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1.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070597

RESUMO

For non-small cell lung cancer (NSCLC), radiotherapy (RT) and platinum-based chemotherapy (CHT) are among the main treatment options. On the other hand, radioresistance and cytotoxic drug resistance are common causes of failure. The epidermal growth factor receptor (EGFR) plays an important role in radioresponse and therapy resistance. We hypothesized that single nucleotide polymorphisms (SNPs) in the EGFR gene might affect individual sensitivity to these treatments, and thus, therapy outcome and prognosis. The association between functional EGFR SNPs and overall (OS), locoregional recurrence-free (LFRS), and metastasis-free (MFS) survival was examined in 436 patients with unresectable NSCLC receiving RT and platinum-based CHTRT. In a multivariate analysis, the rs712830 CC homozygotes showed reduced OS in the whole group (p = 0.039) and in the curative treatment subset (p = 0.047). The rs712829 TT genotype was strongly associated with decreased LRFS (p = 0.006), and the T-C haplotype was a risk factor for locoregional recurrence in our patients (p = 0.003). The rs2227983 GG alone and in combination with rs712829 T was an indicator of unfavorable LRFS (p = 0.028 and 0.002, respectively). Moreover, significant independent effects of these SNPs on OS, LRFS, and MFS were observed. Our results demonstrate that inherited EGFR gene variants may predict clinical outcomes in NSCLC treated with DNA damage-inducing therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Neoplasias Pulmonares , Proteínas de Neoplasias/genética , Platina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
2.
Medicine (Baltimore) ; 100(25): e26450, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160440

RESUMO

RATIONALE: The guidelines recommended gefitinib as a first-line targeted treatment for stage IV non-small-cell lung cancer (NSCLC) patients with EGFR mutations. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment for patients without T790m mutation. The case is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib. PATIENT CONCERNS: We described a 55-year-old man with good performance status (PS). DIAGNOSES: He was histopathologically diagnosed stage IV lung adenocarcinoma with EGFR mutations in November 2018. INTERVENTIONS: He was administrated with gefitinib daily (250 mg) for activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions,19del), and combined with platinum-based dual-drug chemotherapy. During the target treatments, the optimal efficacy evaluation was partial remission (PR) with a 12-month progression-free survival (PFS) time. Later, the intracranial progression of the patient rendered the treatment change to erlotinib. OUTCOMES: It is surprising that the tumor lesion in brain as well as lung relieved obviously. His progression-free survival (PFS)was nearly 11 months, and the overall survival (OS)was>36 months up to now. The adverse events were tolerable. LESSIONS: This case manifests that re-biopsy of advanced or recurrent NSCLC is beneficial to make a better therapeutic regimen, and erlotinib can be used as a salvage treatment after gefitinib failure.


Assuntos
Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação/métodos , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Quimiorradioterapia/métodos , Resistencia a Medicamentos Antineoplásicos , Substituição de Medicamentos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada , Critérios de Avaliação de Resposta em Tumores Sólidos
3.
Eur Rev Med Pharmacol Sci ; 25(10): 3868-3878, 2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1264763

RESUMO

OBJECTIVE: This study aimed to compare the mortality rate between advanced-stage non-small cell lung cancer patients (NSCLC) with and without COVID-19. This study also explores the possible laboratory characteristics used for prognostication in patients with NSCLC and COVID-19. Additionally, this study evaluated potential differences in laboratory values between the case and control groups. PATIENTS AND METHODS: This is a single-center retrospective cohort study conducted in Dharmais National Cancer Hospital, Indonesia, enrolling patients with NSCLC undergoing chemotherapy or targeted therapy between May 2020 and January 2021. All patients with NSCLC and COVID-19 in these periods were enrolled into the case group. The control group was age-matched NSCLC patients without COVID-19 that was derived from the NSCLC cohort through randomization. RESULTS: There were 342 patients with NSCLC between May 2020 and January 2021. Twenty-seven (7.9%) of the patients were infected by COVID-19. To facilitate comparison, thirty-five age-matched controls with NSCLC were selected from the cohort. The mortality rate in patients with COVID-19 was 46.2%. Eleven patients (40.7%) had severe COVID-19, of which none survived. NLR >8.35 has a sensitivity of 83.3%, specificity of 92.9%, LR+ of 12, and LR- of 0.18. The AUC was 0.946 (95% CI 0.867-1.000), p<0.001. PLR >29.14 has a sensitivity of 75.0%, specificity of 71.4%, LR+ 2.62, LR- 0.35, and AUC 0.851 (95% CI 0.706-0.996), p=0.002. Both NLR and PLR were associated with shorter time-to-mortality in the unadjusted and adjusted model CONCLUSIONS: NLR and PLR are independent predictors of mortality in COVID-19 patients with NSCLC.


