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1.
Artigo em Inglês | MEDLINE | ID: mdl-33015527

RESUMO

PURPOSE: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS: Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CA p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.

2.
J Am Acad Dermatol ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31812621

RESUMO

BACKGROUND: Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. OBJECTIVE: To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared to the gold standard histopathology. METHODS: Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically-defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue and histopathology was correlated with RCM results. RESULTS: Seventy-two patients were included. Mean age was 66.8 years (SD 11.1; 38 - 89 years); 69.4% were males. 70/72 (97.2%) lesions were located on the head neck with mean largest clinical diameter of 1.3cm (0.3 - 5 cm). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared to the histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (kappa 0.71; p<0.001). LIMITATIONS: No RCM imaging beyond initial planned margins was performed. CONCLUSION: RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

3.
Nat Rev Cancer ; 19(12): 686-697, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31519982

RESUMO

A research autopsy is a post-mortem medical procedure performed on a deceased individual with the primary goal of collecting tissue to support basic and translational research. This approach has increasingly been used to investigate the pathophysiological mechanisms of cancer evolution, metastasis and treatment resistance. In this Review, we discuss the rationale for the use of research autopsies in cancer research and provide an evidence-based discussion of the quality of post-mortem tissues compared with other types of biospecimens. We also discuss the advantages of using post-mortem tissues over other types of biospecimens, including the large amounts of tissue that can be obtained and the extent of multiregion sampling that is achievable, which is not otherwise possible in living patients. We highlight how the research autopsy has supported the identification of the clonal origins and modes of spread among metastases, the extent that selective pressures imposed by treatments cause bottlenecks leading to parallel and convergent tumour evolution, and the creation of rare tissue banks and patient-derived model systems. Finally, we comment on the future of the research autopsy as an integral component of precision medicine strategies.


Assuntos
Autopsia , Neoplasias/genética , Neoplasias/fisiopatologia , Neoplasias/terapia , Projetos de Pesquisa , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese , Resistencia a Medicamentos Antineoplásicos , Evolução Molecular , Humanos , Metástase Neoplásica , Medicina de Precisão , Manejo de Espécimes
4.
J Immunol ; 169(10): 5926-33, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12421977

RESUMO

Asthma is a chronic inflammatory disease of the lung resulting in airway obstruction. The airway inflammation of asthma is strongly linked to Th2 lymphocytes and their cytokines, particularly IL-4, IL-5, and IL-13, which regulate airway hyperresponsiveness, eosinophil activation, mucus production, and IgE secretion. Historically, complement was not thought to contribute to the pathogenesis of asthma. However, our previous reports have demonstrated that complement contributes to bronchial hyperreactivity, recruitment of airway eosinophils, IL-4 production, and IgE responses in a mouse model of pulmonary allergy. To define the complement activation fragments that mediate these effects, we assessed the role of the complement anaphylatoxin C3a in a mouse model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA. Analysis by plethysmography after challenge revealed an attenuation in airway hyperresponsiveness in C3aR-deficient mice relative to wild-type mice. C3aR-deficient mice also had an 88% decrease in airway eosinophils and a 59% reduction in lung IL-4-producing cells. Consistent with the reduced numbers of IL-4-producing cells, C3aR-deficient mice had diminished bronchoalveolar lavage levels of the Th2 cytokines, IL-5 and IL-13. C3aR knockout mice also exhibited decreases in IgE titers as well as reduced mucus production. Collectively, these data highlight the importance of complement activation, the C3a anaphylatoxin, and its receptor during Th2 development in this experimental model and implicate these molecules as possible therapeutic targets in diseases such as asthma.


Assuntos
Complemento C3a/metabolismo , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Proteínas de Membrana , Receptores de Complemento/deficiência , Receptores de Complemento/genética , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/imunologia , Células Th2/imunologia , Animais , Antígenos de Fungos/administração & dosagem , Antígenos de Fungos/imunologia , Aspergillus fumigatus/imunologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/patologia , Isotipos de Imunoglobulinas/biossíntese , Isotipos de Imunoglobulinas/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Injeções Intraperitoneais , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/metabolismo , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores de Complemento/fisiologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Células Th2/metabolismo
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