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Background The current nodal classification is unsatisfactory in distinguishing the prognostically heterogeneous N1 or N2 non-small cell lung cancer (NSCLC). Research Question Is the combination of the current N category and the number of metastatic lymph nodes (N-#number) or the combination of the current N category and the ratio of the number of positive to resected lymph nodes (N-#ratio) better than the current N category alone? Study Design and Methods We identified 2,162 patients with N1 or N2 NSCLC from the Surveillance, Epidemiology, and End Results database (2004-2016). We classified these patients into three N-#number categories (N-#number-1, N-#number-2a, N-#number-2b) and three N-#ratio categories (N-#ratio-1, N-#ratio-2a, N-#ratio-2b). Lung cancer-specific survival (LCSS) were compared using the Kaplan-Meier method. The prognostic significance of the new nodal classifications was validated across each tumor size category (≤3 cm, 3-5 cm, 5-7cm, >7 cm). Cox proportional hazards regression was used to evaluate the association between each nodal classification and LCSS. Results The survival curves showed clear differences between each pair of N-#number and N-#ratio categories. A significant tendency toward the deterioration of LCSS from N-#number-1 to N-#number-2b was observed in all tumor size categories. However, the differences between each pair of N-#ratio categories were significant only in tumors from 3 to 7 cm. Although all three nodal classifications were independent prognostic indicators, the N-#number classification provided more accurate prognostic stratifications compared with the N-#ratio classification and the current nodal classification. Interpretation The N-#number classification followed by the N-#ratio classification might be better prognostic determinants than the current nodal classification in prognostically heterogeneous N1 or N2 NSCLC.

Background Lobectomy with systematic lymph node dissection (SND) remains the standard procedure for resectable non–small-cell lung cancer (NSCLC), whereas lobe-specific lymph node dissection (LSND) was reported to have more advantages in perioperative recovery and complication reduction in treating early-stage diseases. Survival outcomes after LSND remains controversial compared with SND. Patients and Methods From 2014 to 2017, data of 546 patients with clinical stage IA solid-dominant NSCLC and who underwent curative lobectomies with LSND (n = 100) or SND (n = 446) at our institution were collected. Propensity score matching was conducted to eliminate the biases. Five-year disease-free survival and overall survival were compared between the groups. Perioperative parameters and postoperative complications were also analyzed. Results Lobectomies with LSND or SND were performed in 100 patients and 446 patients, respectively. After matching, there were 100 patients in each group and no significant differences in 5-year overall survival (P = .473) and disease-free survival (P = .789) were found between the groups. Recurrence patterns were also similar (P = .733). Perioperative parameters were similar, whereas the incidence of postoperative complications in the SND group was found to be significantly higher than that in the LSND group (P = .003). Conclusions Our study demonstrated that LSND has similar efficiency to SND in terms of survival, recurrence, lymph node dissection, and perioperative recovery of patients with clinical stage IA solid-dominant NSCLC, as well as significant advantages in reducing postoperative complications. Therefore, curative lobectomies with LSND may be more suitable and practical for clinical stage IA solid-dominant patients with NSCLC.

Background For early-stage lung adenocarcinoma, determining the extent of surgical resection and lymphadenectomy according to the invasion status of the tumour may be more reliable. Intraoperative frozen section (FS) is a potentially effective method to identify the invasion status while its accuracy is still unknown. This meta-analysis aimed to evaluate the accuracy of FS for the invasion status of lung adenocarcinoma. Methods We conducted a systematic search of PubMed, Embase, Scopus and Cochrane Library databases (from inception to October 26, 2018) to identify studies investigating the accuracy of FS for the invasion status of lung adenocarcinoma. The accuracy of FS was evaluated by calculating the pooled concordance rates (CCR) between FS and final pathology and the pooled sensitivity, specificity, and other parameters of FS for discriminating pre-/minimally invasive adenocarcinoma from invasive adenocarcinoma (IAC). The negative predictive value (NPV) of FS for diagnosing IAC was also calculated to evaluate the chance of underestimation. Results Six eligible studies were included. The pooled CCR for differentiating pre-invasive adenocarcinoma, minimally invasive adenocarcinoma and IAC was 88% (95% CI, 84%–93%). When pre-invasive adenocarcinoma and minimally invasive adenocarcinoma were classified as a group, the pooled CCR, sensitivity, specificity of FS for differentiating pre-/minimally invasive adenocarcinoma from IAC were 95% (95% CI, 94%–97%), 95% (95% CI, 92%–97%), 95% (95% CI, 80%–99%), respectively. The pooled NPV of FS for diagnosing IAC was 95% (95% CI, 92%–97%). Conclusions Intraoperative FS is reliable for identifying the invasion status of lung adenocarcinoma, with high diagnostic accuracy for differentiating pre-/minimally invasive adenocarcinoma from IAC.

