RESUMO
BACKGROUND: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. METHODS: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. RESULTS: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. CONCLUSION: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/tratamento farmacológico , Metilação de DNA/efeitos dos fármacos , Ácidos Hidroxâmicos/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , DNA de Neoplasias/efeitos adversos , DNA de Neoplasias/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Período Pré-Operatório , VorinostatRESUMO
The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m(2) BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Adenocarcinoma/patologia , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , FarmacogenéticaRESUMO
BACKGROUND: Patients with left ventricular dysfunction have an elevated risk of sudden cardiac death. However, the substrate for ventricular arrhythmia in patients with nonischemic cardiomyopathy remains poorly understood. We hypothesized that the distribution of scar identified by MRI is predictive of inducible ventricular tachycardia. METHODS AND RESULTS: Short-axis cine steady-state free-precession and postcontrast inversion-recovery gradient-echo MRI sequences were obtained before electrophysiological study in 26 patients with nonischemic cardiomyopathy. Left ventricular ejection fraction was measured from end-diastolic and end-systolic cine images. The transmural extent of scar as a percentage of wall thickness (percent scar transmurality) in each of 12 radial sectors per slice was calculated in all myocardial slices. The percentages of sectors with 1% to 25%, 26% to 50%, 51% to 75%, and 76% to 100% scar transmurality were determined for each patient. Predominance of scar distribution involving 26% to 75% of wall thickness was significantly predictive of inducible ventricular tachycardia and remained independently predictive in the multivariable model after adjustment for left ventricular ejection fraction (odds ratio, 9.125; P=0.020). CONCLUSIONS: MR assessment of scar distribution can identify the substrate for inducible ventricular tachycardia and may identify high-risk patients with nonischemic cardiomyopathy currently missed by ejection fraction criteria.
Assuntos
Cardiomiopatias/patologia , Imageamento por Ressonância Magnética/métodos , Disfunção Ventricular Esquerda/patologia , Morte Súbita Cardíaca , Humanos , Processamento de Imagem Assistida por Computador , Miocárdio/patologiaRESUMO
OBJECTIVES: We examined whether B-type natriuretic peptides (BNP) can serve as noninvasive markers of pulmonary capillary wedge pressure (PCWP) in the setting of critical illness. BACKGROUND: The BNP and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are highly correlated with left ventricular (LV) filling pressures in patients with depressed LV systolic function. However, their relationship to PCWP in a heterogeneous intensive care unit (ICU) population has not been established. METHODS: We prospectively studied 40 patients in the ICU requiring invasive hemodynamic monitoring. Hemodynamics were recorded simultaneously with blood sampling for BNP and NT-proBNP. RESULTS: The BNP (median 420 pg/ml) and NT-proBNP (median 3,304 pg/ml) levels were markedly elevated, but weakly correlated with PCWP (BNP, r = 0.40, NT-proBNP, r = 0.32) and other cardiac parameters. Peptide levels were approximately four-fold greater in patients with impaired (estimated glomerular filtration rate [eGFR] <60 ml/min) versus normal (eGFR >60 ml/min) renal function, despite similar PCWP, cardiac index, and LV ejection fraction. In addition, both BNP and NT-proBNP showed stronger correlations with PCWP in patients with preserved (BNP, r = 0.58, NT-proBNP, r = 0.73) versus impaired renal function (BNP, r = 0.48, NT-proBNP, r = 0.34). Interaction terms between eGFR and BNP (p = 0.06) and NT-proBNP (p = 0.04) suggest that eGFR modulates the relationship of these peptides to filling pressures. CONCLUSIONS: The BNPs are markedly elevated, yet show only weak correlations to PCWP in ICU patients requiring invasive hemodynamic monitoring. Thus, a single value for BNP or NT-proBNP may not be a clinically useful noninvasive marker of filling pressures in the critically ill patient. This appears to be especially true in patients with impaired renal function.
