Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.144
Filtrar
2.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
3.
PLoS One ; 15(8): e0231807, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756555

RESUMO

BACKGROUND: Lung cancer is increasingly common as a second primary malignancy. However, the clinical characteristics of second primary non-small cell lung cancer after cervical cancer (CC-NSCLC) compared with first primary non-small cell lung cancer (NSCLC1) is unknown. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry between 1998 and 2010 was used to conduct a large population-based cohort analysis. The demographic and clinical characteristics, as well as prognostic data, were systematically analyzed. The overall survival (OS) in the two cohorts was further compared. The risk factors of second primary lung cancer in patients with cervical cancer were also analyzed. RESULTS: A total of 557 patients (3.52%) developed second primary lung cancer after cervical cancer, and 451 were eligible for inclusion in the final analyses. Compared with NSCLC1, patients with CC-NSCLC had a higher rate of squamous cell carcinoma (SCC) (36.59% vs 19.07%, P < 0.01). The median OS was longer for CC-NSCLC than for NSCLC1 before propensity score matching (PSM) (16 months vs. 13 months) but with no significant difference after PSM (16 months vs. 17 months). The high-risk factors for the development of cervical cancer to CC-NSCLC include age 50-79 years, black race [odds ratio (OR) 1.417; 95% confidence interval (CI) 1.095-1.834; P < 0.05], and history of radiotherapy (OR 1.392; 95% CI 1.053-1.841; P < 0.05). CONCLUSION: Age 50-79 years, black race, and history of radiotherapy were independent risk factors for second primary lung cancer in patients with cervical cancer. Patients with CC-NSCLC had distinctive clinical characteristics and better prognosis compared with patients with NSCLC1.


Assuntos
Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Segunda Neoplasia Primária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas , Feminino , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Fatores de Risco , Programa de SEER , Análise de Sobrevida , Neoplasias do Colo do Útero/complicações
4.
PLoS One ; 15(8): e0236021, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745082

RESUMO

BACKGROUND: The National Lung Screening Trial (NLST) demonstrated that annual screening with low dose CT in high-risk population was associated with reduction in lung cancer mortality. Nonetheless, the leading cause of mortality in the study was from cardiovascular diseases. PURPOSE: To determine whether the used machine learning automatic algorithms assessing coronary calcium score (CCS), level of liver steatosis and emphysema percentage in the lungs are good predictors of cardiovascular disease (CVD) mortality and incidence when applied on low dose CT scans. MATERIALS AND METHODS: Three fully automated machine learning algorithms were used to assess CCS, level of liver steatosis and emphysema percentage in the lung. The algorithms were used on low-dose computed tomography scans acquired from 12,332 participants in NLST. RESULTS: In a multivariate analysis, association between the three algorithm scores and CVD mortality have shown an OR of 1.72 (p = 0.003), 2.62 (p < 0.0001) for CCS scores of 101-400 and above 400 respectively, and an OR of 1.12 (p = 0.044) for level of liver steatosis. Similar results were shown for the incidence of CVD, OR of 1.96 (p < 0.0001), 4.94 (p < 0.0001) for CCS scores of 101-400 and above 400 respectively. Also, emphysema percentage demonstrated an OR of 0.89 (p < 0.0001). Similar results are shown for univariate analyses of the algorithms. CONCLUSION: The three automated machine learning algorithms could help physicians to assess the incidence and risk of CVD mortality in this specific population. Application of these algorithms to existing LDCT scans can provide valuable health care information and assist in future research.


Assuntos
Doenças Cardiovasculares/mortalidade , Aprendizado de Máquina , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Fumar Cigarros/efeitos adversos , Fumar Cigarros/epidemiologia , Ensaios Clínicos Fase III como Assunto , Vasos Coronários/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Enfisema/diagnóstico , Enfisema/epidemiologia , Enfisema/etiologia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/epidemiologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologia
5.
PLoS One ; 15(8): e0237723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857771

