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OBJECTIVE: To determine whether RAL affects perioperative outcomes and long-term efficacy in NSCLC patients, compared with traditional VAL. SUMMARY OF BACKGROUND DATA: RAL is a promising treatment for NSCLC. However, its efficacy has not been fully evaluated. METHODS: A single-center, open-labeled prospective randomized clinical trial was launched in May 2017 to compare the efficacy of RAL and VAL. By May 2020, 320 patients were enrolled. The perioperative results of RAL and VAL were compared. RESULTS: The 320 enrolled patients were randomly assigned to the RAL group (n = 157) and the VAL group (n = 163). Perioperative outcomes were comparable between the 2 groups, including the length of hospital stay (P = 0.76) and the rate of postoperative complications (P = 0.45). No perioperative mortality occurred in either group. The total amount of chest tube drainage {830âmL [interquartile range (IQR), 550-1130 mL] vs 685âmL [IQR, 367.5-1160 mL], P = 0.007} and hospitalization costs [$12821 (IQR, $12145-$13924) vs $8009 (IQR, $7014-$9003), P < 0.001] were significantly higher in the RAL group. RAL group had a significantly higher number of LNs harvested [11 (IQR, 8-15) vs 10 (IQR, 8-13), P = 0.02], higher number of N1 LNs [6 (IQR, 4-8) vs 5 (IQR, 3-7), P = 0.005], and more LN stations examined [6 (IQR, 5-7) vs 5 (IQR, 4-6), P < 0.001]. CONCLUSIONS: Both RAL and VAL are safe and feasible for the treatment of NSCLC. RAL achieved similar perioperative outcomes, together with higher LN yield. Further follow-up investigations are required to evaluate the long-term efficacy of RAL. (ClinicalTrials.gov identifier: NCT03134534).
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Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Procedimentos Cirúrgicos Robóticos , Cirurgia Torácica Vídeoassistida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Both robot-assisted Ivor Lewis esophagectomy (RAILE) and conventional thoracoscopic-assisted Ivor Lewis esophagectomy (TAILE) are minimally invasive surgical techniques for the treatment of middle and distal esophageal cancer. However, no research studies comparing early outcomes between RAILE and TAILE have been reported. METHODS: A retrospective analysis was made of 184 patients, 76 in the RAILE group and 108 in the TAILE group, who underwent minimally invasive Ivor Lewis esophagectomy between December 2014 and June 2018. Propensity score-matched analysis was performed between the two groups based on demographics, comorbidities, American Society of Anesthesiologists score, tumor location, tumor size, and pathological stage. Perioperative outcomes were compared. RESULTS: Two conversions to thoracotomy occurred in the RAILE group. There was no 30-day in either group. Sixty-six matched pairs were identified for each group. Within the propensity score-matched cohorts, the operative time in the RAILE group was significantly longer than that in the TAILE group (302.0 ± 62.9 vs. 274.7 ± 38.0 min, P = 0.004). There was no significant difference in the blood loss [200.0 ml (interquartile range [IQR], 100.0-262.5 ml) vs. 200.0 ml (150.0-245.0 ml), P = 0.100], rates of overall complications (28.8 vs. 24.2%, P = 0.554), length of stay [9.0 days (IQR 8.0-12.3 days) vs. 9.0 days (IQR 8.0-11.3 days), P = 0.517], the number of total dissected lymph nodes (19.2 ± 9.2 vs. 19.3 ± 9.5, P = 0.955), and detailed categories of lymph nodes. CONCLUSIONS: RAILE demonstrated comparable early outcomes compared with TAILE and should be considered as an alternative minimally invasive option for treating esophageal cancer.
