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1.
Isr Med Assoc J ; 22(12): 784-787, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33381953

RESUMO

BACKGROUND: Guidelines recommend testing for multiple biomarkers in non-small cell lung cancer (NSCLC) tumors. Blood-based liquid biopsy analyzing cell-free DNA (cfDNA) could be used in addition to tumor biopsy genotyping, especially if tissue/time are limiting. OBJECTIVES: To investigate the clinical utility of early cfDNA analysis (Guardant360® CDx) in treatment-naïve NSCLC patients. METHODS: A prospective cohort of treatment-naïve patients with metastatic NSCLC who underwent tumor and cfDNA analysis between 12/2018 and 2/2019 were included. RESULTS: Ten patients were included: 6 males, median age 70.5 years (range 48-87), 8 prior smokers. Liquid biopsy was sent when cancer cells were detected in the biopsy specimen. Median time from diagnosis to receiving the report on the last biomarker from the tumor biopsy was 20 days (range 9-34); median time from blood draw to receiving the cfDNA findings was 9 days (range 7-12). The median difference between the cfDNA and the tumor analysis reports was 20 days (range 9-28). Actionable biomarkers were identified in four patients by both the biopsy analysis and the cfDNA analysis (2cases with EGFR mutations, one with ROS1 fusion, and one with EML4-ALK fusion for whom the biopsy analysis also identified an EGFR mutation not detected in the cfDNA analysis). Overall, eight patients received treatment (2 died before treatment initiation). Three patients received biomarker-based treatment (1 osimertinib, 1 alectinib, and 1 crizotinib). CONCLUSIONS: These findings suggest that cfDNA analysis should be ordered by the pulmonologists early in the evaluation of patients with NSCLC, which might complement the tumor biopsy.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/uso terapêutico , DNA de Neoplasias/sangue , Feminino , Técnicas de Genotipagem , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Piperidinas/uso terapêutico , Estudos Prospectivos
2.
Medicine (Baltimore) ; 99(46): e23150, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181687

RESUMO

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) have become the preferred therapy as first-line treatment of non-small cell lung cancer patients harboring sensitizing EGFR mutations. However, the prognostic indicators are limited. The present study aimed to assess the prognostic value of immune-inflammation factors, fibrinogen-albumin ratio index (FARI), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) in EGFR-Mutant lung adenocarcinoma patients receiving first-generation EGFR-TKIs treatment.194 patients were included in this retrospective analysis. FARI was calculated as fibrinogen / albumin. Receiver operating characteristic curve was used to evaluate the optimal cut-off value for FARI, NLR, and PLR to progression free survival (PFS). Univariate and multivariate survival analysis were performed to identify factors correlated with PFS and overall survival (OS).Applying cut-offs of ≥0.08 (FARI), ≥3.28 (NLR), and ≥273.85 (PLR), higher FARI or NLR was associated with worse Eastern Cooperative Oncology Group performance status (ECOG PS) (P = .018, .002, respectively), and there were more males in high NLR group (P = .043). In univariate analysis, ECOG PS status, NLR, PLR, and FARI were significantly associated with PFS (P = .017, .004, <.001, .001, respectively) as well as OS (P < .001, = .001, .002, .023, respectively). In multivariate analysis, PLR (hazard ratios [HR] 1.692; 95% CI 1.054-2.715; P = .029) and FARI (HR 1.496; 95% CI 1.031-2.172; P = .034) were independent prognostic factors for PFS. While only ECOG PS status (HR 2.052; 95% CI 1.272-3.310; P = .003) was independently correlated with OS.FARI is independently associated with PFS in EGFR-Mutant lung adenocarcinoma patients receiving first-line EGFR-TKIs treatment.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB/genética , Fibrinogênio/análise , Inibidores de Proteínas Quinases/uso terapêutico , Albumina Sérica Humana/análise , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores/sangue , Contagem de Células Sanguíneas/métodos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão
3.
J Cancer Res Ther ; 16(4): 811-815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930123

