RESUMEN
PURPOSE: Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. METHODS: In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. RESULTS: Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). CONCLUSIONS: Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial.
Asunto(s)
Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/inmunología , Recuento de Linfocitos , Neutrófilos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
Oxidant stress may contribute to acute lung injury under some circumstances. The rapid depletion of plasma gelsolin following major trauma in patients who subsequently develop respiratory distress suggests that this actin-scavenging protein might protect against delayed pulmonary complications. The specific aim of these experiments was to explore the temporal and quantitative relationship between gelsolin levels and lung damage. Gelsolin levels were measured in three murine models of oxidant injury: immunotargeting of pulmonary endothelium with an H2O2-generating enzyme; continuous exposure to >95% O2; and single high-dose thoracic radiation. The degree of lung injury was inversely related to gelsolin levels in mice treated with glucose oxidase-conjugated antibodies against platelet endothelial cell adhesion molecule-1 (p <0.0001). By 60-72 hours of hyperoxic exposure, gelsolin levels had dropped precipitously in all mice who sustained major lung damage (p <0.0001), establishing a quantitative association between gelsolin concentration and hyperoxic lung injury (r = -0.72; 95% confidence interval: ?0.81 to ?0.59). Gelsolin levels modestly but progressively fell in irradiated mice over the 3 days following treatment (p = 0.012) despite the development of only microscopic lung damage during this timeframe. These findings are consistent with the hypothesis that gelsolin depletion is involved in the pathogenesis of acute oxidant lung injury.
Asunto(s)
Gelsolina/sangre , Lesión Pulmonar , Pulmón/efectos de la radiación , Oxidantes/efectos adversos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/etiología , Animales , Especificidad de Anticuerpos/inmunología , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta Inmunológica , Relación Dosis-Respuesta en la Radiación , Glucosa Oxidasa/administración & dosificación , Glucosa Oxidasa/efectos adversos , Hiperoxia/sangre , Hiperoxia/complicaciones , Hiperoxia/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Oxidantes/inmunología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/administración & dosificación , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/efectos adversos , Proteínas/metabolismo , Dosis de Radiación , Estadística como Asunto , Factores de TiempoRESUMEN
BACKGROUND: Diagnosing liver tumors by fine-needle aspiration biopsy is safe and accurate. However, there are cases that prove diagnostically difficult. Traditionally, immunostains for alpha-fetoprotein and polyclonal carcinoembryonic antigen have been used to distinguish adenocarcinomas from hepatocellular carcinomas (HCCs). In poorly differentiated tumors, these immunostains have limitations in both sensitivity and specificity. An hepatocyte-specific immunostain has been described in the surgical pathology literature. To the authors' knowledge, this hepatocyte antibody has not been studied in liver fine-needle aspiration biopsies. The authors examined the Hepatocyte Paraffin 1 (HP1) antibody for its diagnostic utility in this cytologic setting. METHODS: Cell-block material from 40 cases of HCC and 53 cases of metastatic adenocarcinoma were studied. Slides were stained for HP1 by the avidin-biotin complex method following antigen retrieval. The percentage of malignant cells that exhibited coarse granular staining in the cytoplasm was estimated for all cases of HCC, poorly differentiated HCC, and metastatic adenocarcinoma. RESULTS: HP1 was expressed in 83% of all HCCs but in only 56% of poorly differentiated HCCs. Only 2 of 53 (4%) of metastatic tumors expressed HP1. The overall sensitivity of HP1 was 79% and its specificity was 96%. CONCLUSION: HP1 was found to be a specific immunostain that may prove helpful in diagnosing all but the most undifferentiated liver tumors biopsied by fine-needle aspiration.
