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2.
Artigo em Inglês | MEDLINE | ID: mdl-33009489

RESUMO

BACKGROUND: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. METHODS: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. RESULTS: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003). CONCLUSIONS: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

4.
J Pancreat Cancer ; 6(1): 55-63, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32642631

RESUMO

Purpose: Our institution's hepatopancreaticobiliary surgery service (HPBS) has demonstrated low rates of venous thromboembolism (VTE). We sought to determine whether the HPBS's regimented multimodal VTE prophylaxis pathway, which includes the use of mechanical prophylaxis, pharmacological prophylaxis, and ambulation, plays a role in achieving low VTE rates. Methods: We compared pancreatic surgeries in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) participant user file with our institution's data from 2011 to 2016 using univariate, multivariate, and matching statistics. Results: Among 36,435 NSQIP operations, 850 (2.3%) underwent surgery by the HPBS. The HPBS achieved lower VTE rates than the national cohort (2.0% vs. 3.5%, p = 0.018). Upon multivariate analysis, having an operation performed by the HPBS independently conferred lower odds of VTE incidence in the matched cohort (odds ratio = 0.530, p = 0.041). Conclusions: We identified an independent correlation between the HPBS and decreased VTE incidence, which we believe to be due to strict adherence to and team participation in a high risk VTE prophylaxis pathway, including inpatient pharmacological prophylaxis, thromboembolic deterrent stockings, sequential compression devices, and mandatory ambulation.

5.
J Gastrointest Surg ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32500418

RESUMO

BACKGROUND: Treatment guidelines for stage I-III esophageal cancer indicate that management should include surgery in appropriate patients. Variations in utilization of surgery may contribute to racial differences observed in survival. We sought to identify factors associated with racial disparities in surgical resection of esophageal cancer and evaluate associated survival differences. METHODS: Patients diagnosed with stage I-III esophageal cancer from 2004 to 2015 were identified using the National Cancer Database. Matched patient cohorts were created to reduce confounding. Multivariate logistic regression was used to identify factors associated with receipt of surgery. Multi-level modeling was performed to control for random effects of individual hospitals on surgical utilization. RESULTS: A total of 60,041 patients were included (4402 black; 55,639 white). After 1:1 matching, there were 5858 patients evenly distributed across race. For all stages, significantly fewer black than white patients received surgery. Black race independently conferred lower likelihood of receiving surgery in single-level multivariable analysis (OR (95% CI); stage I, 0.67 (0.48-0.94); stage II, 0.76 (0.60-0.96); stage III, 0.62 (0.50-0.76)) and after controlling for hospital random effects. Hospital-level random effects accounted for one third of the unexplained variance in receipt of surgery. Risk-adjusted 1-, 3-, and 5-year mortality was higher for patients who did not undergo surgery. CONCLUSION: Black patients with esophageal cancer are at higher risk of mortality compared to white patients. This increased risk may be influenced by decreased likelihood of receiving surgical intervention for resectable disease, in part because of between-hospital differences. Improving access to surgical care may improve disparities in esophageal cancer survival.

6.
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
7.
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
8.
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
9.
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
10.
Surg Endosc ; 30(8): 3267-78, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26558910

RESUMO

OBJECTIVE: To assess trends in utilization and perioperative outcomes of laparoscopic and open abdominal wall hernia repair. METHODS: Using the ACS-NSQIP database between 2009 and 2012, patients were identified as having an ICD-9 diagnosis of an umbilical, ventral, or incisional hernia as well as a CPT code for a laparoscopic or open abdominal wall hernia repair. A coarsened exact matching procedure was utilized to create a matched cohort to mitigate selection bias. Thirty-day outcomes analysis was done for the aggregate and matched cohorts. Subcategory analysis was performed for inpatient/outpatient status, strangulated/incarcerated hernias, initial/recurrent repairs, and hernia type (umbilical, ventral, incisional). Chi-square analysis was performed to determine the statistical significance of each comparison. RESULTS: In total, 112,074 qualifying patients were identified, 86,566 (77.24 %) open and 25,508 (22.76 %) laparoscopic. Patients undergoing laparoscopic repair were more likely to have preexisting comorbidities, but less likely to experience any postoperative morbidity (11.74 vs. 7.25 %, P < 0.0001), serious morbidity (4.55 vs. 3.02 %, P < 0.0001), or mortality (0.36 vs. 0.24 %, P = 0.0030). Creation of the matched cohort produced 17,394 patients in both the laparoscopic and open groups and resulted in a loss of advantage for the laparoscopic approach in terms of morbidity associated with umbilical hernia repairs (P = 0.0082 vs. P = 0.3172). Patients undergoing laparoscopic repair were still less likely to experience any postoperative (9.57 vs. 4.92 %, P < 0.0001) or serious morbidity (3.37 vs. 1.70 %, P < 0.0001). Hospital length of stay in the matched cohort supported initial primary repairs done by an open approach. CONCLUSION: The laparoscopic approach is used in a minority of abdominal wall hernia repairs, though utilization increased by 40 % from 2009 to 2012. The laparoscopic approach continues to be safer on many fronts, but not all, and is arguably not better for umbilical or primary hernia repairs on the basis of overall morbidity and length of stay.


Assuntos
Hérnia Umbilical/cirurgia , Hérnia Ventral/cirurgia , Herniorrafia/métodos , Hérnia Incisional/cirurgia , Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Parede Abdominal/cirurgia , Adulto , Idoso , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Classificação Internacional de Doenças , Laparotomia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Mortalidade , Estados Unidos/epidemiologia
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