RESUMEN
BACKGROUND & OBJECTIVES: Pathologic evaluation of > 10 lymph nodes (LNs) is considered necessary for accurate lung cancer staging. However, physicians have concerns about increased risk in perioperative mortality (POM) and morbidity with more extensive LN sampling, particularly in the elderly. In this study, we compared the outcomes in elderly patients with stage I non-small cell lung cancer (NSCLC) undergoing extensive (> 10 nodes) and limited (≤ 10 nodes) LN resections. METHODS: Using data from the Surveillance, Epidemiology and End Results registry linked to Medicare records, we identified 4975 patients ≥ 65 years of age with stage I NSCLC who underwent a lobectomy between 1992 and 2002. Risk of perioperative morbidity and POM after the evaluation of ≤ 10 vs. >10 LNs was compared among patients after adjusting for propensity scores. RESULTS: Multiple regression analysis showed similar POM between the two groups (OR, 1,01; 95% CI, 0,71-1,44). Other postoperative complications were similar across groups except for thromboembolic events, which were more common among patients undergoing resection of > 10 LNs (OR, 1,72; 95% CI, 1,12-2,63). CONCLUSIONS: These data suggest that evaluation of > 10 LNs, which allows for more accurate staging, appears to be safe in the elderly patients undergoing lobectomy for stage I NSCLC without compromising postoperative recovery.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Neumonectomía/métodos , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/patología , Comorbilidad , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Escisión del Ganglio Linfático/efectos adversos , Escisión del Ganglio Linfático/mortalidad , Ganglios Linfáticos/cirugía , Masculino , Medicare , Morbilidad , Clasificación del Tumor , Estadificación de Neoplasias , Periodo Perioperatorio , Neumonectomía/efectos adversos , Neumonectomía/mortalidad , Programa de VERF , Análisis de Supervivencia , Estados UnidosRESUMEN
Global alterations in chromatin structure profoundly influence gene expression in thoracic neoplasms, silencing tumor suppressors while facilitating the expression of various cancer testis antigens such as NY-ESO-1. Although recent studies have shown that histone deacetylase inhibitors can potentiate tumor suppressor gene induction mediated by demethylating agents in cancer cells, the ability of these agents to augment cancer testis antigen expression have not been fully defined. The authors designed the current study to determine whether the histone deacetylase inhibitor, depsipeptide FR901228 (DP), could enhance NY-ESO-1 induction mediated by the DNA demethylating agent 5-Aza-2'-deoxycytidine (DAC) in cell lines established primarily from thoracic cancers. Quantitative reverse-transcriptase polymerase chain reaction analysis revealed that, under exposure conditions potentially achievable in clinical settings, DAC dramatically induced NY-ESO-1 expression in cultured cancer lines. DP alone mediated negligible target gene induction but significantly augmented DAC-mediated induction of NY-ESO-1. After DAC or sequential DAC-DP treatment, HLA-A*0201 cancer cells were recognized by an HLA-A*0201 CTL specific for NY-ESO-1. Although sequential DAC/DP exposure did not uniformly enhance immune recognition of target cells compared with DAC alone, this treatment mediated profound induction of apoptosis in cancer cells but not normal human bronchial epithelia. The apoptotic effects of DAC, DP, or sequential DAC-DP did not correlate in an obvious manner with histology, or the magnitude of NY-ESO-1 induction in cancer cells. Although the mechanisms have not been fully defined, sequential DAC-DP treatment may be a novel strategy to augment antitumor immunity in cancer patients.