Assuntos
Plaquetas/citologia , COVID-19/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Linfócitos/citologia , Neutrófilos/citologia , Idoso , Área Sob a Curva , COVID-19/complicações , COVID-19/virologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Indonésia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Sensibilidade e Especificidade , Taxa de Sobrevida
4.
Eur Rev Med Pharmacol Sci ; 25(10): 3868-3878, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34109595

RESUMO

OBJECTIVE: This study aimed to compare the mortality rate between advanced-stage non-small cell lung cancer patients (NSCLC) with and without COVID-19. This study also explores the possible laboratory characteristics used for prognostication in patients with NSCLC and COVID-19. Additionally, this study evaluated potential differences in laboratory values between the case and control groups. PATIENTS AND METHODS: This is a single-center retrospective cohort study conducted in Dharmais National Cancer Hospital, Indonesia, enrolling patients with NSCLC undergoing chemotherapy or targeted therapy between May 2020 and January 2021. All patients with NSCLC and COVID-19 in these periods were enrolled into the case group. The control group was age-matched NSCLC patients without COVID-19 that was derived from the NSCLC cohort through randomization. RESULTS: There were 342 patients with NSCLC between May 2020 and January 2021. Twenty-seven (7.9%) of the patients were infected by COVID-19. To facilitate comparison, thirty-five age-matched controls with NSCLC were selected from the cohort. The mortality rate in patients with COVID-19 was 46.2%. Eleven patients (40.7%) had severe COVID-19, of which none survived. NLR >8.35 has a sensitivity of 83.3%, specificity of 92.9%, LR+ of 12, and LR- of 0.18. The AUC was 0.946 (95% CI 0.867-1.000), p<0.001. PLR >29.14 has a sensitivity of 75.0%, specificity of 71.4%, LR+ 2.62, LR- 0.35, and AUC 0.851 (95% CI 0.706-0.996), p=0.002. Both NLR and PLR were associated with shorter time-to-mortality in the unadjusted and adjusted model CONCLUSIONS: NLR and PLR are independent predictors of mortality in COVID-19 patients with NSCLC.


Assuntos
Plaquetas/citologia , COVID-19/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Linfócitos/citologia , Neutrófilos/citologia , Idoso , Área Sob a Curva , COVID-19/complicações , COVID-19/virologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Indonésia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Sensibilidade e Especificidade , Taxa de Sobrevida
5.
Medicine (Baltimore) ; 100(19): e25762, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106605

RESUMO

ABSTRACT: The aim of this study was to explore the association of rs1836724 single-nucleotide polymorphism (SNP) of ERBB4 with risk and prognosis of non-small cell lung cancer (NSCLC) in the Chinese Han population.The genotype of rs1836724 SNP of ERBB4 from 258 patients with NSCLC and 200 noncancer controls were detected the TaqMan-MGB probes real-time fluorescence polymerase chain reaction. The distribution of genotype and alleles between the 2 groups was compared, and the association between clinicopathological characteristic and rs1836724 SNP was analyzed. Prognosis and influencing factors were analyzed by Kaplan-Meier and Cox regression analysis.There were significant differences in the genotype and allele distribution of ERBB4 rs1836724 between the NSCLC group and control group (P < .05). And CC genotype of rs1836724 was associated with increased risk of NSCLC in the Chinese Han population. Rs1836724 SNP was associated with TNM stage and lymph nodal metastasis (P = .001, P = .007). The median follow-up was 29 months, and the progression-free survival and overall survival of 258 NSCLC patients were 27.91% and 31.39%, respectively. Patients with GG genotype of rs1836724 had poor progression-free survival and overall survival. Rs1836724 SNP was an independent prognostic marker of NSCLC patients, CC genotype had a high risk of poor prognosis (odds ratio = 1.587, 95% confidence interval: 1.079-2.335, P = .019).In Chinese Han populations, rs1836724 SNP of ERBB4 may contribute toward the increased risk and poor prognosis of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Receptor ErbB-4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/etnologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , China/epidemiologia , Feminino , Seguimentos , Genótipo , Técnicas de Genotipagem , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise de Sobrevida
6.
Jpn J Clin Oncol ; 51(7): 1123-1131, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34002234