Pneumonia is a common complication after minimally invasive esophagectomy (MIE), which prolongs hospital stay, adding to the cost and increasing the risk to patients' lives. This study aimed to identify risk factors and establish a predictive nomogram for postoperative pneumonia (PP).This case control study included 609 patients with esophageal cancer who underwent MIE between March 2015 and August 2019 in Cancer Hospital, Chinese Academy of Medical Sciences. We randomly divided the data into training and validation sets in the ratio of 7:3 and performed univariate and multivariate logistic regression analyses to acquire independent risk factors of the training set. We constructed a nomogram based on the independent risk factors. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) plots were used to evaluate the discrimination of the nomogram. Validation set was applied to confirm the predictive value of the nomogram.In the univariate analysis, age, gender, abdominal procedure method, thoracic operative time, duration of chest tube placement, anastomotic leakage, and recurrent laryngeal nerve palsy were found to be correlated with the incidence of PP. In multivariate analysis, all variables except thoracic operative time were found to be independent risk factors for PP. A nomogram was constructed based on these independent risk factors. The C-index of the training and validation sets was 0.769 and 0.734, respectively, and the areas under the curve (AUC) of ROC curves of the training and validation sets were 0.769 and 0.686, respectively. The calibration plots and DCA plots of the training and validation sets showed the accuracy and predictive value of the nomogram.The nomogram could accurately identify the risk factors for PP. We could predict the occurrence of PP based on this nomogram and take corresponding measures to reduce the incidence of PP.

Background Immunotherapy using immune checkpoint inhibitors (ICIs), such as antibody of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) has showed as a promising treatment for esophageal squamous cell carcinoma (ESCC), but resistance is unavoidable. This study aimed to find more immune-related genes to promote the efficiency of immunotherapy. Materials and methods Three datasets were downloaded from Gene Expression Omnibus (GEO) database. Gene differential analysis was performed to identify differentially expressed genes (DEGs), then ceRNA network was constructed based on differentially expressed lncRNAs and mRNAs. Next, Functional enrichment analysis and protein–protein interaction (PPI) network were built to reveal the potential function of mRNAs in ceRNA network. Survival analysis and immune cell infiltration level analysis were utilized to identify prognostic immune-related genes. Finally, pan-cancer analysis was performed to show the role of immune-related genes in other cancers. Results The data of 215 samples in total were obtained from GEO database (98 normal tissues and 117 tumor tissues), and 1685 differentially expressed mRNAs (176 downregulated and 1509 upregulated) and 3 upregulated lncRNAs (MCM3AP-AS1, HCP5 and GUSBP11, all upregulated) were found. ceRNA network was constructed to reveal some special correlation. Function enrichment showed some potential functions of mRNAs in ceRNA network such as mitotic cell cycle process, negative regulation of DNA-binding transcription factor activity, ossification, VEGFA-VEGFR2 signaling pathway, epithelial to mesenchymal transition, embryonic morphogenesis and so on. PPI network showed the physical interactions between each mRNA in ceRNA network. Through survival analysis and immune cell infiltration level analysis, GINS4 was confirmed as an immune-related prognostic gene in ESCC. GSEA showed some potential functions such as negative regulation of monocyte chemotaxis, antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, positive regulation of antigen processing and presentation, dendritic cell antigen processing and presentation and so on. Finally, pan-cancer analysis revealed that GINS4 might be a novel immune-related prognostic gene in ESCC and other cancers. Conclusion Our study suggested that GINS4 was correlated with prognosis and immune cell infiltration level of ESCC and other cancers. It may deserve further investigation as a potential immune-related prognostic biomarker of ESCC and other cancers.