RESUMO

PURPOSE: This study investigated nicotine dependence as an independent risk factor for upper aerodigestive tract (UADT) cancers, including lung and head and neck cancers (HNC). The study aimed to isolate the direct effect of nicotine dependence, independent of tobacco smoking. METHODS: A case-control study with a total of 4957 participants was conducted in Ontario, Canada, of which 2964 categorized as either current or former smokers were used in the analysis. Nicotine dependence of ever-smokers (2360 UADT cases and 604 controls) was measured using the Fagerström Test for Nicotine Dependence. Using mediation analyses and adjusted logistic regression models, we decomposed the direct effect of nicotine dependence and the mediated effect of smoking duration to quantify the risks of lung and HNC. The role of human papillomavirus (HPV) and cancer subtypes were assessed. RESULTS: Most individual nicotine dependence behaviours showed positive associations with lung cancer with approximately 1.8 to 3.5-fold risk increase, and to lesser extent with 1.4 to 2.3-fold risk for HNC. Nicotine dependence is partially accountable for increased risks of lung cancer (OR = 1.20, 95%CI = 1.13-1.28) and HNC (1.12, 95%CI = 1.04-1.19). Nicotine dependence had a greater effect on the risk of HPV-negative oropharyngeal cancer (OR = 3.06, 95%CI = 1.65-5.66) in comparison to HPV-positive oropharyngeal cancer (OR = 1.05, 95%CI = 0.67-1.65). The direct effects of nicotine dependence remained significant after accounting for cumulative tobacco exposures. CONCLUSION: Nicotine dependence increases the risks of lung and HNC cancers after accounting for tobacco smoking, suggesting potential toxic effects of nicotine. These results are informative for the safety consideration of nicotine exposures.


Assuntos
Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias Pulmonares/epidemiologia , Nicotina/efeitos adversos , Tabagismo/epidemiologia , Idoso , Estudos de Casos e Controles , Feminino , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tabagismo/complicações
6.
Medicine (Baltimore) ; 99(30): e21411, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791756

RESUMO

Lung cancer is a common malignancy worldwide, and risk factors include bronchitis, asthma, tuberculosis, smoking, and air pollution. These are also risk factors for spontaneous pneumothorax, a benign disease. We hypothesized that patients who experience a spontaneous pneumothorax have a greater risk to develop lung cancer, and designed a study to determine if this is so.We used the population-based Taiwan Health Insurance Research Database to perform a retrospective cohort study. The database includes more than 99% of the population of Taiwan. We established a 27,405-person pneumothorax cohort and a 109,620 person comparison cohort with data from 2000 to 2009 to evaluate the relationship between spontaneous pneumothorax and lung cancer.Multivariable analysis showed that patients who have had a spontaneous pneumothorax have a greater relative risk to develop lung cancer. The overall hazard ratio was 2.09 (95% confidence interval 1.69-2.58) adjusted by age, gender, hypertension, diabetes mellitus, and chronic lung diseases such as chronic obstructive pulmonary disease, tuberculosis, asthma, bronchitis, and emphysema. A dose effect was present; a high frequency of spontaneous pneumothorax was associated with a greater relative risk to develop lung cancer. If the spontaneous pneumothorax frequency was greater than 2 times per year, the hazard ratio was 34.09 (95% confidence interval 22.74-51.10)Patients with spontaneous pneumothorax have an increased relative risk to develop lung cancer, especially among patients 35 to 49 years of age. The more frequent the occurrence of spontaneous pneumothorax, the greater the relative risk of lung cancer. If the spontaneous pneumothorax frequency was greater than 2 times per year, the increase in risk of lung cancer was more than 30-fold.


Assuntos
Neoplasias Pulmonares/epidemiologia , Pneumotórax/epidemiologia , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Pneumotórax/complicações , Estudos Retrospectivos , Taiwan/epidemiologia
8.
Thorax ; 75(8): 661-668, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32631933