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Adenocarcinoma/cirurgia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/cirurgia , Complicações Pós-Operatórias , Procedimentos Cirúrgicos Robóticos/métodos , Toracoscopia/métodos , Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Estudos RetrospectivosRESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective clinical therapies for advanced non-small cell lung cancer (NSCLC) patients, while resistance to TKIs remains a serious problem in clinical practice. Recently, it has been proposed that targeting mTOR could overcome TKI resistance in NSCLC cells. Forkhead box class O1 (FOXO1) has emerged as an important rheostat that modulates the activity of Akt and mTOR signaling pathway. However, the role of FOXO1 and related regulatory mechanism in TKI resistance in NSCLC remain largely unknown. Here, we find that mTOR-AKT-FOXO1 signaling cascade is deregulated in TKI-resistant NSCLC cells and that FOXO1 was highly phosphorylated and lowly acetylated upon erlotinib treatment. Combination of mTOR or PI3K inhibitor and erlotinib overcomes TKI resistance to inhibit cell growth and induce apoptosis in TKI-resistant NSCLC cells. Furthermore, the phosphorylation and acetylation of FOXO1 are reversely modulated by mTORC2-AKT signaling pathway. FOXO1 mutation analyses reveal that FOXO1 acetylation inhibits cell proliferation and promotes NSCLC cell apoptosis, while the phosphorylation of FOXO1 plays opposite roles in NSCLC cells. Importantly, increasing FOXO1 acetylation by a HDAC inhibitor, depsipeptide, overcomes TKI resistance to effectively induce TKI-resistant NSCLC cell apoptosis. Together, FOXO1 plays dual roles in TKI resistance through posttranslational modifications in NSCLC and this study provides a possible strategy for treatment of TKI-resistant NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Fatores de Transcrição Forkhead/genética , Quinazolinas/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/biossíntese , Inibidores de Proteínas Quinases/administração & dosagem , Processamento de Proteína Pós-Traducional , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/biossínteseRESUMO
PURPOSE: To investigate the effects of autophagy on growth inhibition by gefitinib in non-small cell lung cancer (NSCLC) cell lines and its probable mechanism. METHODS: The mRNA and protein levels of Beclin 1, authophagy related 5 (Atg5) and Atg7 were assessed. H460 and Calu6 NSCLC cell lines were transfected with plasmids expressing green fluorescent protein (GFP)-LC3 and the formation of autophagosome was monitored under fluorescent microscope. In addition, H460 cells were treated with agonists of autophagy (everolimus and 3-methyladenine/ 3MA), AMP-activated protein kinase (AMPK) inhibitor (Compound C) and gefitinib, respectively. Cells were stained and studied under microscope. Cell colonies were counted and growth inhibition was calculated. Phosphorylated acetyl-Coenzyme A carboxylase (ACC) and AMPK were detected. Moreover, H460 cells were transfected with small interfering RNA (siRNA) against AMPK2 subunit and AMPK 2 was knocked down. RESULTS: LCII was accumulated to a higher level after treatment with gefitinib than that without addition of gefitinib, and gefitinib increased GFP punctuated cells. Besides, everolimus enhanced the autophagic process induced by gefitinib. Consistent with this, everolimus enhanced the growth inhibition of gefitinib on H460 cells. Also, incubation with gefitinib could significantly increase AMPK phosphorylation and phosphorylated ACC. Compound C AMPK inhibitor could reverse the activation of gefitinib on autophagy, as determined by Beclin 1, Atg5 and Atg7 mRNA levels. Knockdown of AMPK2 also significantly inhibited the activation of autophagy by gefitinib. CONCLUSION: Inhibition of AMPK by its antagonist (Compound C) or siRNA predominantly blocked the induction of autophagy by gefitinib.
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Proteínas Quinases Ativadas por AMP/fisiologia , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Linhagem Celular Tumoral , Gefitinibe , HumanosRESUMO
Background: DNA repair plays a crucial role in the development and progression of different types of cancers. Nevertheless, little is known about the role of DNA repair-related genes (DRRGs) in esophageal cancer (EC). The present study aimed to identify a novel DRRGs prognostic signature in EC. Methods: Gene set enrichment analysis (GSEA) was performed to screen 150 genes related to DNA repair, which is the most important enrichment gene set in EC. Univariate and multivariate Cox regression analyses were used to screen DRRGs closely associated with prognosis. The difference in the expression of hub DRRGs between tumor and normal tissues was analyzed. Combined with clinical indicators (including age, gender, and tumor stage), we evaluated whether the 4-DRRGs signature was an independent prognostic factor. In addition, we evaluated the prediction accuracy using a receiver operating characteristic (ROC) curve and visualized the model's performance via a nomogram. Results: Four-DRRGs (NT5C3A, TAF9, BCAP31, and NUDT21) were selected by Cox regression analysis to establish a prognostic signature to effectively classify patients into high- and low-risk groups. The area under the curve (AUC) of the time-dependent ROC of the prognostic signature for 1- and 3-year was 0.769 and 0.720, respectively. Compared with other clinical characteristics, the risk score showed a robust ability to predict the prognosis in EC, especially in the early stage of EC. Furthermore, we constructed a nomogram to interpret the clinical application of the 4-DRRGs signature. Conclusions: In conclusion, we identified a prognostic signature based on the DRRGs for patients with EC, which can contribute independent value in identifying clinical outcomes that complement the TNM system in EC.