RESUMO

Background: Lung cancer is one of the most frequent types of cancer and the leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) being highly expressed in lung cancers. Activation of EGFR through oncogenic mutations leads to upregulation of gene expression that may heighten the inflammatory response in certain situations. EGFR acts as a key regulator and a cellular hub for inflammatory cytokine signaling, thereby promoting tumor cell proliferation, invasion, migration, metastases, and survival. The aim of the present study is to determine the serum cytokines levels and EGFR mutation status in lung cancer patients to investigate the association between the EGFR mutation status and cytokines levels with lung cancer patients. Materials and Methods: Blood and tissue samples of lung cancer patients were collected. The EGFR mutations of lung cancer patients were determined by the immunohistochemistry (IHC) and serum cytokines levels of lung cancer patients were determined using ELISA. Results: Statistically significant association of EGFR mutations with adenocarcinoma subtypes and non-smokers were found (P < 0.05). Lung cancer patients with EGFR mutations had significantly higher tumor necrosis factor-alpha levels when compared to lung cancer patients without EGFR mutations (P < 0.01), and EGFR mutation status was not significantly associated with interleukin-6 levels (P = 0.24). Conclusion: EGFR mutation detection by the IHC method is a potentially useful tool to guide clinicians for personalized treatment of lung cancer patients of adenocarcinoma subtype, and cytokines are good biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer patients as well as act as therapeutic targets. This study will provide biomarkers for lung cancer diagnosis and treatments.


Assuntos
Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Citocinas/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fator de Necrose Tumoral alfa/sangue
5.
Nat Commun ; 11(1): 3556, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678093

RESUMO

Early cancer detection greatly increases the chances for successful treatment, but available diagnostics for some tumours, including lung adenocarcinoma (LA), are limited. An ideal early-stage diagnosis of LA for large-scale clinical use must address quick detection, low invasiveness, and high performance. Here, we conduct machine learning of serum metabolic patterns to detect early-stage LA. We extract direct metabolic patterns by the optimized ferric particle-assisted laser desorption/ionization mass spectrometry within 1 s using only 50 nL of serum. We define a metabolic range of 100-400 Da with 143 m/z features. We diagnose early-stage LA with sensitivity~70-90% and specificity~90-93% through the sparse regression machine learning of patterns. We identify a biomarker panel of seven metabolites and relevant pathways to distinguish early-stage LA from controls (p < 0.05). Our approach advances the design of metabolic analysis for early cancer detection and holds promise as an efficient test for low-cost rollout to clinics.


Assuntos
Adenocarcinoma de Pulmão/sangue , Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/sangue , Aprendizado de Máquina , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metabolômica , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
6.
J Breath Res ; 14(3): 036001, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32031993

RESUMO

AIM: Lung adenocarcinoma is characterized by poor prognosis and short survival rates. Therefore, tools to identify the tumoural molecular structure and guide effective diagnosis and therapy decisions are essential. Surgical biopsies are highly invasive and not conducive for patient follow-up. To better understand disease prognosis, novel non-invasive analytic methods are needed. The aim of the present study is to identify the genetic mutations in formalin-fixed paraffin-embedded (FFPE) tissue, plasma, and exhaled breath condensate (EBC) samples by next-generation sequencing and evaluate their utility in the diagnosis and follow-up of patients with lung adenocarcinoma. METHOD: FFPE, plasma, and EBC samples were collected from 12 lung adenocarcinoma patients before treatment. DNA was extracted from the specimens using an Invitrogen PureLink Genomic DNA Kit according to the manufacturer's instructions. Amplicon-based sequencing was performed using Ion AmpliSeq Colon and Lung Cancer Research Panel v2. RESULTS: Genetic alterations were detected in all FFPE, plasma, and EBC specimens. The mutations in PIK3CA, MET, PTEN, SMAD4, and FGFR2 genes were highly correlated in six patients. Somatic and novel mutations detected in tissue and EBC samples were highly correlated in one additional patient. The EGFR p.L858R and KRAS p.G12C driver mutations were found in both the FFPE tissue specimens and the corresponding EBC samples of the lung adenocarcinoma patients. CONCLUSION: The driver mutations were detected in EBC samples from lung adenocarcinoma patients. The analysis of EBC samples represents a promising non-invasive method to detect mutations in lung cancer and guide diagnosis and follow-up.


