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1.
Lung Cancer ; 127: 25-33, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30642547

RESUMO

OBJECTIVES: A malignant pleural effusion (MPE) is a common complication in non-small cell lung cancer (NSCLC) with important staging and prognostic information. Patients with MPEs are often candidates for advanced therapies, however, the current gold standard, cytological analysis of pleural fluid samples, has limited sensitivity. We aimed to demonstrate the feasibility of non-invasive enumeration and immunophenotyping of EpCAM-positive cells in pleural fluid samples for the diagnosis of a MPE in NSCLC patients. MATERIALS AND METHODS: Pleural fluid specimens were prospectively collected from patients with NSCLC and the CellSearch® technology was utilized for the enumeration of pleural EpCAM-positive cells (PECs) and determination of PD-L1 expression on PECs from pleural fluid samples. The diagnostic performance of the enumeration of single PECs and PEC clusters was assessed using receiver operating characteristic (ROC) curves. The Kaplan-Meier method and Cox proportional hazards model was used to assess the impact of PECs and PEC clusters on overall survival (OS). RESULTS: 101 NSCLC patients were enrolled. The median number of PECs was significantly greater in the malignant (n = 84) versus non-malignant group (n = 17) (730 PECs/mL vs 1.0 PEC/mL, p < 0.001). The area under the ROC curve was 0.91. A cutoff value of 105 PECs/mL had a sensitivity and specificity of 73% and 100% for the diagnosis of a MPE, respectively. Among 69 patients with a pathology-confirmed MPE and tissue immunohistochemistry (IHC) results, 15 (22%) had greater than 50% PD-L1+ PECs. Overall concordance between tissue and PEC PD-L1 expression was 76%. Higher numbers of pleural effusion single PECs were associated with inferior overall survival (Cox adjusted HR 1.8, 95% CI: 1.02-3.05 p = 0.043). CONCLUSION: Non-invasive measurement of PECs in NSCLC patients, using an automated, clinically available approach, may improve the diagnostic accuracy of a MPE, allow for immunophenotyping of PECs, and provide prognostic information.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Molécula de Adesão da Célula Epitelial/metabolismo , Neoplasias Pulmonares/diagnóstico , Cavidade Pleural/parasitologia , Derrame Pleural Maligno/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
2.
JAMA Oncol ; 5(2): 173-180, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30325992

RESUMO

Importance: The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non-small cell lung cancer (NSCLC) have not been formally assessed. Objective: To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting. Design, Setting, and Participants: This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management. Plasma NGS was performed using a 73-gene commercial platform. Patients were enrolled at the Hospital of the University of Pennsylvania from April 1, 2016, through January 2, 2018. The database was locked for follow-up and analyses on January 2, 2018, with a median follow-up of 7 months (range, 1-21 months). Main Outcomes and Measures: The number of patients with targetable alterations detected with plasma and tissue NGS; the association between the allele fractions (AFs) of mutations detected in tissue and plasma; and the association of response rate with the plasma AF of the targeted mutations. Results: Among the 323 patients with NSCLC (60.1% female; median age, 65 years [range, 33-93 years]), therapeutically targetable mutations were detected in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF for 113 (35.0%) overall. Ninety-four patients (29.1%) had plasma testing only at the discretion of the treating physician or patient preference. Among the 94 patients with plasma testing alone, 31 (33.0%) had a therapeutically targetable mutation detected, thus obviating the need for an invasive biopsy. Among the remaining 229 patients who had concurrent plasma and tissue NGS or were unable to have tissue NGS, a therapeutically targetable mutation was detected in tissue alone for 47 patients (20.5%), whereas the addition of plasma testing increased this number to 82 (35.8%). Thirty-six of 42 patients (85.7%) who received a targeted therapy based on the plasma result achieved a complete or a partial response or stable disease. The plasma-based targeted mutation AF had no correlation with depth of Response Evaluation Criteria in Solid Tumors response (r = -0.121; P = .45). Conclusions and Relevance: Integration of plasma NGS testing into the routine management of stage IV NSCLC demonstrates a marked increase of the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA , Neoplasias Pulmonares/genética , Mutação , Medicina de Precisão , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Tomada de Decisão Clínica , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos
3.
Pigment Cell Melanoma Res ; 31(1): 73-81, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28786531