RESUMO

INTRODUCTION: Low-dose CT (LDCT) screening of high-risk smokers reduces lung cancer (LC) specific mortality. Determining screening eligibility using individualised risk may improve screening effectiveness and reduce harm. Here, we compare the performance of two risk prediction models (PLCOM2012 and Liverpool Lung Project model (LLPv2)) and National Lung Screening Trial (NLST) eligibility criteria in a community-based screening programme. METHODS: Ever-smokers aged 55-74, from deprived areas of Manchester, were invited to a Lung Health Check (LHC). Individuals at higher risk (PLCOM2012 score ≥1.51%) were offered annual LDCT screening over two rounds. LLPv2 score was calculated but not used for screening selection; ≥2.5% and ≥5% thresholds were used for analysis. RESULTS: PLCOM2012 ≥1.51% selected 56% (n=1429) of LHC attendees for screening. LLPv2 ≥2.5% also selected 56% (n=1430) whereas NLST (47%, n=1188) and LLPv2 ≥5% (33%, n=826) selected fewer. Over two screening rounds 62 individuals were diagnosed with LC; representing 87% (n=62/71) of 6-year incidence predicted by mean PLCOM2012 score (5.0%). 26% (n=16/62) of individuals with LC were not eligible for screening using LLPv2 ≥5%, 18% (n=11/62) with NLST criteria and 7% (n=5/62) with LLPv2 ≥2.5%. NLST eligible Manchester attendees had 2.5 times the LC detection rate than NLST participants after two annual screens (≈4.3% (n=51/1188) vs 1.7% (n=438/26 309); p<0.0001). Adverse measures of health, including airflow obstruction, respiratory symptoms and cardiovascular disease, were positively correlated with LC risk. Coronary artery calcification was predictive of LC (adjOR 2.50, 95% CI 1.11 to 5.64; p=0.028). CONCLUSION: Prospective comparisons of risk prediction tools are required to optimise screening selection in different settings. The PLCOM2012 model may underestimate risk in deprived UK populations; further research focused on model calibration is required.


Assuntos
Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Seleção de Pacientes , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Medição de Risco , Fumar , Tomografia Computadorizada por Raios X , Reino Unido
9.
Med Hypotheses ; 143: 110074, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32645661

RESUMO

The morbidity and mortality of lung cancer are increasing. The Corona Virus Disease 2019 (COVID-19) is caused by novel coronavirus 2019-nCoV-2, leading to subsequent pulmonary interstitial fibrosis with chronic inflammatory changes, e.g., inflammatory factors repeatedly continuously stimulating and attacking the alveolar epithelial cells. Meanwhile, 2019-nCoV-2 can activate PI3K/Akt and ERK signaling pathways, which can play the double roles as both anti-inflammatory and carcinogenic factors. Moreover, hypoxemia may be developed, resulting in the up-regulation of HIF-1 α expression, which can be involved in the occurrence, angiogenesis, invasion and metastasis of lung cancer. Additionally, the immune system in 2019-nCoV-2 infected cases can be suppressed to cause tumor immune evasion. Therefore, we speculate that COVID-19 may be a risk factor of secondary lung cancer.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Lesão Pulmonar/complicações , Neoplasias Pulmonares/etiologia , Pneumonia Viral/complicações , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Interações entre Hospedeiro e Microrganismos , Humanos , Hipóxia/complicações , Modelos Biológicos , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Fibrose Pulmonar/etiologia , Fatores de Risco , Transdução de Sinais , Evasão Tumoral
10.
Nature ; 583(7818): 807-812, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669708

RESUMO

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Marcadores Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Medicina de Precisão , Fumar/genética , Teorema de Bayes , Carcinoma Pulmonar de Células não Pequenas/etiologia , Protocolos Clínicos , Ensaios Clínicos como Assunto , Estudos de Coortes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/etiologia , Oncogenes/genética , Seleção de Pacientes , Fumaça/efeitos adversos , Triagem
11.
Mol Carcinog ; 59(9): 1088-1099, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673443