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BACKGROUND: Pulmonary rehabilitation is essential for airway management after thoracic surgery. Most current pulmonary rehabilitations are composed of 2-4-week exercises, which require significant consumption of medical resources and concerns about disease progression. MATERIALS AND METHODS: This single-center, prospective, randomized controlled trial enrolled smoking patients with pulmonary masses or nodules suitable for lobectomy, aged 18-80, with smoking history (≥20 pack-years). Eligible patients were randomized in a 1:1 ratio into two groups. Patients in the intervention group underwent perioperative breathing exercises based on positive pressure vibration expectoration and three-day preoperative lower limb endurance training. Patients in the control group received routine perioperative care. The primary outcome was in-hospital incidence of postoperative pulmonary complications. Secondary outcomes included postoperative hospital stay, total hospitalization cost, postoperative drainage time, drainage volume, semiquantitative cough strength score, pain score, Borg scale-assessed fatigue, and walking distance on postoperative days 1 and 2. RESULTS: A total of 194 patients were included in the study with 94 in the intervention group and 100 in the control group. Our ultrashort pulmonary rehabilitation program potentially reduced pulmonary complications incidence (24.5% vs. 33.0%), but without statistical significance (P=0.190). No significant differences were found in other perioperative outcomes, except for postoperative semiquantitative cough strength score (3 [interquartile range, 3-3.75] vs. 3 [interquartile range, 2-3], P<0.001) and change in walking distance from postoperative days 1 to 2 (60 [interquartile range, 40-82.5] vs. 30 [interquartile range, 10-60], P=0.003). CONCLUSION: There were no significant differences in postoperative complications and other hospitalizations, but our ultrashort rehabilitation program improved patients' semiquantitative cough strength score and walking distance, indicating potential for better outcomes. This treatment is a safe and effective means of airway management for thoracic surgery in the era of enhanced recovery. (ClinicalTrials.gov Identifier: XXX).
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BACKGROUND: The presence of lymph node (LN) metastasis directly affects the treatment strategy for lung adenocarcinoma (LUAD). Next-generation sequencing (NGS) has been widely used in patients with advanced LUAD to identify targeted genes, while early detection of pathologic LN metastasis using NGS has not been assessed. METHODS: Clinicopathologic features and molecular characteristics of 224 patients from Ruijin Hospital were analyzed to detect factors associated with LN metastases. Another 140 patients from Huashan Hospital were set as a test cohort. RESULTS: Twenty-four out of 224 patients were found to have lymph node metastases (10.7%). Pathologic LN-positive tumors showed higher mutant allele tumor heterogeneity (p < 0.05), higher tumor mutation burden (p < 0.001), as well as more frequent KEAP1 (p = 0.001), STK11 (p = 0.004), KRAS (p = 0.007), CTNNB1 (p = 0.017), TP53, and ARID2 mutations (both p = 0.02); whereas low frequency of EGFR mutation (p = 0.005). A predictive nomogram involving male sex, solid tumor morphology, higher T stage, EGFR wild-type, and TP53, STK11, CDKN2A, KEAP1, ARID2, KRAS, SDHA, SPEN, CTNNB1, DICER1 mutations showed outstanding efficiency in both the training cohort (AUC = 0.819) and the test cohort (AUC = 0.780). CONCLUSION: This study suggests that the integration of genomic profiling and clinical features identifies early-invasive LUAD patients at higher risk of LN metastasis. Improved identification of LN metastasis is beneficial for the optimization of the patient's therapy decisions.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Metástase Linfática , Mutação , Humanos , Masculino , Feminino , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Pessoa de Meia-Idade , Metástase Linfática/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Idoso , Sequenciamento de Nucleotídeos em Larga Escala , Biomarcadores Tumorais/genética , Nomogramas , Adulto , Perfilação da Expressão Gênica , Genômica/métodosRESUMO