Asunto(s)
Antibacterianos/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Depsipéptidos , Proteínas de la Membrana , Neoplasias/patología , Péptidos Cíclicos , Proteínas/inmunología , Linfocitos T Citotóxicos/inmunología , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , Antígenos de Neoplasias/inmunología , Western Blotting , Neoplasias de la Mama , Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Citometría de Flujo , Humanos , Neoplasias Pulmonares , Melanoma , Mesotelioma , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias Pleurales , Proteínas/análisis , Células Tumorales CultivadasRESUMEN
BACKGROUND: Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. METHODS: Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. RESULTS: Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 micromol/L x 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL x 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. CONCLUSIONS: Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Azacitidina/análogos & derivados , Depsipéptidos , Neoplasias Esofágicas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Péptidos Cíclicos , Adenocarcinoma/metabolismo , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , Azacitidina/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Metilasas de Modificación del ADN/antagonistas & inhibidores , Decitabina , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Humanos , Inmunohistoquímica , Melanoma/metabolismo , Proteínas de Neoplasias/genética , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
BACKGROUND: Cancer cells that overexpress c-erbB oncogenes exhibit resistance to chemotherapy, enhanced tumorigenicity, as well as increased propensity for metastasis. The aim of this study was to investigate if depletion of erbB-1/EGFR and erbB-2/HER2neu oncogene products by 17-allylamino 17-demethoxy Geldanamycin (17AAGA) could diminish the metastatic potential of non-small cell lung cancer (NSCLC) cells that express varying levels of the erbB1/erbB2 oncogenes. METHODS: NSCLC cell lines (H460, H358, H322, or H661) were assayed for expression of erbB1 and erbB2, the cell adhesion molecule E-cadherin, secretion of the matrix metalloproteinase 9 (MMP-9), and vascular endothelial cell growth factor (VEGF), as well as their ability to invade Matrigel after 48-hour exposure to 17AAGA. RESULTS: 17AAGA significantly depleted erbB1 or erbB2 levels in NSCLC cells expressing high levels of these proteins, and effectively inhibited their growth with IC50 values ranging from 50 to 90 nmol/L. Moreover, drug treatment enhanced E-cadherin expression in H322 and H358 cells, and inhibited secretion of MMP-9 and VEGF secretion by tumor cells. 17AAGA diminished hypoxia-induced upregulation of VEGF expression as well as growth factor-mediated augmentation of MMP-9 secretion, and profoundly inhibited the ability of H322 and H358 cells to migrate through Matrigel in response to chemoattractants. CONCLUSIONS: In addition to its known antiproliferative and chemosensitization effects, 17AAGA inhibits the metastatic phenotype of lung cancer cells. 17AAGA may be a novel pharmacologic agent for specific molecular intervention in lung cancer patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/patología , Receptor ErbB-2/antagonistas & inhibidores , Rifabutina/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Benzoquinonas , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Relación Dosis-Respuesta a Droga , Factores de Crecimiento Endotelial/antagonistas & inhibidores , Factores de Crecimiento Endotelial/genética , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lactamas Macrocíclicas , Neoplasias Pulmonares/genética , Linfocinas/antagonistas & inhibidores , Linfocinas/genética , Metaloproteinasa 9 de la Matriz/genética , Inhibidores de la Metaloproteinasa de la Matriz , Invasividad Neoplásica , Metástasis de la Neoplasia , Receptor ErbB-2/genética , Rifabutina/análogos & derivados , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Although SV40 oncoproteins have been detected in malignant pleural mesotheliomas (MPMs), their role in the pathogenesis and clinical behavior of these neoplasms remains controversial. In the present study, we sought to define the relevance of SV40 T/t antigen expression in established human mesothelioma cell lines deficient for p16INK4a as well as ARF expression. SV40 early region sequences were readily detected in genomic DNA isolated from pleural mesothelioma lines; however, levels of SV40 T/t antigen expression were highly variable in these cells. An adenoviral vector expressing an antisense transcript to SV40 early region inhibited T antigen expression and mediated significant growth inhibition and apoptosis in T-antigen-positive mesothelioma cells and SV40-transformed COS-7 cells. Abrogation of T/t antigen expression coincided with enhanced p21/WAF-1 expression, suggesting that restoration of p53-mediated pathways may have contributed to the growth inhibition and apoptosis induced by the antisense construct. These effects were not observed after similar treatment of mesothelioma or lung cancer cells containing no SV40 DNA sequences. Collectively, these data suggest that SV40 oncoproteins contribute to the malignant phenotype of pleural mesotheliomas and indicate that interventions designed to abrogate their expression may be efficacious in the treatment of individuals with these neoplasms.