RESUMO

Manganese superoxide dismutase (SOD-2), an important primary antioxidant enzyme located in mitochondria, plays a critical role in tumor progression. Reportedly, the proinflammatory cytokine, tumor necrosis factor (TNF)-α, can increase SOD-2 expression in a human lung adenocarcinoma cell line in vitro, indicating that TNF-α-mediated inflammation may regulate SOD-2 expression, which may be related to cancer promotion. Using a urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mice model, we investigated whether and how TNF-α-mediated inflammation upregulated SOD-2 expression in lung adenocarcinoma. Our results showed that SOD-2 was mostly expressed on surfactant protein-C+ AT-II cells (alveolar type II cell) and tumor cells in IDLA mice, which were surrounded by CD68+ macrophages. Blocking TNF-α-dependent inflammation downregulated SOD-2 expression in inflamed lung tissues at the protumor stage and also inhibited SOD-2 expression in tumor cells in the IDLA model. In human lung adenocarcinoma, both the number of infiltrating CD68+ macrophages and TNF-α expression correlated positively with SOD-2 expression, which is related to lymph node metastasis and TNM stage. We collected the conditioned medium from lipopolysaccharide-activated phorbol myristate acetate-induced THP1 (M1) cells to stimulate A549 and H1299 cells and observed that THP1-M1 upregulated SOD-2 by secreting TNF-α. Blocking SOD-2 expression significantly inhibited TNF-α-induced cell proliferation in A549 and H1299 cells in vitro. Thus, TNF-α-mediated lung inflammation can upregulate SOD-2 expression in lung adenocarcinoma, and macrophages contribute to SOD-2 upregulation by secreting TNF-α.


Assuntos
Adenocarcinoma de Pulmão/patologia , Proliferação de Células , Neoplasias Pulmonares/patologia , Pneumonia/complicações , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Uretana/toxicidade , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Apoptose , Carcinógenos/toxicidade , Citocinas , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Células Tumorais Cultivadas
12.
PLoS One ; 15(6): e0233445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497048

RESUMO

OBJECTIVE: The present study aims to explore the role of smoking factors in the risk of lung cancer and screen the feature risk pathways of smoking-induced lung cancer. METHODS: The expression profiles of the patient data from GEO database were standardized, and differentially expressed genes (DEGs) were analyzed by limma algorithm. Samples and genes were analyzed by Unsupervised hierarchical clustering method, while GO and KEGG enrichment analyses were performed on DEGs. The data of the protein-protein interaction (PPI) network were downloaded from the BioGrid and HPRD databases, and the DEGs were mapped into the PPI network to identify the interaction relationship. The enriched significant pathways were used to calculate the anomaly score and RFE method was used to optimize the feature sets. The model was trained using the support vector machine (SVM) and the predicted results were plotted into ROC curves. The AUC value was calculated to evaluate the predictive performance of the SVM model. RESULTS: A total of 1923 DEGs were obtained, of which 826 were down-regulated and 1097 were up-regulated. Unsupervised hierarchical clustering analysis showed that the diagnosis accuracy of lung cancer smokers was 74%, and that of non-lung cancer smokers was 75%. Five optimal feature pathway sets were obtained by screening, the clinical diagnostic ability of which was detected by SVM model with the accuracy improved to 84%. The diagnostic accuracy was 90% after combining clinical information. CONCLUSION: We verified that five signaling pathways combined with clinical information could be used as a feature risk pathway for identifying lung cancer smokers and non-lung cancer smokers and increased the diagnostic accuracy.


Assuntos
Perfilação da Expressão Gênica , Neoplasias Pulmonares/etiologia , Fumar/efeitos adversos , Máquina de Vetores de Suporte , Área Sob a Curva , Análise por Conglomerados , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Bases de Dados Genéticas , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Mapeamento de Interação de Proteínas , Curva ROC , Fatores de Risco , Transdução de Sinais
13.
Arch Biochem Biophys ; 689: 108439, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32504553

RESUMO

Chronic obstructive pulmonary disease (COPD) and lung cancer are a major cause of morbidity and mortality worldwide, with cigarette smoking being the single most important risk factor for both. Emerging evidence indicates alterations in reverse cholesterol transport-mediated removal of excess cholesterol from lung, and intracellular cholesterol overload to be involved in smoke-promoted COPD and lung cancer development. Since there are currently few effective treatments for COPD and lung cancer, it is important to identify food-derived, biologically active compounds, which can protect against COPD and lung cancer development. High intake of the carotenoid lycopene, as one of phytochemicals, is associated with a decreased risk of chronic lung lesions. This review article summarizes and discusses epidemiologic evidence, in vitro and in vivo studies regarding the prevention of smoke-promoted COPD and lung carcinogenesis through dietary lycopene as an effective intervention strategy. We focus on the recent research implying that lycopene preventive effect is through targeting the main genes involved in reverse cholesterol transport. This review also indicates gaps in knowledge about the function of lycopene against COPD and lung cancer, offering directions for further research.