Background: The long-term survival and perioperative outcomes of robotic-assisted lobectomy (RAL) and video-assisted lobectomy (VAL) in resectable non-small-cell lung cancer (NSCLC) were found to be comparable in retrospective studies, but they have not been investigated in a randomized trial setting. We conducted the RVlob trial to investigate if RAL was non-inferior to VAL in patients with resectable NSCLC. Methods: In this single-center, open-label, and parallel-arm randomized controlled trial conducted in Ruijin Hospital (Shanghai, China) between May 2017 and May 2020, we randomly assigned patients with resectable NSCLC in a 1:1 ratio to receive either RAL or VAL. One of the primary endpoints was 3-year overall survival. Secondary endpoints included 3-year disease-free survival. The Kaplan-Meier approach was used to calculate overall survival and disease-free survival at 3 years. This study was registered with ClinicalTrials.gov, NCT03134534. Findings: A total of 320 patients were randomized to receive RAL (n = 157) or VAL (n = 163). The baseline characteristics of patients were well balanced between the two groups. After a median follow-up of 58.0 months, the 3-year overall survival was 94.6% (95% confidence interval [CI], 91.0-98.3) in the RAL group and 91.5% (95% CI, 87.2-96.0) in the VAL group (hazard ratio [HR] for death, 0.65; 95% CI, 0.33-1.28; P = 0.21); noninferiority of RAL was confirmed according to the predefined margin of -5% (absolute difference, 2.96%; a one-sided 90% CI, -1.39% to ∞; P = 0.0029 for noninferiority). The 3-year disease-free survival was 88.7% (95% CI, 83.6-94.1) in the RAL group and 85.4% (95% CI, 80.0-91.2) in the VAL group (HR for disease recurrence or death, 0.87; 95% CI, 0.50-1.52; P = 0.62). Interpretation: This study is the first randomized trial to show that RAL resulted in non-inferior overall survival compared with VAL in patients with resectable NSCLC. Based on our results, RAL is an equally oncologically effective treatment and can be considered as an alternative to VAL for resectable NSCLC. Funding: National Natural Science Foundation of China (82072557), National Key Research and Development Program of China (2021YFC2500900), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20172005, the 2nd round of disbursement), program of Shanghai Academic Research Leader from Science and Technology Commission of Shanghai Municipality (20XD1402300), Novel Interdisciplinary Research Project from Shanghai Municipal Health Commission (2022JC023), and Interdisciplinary Program of Shanghai Jiao Tong University (YG2023ZD04).
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Background: RNA-binding proteins (RBPs) play a crucial role in regulating RNA turnover and are associated with cancer development. However, little is known about the role of RBPs in esophageal cancer (ESCA). The present study focuses on the association between RBP gene expression and survival in ESCA, addressing the clinical relevance of an RBPs-based prediction model for prognosis. Methods: RNA-sequencing data and clinical information of patients with ESCA were obtained from The Cancer Genome Atlas (TCGA) database. We identified differentially expressed genes in ESCA and intersected them with RBP-encoding genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed with the identified differentially expressed RBPs. Then, a protein-protein interaction (PPI) network was constructed through the STRING database to determine the hub RBPs. Univariate Cox regression analysis and multivariate Cox regression analysis were applied to construct a novel prognostic model based on RBPs. Based on the R package "Caret", we divided patients into the training set and validation set. The efficacy of the prognostic model was evaluated by the area under the receiver operating characteristic (ROC) curve. A nomogram was developed for the prediction of patient survival outcomes. Results: A total of 158 ESCA patients from the TCGA database were included in our analysis. We screened out five prognostic RBPs (CLK1, CIRBP, MRPL13, TNRC6A, and TYW3) through univariate and multivariate Cox regression analysis. CLK1, CIRBP, TNRC6A and TYW3 were downregulated in tumor samples, while MRPL13 was upregulated. A prognostic model constructed with these five RBPs in the training data set accurately stratified ESCA patients into high- and low-risk groups. When the same prognostic model was applied to the test data set and entire cohort, the 5-RBP signature remained an independent prognostic factor in multivariate analysis. The areas under the time-dependent ROC curve of the prognostic model for predicting one-year survival in the training data set, test data set, and entire cohort were 0.789, 0.753, and 0.764, respectively, confirming that this model is a good prognostic model. The nomogram based on the five RBPs and clinical variables could improve individualized outcome predictions and highlight the importance of RBPs in the outcomes of patients with ESCA. Conclusions: Our study provides a potential prognostic model for predicting the prognosis of ESCA patients. The prognostic nomogram could improve individualized outcome predictions for patients with ESCA, therefore providing novel insights into future diagnosis and treatment.