RESUMO

OBJECTIVES: The prognostic role of interstitial pneumonia with emphysema in lung cancer is not fully understood. This study aimed to examine the prognostic role of the presence of emphysema in patients with clinical stage I lung cancer and interstitial pneumonia. METHODS: The presence of interstitial pneumonia and emphysema was evaluated on preoperative high-resolution computed tomography. In total, 836 consecutive patients with clinical stage I lung cancer who underwent complete resection between April 2007 and March 2016 were retrospectively analyzed using the log-rank test and Cox proportional hazard model to examine survival differences. RESULTS: There was a significant difference in 5-year overall survival between patients with interstitial pneumonia and emphysema (n = 65) and those without (n = 771) (62.6% vs. 86.5%; P < 0.001). However, in patients with interstitial pneumonia on high-resolution computed tomography, there was no significant difference in 5-year overall survival between patients with emphysema (n = 65) and those without emphysema (n = 50) (62.6% vs. 59.4%, P = 0.84). Multivariable backward stepwise Cox proportional hazard analysis in patients with interstitial pneumonia showed that histology, %diffusing capacity of the lungs for carbon monoxide, radiologic interstitial pneumonia pattern and surgical procedure were independent prognostic factors for overall survival, but the presence of emphysema was not. CONCLUSIONS: The presence of emphysema was not an independent prognostic factor for overall survival in patients with clinical stage I lung cancer with interstitial pneumonia. Poor survival of patients with IP and emphysema may be due to the presence of interstitial pneumonia.


Assuntos
Doenças Pulmonares Intersticiais/mortalidade , Neoplasias Pulmonares/mortalidade , Enfisema Pulmonar/mortalidade , Idoso , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/patologia , Tomografia Computadorizada por Raios X
7.
J Cancer Res Clin Oncol ; 147(8): 2301-2307, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34003366

RESUMO

PURPOSE: Monitoring mutation status in circulating free DNA (cfDNA) during target therapy could hold significant clinical importance in non-small cell lung cancer (NSCLC). Our aim is to establish if EGFR mutational status change on cfDNA has predictive value that can impact clinical management of NSCLC patients care. METHODS: This study included 30 patients with EGFR-mutated NSCLC. Blood samples were collected at diagnosis (T0) and in 19 patients during therapy (T1). RESULTS: Concordance between T0 and T1 EGFR mutation status for patients evaluable for both samples (n = 19) was 79%, with a sensitivity of 100% (95% CI: 55.5-100.0) and specificity of 60.0% (95% CI: 26.2-86.8). For the patients in oncological therapy with targeted drug and with T1 sample available (n = 18), survival outcomes were evaluated. For both mutation-negative T0 and T1 patients, 12-month progression-free survival (PFS) was 66.7% (95% CI: 27.2-100.0) and 12-month overall survival (OS) was 100% (95% CI: 1.00-1.00); for patients mutated both at T0 and T1, PFS was 22.2% (95% CI: 6.5-75.4%) and OS was 55.6% (95% CI: 20.4-96.1%). CONCLUSION: EGFR mutation status can be assessed using cfDNA for routine purposes and longitudinal assessment of plasma mutation is an easy approach to monitor the therapeutic response or resistance onset.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/genética , Análise Mutacional de DNA/métodos , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Receptores ErbB/análise , Receptores ErbB/genética , Feminino , Humanos , Itália/epidemiologia , Biópsia Líquida , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos
8.
J Cancer Res Clin Oncol ; 147(8): 2239-2248, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34037837