Background: Though the value of lymph node (LN) dissection along bilateral recurrent laryngeal nerve (RLN) has been debated and emphasized in recent years in thoracic esophageal squamous cell carcinoma (ESCC). However, the characteristics of nodal metastasis along RLN chain has not been clarified. This study aimed to investigate the characteristics of nodal metastasis along recurrent laryngeal nerves and the influence of these metastasis on the prognosis of thoracic ESCC.Patients and Methods: 339 eligible patients with thoracic ESCC who underwent esophagectomy with a three-field(3-FL) or two-field(2-FL) lymph node dissection from March 2015 to December 2018 were included in this study, consisting of 282 males and 57 females with a mean age of 60.6 years (range,40-80 years). The association of LN metastasis near RLN with clinicopathologic factors and its influence on survival were analyzed. Results: Among the 339 patients, 96 (28.3%) had LN metastasis along bilateral recurrent laryngeal nerves, 76 (22.4%) with positive LNs along right RLN and 47 (13.9%) along the left RLN. There was a significant difference in the metastasis rate between the LNs along right RLN and along the left RLN (P=0.004). The LN metastasis rate along RLN was significantly correlated with primary tumor locations (upper vs middle vs lower: 35.1% vs 30.9% vs 15.6%; P=0.015), tumor invasion depth (T3/T4 vs T1 vs T2: 36.2% vs 15.8% vs 26.2%, P=0.001 ) and degree of differentiation (well vs moderately vs poorly: 9.3% vs 29.3% vs 33.9%; P=0.009), subcarinal and left tracheobronchial lymph node metastasis (positive vs negative:58.1% vs 25.3%, P＜0.001), abdominal LN metastasis (positive vs negative:41.2% vs 24.0%, P=0.003 ), but was not significantly correlated with age, gender and tumor length. The median follow-up time for this study was 34 months. The cumulative 1-, 2- and 3-year overall survival rates were 95.7%, 86.6% and 82.2% in RLN-LN(-) group versus 81.5%, 67.4% and 53.7% in the RLN-LN(+) group, with a significant difference between two group (HR=2.975,95% CI:1.918-4.614, P＜0.01). Conclusions: The lymph node metastasis along RLNs was significantly correlated with primary tumor locations, tumor invasion depth, tumor differentiation, metastasis in the LNs of other stations, and indicate poor prognosis in ESCC.

Background: Extensive lymph nodes dissection can improve the accuracy of tumor staging and prognosis of the patients with thoracic esophageal cancer, palsy of recurrent laryngeal nerve (RLN) caused by the lymph node (LN) dissection along RLN chain also increase postoperative complications and may affect the prognosis. This study aimed to evaluate the associated postoperative complications after LN dissection along RLNs in the patients with thoracic esophageal squamous cell cancer (ESCC).Methods: 339 eligible patients with thoracic ESCC who underwent radical McKeown or Ivor-Lewis esophagectomy by open or VATS procedures through right thoracic approach with LN dissection along bilateral RLNs were included in this study. Univariate and multivariate logistic regression analysis were conducted to assess the correlation of RLN paralysis (RLNP) with other post-operative complications. Results: 39 of the 339 patients were diagnosed with RLNP (11.5%) postoperatively. The incidence of RLNP in three-field (3FL) LN dissection was significantly higher than that in the two-field (2FL) LN dissection ( 24.0% vs 8.0%, P＜0.001). Compared with the patients without RLNP, the patients with it had a significantly higher incidence of postoperative anastomotic leakage (P=0.029), pulmonary complications (P=0.001) and much longer hospital stay (P=0.001). Two patients died of respiratory failure within 30 days caused by RLNP and were treated by reintubation. Conclusion: RLNP after LN dissection along bilateral RLN in thoracic ESCC was associated with much higher morbidity such as pulmonary complications, anastomotic leakage, and much longer hospital stay. New technologies are required to reduce RLNP incidence and its associated complications.

BackgroundLung adenocarcinoma (LUAD) is the most common type of lung cancer and is a severe threat to human health. Although many therapies have been applied to LUAD, the long-term survival rate of patients remains unsatisfactory. We aim to find reliable immune microenvironment-related lncRNA biomarkers to improve LUAD prognosis.MethodsESTIMATE analysis was performed to evaluate the degree of immune infiltration of each patient in TAGA LUAD cohort. Correlation analysis was used to identify the immune microenvironment-related lncRNAs. Univariate cox regression analysis, LASSO analysis, and Kaplan Meier analysis were used to construct and validate the prognostic model based on microenvironment-related lncRNAs.ResultsWe obtained 1,178 immune microenvironment-related lncRNAs after correlation analysis. One hundred and eighty of them are independent prognostic lncRNAs. Sixteen key lncRNAs were selected by LASSO method. This lncRNA-based model successfully predicted patients’ prognosis in validation cohort, and the risk score was related to pathological stage. Besides, we also found that TP53 had the highest frequency mutation in LUAD, and the mutation of TP53 in the high-risk group, which was identified by our survival model, has a poor prognosis. lncRNA-mRNA co-expression network further suggested that these lncRNAs play a vital role in the prognosis of LUAD.ConclusionHere, we filtered 16 key lncRNAs, which could predict the survival of LUAD and may be potential biomarkers and therapeutic targets.