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BACKGROUND: Dynamic alterations of the tumor immune microenvironment in esophageal squamous cell carcinoma (ESCC) after different neoadjuvant therapies were understudied. METHODS: We used mass cytometry with a 42-antibody panel for 6 adjacent normal esophageal mucosa and 26 tumor samples (treatment-naïve, n=12; postneoadjuvant, n=14) from patients with ESCC. Single-cell RNA sequencing of previous studies and bulk RNA sequencing from The Cancer Genome Atlas were analyzed, flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed. RESULTS: Poor tumor regression was observed in the neoadjuvant chemotherapy group. Radiotherapy-based regimens enhanced CD8+ T cells but diminished regulatory T cells and promoted the ratio of effector memory to central memory T cells. Immune checkpoint blockade augmented NK cell activation and cytotoxicity by increasing the frequency of CD16+ NK cells. We discovered a novel CCR4+CCR6+ macrophage subset that correlated with the enrichment of corresponding chemokines (CCL3/CCL5/CCL17/CCL20/CCL22). We established a CCR4/CCR6 chemokine-based model that stratified ESCC patients with differential overall survival and responsiveness to neoadjuvant chemoradiotherapy combined with immunotherapy, which was validated in two independent cohorts of esophageal cancer with neoadjuvant treatment. CONCLUSIONS: This work reveals that neoadjuvant therapy significantly regulates the cellular composition of the tumor immune microenvironment in ESCC and proposes a potential model of CCR4/CCR6 system to predict the benefits from neoadjuvant chemoradiotherapy combined with immunotherapy.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Terapia Neoadjuvante/métodos , Carcinoma de Células Escamosas/tratamento farmacológico , Linfócitos T CD8-Positivos/patologia , Proteômica , Microambiente TumoralRESUMO
Background: Immunotherapy is a promising novel treatment for esophageal cancer (ESCA). However, previous studies provide limited direct information about the prognostic significance of immune-related genes (IRGs) in primary ESCA development. This study explored the prognostic value of IRGs and infiltrating tumor immune cells in primary ESCA. Methods: The ribonucleic acid (RNA)-sequencing data and clinical information of primary ESCA were downloaded from The Cancer Genome Atlas (TCGA) database. Which included the clinical factors and prognosis outcomes of the ESCA patients. The IRGs were downloaded from the ImmPORT database. Results: We established the robust IRG prognostic signature of 4 IRGs (i.e., heat shock protein family A member 6, Oncostatin M, androgen receptor, and nuclear receptor subfamily 2 group F member 2) in primary ESCA, and divided the ESCA patients into high- and low-risk groups based on overall survival (OS). The Kaplan-Meier curves showed the high predictive ability of the prognostic signature in the training, testing, and full data sets (P=2.407e-03, P=1.044e-02, and P=2.535e-04, respectively). Multivariate Cox regression analyses were performed with age, grade, tumor stage, tumor type and the risk score as covariables. The risk score supports the use of a prognostic signature as an independent prognostic factor [training data set: hazard ratio (HR) =1.185, 95% confidence interval (95% CI): 1.013-1.388, P=0.034; testing data set: HR =2.056, 95% CI: 1.015-4.166, P=0.045; full data set: HR =1.197, 95% CI: 1.059-1.354, P=0.004]. The area under the curve (AUC) of the receiver operating characteristic curve validated the high predictive accuracy of the IRG signature in the training, testing, and full data set (AUCs =0.808, 0.657, and 0.751, respectively). The infiltration level of the activated mast cells was significantly higher in the high-risk group than the low-risk group; thus, infiltrating mast cells are associated with worse OS in ESCA patients. Conclusions: Our IRG prognostic signature provides a new direction to predict the survival of primary ESCA patients and has the potential ability to establish, promote, and improve personalized treatment procedures based on each patient's risk.