RESUMO

BACKGROUND: Targeted cancer therapy has shed light on the treatment of tumor, especially for patients with non-small cell lung cancer. However, only a limited portion of NSCLC patients carrying specific mutations showed an ideal drug response. In addition, DNA methylation status showed a great potential for cancer detection and prognosis prediction. METHODS: Bisulfite sequencing was performed to analyze the DNA methylation of WIF1 promoter in cfDNA and tumor tissue samples collected from NSCLC patients. PFS and OS analyses were carried out to evaluate the prognosis of gefitinib treatment in patients with differential levels of WIF1 DNA methylation. Quantitative real-time PCR was used to analyze the expression of WIF1 mRNA, while immunohistochemistry was performed to assess the expression of WIF1 protein. Furthermore, ELISA was carried out to evaluate the WIF1 activity in plasma. RESULTS: The DNA methylation level of WIF1 promoter was lower in the cfDNA of NSCLC patients with a complete or partial response to gefitinib, and NSCLC patients with hypomethylated WIF1 showed better PFS and OS. The DNA methylation of WIF1 promoter in the resected tumor tissues was consistent with WIF1 DNA methylation in cfDNA, indicating that cfDNA was mainly derived from lung cancer tissues. As a result, the expression of WIF1 in tissue samples and the WIF1 activity in plasma was inhibited in patients with hypermethylated WIF1. Moreover, the cell viability of gefitinib-resistant cells was decreased by the suppressed WIF1 methylation in vitro. And the expression level of WIF1 mRNA was higher in gefitinib-resistant cells overexpressing ALKBH5, a known suppressor of WIF1 methylation. CONCLUSION: In summary, the findings of this study demonstrated that the level of WIF1 methylation in cfDNA was associated with the insusceptibility of gefitinib in the treatment of lung cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Ácidos Nucleicos Livres/metabolismo , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
9.
Medicine (Baltimore) ; 100(21): e25992, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032715

RESUMO

BACKGROUND: Nazartinib is considered a new, permanent, and mutant-selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). It has a demonstrated efficacy to treat patients experiencing EGFR-mutated non-small cell cancer (NSCLC). The present study aims to explore the clinical efficacy and safety of nazartinib in patients experiencing EGFR-mutated NSCLC. MATERIALS AND METHODS: The present study is a prospective, multicentre, open-label experiment seeking to assess the clinical safety as well as efficacy of nazartinib in patients suffering from EGFR-mutated NSCLC. The study will randomly divide 78 patients into experimental and control groups using a ratio of 1:1. Additionally, the study will treat the experimental group with nazartinib, and the control group with other chemotherapeutic agents. Besides, the study will treat both the experimental and control groups with standard treatment for a period of 14 days and will be followed up at least 24 weeks. Overall response rate is the major endpoint. Accordingly, the minor endpoints will include progression-free survival, response time, overall survival, and adverse events. Statistical analysis will be performed by SPSS 25.0 software. DISCUSSION: The study will investigate the clinical safety and efficacy of nazartinib in patients suffering from EGFR-mutated NSCLC. The anticipated results of the study are expected to provide clinical basis for nazartinib to treat patients suffering from EGFR-mutated NSCLC.


Assuntos
Benzimidazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nicotina/análogos & derivados , Inibidores de Proteínas Quinases/administração & dosagem , Benzimidazóis/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estudos Multicêntricos como Assunto , Mutação , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Biomed Res Int ; 2021: 8811751, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33987445