Assuntos
Cuidados Críticos , Peptídeo Natriurético Encefálico/sangue , Proteínas do Tecido Nervoso/sangue , Fragmentos de Peptídeos/sangue , Edema Pulmonar/terapia , Pressão Propulsora Pulmonar/fisiologia , Disfunção Ventricular Esquerda/terapia , Idoso , Biomarcadores/sangue , Cateteres de Demora , Feminino , Taxa de Filtração Glomerular/fisiologia , Hemodinâmica/fisiologia , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Edema Pulmonar/sangue , Estatística como Assunto , Disfunção Ventricular Esquerda/sangueRESUMO
BACKGROUND: UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS). RESULTS: Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug-related >or= grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a twice-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Esquema de Medicação , Feminino , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva , Tegafur/administração & dosagem , Uracila/administração & dosagemRESUMO
BACKGROUND: Magnetocardiography (MCG) is a noninvasive technology that measures the magnetic field of the heart by superconducting quantum interference devices (SQUID) sensors. The novelty of the present system is that the sensors can be operated without electromagnetic shielding of the examination room, thus allowing the system to be easily installed in the emergency department or chest pain unit. Studies in shielded rooms, found that this imaging modality may have better sensitivity as compared to ECG in detecting ischemia. We aimed (1) to assess the reproducibility, intra-observer, and interobserver interpretation variability and (2) to assess the MCG maps in the presence of coronary narrowings. METHODS AND RESULTS: All measurements were performed in a nonshielded room. For the first part of the study, two MCG maps were recorded in 24 otherwise healthy volunteers (age 20-44 years, median 24, 16 male) in an interval ranging from 2 to 48 hours. The maps were interpreted using the CardioMag software for contour maps, averaged MCG time traces, and waveform morphology of repolarization by two observers blinded to each other. The parameters tested had low disagreement between repeated measurements. The correlations of the intra-observer and interobserver interpretation were excellent. Secondly, MCG maps were obtained in 29 patients referred for angiography due to suspected coronary artery disease. Nineteen of them had coronary narrowings defined as more than 50%. In this group, 16 (84.2%) had abnormal MCG maps as compared to only 5 (26.3%) who had abnormal ECGs (P < 0.01). CONCLUSIONS: MCG maps can be successfully obtained in a nonshielded room and allow feasible, accurate, and reproducible measurements with little intra-observer and interobserver variability. Ischemic changes in the heart's magnetic field may occur before electrical changes. Our pilot data suggests that this imaging modality may potentially offer better sensitivity as compared to rest ECG in detecting ischemia in a cohort of patients who had coronary narrowings identified by angiography.
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Fenômenos Eletromagnéticos , Testes de Função Cardíaca/métodos , Isquemia Miocárdica/diagnóstico , Algoritmos , Desenho de Equipamento , Humanos , Reprodutibilidade dos Testes , SoftwareRESUMO
BACKGROUND: Chronic kidney disease is associated with an increased risk of ischemic and bleeding complications after percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, has been shown to reduce adverse bleeding events compared to unfractionated heparin in patients undergoing PCI. However, the effect of diminished renal function on the safety and efficacy of bivalirudin for PCI is unknown. We aimed to test the safety of bivalirudin in routine practice and to assess whether this benefit was influenced by renal function. METHODS AND RESULTS: The interaction between renal impairment and benefit from bivalirudin was assessed in 115 consecutive patients (age 68.5+/-12.1, 45% female) undergoing PCI. Bivalirudin dosing was adjusted based on renal function. Creatinine clearance (CrCl) was calculated using the Cockroft-Gault formula. The composite endpoints of in-hospital death, myocardial infarction or revascularization and bleeding events were assessed. Overall, these events occurred in 10 (8.7%) patients. Patients with a CrCl<60 ml/min had a significantly increased risk for in-hospital complications (18.6 versus 2.78%, P = 0.011). Univariate analysis for MACE and bleeding were significant for CrCl<60 ml/min OR: 2.54 (95% CI: 1.61-39.7, P = 0.011), age OR: 3.29 (95% CI: 1.07-1.39, P<0.001) and female gender OR: 2.1 (95% CI: 0.036-0.89, P = 0.036). Risk of complications increased with decreasing renal function: 2.7, 14.2, and 37.5% for CrCl of >60, 30-60 or <30 ml/min, respectively, P = 0.002). CONCLUSION: Advanced age, renal dysfunction, and female gender remain important risk factors for ischemic and bleeding complications in patients undergoing PCI with bivalirudin.
Assuntos
Angioplastia Coronária com Balão , Antitrombinas/uso terapêutico , Doença das Coronárias/epidemiologia , Doença das Coronárias/terapia , Falência Renal Crônica/epidemiologia , Fragmentos de Peptídeos/uso terapêutico , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Comorbidade , Creatinina/urina , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hirudinas , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Fatores de RiscoRESUMO
In the therapy of ST-segment elevation myocardial infarction (MI), the close relationship between early reperfusion of the infarct-related artery and improved outcomes has focused research on improving the speed and efficacy of pharmacologic reperfusion therapy. Recently, it has become appreciated that even among patients who achieve normal epicardial reperfusion after reperfusion therapy, myocardial and microvascular perfusion may be inadequate. Such patients are at increased risk for the development of death and congestive heart failure. The addition of glycoprotein (GP) IIb/IIIa antagonists to standard fibrinolytic therapy has been shown to improve both epicardial and myocardial reperfusion. This article focuses on emerging data regarding the combination of GP IIb/IIa antagonists and standard fibrinolytic agents for the treatment of acute ST-segment elevation MI.