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The effects of autophagy and apoptosis in the prognostic assessment and treatment of Esophageal squamous cell carcinoma (ESCC) remain to be elucidated. Here, we conducted a retrospective study on the histopathology of ESCC, investigated the expression of Beclin-1 and Bcl-2 proteins (both autophagy- and apoptosis-related) in esophageal cancer tissue, and analyzed the significance of these proteins for the prognosis of ESCC. In the present study, the expression level of Beclin-1 in ESCC was significantly lower than that in adjacent tissues (p < 0.01), whereas the expression level of Bcl-2 showed the opposite pattern (p < 0.01). Furthermore, low expression of Beclin-1 was associated with more advanced ESCC stages and lymph node metastasis. However, high expression of Bcl-2 was associated with more advanced ESCC stages, deeper tumor invasion, and lymph node metastasis. Moreover, the relationship between Bcl-2 expression and OS was not significant (p > 0.05), whereas Beclin-1 expression was significantly associated with OS (p < 0.05). Subgroup analysis showed that Beclin-1 expression was significantly associated with OS in the high-Bcl-2-expression group but not in the low-Bcl-2-expression group. Importantly, Beclin-1 upregulation or downregulation significantly upregulated or downregulated invasion, respectively, in EC9706 cells in combination with high expression but not low expression of Bcl-2. These findings reveal that differences in autophagy and apoptotic states and their activities may promote malignant tumor differentiation, which could lead to a more aggressive esophageal squamous cell phenotype and a worse survival prognosis. Here, Beclin-1 was shown to be a promising prognostic biomarker and therapeutic target for patients with ESCC in the high-Bcl-2-expression population.
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Proteína Beclina-1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose , Autofagia , Proteína Beclina-1/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Movimento Celular , China/epidemiologia , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/epidemiologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
BACKGROUND: Prolonged air leak (PAL) is one of the most common postoperative complications after lung surgery. This study aimed to identify risk factors of PAL after lung resection and develop a preoperative predictive model to estimate its risk for individual patients. METHODS: Patients with pulmonary malignancies or metastasis who underwent pulmonary resection between January 2014 and January 2018 were included. PAL was defined as an air leak more than 5 days after surgery, risk factors were analyzed. Forward stepwise multivariable logistic regression analysis was performed to identify independent risk factors, and a derived nomogram was built. Data from February 2018 to September 2018 were collected for internal validation. RESULTS: A total of 1,511 patients who met study criteria were enrolled in this study. The overall incidence of PAL was 9.07% (137/1,511). Age, percent forced expiratory volume in 1 second, surgical type, surgical approach and smoking history were included in the final model. A nomogram was developed according to the multivariable logistic regression results. The C-index of the predictive model was 0.70, and the internal validation value was 0.77. The goodness-of-fit test was non-significant for model development and internal validation. CONCLUSIONS: The predictive model and derived nomogram achieved satisfied preoperative prediction of PAL. Using this nomogram, the risk for an individual patient can be estimated, and preventive measures can be applied to high-risk patients.
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BACKGROUND: Autophagy has a dual function in cancer, and its role in carcinogenesis of the esophagus remains poorly understood. In the present study, we explored the prognostic value of autophagy in esophageal cancer (ESCA), one of the leading causes of cancer-related deaths worldwide. METHODS: Using ESCA RNA-sequencing (RNA-Seq) data from 158 primary patients with ESCA, including esophageal adenocarcinoma and esophageal squamous cell carcinoma, were downloaded from The Cancer Genome Atlas (TCGA) for this study. We obtained differentially expressed autophagy-related genes (ARGs) by the "limma" package of R. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses unveiled several fundamental signaling pathways associated with the differentially expressed ARGs in ESCA. Univariate Cox regression analyses were used to estimate associations between ARGs and overall survival (OS) in the TCGA ESCA cohort. A Cox proportional hazards model (iteration =1,000) with a lasso penalty was used to create the optimal multiple-gene prognostic signature utilizing an R package called "glmnet". RESULTS: A prognostic signature was constructed with four ARGs (DNAJB1, BNIP1, VAMP7 and TBK1) in the training set, which significantly divided ESCA patients into high- and low-risk groups in terms of OS [hazard ratio (HR) =1.508, 95% confidence interval (CI): 1.201-1.894, P<0.001]. In the testing set, the risk score remained an independent prognostic factor in the multivariate analyses (HR =1.572, 95% CI: 1.096-2.257, P=0.014). The area under the curve (AUC) of the receiver operating characteristic (ROC) predicting 1-year survival showed a better predictive power for the prediction model. The AUC in training and testing cohorts were 0.746 and 0.691, respectively. Therefore, the prognostic signature of the four ARGs was successfully validated in the independent cohort. CONCLUSIONS: The prognostic signature may be an independent predictor of survival for ESCA patients. The prognostic nomogram may improve the prediction of individualized outcome. This study also highlights the importance of autophagy in the outcomes of patients with ESCA.
