RESUMEN
BACKGROUND: Guidelines for the use of chemotherapy and endocrine therapy recently recommended that estrogen receptor (ER) status be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. In clinical practice, a range of thresholds are used; a common one is 10% positivity. Data addressing the optimal threshold with regard to the efficacy of endocrine therapy are lacking. In this study, we compared patient, tumor, treatment and survival differences among breast cancer patients using ER-positivity thresholds of 1% and 10%. METHODS: The study population consisted of patients with primary breast carcinoma treated at our center from January 1990 to December 2011 and whose records included complete data on ER status. Patients were separated into three groups: ≥10% positive staining for ER (ER-positive ≥10%), 1%-9% positive staining for ER (ER-positive 1%-9%) and <1% positive staining (ER-negative). RESULTS: Of 9639 patients included, 80.5% had tumors that were ER-positive ≥10%, 2.6% had tumors that were ER-positive 1%-9% and 16.9% had tumors that were ER-negative. Patients with ER-positive 1%-9% tumors were younger with more advanced disease compared with patients with ER-positive ≥10% tumors. At a median follow-up of 5.1 years, patients with ER-positive 1%-9% tumors had worse survival rates than did patients with ER-positive ≥10% tumors, with and without adjustment for clinical stage and grade. Survival rates did not differ significantly between patients with ER-positive 1%-9% and ER-negative tumors. CONCLUSIONS: Patients with tumors that are ER-positive 1%-9% have clinical and pathologic characteristics different from those with tumors that are ER-positive ≥10%. Similar to patients with ER-negative tumors, those with ER-positive 1%-9% disease do not appear to benefit from endocrine therapy; further study of its clinical benefit in this group is warranted. Also, there is a need to better define which patients of this group belong to basal or luminal subtypes.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/clasificación , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal no Infiltrante/clasificación , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/terapia , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. RESULTS: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. CONCLUSION: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. CLINICAL TRIAL NUMBER: NCT00499603.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante/métodos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Everolimus , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Many pleural diseases involve fibrin deposition within the pleural cavity, an event that necessarily involves the mesothelium. This study of human pleural mesothelial cells (HPMC) was designed to determine how the mesothelium initiates and sustains the coagulation process. We used functional assays for activation of both factor X and prothrombin to examine expression and assembly of procoagulant activity by human pleural mesothelial cells in culture. The rates of factor Xa and thrombin formation were calcium-dependent. The rate of factor Xa formation in the presence of added factor VII increased in a concentration-dependent manner, suggesting that tissue factor is the primary procoagulant associated with HPMC. The fact that direct binding of radioiodinated factor VIIa to HPMC was specific, concentration-dependent and saturable confirms that tissue factor is expressed on the cell surface. The rate of thrombin formation increased with factor Xa concentration, and the rate was 5-, 6-fold higher in presence of added factor Va indicating that HPMC support expression of prothrombinase activity. Further, direct binding of radioiodinated factor Xa to HPMC was specific, concentration-dependent and saturable, confirming that the cells support the assembly of the prothrombinase complex.
Asunto(s)
Factores de Coagulación Sanguínea/biosíntesis , Pleura/metabolismo , Células Cultivadas , Células Epiteliales , Epitelio/metabolismo , Factor Xa/biosíntesis , Humanos , Pleura/citología , Trombina/biosíntesis , Tromboplastina/metabolismoRESUMEN