RESUMO

It is aimed at investigating the changes of serum soluble programmed death-ligand 1 (sPD-L1) expression level in nonsmall cell lung cancer (NSCLC) before and after radiotherapy, the correlation of PD-L1, PD-1, and proteins of Akt (protein kinase B), mTOR, and HIF-1α, and the molecular mechanism of the PD-1/PD-L1 pathway in the development of NSCLS. A total of 126 NSCLC patients receiving radiotherapy in Liaoning Cancer Hospital from September 2018 to September 2019 were selected as the observation group, and another 58 healthy volunteers were selected as the control group. NSCLC patients were divided into group A (stage I-II, stereotactic radiotherapy) and group B (stage III, intensity-modulated radiation therapy) according to the cancer stage. The efficacy of radiotherapy was evaluated, and sPD-L1 expression was detected by ELISA. The immunohistochemical staining was adopted to detect protein expressions of Akt, mTOR, and HIF-1α in NSCLC tissues. The correlation between their expression and expression of PD-L1 and PD-1 was analyzed. The results showed that the overall response rate (ORR) of group A was 89.29%, the clinical benefit response (CBR) was 96.43%, the median survival time (MST) was 25 months, and the survival rate within three years was 72.56%. In group B, the ORR was 70.41%, the CBR was 97.96%, the MST was 18 months, and the survival rate within three years was 34.67%. Comparison of overall serum sPD-L1 expression in the control group, group A, and group B and between groups before radiotherapy was statistically significant (P < 0.01). After radiotherapy, serum sPD-L1 expression in group A and group B decreased compared with that before radiotherapy (P < 0.01). Among NSCLC patients, the positive expression rate of Akt, mTOR, and HIF-1α was 71.32%, 41.26%, and 80.65%, respectively. PD-L1 expression and Akt, mTOR, and HIF-1α expression showed a significant correlation. PD1 expression and Akt, mTOR, and HIF-1α expression also showed a significant correlation. It indicated that the expression level of sPD-L1 in NSCLC patients was higher than that in normal subjects, but the expression level of sPD-L1 was decreased after radiotherapy. PD-1/PD-L1 may play important roles in NSCLC procession through the Akt/mTOR and HIF-1α pathway.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1/metabolismo , Idoso , Antígeno B7-H1/sangue , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Estudos de Casos e Controles , Feminino , Humanos , Pulmão/química , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/sangue
11.
Nucleic Acids Res ; 49(10): 5684-5704, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33956155

RESUMO

Combinatorial CRISPR-Cas screens have advanced the mapping of genetic interactions, but their experimental scale limits the number of targetable gene combinations. Here, we describe 3Cs multiplexing, a rapid and scalable method to generate highly diverse and uniformly distributed combinatorial CRISPR libraries. We demonstrate that the library distribution skew is the critical determinant of its required screening coverage. By circumventing iterative cloning of PCR-amplified oligonucleotides, 3Cs multiplexing facilitates the generation of combinatorial CRISPR libraries with low distribution skews. We show that combinatorial 3Cs libraries can be screened with minimal coverages, reducing associated efforts and costs at least 10-fold. We apply a 3Cs multiplexing library targeting 12,736 autophagy gene combinations with 247,032 paired gRNAs in viability and reporter-based enrichment screens. In the viability screen, we identify, among others, the synthetic lethal WDR45B-PIK3R4 and the proliferation-enhancing ATG7-KEAP1 genetic interactions. In the reporter-based screen, we identify over 1,570 essential genetic interactions for autophagy flux, including interactions among paralogous genes, namely ATG2A-ATG2B, GABARAP-MAP1LC3B and GABARAP-GABARAPL2. However, we only observe few genetic interactions within paralogous gene families of more than two members, indicating functional compensation between them. This work establishes 3Cs multiplexing as a platform for genetic interaction screens at scale.


Assuntos
Autofagia/genética , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Técnicas de Inativação de Genes/métodos , Redes Reguladoras de Genes/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Carcinoma de Células Escamosas/mortalidade , Proliferação de Células/genética , Sobrevivência Celular/genética , Bases de Dados Genéticas , Biblioteca Gênica , Genes Essenciais , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/mortalidade , Modelos Genéticos , RNA Guia , RNA-Seq , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
12.
BMC Cancer ; 21(1): 402, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853552

RESUMO

OBJECTIVE: This research describes the clinical pathway and characteristics of two cohorts of patients. The first cohort consists of patients with a confirmed diagnosis of lung cancer while the second consists of patients with a solitary pulmonary nodule (SPN) and no evidence of lung cancer. Linked data from an electronic medical record and the Louisiana Tumor Registry were used in this investigation. MATERIALS AND METHODS: REACHnet is one of 9 clinical research networks (CRNs) in PCORnet®, the National Patient-Centered Clinical Research Network and includes electronic health records for over 8 million patients from multiple partner health systems. Data from Ochsner Health System and Tulane Medical Center were linked to Louisiana Tumor Registry (LTR), a statewide population-based cancer registry, for analysis of patient's clinical pathways between July 2013 and 2017. Patient characteristics and health services utilization rates by cancer stage were reported as frequency distributions. The Kaplan-Meier product limit method was used to estimate the time from index date to diagnosis by stage in lung cancer cohort. RESULTS: A total of 30,559 potentially eligible patients were identified and 2929 (9.58%) had primary lung cancer. Of these, 1496 (51.1%) were documented in LTR and their clinical pathway to diagnosis was further studied. Time to diagnosis varied significantly by cancer stage. A total of 24,140 patients with an SPN were identified in REACHnet and 15,978 (66.6%) had documented follow up care for 1 year. 1612 (10%) had no evidence of any work up for their SPN. The remaining 14,366 had some evidence of follow up, primarily office visits and additional chest imaging. CONCLUSION: In both cohorts multiple biopsies were evident in the clinical pathway. Despite clinical workup, 70% of patients in the lung cancer cohort had stage III or IV disease. In the SPN cohort, only 66% were identified as receiving a diagnostic work-up.


