RESUMO
BACKGROUND: Gastric adenocarcinoma (GAC) is the third deadliest malignant neoplasm worldwide, mostly because of late disease diagnosis, low chemotherapy response rates, and an overall lack of tumor biology understanding. Therefore, tools for prognosis and prediction of treatment response are needed. Quantification of circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) and their expression of biomarkers has potential clinical relevance. Our aim was to evaluate CTCs and CTM and their expression of HER2 and plakoglobin in patients with nonmetastatic GAC, correlating the findings to clinicopathological data. MATERIALS AND METHODS: CTC enrichment was performed with isolation by size of epithelial tumor cells, and the analysis was performed with immunocytochemistry and microscopy. Two collections were made: one at diagnosis (55 samples before neoadjuvant treatment) and one after surgery and before adjuvant therapy (33 samples). RESULTS: A high detection rate of CTCs (90%) was observed at baseline. We evaluated HER2 expression in 45/55 biopsy samples and in 42/55 CTC samples, with an overlap of 36 subjects. Besides the good agreement observed for HER2 expression in primary tumors and paired CTCs for 36 cases (69.4%; κ = 0.272), the analysis of HER2 in CTCs showed higher positivity (43%) compared with primary tumors (11%); 3/5 patients with disease progression had HER2-negative primary tumors but HER2-positive CTCs. A significant CTC count drop in follow-up was seen for CTC-HER2-positive cases (4.45 to 1.0 CTCs per mL) compared with CTC-HER2-negative cases (2.6 to 1.0 CTCs per mL). The same was observed for CTC-plakoglobin-positive cases (2.9 to 1.25 CTCs per mL). CONCLUSION: CTC analysis, including their levels, plakoglobin, and HER2 expression, appears to be a promising tool in the understanding the biology and prognosis of GAC. IMPLICATIONS FOR PRACTICE: The analysis of circulating tumor cell levels from the blood of patients with gastric adenocarcinoma, before and after neoadjuvant treatment, is useful to better understand the behavior of the disease as well as the patients more likely to respond to treatment.
Assuntos
Embolia/patologia , Células Neoplásicas Circulantes/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biomarcadores Tumorais/sangue , Embolia/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/cirurgia , Taxa de SobrevidaRESUMO
BACKGROUND: Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non-vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking. METHODS AND RESULTS: We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarin-controlled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01). CONCLUSION: Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin.
Assuntos
Fibrilação Atrial/complicações , Embolia/prevenção & controle , Fator Xa/uso terapêutico , Infarto do Miocárdio/complicações , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Terapia Trombolítica/métodos , Varfarina/uso terapêutico , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Coagulação Sanguínea , Método Duplo-Cego , Embolia/sangue , Embolia/etiologia , Inibidores do Fator Xa/uso terapêutico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Warfarin reduces ischemic stroke in atrial fibrillation, but has numerous limitations. Novel oral anticoagulants provide more predictable anticoagulation with fewer shortcomings. HYPOTHESIS: Novel oral anticoagulants are superior to warfarin to prevent stroke or systemic embolism. METHODS: Phase III randomized warfarin-controlled trials enrolling >3000 patients that reported clinical efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through October 2012. Two reviewers extracted data; differences were resolved by consensus. The end points analyzed were stroke or systemic embolism (primary efficacy composite); all-cause mortality, ischemic stroke, systemic embolism (individually, secondary efficacy); and hemorrhagic stroke, major bleeding (individually, safety). The Mantel-Haenszel method was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI) from fixed-effects (if homogenous) or random-effects models (if heterogeneous). RESULTS: In 5 studies of 51895 patients, the composite of stroke or systemic embolism (RR: 0.82; 95% CI: 0.69-0.98; P = 0.03) and all-cause mortality (RR: 0.91; 95% CI: 0.85-0.96; P = 0.0026, respectively) were reduced with the novel agents. Factor Xa inhibitors significantly reduced the primary composite (RR: 0.84; 95% CI: 0.74-0.94; P = 0.004) and all-cause mortality (RR: 0.91; 95% CI: 0.84 - 0.98; P = 0.01). Direct thrombin inhibitor achieved results similar to the overall meta-analysis (drug class-outcome interactions P = 0.47 for primary outcome, P = 1.00 for mortality). Compared with warfarin, novel anticoagulants markedly reduced hemorrhagic stroke (RR: 0.51; 95% CI: 0.41-0.64; P < 0.0001). CONCLUSIONS: Novel oral anticoagulants may be superior to warfarin in patients with atrial fibrillation, reducing the composite of stroke or systemic embolism and lowering all-cause mortality. The benefit is largely due to fewer hemorrhagic strokes.
Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Embolia/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Administração Oral , Anticoagulantes/efeitos adversos , Antitrombinas/administração & dosagem , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/mortalidade , Distribuição de Qui-Quadrado , Ensaios Clínicos Fase III como Assunto , Embolia/sangue , Embolia/etiologia , Embolia/mortalidade , Inibidores do Fator Xa , Hemorragia/induzido quimicamente , Humanos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Resultado do Tratamento , Varfarina/efeitos adversosRESUMO
BACKGROUND: Atrial fibrillation is associated to a high risk of systemic embolism and to hypercoagulability. AIM: To evaluate the activation of the coagulation cascade through determinations of the thrombin-antithrombin complex in patients with atrial fibrillation and to correlate this data with the clinical and echocardiographic risk factors for systemic embolism. PATIENTS AND METHODS: In 53 patients with atrial fibrillation plasma levels of the thrombin-antithrombin complex were determined on admission to a coronary care unit and 30 days later. Using a univariate and multiple regression analysis, the association basal thrombin-antithrombin with the duration of the arrhythmia, age over 70 years, previous use of antiplatelet agents, history of hypertension, mitral valve disease, diabetes, heart failure, previous systemic embolism, left atrial diameter and the presence of spontaneous contrast echo or thrombus in the left atrial appendage, was studied. RESULTS: Basal thrombin-antithrombin values were 40.1 +/- 69 mg/L (Median 8.34 [3.0-47.5]) compared to 2.7 +/- 3.3 mg/L in healthy controls (p < 0.001). No significant correlation was found between activation of the coagulation cascade and risk factors for systemic embolism. There were no significant differences in thrombin-antithrombin values between patients with chronic or paroxysmal atrial fibrillation (29.5 +/- 43 mg/L and 49.4 +/- 83 mg/L respectively). Mean thrombin-antithrombin values in patients under antiplatelet agents were lower than in those without treatment (17.3 +/- 43 vs 66.8 +/- 127 mg/L; p = 0.018). CONCLUSIONS: The activation of the coagulation cascade in patients with atrial fibrillation was confirmed. However, no association of this activation with well known clinical and echocardiographic risk factors for systemic embolism, was found. Previous antiplatelet treatment prevented a higher activation of the coagulation cascade.