Asunto(s)
Adenocarcinoma/patología , Adenocarcinoma/secundario , Anticuerpos Monoclonales , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Adenocarcinoma/inmunología , Biopsia con Aguja , Carcinoma Hepatocelular/inmunología , Diagnóstico Diferencial , Hepatocitos/inmunología , Humanos , Neoplasias Hepáticas/inmunologíaRESUMEN
Vascular immunotargeting is a novel approach for site-selective drug delivery to endothelium. To validate the strategy, we conjugated glucose oxidase (GOX) via streptavidin with antibodies to the endothelial cell surface antigen platelet endothelial cell adhesion molecule (PECAM). Previous work documented that 1) anti-PECAM-streptavidin carrier accumulates in the lungs after intravenous injection in animals and 2) anti-PECAM-GOX binds to, enters, and kills endothelium via intracellular H(2)O(2) generation in cell culture. In the present work, we studied the targeting and effect of anti-PECAM-GOX in animals. Anti-PECAM-GOX, but not IgG-GOX, accumulated in the isolated rat lungs, produced H(2)O(2,) and caused endothelial injury manifested by a fourfold elevation of angiotensin-converting enzyme activity in the perfusate. In intact mice, anti-PECAM-GOX accumulated in the lungs (27 +/- 9 vs. 2.4 +/- 0.3% injected dose/g for IgG-GOX) and caused severe lung injury and 95% lethality within hours after intravenous injection. Endothelial disruption and blebbing, elevated lung wet-to-dry ratio, and interstitial and alveolar edema indicated that anti-PECAM-GOX damaged pulmonary endothelium. The vascular injury in the lungs was associated with positive immunostaining for iPF(2alpha)-III isoprostane, a marker for oxidative stress. In contrast, IgG-GOX caused a minor lung injury and little (5%) lethality. Anti-PECAM conjugated with inert proteins induced no death or lung injury. None of the conjugates caused major injury to other internal organs. These results indicate that an immunotargeting strategy can deliver an active enzyme to selected target cells in intact animals. Anti-PECAM-GOX provides a novel model of oxidative injury to the pulmonary endothelium in vivo.
Asunto(s)
Endotelio Vascular/enzimología , Marcación de Gen , Glucosa Oxidasa/genética , Estrés Oxidativo , Circulación Pulmonar , Enfermedades Vasculares/inducido químicamente , Animales , Anticuerpos/genética , Anticuerpos/inmunología , Anticuerpos/metabolismo , Anticuerpos/farmacología , Glucosa Oxidasa/inmunología , Glucosa Oxidasa/metabolismo , Técnicas In Vitro , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Ratones , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/inmunología , Ratas , Distribución Tisular , Enfermedades Vasculares/patologíaRESUMEN
OBJECTIVE: To determine whether various methods of fixation of surgical pathology specimens from breast carcinomas would influence the outcome of evaluation of the expression levels of c-erbB-2 (HER-2). For this, comparisons were made between (1) alcohol-fixed (95%) and air-dried smears from fresh surgical pathology specimens of breast carcinomas, and (2) formalin-fixed, paraffin-embedded tissue sections of the same specimens. STUDY DESIGN: Alcohol-fixed and air-dried smears or touch preparations were made from 30 fresh mastectomy/lumpectomy surgical pathology specimens from breast carcinomas. Immunohistochemistry was performed using the c-erbB-2 primary antibody against the extracellular domain of the c-erbB-2 gene product. Staining was simultaneously performed on formalin-fixed, paraffin-embedded tissue sections of the same specimens. A semiquantitative approach was used for evaluation of immunostaining by three independent investigators, and a consensus was reached. RESULTS: A total of 30 cases were reviewed. Tissue positivity was determined for c-erbB-2 in: 73% of alcohol-fixed specimens (n = 13 [3+] and n = 9 [2+]), 67% of air-dried smears (n = 9 [+3] and n = 11 [+2]) and 47% (n = 8 [+3]) and n = 6 [+2]) of formalin-fixed, paraffin-embedded tissue specimens. All formalin-fixed tissue specimens that were determined to positively express c-erbB-2 were also found to be positive on the alcohol-fixed smears. CONCLUSION: The incidence of c-erbB-2 expression in fresh cytologic material is significantly higher (P < .05) than in formalin-fixed, paraffin-embedded tissue. Alcohol-fixed smears demonstrate a slightly higher percentage of cell staining and stronger intensity of c-erbB-2 expression than the matched, air-dried smears. This is a sensitive and simple processing method that can be routinely applied in surgical pathology or fine needle aspiration biopsy specimens for the detection of c-erbB-2 (HER-2), with clinical implications.