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OBJECTIVE: The question of whether the tumor mutation burden (TMB) is associated with either improved survival outcomes or improvement of immunotherapies remains controversial in various malignancies. The aim of this study is to investigate the genomic landscape of the relationship between TMB and immune cell infiltration in thymic epithelial tumors (TETs). METHODS: We downloaded somatic mutation data, transcriptome sequencing data, and clinical information of TETs from the Cancer Genome Atlas (TCGA) database. We assessed the abundance of 22 immune fractions between low-TMB (TMB-L) and high-TMB (TMB-H) groups using the "CIBERSORT" package. RESULTS: Missense mutation had the highest frequency of mutation among the nine variant classifications in TETs. Higher TMB levels were associated with poor survival outcomes (P<0.05), and higher Masaoka stages (P<0.05). More importantly, TMB levels were much higher in the thymic cancer than in thymoma (P<0.01). The infiltration levers of naive CD4(+) T cells and regulatory T cells were significantly higher in the TMB-L group than in the TMB-H group, and this was further associated with better overall survival (OS) in patients with TETs. CONCLUSION: The present study indicates that the prognosis of TMB-H patients with TETs is significantly poorer than is that of TMB-L patients, which might result from the different levels of infiltration of naive CD4(+) T cells and regulatory T cells.
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Linfócitos do Interstício Tumoral/metabolismo , Taxa de Mutação , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias do Timo/metabolismo , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genômica/métodos , Humanos , Linfócitos do Interstício Tumoral/fisiologia , Mutação/genética , Neoplasias Epiteliais e Glandulares/genética , Prognóstico , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transcriptoma/genética , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: The perioperative outcomes of the use of stapling devices versus electrocautery to dissect intersegmental planes in patients undergoing segmentectomy for small pulmonary lesions is still unclear. The aim of this randomized controlled trial was to compare the perioperative outcomes of these two methods. METHODS: A single-center, prospective, participant-blinded, randomized controlled trial (NCT03192904) was conducted with a preplanned sample size of 136. The primary outcome was the incidence of postoperative complications. Secondary outcomes included duration of operation, blood loss during operation, first-day drainage volume, duration of drainage, postoperative hospital stay, loss of lung function, and medical costs. RESULTS: The trial was stopped early as a result of a marked difference in the primary outcome between groups at a scheduled interim check of the data after recruiting 70 patients. The incidence of postoperative complications (eg, air leakage) was higher in the electrocautery group than in the stapler device group (11/32, 34.4% vs 2/33, 6.1%, P = .004). There were no differences in duration of operation, blood loss during operation, first-day drainage volume, duration of drainage, postoperative hospital stays, loss of lung function, or total medical cost, although the per-patient cost of medical materials was higher in the stapler device group (US$4214.6 ± 1185.4 vs $3260.1 ± 852.6, P < .001). CONCLUSIONS: Among patients undergoing segmentectomy, the use of stapler devices to divide intersegmental planes decreased postoperative complications without further compromising lung function or increasing economic burden.
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Dissecação/métodos , Eletrocoagulação/efeitos adversos , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Grampeamento Cirúrgico/efeitos adversos , Adulto , Dissecação/efeitos adversos , Dissecação/instrumentação , Eletrocoagulação/instrumentação , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Pneumonectomia/efeitos adversos , Pneumonectomia/instrumentação , Estudos Prospectivos , Grampeadores CirúrgicosRESUMO
In this study, we present a case of 65-year-old male patient with suspected Sjögren's syndrome-related interstitial lung disease (SS-ILD) with initial symptoms of limb edema and acute respiratory failure. He was treated with immunosuppressor, respiratory support, dialysis, immunomodulatory, and anti-inflammatory medications. However, no significant response was shown to anti-fibrotic treatments and his respiratory function deteriorated. Double lung transplantation was thus indicated considering the irreversible interstitial changes in both lungs. The surgical procedure was complicated, and the role of enhanced recovery after surgery (ERAS) for this critical patient was discussed. The patient experienced hemorrhage, pulmonary infection, and peripheral neuropathy after surgery, but he was cured by the multidisciplinary team. He had a satisfactory quality of life at 1-year follow-up. This case report describes the details of double lung transplantation in a patient with advanced SS-ILD. Important considerations include the indications for and timing of transplantation, the effects of long-term immunosuppression on wound healing, and extrapulmonary organ dysfunction. Based on a review of the published literature and a consideration of the short-term outcomes, lung transplantation for this individual with an autoimmune disease appears to be safe and feasible. SS-ILD should not be a contraindication to transplantation; however, patients with advanced pulmonary involvement should be carefully selected after a multidisciplinary evaluation. More long-term follow-up and further comparative studies are needed in the future.