Assuntos
Procedimentos Clínicos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Nódulo Pulmonar Solitário , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Biópsia , Tomada de Decisão Clínica , Estudos de Coortes , Gerenciamento Clínico , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Padrões de Prática Médica , Sistema de Registros , Programa de SEER , Nódulo Pulmonar Solitário/diagnóstico , Adulto Jovem
13.
BMC Cancer ; 21(1): 426, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33865364

RESUMO

BACKGROUND: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. METHODS: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. RESULTS: Data of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001). CONCLUSION: Although the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Quimioterapia de Indução , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Quimioterapia de Manutenção , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
14.
Int J Mol Sci ; 22(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916522

RESUMO

Our previous study found that zinc finger protein 71 (ZNF71) mRNA expression was associated with chemosensitivity and its protein expression was prognostic of non-small-cell lung cancer (NSCLC). The Krüppel associated box (KRAB) transcriptional repression domain is commonly present in human zinc finger proteins, which are linked to imprinting, silencing of repetitive elements, proliferation, apoptosis, and cancer. This study revealed that ZNF71 KRAB had a significantly higher expression than the ZNF71 KRAB-less isoform in NSCLC tumors (n = 197) and cell lines (n = 117). Patients with higher ZNF71 KRAB expression had a significantly worse survival outcome than patients with lower ZNF71 KRAB expression (log-rank p = 0.04; hazard ratio (HR): 1.686 [1.026, 2.771]), whereas ZNF71 overall and KRAB-less expression levels were not prognostic in the same patient cohort. ZNF71 KRAB expression was associated with epithelial-to-mesenchymal transition (EMT) in both patient tumors and cell lines. ZNF71 KRAB was overexpressed in NSCLC cell lines resistant to docetaxel and paclitaxel treatment compared to chemo-sensitive cell lines, consistent with its association with poor prognosis in patients. Therefore, ZNF71 KRAB isoform is a more effective prognostic factor than ZNF71 overall and KRAB-less expression for NSCLC. Functional analysis using CRISPR-Cas9 and RNA interference (RNAi) screening data indicated that a knockdown/knockout of ZNF71 did not significantly affect NSCLC cell proliferation in vitro.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/biossíntese , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Docetaxel/farmacologia , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Neoplasias/genética , Paclitaxel/farmacologia , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Taxa de Sobrevida
15.
Medicine (Baltimore) ; 100(16): e25246, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879658

RESUMO

ABSTRACT: Lung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Idoso , Biomarcadores Tumorais/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Bases de Dados Genéticas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Análise de Sobrevida
16.
Cochrane Database Syst Rev ; 4: CD013257, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33930176

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced non-small cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. OBJECTIVES: To determine the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. SEARCH METHODS: We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. SELECTION CRITERIA: We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard first-line therapy (platinum-based chemotherapy +/- bevacizumab). All data come from 'international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed meta-analyses where appropriate using the random-effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. MAIN RESULTS: Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both first-line single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 ≥ 50 being considered the most clinically useful cut-off level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 ≥ 50. Single-agent ICI In the PD-L1 expression ≥ 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PD-L1 expression ≥ 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low-certainty evidence). More information about efficacy of single-agent ICI compared to platinum-based chemotherapy according to the level of PD-L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double-agent ICI Double-ICI treatment probably prolonged OS compared to platinum-based chemotherapy in people with PD-L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate-certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD-L1 groups. Treatment related AEs were not reported according to PD-L1 expression levels. The frequency of grade 3-4 AEs may not differ between double-ICI treatment and platinum-based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low-certainty evidence). More information about efficacy of double-agent ICI according to the level of PD-L1 expression and to TMB status is available in the full text. AUTHORS' CONCLUSIONS: Authors' conclusions The evidence in this review suggests that single-agent ICI in people with NSCLC and PD-L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression-free survival and overall response rate when compared to platinum-based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD-L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum-based chemotherapy, but its effect on progression-free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups. This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/metabolismo , Bevacizumab/efeitos adversos , Viés , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Compostos de Platina/efeitos adversos , Compostos de Platina/uso terapêutico , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
BMC Cancer ; 21(1): 348, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794813