Assuntos
Anticarcinógenos/uso terapêutico , Antioxidantes/uso terapêutico , Fumar Cigarros/efeitos adversos , Neoplasias Pulmonares/prevenção & controle , Licopeno/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Animais , Anticarcinógenos/metabolismo , Antioxidantes/metabolismo , Colesterol/metabolismo , Suplementos Nutricionais , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Licopeno/metabolismo , Lycopersicon esculentum/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia
14.
Anticancer Res ; 40(6): 3435-3444, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487642

RESUMO

BACKGROUND/AIM: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination. PATIENTS AND METHODS: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing. RESULTS: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type. CONCLUSION: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099).


Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , DNA de Neoplasias , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Células Neoplásicas Circulantes/patologia , Idoso , Idoso de 80 Anos ou mais , DNA de Neoplasias/sangue , Suscetibilidade a Doenças , Feminino , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único
15.
Respir Investig ; 58(5): 344-354, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32586780

RESUMO

Primary cultures of human lung epithelial cells are ideal representatives of normal lung epithelial cells, and while there are certain novel approaches for the long-term culture of lung epithelial cells, the cells eventually undergo irreversible growth arrest, limiting their experimental utility, particularly the ability to widely distribute these cultures and their clonal derivatives to the broader research community. Therefore, the establishment of immortalized normal human lung epithelial cell strains has garnered considerable attention. The number and type of oncogenic changes necessary for the tumorigenic transformation of normal cells could be determined using "normal" cell lines immortalized with the simian virus 40 (SV40) large T antigen (LT). A primary report suggested that LT, human telomerase reverse transcriptase (hTERT), and oncogenic RAS transformed normal lung epithelial cells into tumorigenic cells. Since LT inactivates the tumor suppressors p53 and RB, at least four alterations would be necessary. However, the SV40 small T antigen (ST), a different oncoprotein, was also introduced simultaneously with LT in the above-mentioned study. Furthermore, the possible uncharacterized functions of LT remained largely obscure. Therefore, no definitive conclusion could be arrived in these studies. Subsequent studies used methods that did not involve the use of oncoproteins and revealed that at least five genetic changes were necessary for full tumorigenic transformation. hTERT-immortalized normal human lung epithelial cell lines established without using viral oncoproteins were also used for investigating several aspects of lung cancer, such as epithelial to mesenchymal transition and the cancer stem cell theory. The use of immortalized normal lung epithelial cell models has improved our understanding of lung cancer pathogenesis and these models can serve as valuable research tools.


Assuntos
Células Epiteliais , Neoplasias Pulmonares , Pulmão/citologia , Antígenos Virais de Tumores , Transformação Celular Neoplásica/genética , Senescência Celular , Transição Epitelial-Mesenquimal , Humanos , Pulmão/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas , Proteínas Oncogênicas , Vírus 40 dos Símios/imunologia , Telomerase , Telômero , Proteínas Virais
16.
Cancer Sci ; 111(9): 3236-3244, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32589309

RESUMO

Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain elusive. In this study, the zinc finger protein ZNF251 was found to be upregulated in clinical lung cancer samples, and it promoted the growth of lung cancer cells and the growth of primary lung KPC cells from mouse models (Ad-Cre, KrasG12D , and P53f/f ). In studying the molecular mechanism, ZNF251 was found to inhibit the expression of dual-specificity phosphatase 6, a negative regulator of ERK activation, by directly binding to its promoter region. Taken together, our data indicate the tumor-promoting effects of ZNF251 in lung cancer and suggest that ZNF251 is a therapeutic target.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Progressão da Doença , Fosfatase 6 de Especificidade Dupla , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Fosforilação , RNA Mensageiro/genética
17.
Jpn J Clin Oncol ; 50(9): 1009-1017, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32548629

