RESUMO
VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a genetically defined disorder identified in 2020, describing patients with inflammatory syndromes associated with haematological dysfunction. It is a severe, treatment-resistant condition, with estimated mortality between 40% and 63%. A wide range of cutaneous manifestations have been described. Here, we report on two patients with treatment-resistant neutrophilic dermatosis and myelodysplastic syndrome, who were subsequently diagnosed with VEXAS syndrome. Our cases highlight the need for dermatologists' awareness of this novel condition and to initiate early referral to haematologists for appropriate multidisciplinary care.
Assuntos
Síndromes Mielodisplásicas , Síndrome de Sweet , Humanos , Síndrome de Sweet/diagnóstico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , MutaçãoAssuntos
Abdome/diagnóstico por imagem , Carcinoma/patologia , Obstrução Intestinal/etiologia , Neoplasias da Próstata/patologia , Neoplasias Retais/secundário , Neoplasias do Colo Sigmoide/secundário , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Carcinoma/cirurgia , Evolução Fatal , Humanos , Obstrução Intestinal/patologia , Laparotomia/métodos , Masculino , Nitrilas/administração & dosagem , Nitrilas/uso terapêutico , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Neoplasias Retais/complicações , Neoplasias Retais/diagnóstico , Neoplasias Retais/cirurgia , Neoplasias do Colo Sigmoide/complicações , Neoplasias do Colo Sigmoide/diagnóstico , Neoplasias do Colo Sigmoide/cirurgia , Tomógrafos Computadorizados , Compostos de Tosil/administração & dosagem , Compostos de Tosil/uso terapêuticoRESUMO
PURPOSE: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers. EXPERIMENTAL DESIGN: Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling. RESULTS: Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition. CONCLUSIONS: We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.
Assuntos
Dosagem de Genes , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclina E/genética , Ciclina E/fisiologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Amplificação de Genes , Deleção de Genes , Histona Acetiltransferases/genética , Histona Acetiltransferases/fisiologia , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Coativador 3 de Receptor Nuclear , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/fisiologia , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Transativadores/genética , Transativadores/fisiologiaRESUMO
PURPOSE: The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features. EXPERIMENTAL DESIGN: Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results. RESULTS: Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends. CONCLUSION: Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
Assuntos
Biomarcadores Tumorais/análise , Perfilação da Expressão Gênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adulto , Idoso , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Lasers , Microdissecção , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/mortalidade , Prognóstico , Análise Serial de TecidosRESUMO
Thyroid nodules are common and occur in up to 50% of the adult population; however, less than 7% of thyroid nodules are malignant. High-resolution ultrasonography (US) is commonly used to evaluate the thyroid gland, but US is frequently misperceived as unhelpful for identifying features that distinguish benign from malignant nodules. Microcalcifications are one of the most specific US findings of a thyroid malignancy. Other useful US features include a marked hypoechogenicity, irregular margins, and the absence of a hypoechoic halo around the nodule. Lymphadenopathy and local invasion of adjacent structures are highly specific features of thyroid malignancy but are less commonly seen. The number, size, and interval growth of nodules are nonspecific characteristics. Suspicious US features may be useful for selecting patients for fine-needle aspiration biopsy when incidental nodules are discovered and when multiple nodules are present. Common interpretative pitfalls that may lead to failure to recognize a malignancy include mistaking cystic or calcified nodal metastases for nodules in a multinodular thyroid, mistaking diffusely infiltrative thyroid carcinomas and multifocal carcinomas for benign disease, and failing to recognize microcalcifications in papillary thyroid cancer.