RESUMO

BACKGROUND: Angiogenesis assessment is important for personalized therapeutic intervention in patients with non-small-cell lung cancer (NSCLC). This study investigated whether radiologic parameters obtained by dynamic contrast-enhanced (DCE)-integrated magnetic resonance-positron emission tomography (MR-PET) could be used to quantitatively assess tumor angiogenesis in NSCLC. METHODS: This prospective cohort study included 75 patients with NSCLC who underwent DCE-integrated MR-PET at diagnosis. The following parameters were analyzed: metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), reverse reflux rate constant (kep), volume transfer constant (Ktrans), blood plasma volume fraction (vp), extracellular extravascular volume fraction (ve), apparent diffusion coefficient (ADC), and initial area under the time-to-signal intensity curve at 60 s post enhancement (iAUC60). Serum biomarkers of tumor angiogenesis, including vascular endothelial growth factor-A (VEGF-A), angiogenin, and angiopoietin-1, were measured by enzyme-linked immunosorbent assays simultaneously. RESULTS: Serum VEGF-A (p = 0.002), angiogenin (p = 0.023), and Ang-1 (p <  0.001) concentrations were significantly elevated in NSCLC patients compared with healthy individuals. MR-PET parameters, including MTV, Ktrans, and kep, showed strong linear correlations (p <  0.001) with serum angiogenesis-related biomarkers. Serum VEGF-A concentrations (p = 0.004), MTV values (p <  0.001), and kep values (p = 0.029) were significantly higher in patients with advanced-stage disease (stage III or IV) than in those with early-stage disease (stage I or II). Patients with initial higher values of angiogenesis-related MR-PET parameters, including MTV > 30 cm3 (p = 0.046), Ktrans > 200 10- 3/min (p = 0.069), and kep > 900 10- 3/min (p = 0.048), may have benefited from angiogenesis inhibitor therapy, which thus led to significantly longer overall survival. CONCLUSIONS: The present findings suggest that DCE-integrated MR-PET provides a reliable, non-invasive, quantitative assessment of tumor angiogenesis; can guide the use of angiogenesis inhibitors toward longer survival; and will play an important role in the personalized treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Medicina de Precisão/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida
18.
J Surg Oncol ; 124(1): 124-134, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33844848

RESUMO

BACKGROUND AND OBJECTIVES: The aim of this study was to demonstrate whether academic thoracic surgeons could achieve morbidity and mortality rates in community hospitals equivalent to those seen in National Lung Screening Trial (NLST). METHODS: This was a retrospective review of community hospital lung cancer procedures for clinical Stage I-III non-small-cell lung cancers from 2007 through 2014. Variables include age, comorbidities, computed tomography (CT) characterization, and operative techniques. RESULTS: There were 177 patients who had lung cancers removed by a minimally invasive approach (79%), including lobectomy in 127 (72%), segmentectomy in 4 (2%), and wedge-resections in 46 (26%). The median patient age was 71 years (interquartile range [IQR], 63-76). The cohort was primarily female (58%), clinical Stage I (82%), with a median tumor size of 2.3 cm (IQR, 1.5-3.3). The median length of stay was 6 days (range: 1-35). Complications were experienced by 78 (44.1%) patients, most commonly atrial fibrillation in 20 (11.3%) followed by air-leak in 19 (10.7%). There were no in-hospital deaths. Tumor location and extent of resection were associated with complications, while larger tumor size, margin contour, and resection method were associated with air-leak (all p < 0.05). Higher clinical stage and larger tumor size were associated with occult Stage III disease (both p < 0.05). CONCLUSIONS: The low morbidity and mortality rates from the NLST were achievable in a community setting for early-stage lung cancer. Characterization of cancers using CT imaging identified factors most commonly associated with postoperative complications and the presence of occult Stage III disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/epidemiologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Feminino , Hospitais Comunitários , Humanos , Tempo de Internação , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pneumonectomia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
19.
J Cardiothorac Surg ; 16(1): 84, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858453