RESUMO
BACKGROUND: Anastomosis leakage after esophagectomy is a major threat which leads to many subsequent complications even mortality. But current diagnosis and treatment methods are inefficient. This retrospective study aims to evaluate the utilization of endoscope-assisted mediastinal drainage therapy in treatment for anastomosis leakage after esophagectomy. METHODS: Between January 2014 and June 2018, 51 patients were confirmed anastomosis leakage using gastroscopy. Of them, 23 patients were treated with endoscope-assisted mediastinal drainage therapy (drainage group); and the other 28 patients received endoscope-assisted biomedical fibrin glue occlusion (occlusion group). Short-term clinical outcomes were examined. Factors related to length of postoperative hospitalization (LPH) was analyzed. RESULTS: Endoscope provided highly accurate information on the condition of anastomosis leakage. And there was no evidence that early endoscopy could cause damage to the anastomosis or gastric conduit. One patient from drainage group and two from occlusion group discharged against medical advice. Other 48 patients were completely cured without reoperation or mortality. The median LPH was 32 days in drainage group (range from 17 to 80 days) and 81 days in occlusion group (range from 32 to 190 days), respectively (P<0.05). Linear regression indicated statistically significant correlation between LPH and length from diagnosis to drainage or occlusion (R=0.688, P<0.001). CONCLUSIONS: Endoscope-assisted mediastinal drainage therapy is a satisfactory treatment for anastomosis leakage. Early diagnosis and treatment may facilitate the recovery of anastomosis leakage and reduce LPH.
RESUMO
PURPOSE: This study aims to discuss the appropriate treatment strategy for spontaneous esophageal rupture. METHODS: Clinical data from twenty-one cases were retrospectively analyzed. The parameters included etiology, time interval between onset and treatment, therapy methods, prognosis, and length of stay. RESULTS: The ratio of males/females was 17/4, age range was 32-82 years (mean = 43.1), and the time interval between onset and treatment was as follows: <24 h: nine cases (42.8%); 24-48 h: six cases (28.6%); and >72 h: six cases (28.6%). All patients underwent operative treatment, and the following primary healing rates were achieved: <24 h: 88.9%, 24-48 h: 66.7%, and >72 h: 0. No patients died in this study. All patients were discharged with recovery, and the average hospitalization times were 18.1 days (<24 h), 27.8 days (24-48 h), and 51.2 days (>72 h). CONCLUSIONS: Surgical treatment remains an effective method for treating spontaneous esophageal rupture, and the shorter the time interval between onset and treatment, possibly the better the prognosis.
Assuntos
Perfuração Esofágica/cirurgia , Doenças do Mediastino/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ruptura Espontânea , Adulto JovemRESUMO
PURPOSE: To investigate the correlation between the status of epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs) and esophageal squamous cell carcinoma (ESCC). METHODS: The demographic data and blood samples of 21 patients with ESCC were collected retrospectively. CTCs were enriched by using optimized CanPatrolTM CTC enrichment technique. CTCs were identified and characterized according to the EMT markers (e-CTCs: epithelial CTCs; mix-CTCs: epithelial-mesenchymal-mixed CTCs; m-CTCs: mesenchymal CTCs). The correlation between CTCs and demographic data was analyzed. RESULTS: Total 129 CTCs were detected in all the patients: 11(8.5%) CTCs of them were e-CTCs, 76(58.9%) were mix-CTCs, and 42(32.6%) were m-CTCs. The average number of CTCs from each patient was 6.1 ± 7.1 which included 0.5 ± 0.9 of e-CTCs, 3.6 ± 5.2 of mix-CTCs, and 2.0 ± 2.7 of m-CTCs; the difference between the three groups was significant (P = 0.017): the number of total CTCs was correlated with the number of mix-CTCs (R2 = 0.883, P < 0.01) and m-CTCs (R2 = 0.639, P < 0.01) but not e-CTCs (R2 = 0.012, P = 0.641) and the number of CTCs was correlated with the N stage and TNM stage in this study (R2 = 0.698 and R2 = 0.359). CONCLUSIONS: Mix-CTCs and m-CTCs might play an important role in progression of ESCC; the number of CTCs in ESCC might have the potential to be a predictor of prognosis.