RESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. PATIENTS AND METHODS: In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. RESULTS: In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1- tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). CONCLUSION: Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.
Assuntos
Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/secundário , Seguimentos , Humanos , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated complication, amyloidosis. The 2009 U.S. Food and Drug Administration approval of colchicine as a new drug had research consequences. Recent investigations with large cohorts of patients with gout who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatological uses include the treatment of epidermolysis bullosa acquisita, leucocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine.
Assuntos
Colchicina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Supressores da Gota/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Colchicina/história , Colchicina/farmacologia , Febre Familiar do Mediterrâneo/tratamento farmacológico , Gota/tratamento farmacológico , Gota/história , Supressores da Gota/história , Supressores da Gota/farmacologia , História do Século XIX , História do Século XXI , História Antiga , Humanos , Doenças Reumáticas/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Estomatite Aftosa/tratamento farmacológico , Moduladores de Tubulina/farmacologiaRESUMO
Sarcoidosis is an uncommon disease of granulomatous inflammation. Genetic predisposition to sarcoidosis is indicated by observations of familial clustering, increased concordance in monozygotic twins over other siblings, and variations in susceptibility and disease presentation among different ethnic groups. Published studies on sarcoidosis have investigated a variety of genetic associations. These studies used techniques ranging from classic human lymphocyte antigen genotype correlations to genome-wide linkage scans. Results have both supported and refuted disease associations with a number of genes potentially involved in the pathogenesis of sarcoidosis. Here, we review representative studies concerning the genetics of sarcoidosis. While investigations to date have failed to identify a unifying genetic signature associated with sarcoidosis, numerous studies have identified genetic associations with disease subtypes or within specific populations. These studies suggest that genetic susceptibility to sarcoidosis is complex and polygenic in nature. Future studies will help clarify the genetics of sarcoidosis and allow for the development of diagnostic, prognostic and therapeutic technologies.
Assuntos
Predisposição Genética para Doença , Sarcoidose/genética , Animais , Humanos , Complexo Principal de Histocompatibilidade , Sarcoidose/imunologiaAssuntos
Fármacos Dermatológicos/efeitos adversos , Ácido Fólico/administração & dosagem , Metotrexato/efeitos adversos , Psoríase/tratamento farmacológico , Custos e Análise de Custo , Fármacos Dermatológicos/administração & dosagem , Interações Medicamentosas , Humanos , Metotrexato/administração & dosagem , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The increased risk of second malignancies, including nonmelanoma skin cancers, in cutaneous T-cell lymphoma (CTCL) patients has been well documented. However, relatively few studies of malignant melanoma in CTCL patients have been reported. METHODS: A database of 250 CTCL patients registered over a 3-year period was searched to identify patients with diagnoses of both mycosis fungoides (MF) and malignant melanoma. RESULTS: We identified six cases of MF associated with malignant melanoma and one associated with dysplastic nevus syndrome, which is a marker of increased risk of melanoma. In four patients, melanoma was diagnosed along with or before MF. In the remaining two patients, MF was diagnosed prior to melanoma, although dysplastic nevi were noted at the time MF was diagnosed. These two patients received treatment for their MF (one with topical nitrogen mustard and another with radiation therapy and nitrogen mustard) prior to the histologic confirmation of melanoma. Six patients had early stages of MF (IA or IB), while one patient presented with simultaneous erythrodermic mycosis fungoides involving the lymph nodes as well as melanoma metastatic to the lymph nodes from an unknown primary. CONCLUSION: There is an elevated prevalence of malignant melanoma in MF patients compared to the general US population (P < 0.00001) with a relative risk of 15.3 for observing malignant melanoma in MF patients (95% confidence interval 7.0-33.8). Possible pathologic links between the two diagnoses include effects of mycosis fungoides therapies, immunosuppression secondary to mycosis fungoides, and genetic alterations in the p16 tumor suppressor protein.
Assuntos
Síndrome do Nevo Displásico/diagnóstico , Melanoma/diagnóstico , Micose Fungoide/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de RegistrosRESUMO
Dysgenesis of the anterior segment of the eye delineates a spectrum of human developmental disorders that show wide phenotypic and genetic heterogeneity. It is also frequently associated with cataracts and glaucoma resulting in visual disability in childhood. The recently described forkhead transcription factor gene Foxe3 was shown to be involved in the dysgenetic lens phenotype in mice, which is characterized by small cataractic lens and anterior segment anomalies. Here we report an identification and characterization of the human ortholog of this gene, FOXE3. The gene was found to be expressed in the anterior lens epithelium and to be mutated in patients with ocular disorders. An insertion of G in the coding region of the FOXE3 gene that occurred 15 nucleotides upstream of the stop codon was identified in a family with anterior segment ocular dysgenesis and cataracts. The mutation causes a frameshift that results in an abnormal sequence of five terminal amino acids and an addition of 111 amino acids to the predicted protein. The mutation was present in two affected individuals from this family and was not identified in 180 normal control chromosomes.
Assuntos
Câmara Anterior/anormalidades , Catarata/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Catarata/patologia , DNA/química , DNA/genética , Análise Mutacional de DNA , Epitélio/metabolismo , Epitélio/patologia , Saúde da Família , Fatores de Transcrição Forkhead , Mutação da Fase de Leitura , Expressão Gênica , Frequência do Gene , Humanos , Cristalino/metabolismo , Cristalino/patologia , Camundongos , Dados de Sequência Molecular , Mutagênese Insercional , Mutação , Mutação de Sentido Incorreto , Linhagem , Homologia de Sequência de AminoácidosRESUMO
Here we report the isolation of a novel forkhead gene, Foxe3, that plays an important role in lens formation. During development Foxe3 is expressed in all undifferentiated lens tissues, and is turned off upon fiber cell differentiation. Foxe3 maps to a chromosomal region containing the dysgenetic lens (dyl) mutation. Mice homozygous for dyl display several defects in lens development. dyl mice also show altered patterns of crystallin expression suggesting a dysregulation of lens differentiation. We have identified mutations in Foxe3 that cosegregate with the dyl phenotype and are a likely cause of the mutant phenotype. Head ectoderm expression of Foxe3 is absent in Rx-/- and Small eye embryos indicating that Rx and Pax6 activity are necessary for Foxe3 expression.