BackgroundA detailed means of prognostic stratification in patients with non-small cell lung cancer (NSCLC) is urgently needed to support individualized treatment plans. Recently, microRNAs (miRNAs) have been used as biomarkers due to their previously reported prognostic roles in cancer. This study aimed to construct an immune-related miRNA signature that effectively predicts NSCLC patient prognosis.MethodsThe miRNAs and mRNA expression and mutation data of NSCLC was obtained from The Cancer Genome Atlas (TCGA). Immune-associated miRNAs were identified using immune scores calculated by the ESTIMATE algorithm. LASSO-penalized multivariate survival models were using for development of a tumor immune-related miRNA signature (TIM-Sig), which was evaluated in several public cohorts from the Gene Expression Omnibus (GEO) and the CellMiner database. The miRTarBase was used for constructing the miRNA-target interactions.ResultsThe TIM-Sig, including 10 immune-related miRNAs, was constructed and successfully predicted overall survival (OS) in the validation cohorts. TIM-Sig score negatively correlated with CD8+ T cell infiltration, IFN-γ expression, CYT activity, and tumor mutation burden. The correlation between TIM-Sig score and genomic mutation and cancer chemotherapeutics was also evaluated. A miRNA-target network of 10 miRNAs in TIM-Sig was constructed. Further analysis revealed that these target genes showed prognostic value in both lung squamous cell carcinoma and adenocarcinoma.ConclusionsWe concluded that the immune-related miRNAs demonstrated a potential value in clinical prognosis.

Background: Lung cancer is the leading cause of cancer-related death. Even if early detection has been applied and proved to be effective, the survival outcomes are still poor. Thus, to find out novel prognostic factors is of great significance to identify high-risk patients and guide individualized precise treatment in order to reduce recurrence and improve survival outcomes.Methods: Tissue samples and clinicopathologic data of 244 stage T1 NSCLC patients were collected. We investigated CXCR5 expression using immunochemical method and analyzed its correlation with pathologic subtypes and prognosis.Results: Elevated level of positive CXCR5 expression was found in tumor tissues (pp=0.030) and recurrences (ppp=0.038) and patients with solid or micropapillary predominant NSCLC had a significantly worse prognosis. CXCR5 expression was proved to be an independent prognostic factor for DFS through multivariate analysis.Conclusions: CXCR5 expression has been proved to be an independent prognostic factor for stage T1 NSCLC patients. In addition, CXCR5 was also found to be relevant to cancer recurrence, and this indicated that CXCR5 may play an important role in lymph node and distant metastasis.

Background The pathologic stages of lymph nodes usually differ from preoperatively predicted in lung cancers and it is difficult to predict the metastasis of lymph nodes for the patients diagnosed as clinical stage IA non-small cell lung cancers (NSCLC). This study aimed to investigate the patterns of lymph node metastasis and the risk factors predicting lymph node metastasis in the patients with clinical stage IA NSCLCs. Methods All patients diagnosed as clinical stage IA NSCLC from July 2013 to June 2017 in our center were retrospectively reviewed, and a total number of 1,543 patients who underwent anatomical lobectomy with systematic lymph node dissection were enrolled in this study. Multivariate logistic regression analysis was performed to identify the risk factors predicting lymph node metastasis, and Fisher's exact test was used to confirm the lymph node spread mode according to the locations of primary tumors. Results Totally, lymph node metastases presented in 131 patients (8.5%) in this series. Sixty-three patients presented N1 diseases, 17 patients showed only skipped N2 diseases, and 51 patients had simultaneous N1 and N2 positive lymph nodes. No lymph node metastasis was found in the patients with pure ground grass opacity (GGO). When patients were arbitrarily divided into six groups by the longest tumor diameter of ≤0.5, 0.6-1, 1.1-1.5, 1.6-2.0, 2.1-2.5, 2.6-3 cm, the lymph node metastasis rates of each group were 0% (0/20), 1.5% (4/264), 4.7% (20/429), 8.6% (29/336), 13.1% (38/290), 19.6% (40/204), respectively. When the patients with pure GGO were excluded, the lymph node metastasis rates in the patients with partial or total solid tumors were 0% (0/10), 2.4% (4/164), 6.6% (20/303), 11.7% (29/249), 16.0% (38/238) and 23.1% (40/173). The cut off value showed by receiver operating characteristic (ROC) curve for tumor size was 1.95 cm, and the area under the curve (AUC) was measured as 0.681 (P