Assuntos
Testes Respiratórios/métodos , Expiração , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Biologia Molecular/métodos , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética
7.
Oncology ; 98(5): 303-310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32097938

RESUMO

INTRODUCTION: Interaction of OX40 and OX40 ligand (OX40L) is associated with immune activation. OX40-OX40L axis is also suggested to play a role in immunity against several solid malignancies. OBJECTIVE: In this study, serum OX40 and OX40L levels in patients with advanced lung adenocarcinoma were assessed and their correlation with survival and clinicopathologic parameters was determined. METHODS: Serum samples were collected from patients with advanced lung adenocarcinoma, then OX40 and OX40L were quantified via enzyme-linked immunosorbent assay. Immunohistochemical (IHC) analysis of OX40 and OX40L in resected primary lesions was also performed. The association between OX40 and OX40L levels and clinicopathologic status and patient survival was retrospectively analyzed. RESULTS: A total of 56 patients were analyzed. Median serum OX40 and OX40L levels were 156.2 pg/mL and 186.6 pg/mL, respectively. IHC analysis in 5 patients indicated high positivity of OX40 in tumor-infiltrating lymphocytes and of OX40L in tumor cells in mucinous adenocarcinoma. Patients with a high OX40 level (≥152.2 pg/mL) had poorer prognosis than those with a low serum OX40 level (median survival, 7.36 vs. 21.19 months, respectively, p = 0.04). Patients with a high OX40L level (≥207.3 pg/mL) had poorer prognosis than those with a low serum OX40L level (median survival, 7.36 vs. 14.26 months, respectively, p = 0.04). In the subset of patients treated with immune checkpoint inhibitors (ICIs) (n = 12), those with a high OX40L level were found to have longer survival from ICI initiation than those with a low OX40L level (p = 0.023). CONCLUSIONS: High OX40 and OX40L levels are associated with poor prognosis and may reflect the immune-exhausted status against lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/mortalidade , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Ligante OX40/sangue , Receptores OX40/sangue , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Estudos Retrospectivos
9.
Zhongguo Fei Ai Za Zhi ; 23(2): 84-90, 2020 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-32093452

RESUMO

BACKGROUND: The patients with advanced lung adenocarcinoma should select targeted drugs based on the type of tumor epidermal growth factor receptor (EGFR) gene mutation. However, it is difficult to collect tumor tissue of advanced lung adenocarcinoma, and some experts agree that peripheral blood can be used as a substitute for tumor tissue as a test specimen. This paper aimed to investigate the clinical value of ddPCR and super-amplification refractory mutation system (ARMS) in detecting EGFR gene mutation in peripheral blood of patients with advanced lung adenocarcinoma. METHODS: A total of 119 patients diagnosed in Beijing Chest Hospital Affiliated to Capital Medical University from February 2016 to February 2019 were collected, and the sensitivity and specificity of plasma ctDNA EGFR gene mutation detected by ddPCR and super-arms were compared. Some patients with positive EGFR gene mutations received oral treatment with first-line EGFR tyrosine kinase inhibitors (EGFR-TKI). The patients were divided into subgroups according to the test results. In group 1, both ddPCR and super-arms showed positive EGFR gene mutation results, with 21 cases. In group 2, ddPCR and super-arms detection of EGFR gene mutation were all negative, with 16 cases. In group 3, the ddPCR test was positive and the super-arms test was negative, with 5 cases. In group 4, the ddPCR test result was negative while the super-arms test result was positive. Since the number of patients in group 4 was 0, no statistics were included. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate the short-term outcome, and progression-free survival (PFS) was compared with survival analysis to evaluate the long-term outcome. RESULTS: EGFR mutations were detected in 58 (48.7%) of 119 patients with advanced lung adenocarcinoma. The coincidence rate between ddPCR and EGFR gene mutation in tumor tissues was 82.4% (Kappa=0.647, P<0.001), the sensitivity was 74.1%, and the specificity was 90.2%. However, the coincidence degree of super-arms test and tissue test was 71.4%, the sensitivity was only 58.6%, and the specificity was 83.6%. The ORR and DCR values in group 3 were lower than those in group 1 and 2, but there was no significant difference in ORR between groups (P>0.05). Survival analysis showed that the PFS of the three groups was compared. The difference was not statistically significant (χ²=2.221, P=0.329). CONCLUSIONS: ddPCR, as a high sensitivity and specificity liquid gene detection method, can be used as a reliable method to detect the mutation of plasma ctDNA EGFR gene in patients with advanced lung adenocarcinoma. The results of plasma genetic testing can also be used as the basis for predicting the efficacy of EGFR-TKIs in patients.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Reação em Cadeia da Polimerase/métodos , Adenocarcinoma de Pulmão/sangue , Idoso , Idoso de 80 Anos ou mais , DNA Tumoral Circulante/sangue , Receptores ErbB/sangue , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Mutação
10.
Int J Cancer ; 146(9): 2394-2405, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/sangue , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Inflamação/complicações , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/etiologia , Adulto , Idoso , Carcinoma de Células Grandes/sangue , Carcinoma de Células Grandes/etiologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/imunologia , Cinurenina/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Prognóstico , Estudos Prospectivos , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/etiologia , Triptofano/sangue
11.
J Clin Lab Anal ; 34(1): e23027, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31489711