RESUMO

BACKGROUND: Surgical resection of pulmonary metastases leads to prolonged survival if strictly indicated. Usually, thoracotomy with manual palpation of the entire lung with lymph node dissection or sampling is performed. The aim of this study was to evaluate the role of video-assisted thoracoscopic surgery (VATS) in pulmonary metastectomy with curative intent. METHODS: In this study, all patients with suspected pulmonary metastasis (n = 483) who visited the Center for Thoracic Surgery in Regensburg, between January 2009 and December 2017 were analysed retrospectively. RESULTS: A total of 251 patients underwent metastectomy with curative intent. VATS was performed in 63 (25.1%) patients, 54 (85.7%) of whom had a solitary metastasis. Wedge resection was the most performed procedure in patients treated with VATS (82.5%, n = 52) and thoracotomy (72.3%, n = 136). Postoperative revisions were necessary in nine patients (4.8%), and one patient died of pulmonary embolism after thoracotomy (0.5%). Patients were discharged significantly faster after VATS than after thoracotomy (p < 0.001). Complete (R0) resection was achieved in 89% of patients. The median recurrence-free survival was 11 months (95% confidence interval 7.9-14.1). During follow-up, eight (12.7%) patients in the VATS group and 42 (22.3%) patients in the thoracotomy group experienced recurrence (p = 0.98). The median overall survival was 61 months (95% confidence interval 46.1-75.9), and there was no significant difference with regard to the surgical method used (p = 0.34). CONCLUSIONS: VATS metastasectomy can be considered in patients with a solitary lung metastasis. An open surgical approach with palpation of the lung showed no advantage in terms of surgical outcome or survival.


Assuntos
Neoplasias Pulmonares/cirurgia , Metastasectomia , Pneumonectomia/mortalidade , Cirurgia Torácica Vídeoassistida , Toracotomia , Idoso , Feminino , Humanos , Pulmão/cirurgia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Metastasectomia/efeitos adversos , Metastasectomia/mortalidade , Pessoa de Meia-Idade , Pneumonectomia/métodos , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida/mortalidade , Toracotomia/mortalidade
20.
Biomed Res Int ; 2021: 1780860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791360

RESUMO

Background: Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, and the majority of NSCLC patients are diagnosed at the advanced stage. Chemotherapy is still the main treatment at present, and the overall prognosis is poor. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs) as the representative have been extensively applied for treating various types of cancers. Tumor mutation burden (TMB) as a potential biomarker is used to screen appropriate patients for treatment of ICIs. To verify the predictive efficacy of TMB, a systematic review and meta-analysis were conducted to explore the association between TMB and ICIs. Method: PubMed, EMBASE, Cochrane Library, and son on were systematically searched from inception to April 2020. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were estimated. Results: A total of 11 studies consisting of 1525 nonsmall cell lung cancer (NSCLC) patients were included. Comparison of high and low TMB: pooled HRs for OS, 0.57 (95% CI 0.32 to 0.99; P = 0.046); PFS, 0.48 (95% CI 0.33 to 0.69; P < 0.001); ORR, 3.15 (95% CI 2.29 to 4.33; P < 0.001). Subgroup analysis values: pooled HRs for OS, 0.75 (95% CI 0.29 to 1.92, P = 0.548) for blood TMB (bTMB), 0.44 (95% CI 0.26 to 0.75, P = 0.003) for tissue TMB (tTMB); for PFS, 0.54 (95% CI 0.29 to 0.98, P = 0.044) and 0.43 (95% CI 0.26 to 0.71, P = 0.001), respectively. Conclusions: These findings imply that NSCLC patients with high TMB possess significant clinical benefits from ICIs compared to those with low TMB. As opposed to bTMB, tTMB was thought more appropriate for stratifying NSCLC patients for ICI treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Intervalo Livre de Progressão , Taxa de Sobrevida
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