnadienodiois/uso terapêutico , Reprodutibilidade dos Testes , Subpopulações de Linfócitos T/patologia , Tacrolimo/administração & dosagem , Tacrolimo/análogos & derivados , Tacrolimo/uso terapêutico , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/uso terapêutico , Vitiligo/imunologia , Vitiligo/patologia , Antígeno gp100 de Melanoma/análiseRESUMO
INTRODUCTION: Transdermal drug delivery has several known advantages over the oral route and hypodermic injections. The number of drugs that can be taken up transdermally is, however, limited owing to the innate barrier function of the skin. New transdermal drug candidates need to be tested extensively before being used on humans. In this regard, in vitro permeation methods are highly important to predict in vivo permeation of drugs. AREAS COVERED: This review illustrates how different types of reconstructed skin models are being used as alternatives to human and pig skin for in vitro permeation testing of drugs. Insights into how various factors (including the physicochemical nature of molecules and formulations) or skin properties might affect the permeability of drugs in reconstructed skin models are provided. Also, opportunities and pitfalls of reconstructed skin models are highlighted. EXPERT OPINION: Many studies have revealed that the permeability of reconstructed skin models is much higher compared with human excised skin. This is in accordance with the incomplete barrier found in these models. Nevertheless, the reconstructed skin models available today are useful tools for estimating the rank order of percutaneous absorption of a series of compounds with different physicochemical properties. A major challenge in the further development of reconstructed skin models for drug delivery studies is to obtain a barrier function similar to in vivo skin. Whether this goal will be achieved in the near future is uncertain and will be, in the authors' opinion, a very difficult task.