RESUMO

OBJECTIVE: The aim of this study was to explore the predictive value of carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCAg), and neuron-specific enolase (NSE) in the prediction of anaplastic lymphoma kinase (ALK) mutations in advance stage non-small cell lung cancer (NSCLC). SUBJECTS AND METHODS: A total of 482 cases with untreated lung adenocarcinoma were retrospectively reviewed. Finally, 72 patients with stage IV were enrolled because of intact data of the detection of ALK rearrangement and serum tumor markers, as well they have not received any previous anticancer therapy. We used the one-way ANOVA analysis, correlation analysis, and multiple logistic regression analysis to evaluate the relationship between the level of serum tumor markers and ALK mutations. RESULTS: Fifteen cases with ALK mutations and 57 cases without mutations were identified. The result of the one-way ANOVA analysis showed only CEA was significantly associated with ALK mutations (95% CI:39.05-148.88; P = .001). The area under the ROC curve (AUC) of CEA was 0.705 (95%CI:0.567-0.843; P = .015). However, no significant association was observed between CEA and ALK mutations though the result of correlation analysis (P = .069) and multivariate logistic regression analysis (OR = 0.988, 95% CI: 0.972-1.003, P = .111). CONCLUSIONS: In our study, we performed on the patients with stage IV lung adenocarcinoma in our region and found preoperative serum levels of SCCAg, CYRF21-1, and NSE not suitable for the detection of ALK mutation. Although we observed a significant association between CEA and ALK mutations; however, it was not strong enough to distinguish ALK status for the patients in our region.


Assuntos
Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma de Pulmão/enzimologia , Adulto , Idoso , China , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Curva ROC
12.
Asia Pac J Clin Oncol ; 16(1): 63-69, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31721468