The potential importance of pleural fibrin deposition in the pathogenesis of pleural injury is supported by both clinical and experimental observations. We hypothesized that the local equilibrium between procoagulant and fibrinolytic activities is disrupted to favor fibrin deposition in exudative pleuritis. To test this hypothesis, we characterized procoagulant and fibrinolytic activities in pleural exudates from patients with pneumonia, lung cancer, or empyema and transudates from patients with congestive heart failure. Procoagulant activity was generally increased in exudative processes and was due mainly to tissue factor. All effusions contained antithrombin III and inhibited factor Xa and thrombin, but endogenous prothrombinase or thrombin activities were variably detected. Pleural fluid fibrinolytic activity was increased in congestive heart failure and was due to both tissue plasminogen activator and urokinase. Depressed fibrinolytic activity was found in pleural exudates despite increased concentrations of plasminogen, mainly glu-1-plasminogen, and was due to inhibition of plasminogen activation by plasminogen activator inhibitors 1 and 2 and of plasmin, in part by alpha 2-antiplasmin. Concentrations of PAI-1 in exudative pleural fluids were increased up to 913-fold, compared with normal pooled plasma. Exudative pleural effusions are characterized by increased procoagulant and depressed fibrinolytic activity, favoring fibrin deposition in the pleural space. The balance of these activities is reversed and favors fibrin clearance in congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Fibrina/metabolismo , Pleura/metabolismo , Derrame Pleural/fisiopatología , Coagulación Sanguínea , Factores de Coagulación Sanguínea/fisiología , Empiema/complicaciones , Fibrinólisis , Insuficiencia Cardíaca/complicaciones , Humanos , Derrame Pleural/etiología , Derrame Pleural/metabolismo , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/fisiopatología , Neumonía/complicacionesRESUMEN
The epithelial lining of the airways is subject to injury through several processes, including infections, bronchiolitis, and fume exposures. Because airway fibrin deposition influences the course of local injury, we examined how two inflammatory cytokines influenced fibrin formation and clearance in human tracheal epithelial cells (TEC). TEC were treated with transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha). TNF-alpha increased release of tissue factor (TF)-related procoagulant activity that, through generation of factor Xa, promotes assembly of the prothrombinase complex at the cell surface. Fibrinolytic activity was plasminogen dependent and due to both urokinase (uPA) and tissue plasminogen activator (tPA). The cells expressed plasminogen activator inhibitor 1 (PAI-1), but relatively little PAI-2. Depression of fibrinolysis by TGF-beta correlated with increased PAI-1. Conversely, TNF-alpha increased plasminogen activator (PA) activity due to increased uPA. Fibrinolytic activity was inhibited by actinomycin D and cyclohexamide, but changes in mRNAs for uPA, tPA, PAI-1, and TF by either cytokine were not appreciable. PAI-2 mRNA was not found. The data indicate that TGF-beta decreases the fibrinolytic capacity of TEC, suggesting that this cytokine promotes fibrin retention. TNF-alpha increases expression of both procoagulant and fibrinolytic activities; this differential regulation could favor both pericellular fibrin formation and dissolution.
Asunto(s)
Factores de Coagulación Sanguínea/metabolismo , Fibrinólisis/efectos de los fármacos , Tráquea/fisiología , Factor de Crecimiento Transformador beta/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Secuencia de Bases , Células Cultivadas , Epitelio/efectos de los fármacos , Epitelio/fisiología , Factor X/metabolismo , Factor Xa/metabolismo , Fibrina/metabolismo , Humanos , Datos de Secuencia Molecular , Inhibidor 1 de Activador Plasminogénico/genética , Activadores Plasminogénicos/genética , ARN Mensajero/análisis , Tráquea/efectos de los fármacosRESUMEN
The mesothelium contains both procoagulant and fibrinolytic activities. An imbalance between these activities could account for the abnormal fibrin turnover and pleural fibrin deposition that is characteristic of pleural inflammation. Procoagulant activity of human pleural mesothelial cells (HPMC) is in part due to tissue factor, and the prothrombinase complex can also assemble at the HPMC surface. HPMC express tissue plasminogen activator (tPA) but no detectable fibrinolytic activity in a fibrin plate assay. Inhibition of HPMC fibrinolytic activity is due, in part, to elaboration of plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) as well as antiplasmins. Synthesis of PAI-1 and PAI-2 is inhibited by actinomycin D and cyclohexamide. HPMC PAI-1 is increased by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), as is tPA release, while PAI-1 mRNA is unchanged and tPA mRNA is increased. PAI-2 release is induced by TNF-alpha and TGF-beta. Because they are a rich source of PAI-1 and PAI-2, HPMC may contribute to the high levels of these inhibitors in pleural exudates. Stimulation of HPMC by TNF-alpha or TGF-beta in vitro did not alter HPMC procoagulant activity nor the balance of elevated PAI and antiplasmins relative to PA, changes that collectively favor formation and persistence of pericellular fibrin.