RESUMO

To determine the feasibility of liquid biopsy for monitoring of patients with advanced melanoma, cell-free DNA was extracted from plasma for 25 Stage III/IV patients, most (84.0%) having received previous therapy. DNA concentrations ranged from 0.6 to 390.0 ng/ml (median = 7.8 ng/ml) and were positively correlated with tumor burden as measured by imaging (Spearman rho = 0.5435, p = .0363). Using ultra-deep sequencing for a 61-gene panel, one or more mutations were detected in 12 of 25 samples (48.0%), and this proportion did not vary significantly for patients on or off therapy at the time of blood draw (52.9% and 37.5% respectively; p = .673). Sixteen mutations were detected in eight different genes, with the most frequent mutations detected in BRAF, NRAS, and KIT. Allele fractions ranged from 1.1% to 63.2% (median = 29.1%). Among patients with tissue next-generation sequencing, nine of 11 plasma mutations were also detected in matched tissue, for a concordance of 81.8%.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Melanoma/diagnóstico , Mutação , Neoplasias Cutâneas/diagnóstico , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Melanoma/sangue , Melanoma/genética , Pessoa de Meia-Idade , Projetos Piloto , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética
4.
Clin Cancer Res ; 22(23): 5772-5782, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27601595

RESUMO

PURPOSE: The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. EXPERIMENTAL DESIGN: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. RESULTS: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. CONCLUSIONS: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772-82. ©2016 AACR.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
J Am Acad Orthop Surg ; 14(2): 101-12, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16467185

RESUMO

Children with early onset scoliosis typically present before age 5 years. Radiographic criteria help to distinguish progressive cases from those that will spontaneously resolve. Severe cardiopulmonary problems may occur in untreated progressive cases. A comprehensive evaluation should be performed to identify commonly associated conditions, such as plagiocephaly, congenital heart disease, inguinal hernia, and hip dysplasia. For curves >20 degrees , magnetic resonance imaging of the neural axis is indicated to rule out occult central nervous system lesions. Surgical management should be considered when nonsurgical measures, including bracing and casting, fail to arrest progression. Surgical methods continue to evolve and are primarily directed at obtaining and maintaining curve correction while simultaneously preserving spinal and trunk growth.


Assuntos
Escoliose/terapia , Algoritmos , Fenômenos Biomecânicos , Pré-Escolar , Progressão da Doença , Humanos , Próteses e Implantes , Alvéolos Pulmonares/crescimento & desenvolvimento , Remissão Espontânea , Escoliose/complicações , Escoliose/fisiopatologia , Fusão Vertebral , Coluna Vertebral/crescimento & desenvolvimento , Toracoplastia , Resultado do Tratamento
6.
J Hand Surg Am ; 30(3): 479-82, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15925155

RESUMO

We report a case of delayed rupture of the flexor digitorum superficialis and profundus tendons after the use of local corticosteroid injections for trigger finger. The treatment involved the exploration, debridement, and placement of a silicone rod for planned flexor digitorum profundus staged reconstruction.


Assuntos
Glucocorticoides/uso terapêutico , Traumatismos dos Tendões/cirurgia , Tendões/cirurgia , Tenossinovite/tratamento farmacológico , Triancinolona Acetonida/uso terapêutico , Idoso , Desbridamento , Humanos , Masculino , Próteses e Implantes , Recidiva , Retratamento , Ruptura/cirurgia , Silicones , Traumatismos dos Tendões/diagnóstico , Tenossinovite/complicações , Fatores de Tempo
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