RESUMO

AIM: Valuable and convenient prognostic predictors are essential for targeted therapy of non-small cell lung cancer (NSCLC). Patients with early-stage cancer and EGFR mutations who's neutrophils-to-lymphocytes rate (NLR) could be prognostic factor to evaluate efficacy. However, the prognostic role of NLR in patients receiving ALK inhibitors has not been established. Additionally, the relation between the efficacy of ALK inhibitors and derived NLR (dNLR), platelets-to-lymphocytes rate (PLR), white blood cells (WBC) and hemoglobin (HGB) are still unknown. METHODS: This is a retrospective single-center study and enrolled 113 staged IIIB-IV ALK-positive NSCLC patients who had received crizotinib treatment. Pretreatment NLR, dNLR, PLR, WBC, HGB were collected and calculated. Cox regression analysis were conducted to study the prognostic roles of NLR, dNLR, PLR, WBC, and HGB on progression-free survival (PFS) and overall survival (OS). Z-test was utilized to identify the difference among all predictive factors' receiver-operating characteristics (ROC) curves. RESULTS: The median PFS and OS were 10.1 and 23.4 months. Elevated NLR, dNLR, PLR and decreased HGB were associated with worse PFS (95% confidence interval [CI], 1.078-2.304, P = 0.018; 95% CI, 1.043-2.222, P = 0.028; 95% CI, 1.257-2.757, P = 0.002; 95% CI, 0.368-0.843, P = 0.005, respectively) and OS (95% CI, 1.698-5.721, P < 0.001; 95% CI, 1.273-3.984, P = 0.005; 95% CI, 2.174-6.347, P < 0.001; 95% CI, 0.246-0.710, P = 0.001, respectively). Z-test revealed there were no significant differences between single factors or combination of them to predict the efficacy. CONCLUSIONS: Trend of NLR, dNLR, PLR and WBC could be used to identify patients progress status in ALK-positive NSCLC patients receiving crizotinib. Combination of all biomarkers is no superior to single biomarker.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores/sangue , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/uso terapêutico , Linfócitos/patologia , Neutrófilos/patologia , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida
13.
Medicine (Baltimore) ; 98(42): e17601, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626137

RESUMO

BACKGROUND: Lung adenocarcinoma (LA) is a most common form of non-small cell lung cancer (NSCLC). To date, there are still no effective early diagnosis methods for patients to be cured in time. Noncoding RNA plays an important role in oncogenesis and tumor development. The expression profile of circular RNA (circRNA) in peripheral whole blood (PWB) of LA has not been systematically investigated. In this study, we identified the differentially expressed (DE) circRNAs in PWB of LA by high-throughput sequencing. METHODS: Five paired LA and normal participants PWB samples were chosen to investigate the expression profile of circRNAs by high-throughput sequencing. Twenty LA and 10 normal controls PWB samples were subjected to reverse-transcription polymerase chain reaction (RT-PCR) for validation of circRNAs expression profile. Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and circRNA-miRNA network analysis was also performed to predict the function of circRNAs in PWB. RESULTS: A total of 10566 circRNAs were identified and annotated, most of the circRNAs were exonic (78.14%). Statistical analysis revealed 4390 DE circRNAs, in which were 3009 upregulated circRNAs and1381downregulated circRNAs in LA. RT-PCR results showed that circRNA expression in LA was higher than that in controls. GO functional analysis, KEGG pathway analysis, and circRNA-miRNA network analysis all showed that circRNAs correlated with tumor development and progression to a certain degree. The current study is the first to systematically characterize and annotate circRNA expression in PWB of LA. Some host genes of the DE circRNAs were involved in tumor signaling pathway and had complicated correlations with tumor related miRNAs, indicating that circRNAs might involve in development and progression of LA. CONCLUSIONS: Our study revealed that circRNAs were abnormally expressed in PWB of LA, which might offer potential targets for the early diagnosis of the disease and new genetic insights into LA.


Assuntos
Adenocarcinoma de Pulmão/genética , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , RNA/genética , Adenocarcinoma de Pulmão/sangue , Perfilação da Expressão Gênica/métodos , Humanos , RNA/biossíntese , RNA Circular , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Regulação para Cima
14.
Bull Exp Biol Med ; 167(6): 771-778, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31655998

RESUMO

Copy number variation of some gene loci in lung tumor cells extracted by laser capture microdissection and in cell-free DNA in the plasma of patients with lung cancer was analyzed for identification of potential molecular markers. Tissue specimens fixed in formalin and embedded in paraffin blocks (FFPE-blocks) from 90 patients and extracellular DNA from plasma samples of 70 patients and 30 donors were used. Copy number variation was assayed for 30 genes (BAX, BCL2, C-FLAR, P53, MDM2, CASP9, CASP3, CASP8, SOX2, OCT4, PIK3, MKI67, HV2, HIF1A1, XRCC1, MMP1, TERT, CTNNB1, KRAS, EGFR, GRB2, SOS1, MAPK1, STAT1, BRAF, FTO, and mir3678) and reference loci (ACTB, B2M, and GAPDH) by the real-time quantitative PCR. Changed copy numbers were detected for genes responsible for apoptosis regulation (BAX, P53, and CASP3), proliferation (SOX2), DNA reparation (XRCC1), oxidative phosphorylation (HV2), EGFR signaling pathway (GRB2, SOS1, MAPK1, STAT1, and BRAF), and for mir3678 gene in lung tumor cells and extracellular DNA.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Variações do Número de Cópias de DNA , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , DNA Tumoral Circulante/análise , DNA Tumoral Circulante/sangue , Estudos de Coortes , Análise Mutacional de DNA/métodos , Feminino , Humanos , Microdissecção e Captura a Laser , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Reação em Cadeia da Polimerase em Tempo Real , Fixação de Tecidos
15.
J Transl Med ; 17(1): 339, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597567

RESUMO

INTRODUCTION: Pemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), however, the efficacy and safety is varying from individuals. There is a need to better understand the genetic variations associated with platinum response. MATERIALS AND METHODS: We performed next-generation sequencing (NGS) based on BGI Oseq-ctDNA panel to analyze 98 longitudinal plasma samples from 32 lung adenocarcinoma patients during platinum-based chemotherapy, and a bioinformatic pipeline was developed to detect point mutations. RESULTS: We found that mutation burden was decreased after chemotherapy, which reflected chemotherapy sensitivity, especially the frequency of C>G and C>A substitutions. Moreover, neoplastic cells carrying a specific set of somatic mutations, such as EGFR(L858R), KRAS (p.G12C) were obviously correlated with platinum treatment. In addition, the MAPK pathway was found to have a pivotal role in NSCLC and platinum based response. Finally, we found that smokers benefit less from platinum-based chemotherapy. CONCLUSIONS: Collectively, this work described the dynamic changes of ctDNA mutation status during platinum-based treatment, which may contribute to advanced lung adenocarcinoma patients stratification and precision treatment.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/sangue , Adulto , Idoso , DNA Tumoral Circulante/genética , Estudos de Coortes , Feminino , Inativação Gênica , Humanos , Estudos Longitudinais , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Mutação/genética , Platina/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Fumar/efeitos adversos
16.
Zhongguo Fei Ai Za Zhi ; 22(9): 568-573, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31526460

RESUMO

BACKGROUND: The tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation may have a positive effect, but most patients may develop drug resistance, therefore, the detection of the developing time in drug resistance and the research of the mechanism of drug resistance are need to be solved. While the emerge of next generation sequencing (NGS) have make it possible. The aim of this study is to monitor the efficacy of targeted therapy by studying the variation of circulating tumor DNA (ctDNA) mutation frequency and gene mutation spectrum through the targeted therapy. METHODS: Our center enrolled 22 patients with EGFR mutation detected by tissue or peripheral blood, and collect 8 mL of peripheral blood of the patients for ctDNA sequencing in different phases, before systematic prior treatment, followed-up by 2 months and disease progression after TKI administration. RESULTS: Patients with EGFR gene mutation may acquire a longer median survival time after receiving targeted drug therapy, due to the drop of mutation abundances, while the therapy may have a minor effect in patients which their mutation abundances have slightly decreased compared to the statistics before the cession (P=0.015,3). The significantly reduced group median progression was associated with a longer survival [progression free survival (PFS)=390 d]. At the same time, we found out that when related to TP-53 gene mutation, the effect of targeted drug therapy for EGFR-sensitive mutation was unsatisfactory (the median PFS was 120 d compared with 630 d, P=0.000,2). CONCLUSIONS: Patients who has lower mutation abundance with EGFR sensitive mutations after TKI treatment may have a longer survival period (P<0.05), and the mutation abundance were not significantly dropping or accompanied by other mutations may indicating TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , DNA Tumoral Circulante/sangue , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
17.
Eur J Cancer ; 120: 86-96, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31499384

RESUMO

PURPOSE: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population. EXPERIMENTAL DESIGN: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival. RESULTS: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients. CONCLUSIONS: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents. TRIAL REGISTRATION ISRCTN NUMBER: ISRCTN02370070.


Assuntos
Adenocarcinoma de Pulmão/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma de Células Escamosas/sangue , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/sangue , Platina/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Proteínas Sanguíneas/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Taxa de Sobrevida
18.
Asian Pac J Cancer Prev ; 20(8): 2405-2407, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450913

RESUMO

Background: To investigate the clinical value of HE4 detection in the diagnosis of lung cancer and the clinical significance of combined detection with CEA, NSE and CYFRA21-1. Methods: 90 cases of lung cancer, 30 cases of pulmonary tuberculosis, 30 cases of pneumonia and 30 cases of health physical examination were selected. The levels of serum HE4, CYFRA21-1, CEA and NSE were detected by electrochemiluminescence method. Statistical analysis was performed to observe the sensitivity and specificity. Results: The levels of serum HE4, CEA, NSE and CYFRA21-1 in lung cancer group were significantly higher than those in tuberculosis group and health physical examination group. There was no significant difference in the levels of HE4, CEA and NSE between the lung cancer group and the pneumonia group, the difference of CYFRA21-1 level was statistically significant (p<0.05).With health physical examination group as normal controls, the sensitivity and specificity of combined detection of HE4, CEA, NSE and CYFRA21-1 in the diagnosis of lung cancer were 82.2% and 90.0%,and the area under the curve (AUC) was 0.907, followed by HE4 (0.867), CYFRA21-1 (0.787), CEA (0.752) and NSE (0.747). Conclusion: HE4 can be used as a serological marker for the diagnosis of lung cancer. The combined detection of HE4, CEA, NSE and CYFRA21-1 can improve the diagnosis of lung cancer. Serum HE4 levels are highly specific in distinguishing between lung cancer patients and normal population, and are equivalent to CYFRA21-1; but they are less specific than CYFRA21-1 in distinguishing lung cancer patients from pneumonia patients.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análise , Adenocarcinoma de Pulmão/sangue , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma de Células Escamosas/sangue , Proteínas de Transporte/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Queratina-19/sangue , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Carcinoma de Pequenas Células do Pulmão/sangue
19.
Clin Cancer Res ; 25(23): 7058-7067, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31439586

RESUMO

PURPOSE: No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer.Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B-time D), and after surgery (time P1-time P3). Next-generation sequencing-based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection. RESULTS: Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively (P = 0.657), whereas at time P2 was 278 days and 637 days, respectively (P = 0.002). CONCLUSIONS: ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
20.
Cancer Biomark ; 26(2): 139-150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356196

RESUMO

BACKGROUND: No tumor biomarker (TM) is available for de novo metastatic lung adenocarcinoma. OBJECTIVE: To examine the serum levels of carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen (CA) 19-9, CA125, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), and lactate dehydrogenase (LDH) to predict de novo metastatic lung adenocarcinoma. METHODS: This was a retrospective study of geriatric (⩾ 60 years of age) patients with lung cancer diagnosed at Shanxi Cancer Hospital from 02/2012 to 12/2017. CEA, CYFRA21-1, CA199, NSE, CA125, TPA, and TPS were detected by ELISA and LDH was detected by LDH kit. Their predictive value was assessed using receiver operating characteristic (ROC) curves and multivariable logistic regression. RESULTS: The positive rates of LDH and TMs were higher in the metastatic group (all P< 0.05). The best single TMs were CYFRA21-1 (70.5% sensitivity) and CA199 (92.0% specificity). When using any two, the best were CYFRA21-1+TPA (77.1% sensitivity) and CA199+TPA or NSE (both 84.1% specificity). High LDH and CA125 statuses were each independently associated with brain, bone, liver, and lung metastases (all P< 0.05). CONCLUSIONS: Abnormal level of LDH and TMs, alone or in combination, had predictive value for metastasis in geriatric patients with lung adenocarcinoma; these indicators were also associated with the metastatic site.


Assuntos
Adenocarcinoma de Pulmão/secundário , Biomarcadores Tumorais/sangue , L-Lactato Desidrogenase/sangue , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/terapia , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Feminino , Seguimentos , Proteínas Ligadas por GPI/sangue , Humanos , Queratina-19/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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