Asunto(s)
Fibrina/metabolismo , Derrame Pleural/metabolismo , Secuencia de Bases , Factores de Coagulación Sanguínea/metabolismo , Células Cultivadas , Cicloheximida/farmacología , Dactinomicina/farmacología , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Epitelio/patología , Fibrinólisis , Fibroblastos/metabolismo , Humanos , Inflamación , Pulmón/metabolismo , Mesotelioma , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 2 de Activador Plasminogénico/genética , Derrame Pleural/patología , Protrombina/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , Activador de Tejido Plasminógeno/genética , Factor de Crecimiento Transformador beta/farmacología , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/farmacología , Activador de Plasminógeno de Tipo Uroquinasa/genéticaRESUMEN
Lung injury induced by 100% O2 over 6 days is characterized by markedly less alveolar fibrin and rare hyaline membranes in premature versus adult baboons. To determine the mechanism(s) underlying alveolar fibrin deposition in the evolution of hyaline membrane disease (HMD) through diffuse alveolar damage (DAD) and bronchopulmonary dysplasia (BPD), we measured procoagulant and fibrinolytic activities in lung lavage of premature baboons with HMD, those treated with 100% O2 for 6 days (DAD) or for 7 days followed by 14 days 80% O2 (BPD). Lavage procoagulant activity, mainly due to tissue factor associated with Factor VII, was increased by hyperoxia. Plasminogen-dependent fibrinolytic activity, due to both tissue plasminogen activator and urokinase, was stable or increased after hyperoxia. Plasminogen activator inhibitor 1 (PAI-1) was detectable in lavage of animals with HMD but not those with evolving DAD or BPD. Antiplasmin activity was stable or decreased. Although plasminogen was undetectable in lavage, D-dimer was increased in lavage of the groups exposed to hyperoxia versus HMD. The defect in plasminogen activator activity in lavage fluids of adult baboons with DAD induced by O2 does not occur in premature baboons with HMD, evolving DAD, or BPD. Expression of fibrinolytic activity in the lower respiratory tract of premature baboons is dependent on local access to plasminogen, which is present in relatively low concentrations in plasma of these animals.
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patología , Fibrina/análisis , Fibrina/metabolismo , Fibrinólisis , Enfermedad de la Membrana Hialina/metabolismo , Enfermedad de la Membrana Hialina/patología , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Displasia Broncopulmonar/etiología , Factor VII/análisis , Humanos , Enfermedad de la Membrana Hialina/inducido químicamente , Enfermedad de la Membrana Hialina/complicaciones , Recién Nacido , Masculino , Oxígeno , Papio , Inhibidor 1 de Activador Plasminogénico/análisis , Respiración Artificial/efectos adversos , Activador de Tejido Plasminógeno/farmacología , Activador de Plasminógeno de Tipo Uroquinasa/farmacologíaRESUMEN
Extravascular fibrin deposition characterizes diverse forms of lung and pleural injury. Fibrin formation in these compartments is locally potentiated by the assembly and expression of the prothrombinase procoagulant complex (factors Xa, Va and II) at the surface of human lung fibroblasts and pleural mesothelial cells. We sought to identify structural domains on factor Xa that mediate expression of prothrombinase activity by these cells. In order to accomplish this objective, we used panels of monoclonal antibodies (MoAbs) to factor X to block prothrombinase assembly and function on the surface of cultured human lung fibroblasts and pleural mesothelial cells. Of 30 factor X MoAbs that recognized native factors X and Xa, 10 completely inhibited factor Xa function (prothrombin activation), and five others neutralized Xa function without affecting cell-binding, presumably by blocking the prothrombin binding site. Western blots showed that these inhibitory MoAbs reacted with the Xa heavy-chain. One MoAb that recognized the factor Xa light-chain blocked prothrombin activation at the factor Va binding site. Our results indicate that prothrombinase activity at the surface of lung parachymal or pleural cells can be blocked by MoAbs that interact with either the heavy- or light-chain of factors X. Antibodies that neutralize cell surface-expressed prothrombin activation offer a potential means to arrest pericellular fibrin formation in the lung and pleural space.
Asunto(s)
Factores de Coagulación Sanguínea/metabolismo , Factor V/metabolismo , Factor X/metabolismo , Factor Xa/metabolismo , Pulmón/metabolismo , Pleura/fisiología , Protrombina/metabolismo , Animales , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/inmunología , Células Cultivadas , Factor X/inmunología , Femenino , Fibroblastos , Humanos , Pulmón/citología , Ratones , Ratones Endogámicos BALB C , Unión ProteicaRESUMEN
We studied the changes of coagulation and fibrinolysis in bronchoalveolar lavage (BAL) and plasma obtained serially at intervals after the onset of adult respiratory distress syndrome (ARDS). BAL procoagulant activity was increased at 3 days and tended to decrease thereafter. Tissue factor associated with factor VII was the major BAL procoagulant. Fibrinopeptide A was increased, indicating increased thrombin-mediated conversion of fibrinogen to fibrin. Fibrinolytic activity was usually undetectable in BAL at 3 days post-ARDS and remained depressed for up to 14 days despite unchanged concentrations of urokinase and variably detectable tissue plasminogen activator. Depressed fibrinolytic activity was associated with increased antiplasmin activity and plasminogen activator inhibitor 1 (PAI-1) while PAI-2 concentrations approximated those of control samples and did not change during evolving ARDS. Evidence of systemic coagulopathy and increased systemic fibrin degradation were commonly found in serial ARDS plasma samples, consistent with accelerated vascular and/or extravascular fibrin deposition in these patients. The data indicate that intra-alveolar as well as systemic derangements of fibrin turnover are common features of evolving ARDS. Concurrent local abnormalities of both coagulation and fibrinolytic pathways favor persistence of alveolar fibrin for up to 14 days after clinical recognition of ARDS.
Asunto(s)
Fibrina/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Adulto , Anciano , Coagulación Sanguínea , Líquido del Lavado Bronquioalveolar/metabolismo , Líquido del Lavado Bronquioalveolar/patología , Fibrinógeno/análisis , Fibrinólisis , Humanos , Persona de Mediana Edad , Proteínas/metabolismo , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/patología , Trombina/análisisRESUMEN
Premature infants who have self-limited respiratory distress syndrome (RDS) rapidly improve, whereas infants with a complicated respiratory course are more likely to develop bronchopulmonary dysplasia (BPD), a chronic lung disorder that is the result of prolonged lung injury and impaired healing. The balance of competing activities of coagulation and fibrinolysis may contribute to the premature lung's response to acute injury and determine, in part, whether there is early resolution or protracted alveolar inflammation. To determine the relative activities of the coagulation and fibrinolytic pathways in neonatal lung injury, procoagulant (PC) and plasminogen activator (PA) activities were measured in undiluted cell-free lung lavage samples obtained serially over the first 28 days of life from 11 infants with self-limited RDS, 11 infants with evolving BPD, and 5 mechanically ventilated control infants without lung disease. Lung lavage from all three groups contained readily detectable procoagulant activity due mainly to the tissue factor-Factor VII complex. Plasminogen activator activity was relatively high in control lavage samples but depressed on the first day of life in the two groups of infants with lung disease: median, 0.3814 IU/ml (control); 0.0541 IU/ml (RDS); and 0.0454 IU/ml (BPD), p < 0.05 in each case compared with control. Two infants with severe lung disease had no detectable plasminogen activator activity in lung lavage on the first day of life. Depressed fibrinolytic activity correlated with severity of lung disease assessed radiographically and by pulmonary function measurements. Plasminogen activator activity was due to both tissue plasminogen activator and urokinase.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Displasia Broncopulmonar/etiología , Fibrina/metabolismo , Fibrinólisis , Recien Nacido Prematuro , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Puntaje de Apgar , Baltimore/epidemiología , Peso al Nacer , Displasia Broncopulmonar/epidemiología , Estudios de Evaluación como Asunto , Femenino , Fibrina/química , Edad Gestacional , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Masculino , Inhibidor 1 de Activador Plasminogénico/química , Inhibidor 2 de Activador Plasminogénico/química , Valor Predictivo de las Pruebas , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Factores de Riesgo , Activador de Tejido Plasminógeno/química , Activador de Plasminógeno de Tipo Uroquinasa/químicaRESUMEN
Malignant mesothelioma (MM) is a locally aggressive tumor that spreads by poorly understood mechanisms. Because neoplastic spread has been linked to altered fibrin turnover, we used immunohistochemistry of nine MM and three fibrous tumors of the pleura to confirm in vivo fibrin deposition and expression of selected coagulation and fibrinolytic reactants in MM. Tumor-associated fibrin was readily detectable at site of tissue invasion. Little fibrin was distributed within the tumor, but tissue factor and tissue factor pathway inhibitor, urokinase, urokinase receptor, and plasminogen activator inhibitors 1 and 2 were all detected in either epithelioid or sarcomatous areas of MM. We used the MS-1 human pleural mesothelioma cell line to determine how expression of these reactants is regulated. Fibrinolytic activity of MS-1 is mainly due to urokinase and is responsive to cytokine stimulation. Functional extrinsic activation and prothrombinase complexes assemble at the cell surface. MM express procoagulants as well as fibrinolytic reactants in vivo and in vitro that promote local fibrin formation and remodeling. Fibrin deposition occurs primarily at areas of tissue invasion and could promote local extension of this neoplasm. Sparsity of fibrin within the central portions of the tumor stroma suggests that local resorption of transitional fibrin occurs at sites of established MM.