RESUMO

OBJECTIVE: Tar concentration in cigarette brands is chronologically decreasing in the USA and Japan. However, studies investigating lung cancer risk with cumulative tar exposure in Western and Asian countries are insufficient. To investigate the risk of lung cancer with cumulative cigarette tar exposure, we conducted a case-control study among Japanese current smokers. METHODS: This study used data from the US-Japan lung cancer joint study in 1993-1998. A total of 282 subjects with histologically confirmed lung cancer and 162 hospital and 227 community controls were included in the study, and two control groups were combined. The information regarding tar concentration was obtained from the published documents and additional estimation using the equation of regression. Cumulative tar concentration was calculated by multiplying the annual value of brand-specific tar concentration by years of smoking. The odds ratios and 95% confidence intervals for lung cancer with cumulative tar exposure were estimated using a logistic model. RESULTS: The odds ratios for lung cancer with both lower (1-59.8 × 105 mg) and higher (>59.8 × 105 mg) total cumulative tar exposure were statistically significant (3.81, 2.23-6.50 and 11.64, 6.56-20.67, respectively) with increasing trend (P < 0.001). The stratification analysis showed higher odds ratios in subjects with higher cumulative tar exposure regardless of inhalation, duration of smoking filtered cigarettes and histological type. CONCLUSIONS: This study showed that cumulative tar exposure is a dose-dependent indicator for lung cancer risk, and low-tar exposure was still associated with increased cancer risk.


Assuntos
Neoplasias Pulmonares/etiologia , Fumantes/estatística & dados numéricos , Fumar/efeitos adversos , Alcatrões/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Japão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários
19.
Cancer Res ; 80(14): 3009-3022, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32366477

RESUMO

HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of HACE1 has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that HACE1 is frequently mutated in human lung cancer. In mice, loss of Hace1 led to enhanced progression of KRasG12D -driven lung tumors. Additional ablation of the oncogenic GTPase Rac1 partially reduced progression of Hace1-/- lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in Hace1-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both Rac1 and Rac2 fully averted the increased progression of KRasG12D -driven lung tumors in Hace1-/- mice. In patients with lung cancer, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, whereas elevated expression of RAC1 and RAC2 was associated with poor prognosis. This work defines HACE1 as a crucial regulator of the oncogenic activity of RAC-family GTPases in lung cancer development. SIGNIFICANCE: These findings reveal that mutation of the tumor suppressor HACE1 disrupts its role as a regulator of the oncogenic activity of RAC-family GTPases in human and murine lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/14/3009/F1.large.jpg.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/prevenção & controle , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rac de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinogênese/patologia , Proliferação de Células , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prognóstico , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
20.
Occup Environ Med ; 77(8): 520-526, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32398293

RESUMO

OBJECTIVES: There are established methods for occupational epidemiological cohort analysis, such as proportional hazards regression, that are well suited to aetiological research and yield parameter estimates that allow for succinct communication among academics. However, these methods are not necessarily well suited for evaluation of health impacts of policy choices and communication to decision makers. An informed decision about a policy that impacts health and safety requires a valid estimate of the policy's potential impact. METHODS: We propose methods for data summarisation that may facilitate communication with managers, workers and their advocates. We calculate measures of effect in a framework for competing events, graphically display potential impacts on cause-specific mortality under policy alternatives and contrast these results to estimates obtained using standard Poisson regression methods. Methods are illustrated using a cohort mortality study of 28 546 Ontario uranium miners hired between 1950 and 1996 and followed through 2007. RESULTS: A standard regression analysis yields a positive association between cumulative radon progeny exposure and all-cause mortality (log(RR per 100 WLM)=0.09; SE=0.02). The proposed method yields an estimate of the expected gain in life expectancy (approximately 6 months per worker) and reduction of 261 lung cancer deaths under a policy that eliminated occupational radon progeny exposure. CONCLUSIONS: The proposed method shifts attention from covariate-adjusted risk ratios or rate ratios to estimates of deaths that are avoided or delayed under a potential policy. The approach may help inform decision-making and strengthen the connection of epidemiological approaches to data analysis with developments in decision theory and systems engineering to improve health and safety.


Assuntos
Teoria da Decisão , Expectativa de Vida , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Estudos de Coortes , Métodos Epidemiológicos , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Mineradores , Neoplasias Induzidas por Radiação/mortalidade , Ontário/epidemiologia , Produtos de Decaimento de Radônio/efeitos adversos , Análise de Regressão , Urânio
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA