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Background: The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients., Methods: Matched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort (n = 195) and validated in an independent cohort (DYNAMIC, n = 36)., Results: Tumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48-6.42; P = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96-8.20; P = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse., Conclusions: The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance., Trial Registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826). https://clinicaltrials.gov/ct2/show/NCT03634826 ., (© 2023. The Author(s).)

Introduction: No consensus has been achieved on the benefit of radiotherapy for resected stage IIIA NSCLC patients. The division of stage IIIA has changed significantly in 2017. This study aims to explore the effects of radiotherapy on the survival of patients with resectable stage IIIA NSCLC in the new era., Patients and Methods: Patients diagnosed with NSCLC between 2010 and 2018 were identified in the 8th edition TNM classification from the Surveillance, Epidemiology, and End Results database. A nomogram was developed by integrating all independent predictors for lung cancer-specific survival (LCSS). The Propensity Score Matching (PSM) and subgroup analysis were applied to mitigate potential bias. Survival analyses were conducted using the Kaplan Meier curves and Cox proportional hazards regression., Results: A total of 2632 stage IIIA NSCLC patients were enrolled. The C-index of the nomogram for the prediction of LCSS was 0.636 (95% CI, 0.616-0.656). In the group of patients with N2 stage who featured more than 5 positive regional lymph nodes, compared with non-PORT, PORT did prolong postoperative survival time (50 vs. 31 months; P= .005). N2 patients with visceral pleural invasion (VPI), older (age >65), or had a larger tumor (size >3 cm) could also benefit from adjuvant radiotherapy., Conclusion: Treatment protocol for stage IIIA NSCLC patients should be individualized. Based on our findings, N2 patients with more than 5 positive regional lymph nodes, VPI, larger tumor size (greater than 3 cm), and older (age above 65) could benefit from adjuvant radiotherapy. Further well-designed randomized trials are warranted., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Liquid biopsy has been widely researched for early diagnosis, prognostication and disease monitoring in lung cancer, but there is a need to investigate its clinical utility for early-stage non-small cell lung cancer (NSCLC)., Methods: We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated., Results: In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06-8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97-7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD - patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy., Conclusions: In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application., (© 2022. The Author(s).)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The randomized, open-label, phase II EVAN study investigated the efficacy (disease-free survival [DFS] and 5-year overall survival [OS]) and safety of erlotinib versus vinorelbine/cisplatin as adjuvant chemotherapy after complete resection (R0) for stage III epidermal growth factor receptor ( EGFR ) mutation+ non-small-cell lung cancer. We describe the updated results at the 43-month follow-up. In EVAN, patients were randomly assigned (1:1) to erlotinib (n = 51) or vinorelbine/cisplatin (n = 51). The median follow-up was 54.8 and 63.9 months in the erlotinib and chemotherapy arms, respectively. With erlotinib, the respective 5-year DFS by Kaplan-Meier analysis was 48.2% (95% CI, 29.4 to 64.7) and 46.2% (95% CI, 27.6 to 62.9) in the intention-to-treat and per-protocol populations. The median OS was 84.2 months with erlotinib versus 61.1 months with chemotherapy (hazard ratio, 0.318; 95% CI, 0.151 to 0.670). The 5-year survival rates were 84.8% and 51.1% with erlotinib and chemotherapy, respectively. In whole-exome sequencing analysis, frequent genes with variants co-occurring at baseline were TP53 , MUC16 , FAM104B , KMT5A , and DNAH9 . With erlotinib, a single-nucleotide polymorphism mutation in UBXN11 was associated with significantly worse DFS ( P = .01). To our knowledge, this study is the first to demonstrate clinically meaningful OS improvement with adjuvant erlotinib compared with chemotherapy in R0 stage III EGFR+ non-small-cell lung cancer.

Background: Thoracoscopic segmentectomy is a common surgical procedure in thoracic surgery today. However, identifying the intersegmental plane is difficult in the surgical process. Therefore, we evaluated the feasibility of the arterial ligation method for determining the intersegmental plane and compared the demarcation status with the intravenous indocyanine green (ICG)., Methods: We retrospectively reviewed the records of 35 patients with peripheral small lung nodules who underwent thoracoscopic segmentectomy between May and December 2020. First, the preoperative three-dimensional reconstruction was performed to distinguish the location of lung nodules and the anatomical structures of targeted segmental arteries, veins, and bronchi. Second, the targeted segmental arteries were ligated, and the intersegmental plane was determined by the inflation-deflation technique. The waiting time for the appearance of the inflation-deflation line was recorded. Thirdly, the intersegmental plane was identified again using the ICG fluorescence method. Finally, the consistency of the two intersegmental planes was evaluated., Results: The intersegmental planes were successfully observed in all patients using the arterial ligation method. Thirty-four patients underwent segmentectomy as planned, and one patient finally underwent lobectomy due to insufficient surgical margin. The waiting time for the appearance of the intersegmental plane by arterial ligation method was 13.7 ± 3.2 min (6-19 min). The intersegmental planes determined by the arterial ligation method and the ICG fluorescence method were comparable, with a maximum distance of no more than 5 mm between the two planes. The mean operative duration was 119.1 ± 34.9 min, and the mean blood loss was 76.9 ± 70.3 ml. No evident air leakage was found during the operation. Only one patient experienced a prolonged air leak (≥ 5 days) during the postoperative recovery. No atelectasis occurred in all cases. The chest tube duration was 3.1 ± 0.9 days., Conclusion: The arterial ligation method can efficiently and accurately identify the intersegmental plane, comparable to the ICG fluorescence method., (© 2022. The Author(s).)

Background: Video-assisted thoracic surgery (VATS) has been widely used in the surgical treatment of thoracic diseases, and it suggested surgical and oncological advantages compared with open surgery. However, reports on the application of VATS in surgery of small cell lung cancer (SCLC) are scarce. This study aimed to explore the advantages and disadvantages of different surgical approaches in the treatment of pathological stage T1(pT1) SCLC in terms of safety, clinical outcomes, and lymph node dissection., Patients and Methods: Patients who underwent lobectomy for pT1 SCLC between January 2014 and September 2017 were identified from the National Collaborative Lung Cancer Database (LinkDoc Database). The patients were stratified based on the surgery approach (VATS or open lobectomy). Perioperative outcomes and long-term survival were analyzed using SPSS software., Results: A total of 169 patients with pT1 SCLC met the criteria and were enrolled for this study, including 110 cases of VATS lobectomies and 59 cases of open lobectomies. VATS lobectomy was associated with less blood loss than open surgery (168.1 ± 237.4 vs. 340.0 ± 509.8 mL, P = .002). Open lobectomy harvested more N2 LNs (11.8 ± 8.2 vs. 8.4 ± 5.8, P = .048) and identified more metastasis positive LNs (3.1 ± 6.0 vs. 1.4 ± 3.0, P = .050). Open lobectomy associated with longer overall survival (OS) but has no statistical difference (23.4 ± 13.2 vs. 20.2 ± 10.9, P = .070)., Conclusion: Open lobectomy had better lymph node dissection results, and comparable postoperative complications, postoperative hospital stay, and OS to VATS lobectomy. Further studies may still be needed to confirm the recommendation of thoracoscopic approach as a routine surgical procedure for operable SCLC, and until then, open surgery should still be considered., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Three-dimensional reconstruction of chest computerized tomography (CT) excels in intuitively demonstrating anatomical patterns for pulmonary segmentectomy. However, current methods are labor-intensive and rely on contrast CT. We hereby present a novel fully automated reconstruction algorithm based on noncontrast CT and assess its performance both independently and in combination with surgeons., Methods: A retrospective pilot study was performed. Patients between May 2020 to August 2020 who underwent segmentectomy in our single institution were enrolled. Noncontrast CTs were used for reconstruction. In the first part of the study, the accuracy of the demonstration of anatomical variants by either automated or manual reconstruction algorithm were compared to surgical observation, respectively. In the second part of the study, we tested the accuracy of the identification of anatomical variants by four independent attendees who reviewed 3-D reconstruction in combination with CT scans., Results: A total of 20 cases were enrolled in this study. All segments were represented in this study with two left S1-3, two left S4 + 5, one left S6, five left basal segmentectomies, one right S1, three right S2, 1 right S2b + 3a, one right S3, two right S6 and two right basal segmentectomies. The median time consumption for the automated reconstruction was 280 (205-324) s. Accurate vessel and bronchial detection were achieved in 85% by the AI approach and 80% by Mimics, p = 1.00. The accuracy of vessel classification was 80 and 95% by AI and manual approaches, respectively, p = 0.34. In real-world application, the accuracy of the identification of anatomical variant by thoracic surgeons was 85% by AI+CT, and the median time consumption was 2 (1-3) min., Conclusions: The AI reconstruction algorithm overcame defects of traditional methods and is valuable in surgical planning for segmentectomy. With the AI reconstruction, surgeons may achieve high identification accuracy of anatomical patterns in a short time frame., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

Background: Lung cancer has the highest mortality in China. Different treatments are of great significance to the prognosis of patients. By comparing stage Ia non-small cell lung cancer (NSCLC) patients' survival rates for ablation and for sub-lobectomy, we studied the difference in the effects of the two treatments on patient prognosis., Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we screened eligible patients with stage Ia NSCLC from January 2004 to December 2015. Then, 228 patients treated with ablation and 228 patients treated with sub-lobotomy were then selected based on propensity score matching. After stratification, matching, and adjustment the Kaplan-Meier analysis was performed to compare the overall survival rates of patients treated with the two procedures., Results: The Kaplan-Meier survival analysis showed that there is a significant difference between the ablation group and the sub-lobectomy group (P<0.05). In the univarlable analysis, the hazard ratio (HR) of sub-lobotomy group was 0.571 (95%CI: 0.455-0.717) compared with the ablation group. Patients treated with sub-lobectomy had a 0.571 times greater risk of adverse outcomes than those treated with ablation. In the multivariable analysis, the HR for sub-lobectomy group was 0.605 (95%CI: 0.477-0.766) compared with the ablation group. Patients treated with sub-lobectomy had a 0.605 time greater risk of adverse outcomes than those treated with ablation. The results suggested that the overall survival rate of patients with stage Ia NSCLC treated with sub-lobotomy was higher than that of patients treated with ablation., Conclusions: This study suggests that there is a significant difference in overall survival of stage Ia NSCLC patients treated with ablation and with sub-lobotomy. Patients treated with sub-lobotomy for stage Ia NSCLC had higher overall survival than those treated with ablation.

Objectives: This study aimed to evaluate the effect of postoperative radiotherapy (PORT) in patients with resected pathologic N2 (pN2) non-small cell lung cancer (NSCLC) with different locoregional recurrence (LRR) risks., Materials and Methods: The primary cohort and validation cohort were retrieved from two independent medical centres. Data for all consecutive patients with completely resected pathologic stage T1-3N2M0 NSCLC were analysed. Patients without PORT in the primary cohort were identified as a training set. Significant prognostic factors for LRR were identified by the Fine-Gray model to develop a prognostic index (PI) in the training set., Results: The primary cohort consisted of 357 patients who met the eligibility criteria (training set, 287 patients without PORT). The external validation cohort consisted of 1044 patients who met the eligibility criteria (validation set, 711 patients without PORT). Heavy cigarette smoking history, clinical N2 status (cN2), and the number of positive lymph nodes >4 were identified as independent risk factors. The PI was computed as follows: PI＝0.8*smoking history＋0.5*cN2＋0.7*the number of involved lymph nodes (reference level was assigned the value 1 and risk level the value 2). In the low-risk group (PI score< = 3), PORT showed a trend towards decreased LRR rates but not significantly improved overall survival (OS). In the high-risk group (PI score>3), PORT significantly reduced the risk of LRR and improved OS., Conclusions: We constructed and validated a PI to predict individually the effect of PORT in patients with completely resected pN2 NSCLC. Patients with a higher PI score can benefit from PORT in terms of OS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.

Background: The majority of previous studies of the clinical outcome of video-assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non-small cell lung cancer (pN2 NSCLC) have been single-center experiences with small patient numbers. The aim of this study was therefore to investigate these procedures but in a large cohort of Chinese patients with pathological N2 NSCLC in real-world conditions., Methods: Patients who underwent lobectomy for pN2 NSCLC by either VATS or thoracotomy were retrospectively reviewed from 10 tertiary hospitals between January 2014 and September 2017. Perioperative outcomes and overall survival of the patients were analyzed. Cox regression analysis was performed to identify potential prognostic factors. Propensity-score analysis was performed to reduce cofounding biases and compare the clinical outcomes between both groups., Results: Among 2144 pN2 NSCLC, 1244 patients were managed by VATS and 900 by open procedure. A total of 305 (24.5%) and 344 patients died during VATS and the thoracotomy group during a median follow-up of 16.7 and 15.6 months, respectively. VATS lobectomy patients had better overall survival when compared with those undergoing the open procedure (P < 0.0001). Multivariate COX regression analysis showed VATS lobectomy independently favored overall survival (HR = 0.75, 95% CI: 0.621-0.896, P = 0.0017). Better perioperative outcomes, including less blood loss, shorter drainage time and hospital stay, were also observed in patients undergoing VATS lobectomy (P < 0.05). After propensity-score matching, 169 patients in each group were analyzed, and no survival difference were found between the two groups. Less blood loss was observed in the VATS group, but there was a longer operation time., Conclusions: VATS lobectomy might be a feasible alternative to conventional open surgery for resectable pN2 NSCLC., Key Points: Significant findings of the study: VATS lobectomy has comparative OS in pN2 NSCLC versus open procedure in resectable patients., What This Study Adds: VATS lobectomy might be feasible for pN2 NSCLC., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: N2 non-small cell lung cancer (NSCLC) without N1 involvement, also known as skip metastases (pN0N2), has been suggested as a subgroup of heterogeneous N2 disease with better survival. This real-world observational study aimed to elucidate the prognostic impacts of skip N2 metastases using a large number of pathologic N2 NSCLC from 10 participating centers in China., Materials and Methods: Medical records of pN2 NSCLC patients after surgical resection at 10 thoracic surgery centers between January 2014 and September 2017 were retrospectively reviewed based on the LinkDoc database. Clinical data on patient demographics, tumor characteristics, treatments and clinical outcomes were collected. Overall survival of patients with and without skip metastases was evaluated and compared by Kaplan-Meier method and Log-rank test. Cox proportional hazard model was established to identify potential prognostic predictors. Subgroup analysis was carried out to further explore the prognostic significance of skip metastases., Results: Among 2653 surgically resected N2 patients, 881 (33.2%) had skip metastases. Patients with skip N2 had a significant better overall survival (P = 0.0019). Multivariate COX regression analysis showed borderline significance of skip metastases (HR = 0.81, 95%CI: 0.645-1.017, P = 0.0698) after adjustment for other covariates. Other independent prognostic predictors included smoking history, tumor location, stage and N2 station involved (P < 0.05). Subgroup analysis demonstrated significant survival benefits of skip N2 in most subpopulations., Conclusions: This study suggested a prognostic benefit of skip N2 metastases in real world practice. Further subdivision of N2 disease is warranted for better patient management and prognostic prediction (NCT03429192)., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: Minimally invasive surgery provides an ideal method for pathologic diagnosis and curative intent of small pulmonary nodules (SPNs); however, the main problem with thoracoscopic resection is the difficulty in locating the nodules. The goal of this study was to determine the safety and feasibility of a new localization technique tailored for SPNs., Methods: A computed tomography (CT)-guided technique, which has a tri-colored suture and claw with 4 fishhook-shaped hooks, was designed to localize SPN preoperatively. Then a multicenter, prospective study was conducted to evaluate the safety and feasibility of this device. The primary endpoints included safety (asymptomatic/symptomatic pneumothorax or parenchymal hemorrhage, and unanticipated adverse effects) and success rate (precise placement and device fracture, displacement, or dislodgement). The secondary endpoints included feasibility (duration of the localization procedure and device fracture or fault) and patient comfort (pain)., Results: A total of 90 SPNs were localized from 80 patients. Overall, no symptomatic complications requiring medical intervention, with the exception of asymptomatic pneumothorax (n = 7 [7.8%]) and lung hemorrhages (n = 5 [5.6%]), were observed. The device was successfully placed without dislodgment or movement in 87 of 90 lesions (96.7%). The median nodule size was 0.70 cm (range, 0.30-1.0 cm). The median duration of the procedure was 15 minutes (range, 7-36 minutes). No patient complained of notable pain during or after the procedure., Conclusions: This new device for SPNs is safe, and has a high success rate, feasibility and good tolerance., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Preoperative assessment of tumor invasiveness is essential to avoid overtreatment for patients with small-sized ground-glass nodules (GGNs) of 10 mm or less in diameter. However, it is difficult to determine the pathological state by computed tomography (CT) examination alone. Aberrant glycans has emerged as a tool to identify novel potential disease biomarkers. In this study, we used a lectin microarray-based strategy to investigate whether glycosylation changes in plasma immunoglobulin G (IgG) provide additional information about the invasiveness of small GGNs before surgery. Two independent cohorts (discovery set, n = 92; test set, n = 210) of GGN patients were used. Five of 45 lectins ( Sambucus nigra agglutinin, SNA; Datura stramonium agglutinin, DSA; Galanthus nivalis agglutinin, GNA; Euonymus europaeus lectin, EEL; and Vicia villosa agglutinin, VVA) were identified as independent factors associated with pathological invasiveness of small GGNs ( p < 0.01). Receiver-operating characteristic (ROC) curve analysis indicated the combination of these five lectins could significantly improve the accuracy of CT in diagnosing invasive GGNs, with an area under the curve (AUC) of 0.792 ( p < 0.001), a sensitivity of 74.6%, and specificity of 74.4%, which was superior to current clinical biomarkers. These results suggest that the multilectin assay based on plasma IgG glycosylation may be a useful in vitro complementary test to enhance preoperative determination of the invasiveness of GGNs and guide surgeons to select proper clinical management to avoid overtreatment.

Purpose: No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer. Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B-time D), and after surgery (time P1-time P3). Next-generation sequencing-based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection., Results: Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively ( P = 0.657), whereas at time P2 was 278 days and 637 days, respectively ( P = 0.002)., Conclusions: ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance., (©2019 American Association for Cancer Research.)

Purpose: N2 lymph-node metastases occur in approximately 6-17% of the patients with T1-2 non-small cell lung cancer (NSCLC). However, the clinical characteristics of N2 patients are not fully understood., Methods: This retrospective, multi-center analysis included T1 NSCLC patients receiving surgical resection during a period from Jan 2nd, 2014 to Dec 27th, 2017. The diagnosis was pathologically verified in all cases. Univariate and multivariate logistic regression analyses were conducted to analyze the factors that are associated with pN2 lymph-node metastases., Results: A total of 10,885 patients (48.4% men; 84.7% adenocarcinoma) were included in the analysis. The mean age was 59.0 ± 9.9 years. The mean tumor size was 1.8 ± 0.8 cm. Of the patients, 3260 (29.9%) were smokers or ex-smokers. Lymph-node metastases were verified in 1808 (16.6%) patients, and 1167 (10.7%) patients had N2 lymph-node metastases. The multivariate analyses indicated that larger tumor size, lower differentiation, CEA level ≥ 5 ng/mL, vascular invasion (+), and pleural involvement (+) were associated with higher percentages of N2 lymph-node metastases (p < 0.001 for all)., Conclusions: This study demonstrated the significant association between N2 lymph-node metastases and tumor size and differentiation, CEA levels, and status of vascular invasion and pleural involvement.

Background: This study aimed to explore adjuvant chemotherapy (ACT) candidates based on a recurrence risk-scoring model in completely lobectomized stage I patients with lung adenocarcinoma (LAD)., Methods: A retrospective study was performed on 4606 patients (non-ACT group: n = 3514; ACT group: n = 1092) who underwent complete lobectomy for LAD at Shanghai Chest Hospital from 2008 to 2014. The nomogram predicting recurrence-free survival (RFS) was developed in the non-ACT group using Cox proportional hazards regression. The nomogram-based risk score was calculated in the entire cohort. Differences of RFS between the non-ACT and ACT groups were compared as stratified by the risk score. The score cut-off points were determined using the X-tile software., Results: Six independent predictors, including age, sex, tumor size, pathological subtype, visceral pleural invasion (VPI), and lymphovascular invasion (LVI) were associated with RFS. The nomogram more accurately predicted RFS than the 8th TNM staging {C-index: 0.784 [95% confidence interval (CI) 0.756-0.812] vs. 0.719 (95% CI 0.689-0.749), p = 0.0017}. A significant RFS difference was observed among the low-, intermediate- and high-risk groups (p < 0.0001), as divided by the optimal cut-points of risk score (203 and 244). ACT did not improve RFS for patients at intermediate-risk, or was even detrimental for low-risk patients; however, improved RFS was observed in ACT receivers at high-risk (p = 0.0416). ACT candidates with a risk score ≥ 245 constituted 2.6% of stage I patients., Conclusions: The nomogram provided an individual prediction of RFS for stage I LAD following lobectomy. High-risk patients (score ≥ 245) may benefit from postoperative ACT.

Background: Detection of circulating tumor DNA (ctDNA) is a promising method for postoperative surveillance of lung cancer. However, relatively low positive rate in early stage patients restricts its application. Aberrant methylation of ctDNA can be detected in blood samples, and may provide a more sensitive method. This study is designed to systematically evaluate and compare the detection of aberrant methylation and mutations in ctDNA among surgical non-small cell lung cancer (NSCLC) patients, aiming to investigate the feasibility of ctDNA detection as a means of lung cancer surveillance., Methods: This is a prospective observational study. Consecutive surgical NSCLC patients will be recruited. Blood samples will be collected both before and after surgery (during the follow-up period), while matching tumor tissues and tumor-adjacent normal tissues will be collected during surgery. Quantitative analysis of aberrant methylation and mutations of ctDNA will be conducted in combination with a three-year follow-up data., Discussion: This is the first registered prospective study designed to investigate the feasibility of ctDNA methylation detection as a means of postoperative lung cancer surveillance. We will systematically evaluate and compare the quantitative detection of ctDNA mutations and ctDNA methylation in surgical NSCLC patients, combining with the follow-up information. By integrating genetic and epigenetic information of ctDNA, more effective strategies for postoperative surveillance may be defined., Trial Registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826; Pre-results).

Lessons Learned: The findings of this prospective, single-arm, phase II study showed that neoadjuvant erlotinib was well tolerated and might improve the radical resection rate in patients with stage IIIA-N2 epidermal growth factor receptor mutation-positive non-small cell lung cancer (NSCLC).Erlotinib shows promise as a neoadjuvant therapy option in this patient population.Next-generation sequencing may be useful for predicting outcomes with preoperative tyrosine kinase inhibitors (TKIs) in patients with NSCLC.Large-scale randomized controlled trials investigating the role of TKIs in perioperative therapy, combining neoadjuvant and adjuvant treatments to enhance personalized therapy for patients in this precision medicine era, are warranted., Background: Information on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as neoadjuvant therapy in non-small cell lung cancer (NSCLC) is scarce. We evaluated whether neoadjuvant erlotinib improves operability and survival in patients with stage IIIA-N2 EGFR mutation-positive NSCLC., Methods: We conducted a prospective, single-arm, phase II study. Patients received erlotinib 150 mg per day for 56 days in the neoadjuvant period. The primary endpoint was the radical resection rate., Results: Nineteen patients were included in the final analysis. After erlotinib treatment, 14 patients underwent surgery. The radical resection rate was 68.4% (13/19) with a 21.1% (4/19) rate of pathological downstaging. The objective response rate was 42.1%; 89.5% (17/19) of patients achieved disease control, with a 10.3-month median disease-free survival among patients who underwent surgery. Among all 19 patients who received neoadjuvant therapy, median progression-free survival (PFS) and overall survival were 11.2 and 51.6 months, respectively. Adverse events (AEs) occurred in 36.8% (7/19) of patients, with the most common AE being rash (26.3%); 15.8% experienced grade 3/4 AEs. Quality of life (QoL) improvements were observed after treatment with erlotinib for almost all QoL assessments. Effects of TP53 mutation on prognosis were evaluated in eight patients with adequate tissue samples. Next-generation sequencing revealed that most patients had a TP53 gene mutation (7/8) in addition to an EGFR mutation. No TP53 mutation, or very low abundance, was associated with longer PFS (36 and 38 months, respectively), whereas high abundance was associated with short PFS (8 months)., Conclusion: Neoadjuvant erlotinib was well tolerated and may improve the radical resection rate in this patient population. Next-generation sequencing may predict outcomes with preoperative TKIs., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Purpose: Small cell lung cancer (SCLC) is considered a systemic disease and surgery is generally not recommended to treat it. High heterogeneity within the tumor and preoperative diagnostic capabilities can sometimes fail to identify SCLC correctly, leading to a subset of unexpected SCLC patients that are diagnosed only after pulmonary resections., Methods: We retrospectively reviewed the clinical records of patients who were diagnosed as having SCLC only after surgery between 2008 and 2015 at a single institution., Results: A total of 125 unexpected SCLC patients were identified, including those with pure (p-SCLC; n = 76, 60.8%) and combined (c-SCLC; n = 49, 39.2%) SCLC. Highly differential diagnoses were observed between pre- and postoperative tissue examinations. Sixty-nine (55.2%) patients with postoperatively pathological-proven SCLC, including 31 with p-SCLC and 38 with c-SCLC, were diagnosed preoperatively with poorly differentiated carcinoma (n = 23), squamous carcinoma (n = 14), adenocarcinoma (n = 10), malignant cells with necrosis (n = 10), large cell carcinoma (n = 8), or carcinoid (n = 4). Also, inconsistencies between the clinical (c-) and pathological (p-) stages were found in this cohort, which were less common in patients with preoperative PET examination than those without (24.4% vs. 43.8%; p = 0.032). Multivariable analyses showed that higher p-stage (hazards ratio (HR) = 1.7349, p = 0.0025), sub-lobar resection (HR = 1.9078, p = 0.0395), and a lack of prophylactic cranial irradiation treatment (PCI, HR = 0.3873, p = 0.0057) were unfavorable prognostic factors for overall survival., Conclusion: Non-resection approaches reveal an inadequate diagnosis of SCLC. PET examination facilitates the evaluation of the clinical staging of SCLC. For unexpected SCLC undergoing resection, favorable outcomes can be achieved if radical resection and postoperative PCI are performed.

Background: Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC., Methods: In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m 2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m 2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175., Findings: Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8-43·1). 2-year disease-free survival was 81·4% (95% CI 69·6-93·1) in the erlotinib group and 44·6% (26·9-62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194-2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5-58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported., Interpretation: Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC., Funding: National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: This retrospective research was designed to investigate the relationship between pT1N0M0 invasive adenocarcinoma (IADC) harboring solid (SOL) and/or micropapillary (MIP) components and its prognosis following lobectomy., Methods: Clinical data of pT1N0M0 IADC patients were retrospectively collected from Shanghai Chest Hospital. Survival curves were plotted by Kaplan-Meier methods. Multivariable cox regressions were conducted to discover the independent risk factors of recurrence-free survival (RFS) and overall survival (OS), through which nomograms were performed to visualize the risk of recurrences and outcomes in personalized information., Results: Totally, 1965 patients were enrolled, including 248 harboring SOL/MIP and 1717 not. IADC demonstrated worse 5-year RFS (81.9 vs. 92.2%, p < 0.001) and OS (85.7 vs. 94.4%, p < 0.001) when harboring SOL and/or MIP components. And this status became an independent factor associated with poorer RFS (HR 2.445, 95% CI 1.565-3.821, p < 0.001) and OS (HR 2.139, 95% CI 1.180-3.878, p = 0.012) instead of novel classification of IADC predominant patterns. No difference existed between SOL/MIP predominant and minor patterns. In addition, age > 60, smoking, post-chemotherapy and T1b were all indicating poorer RFS and smoking was also related with worse OS. The c-indexes of nomograms were 0.723 for RFS (95% CI, 0.662-0.784) and 0.703 for OS (95% CI, 0.629-0.777) respectively., Conclusions: Once the pT1N0M0 IADC harboring SOL/MIP, it strongly indicated the worse clinical recurrence and survival outcome, no matter whether the SOL and/or MIP was predominant. Smoking was correlated with worse prognosis for those patients. Age > 60 and stage T1b also indicated poorer RFS. Whether post-chemotherapy was harmful to pT1N0M0 IADC patients needed further research.

Lung cancer is one of the most common cancers and the predominant cause of cancer-related death in the world. The low accuracy of early detection techniques and high risk of relapse greatly contribute to poor prognosis. An accurate clinical tool that can assist in diagnosis and surveillance is urgently needed. Circulating tumor DNA (ctDNA) is free DNA shed from tumor cells and isolated from peripheral blood. The genomic profiles of ctDNA have been shown to closely match those of the corresponding tumors. With the development of approaches with high sensitivity and specificity, ctDNA plays a vital role in the management of lung cancer as a result of its reproducible, non-invasive, and easy-to-obtain characteristics. However, most previous studies have focused on advanced lung cancer. Few studies have investigated ctDNA in the early stages of the disease. In this review, we focus on ctDNA obtained from patients in the early stage of lung cancer, provide a summary of the related literature to date, and describe the main approaches to ctDNA and the clinical applications., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: The aim of this study was to compare the short-term and mid-term results of patients with centrally located lung cancer who underwent bronchial sleeve resection by robotic system or thoracotomy., Methods: From September 2014 to September 2015, 103 patients, including 17 robotic and 86 open cases, were included in our study. All the clinicopathological data, operative details and follow-up information were investigated., Results: There were no intraoperative deaths. The mean console time was 113.59 min. The operative time for robotic surgery (155.06 ± 44.75 min), even in our initial cases, was comparable to that for thoracotomy (150.30 ± 47.84 min, P = 0.71). The 30-day mortality rate in the robotic and thoracotomy groups was 1 (6%) patient and 2 (2%) patients, respectively, with no significant difference (P = 0.43). A total of 4 (24%) patients in the robotic group and 22 (26%) patients in the thoracotomy group experienced postoperative complications (P = 0.86). In multivariable analysis, tumour size and postoperative radiotherapy were significant predictors of relapse-free survival, whereas only the intensive care unit stay was a significant predictor of overall survival. There was no significant difference in relapse-free survival (log-rank P = 0.16) and overall survival (log-rank P = 0.59) between the 2 groups., Conclusions: Robotic surgery for bronchial sleeve resection is safe and feasible and has similar oncological outcomes compared with open procedures. But long-term survival still needs to be investigated., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non-small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients., Methods and Analysis: This is a prospective observational study to determine the elimination rate of circulating tumour DNA after surgery. Consecutive patients with suspected lung cancer who undergo curative-intent lung resection will be enrolled. 10 mL blood samples are taken by intravenous puncture. Plasma samples are obtained before surgery (time A) and at a series of scheduled time-points (2 min to 72 hours, time B to F) after tumour resection. DNA is prepared from 4 mL of purified plasma. A multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) is used to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, PIK3CA, TP53, ALK, RET and MET plasma DNA variants. Positive plasma mutations are validated in tumour tissue and normal lung tissue by targeted sequencing., Ethics and Dissemination: Ethical approval has been obtained from the Peking University People's Hospital Medical Ethics Committee (2016PHB156-01). Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals., Trial Registration Number: NCT02965391; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: This retrospective study was designed to find out the potential indications of completion lobectomy (CL) during wedge resection (WR) operation among patients with lung adenocarcinoma (ADC) ≤3 cm, by the use of Shanghai Chest Hospital Lung Cancer Database., Patients and Methods: There were totally 1938 patients in this study, including 746 WRs and 1192 CLs. The propensity score matching (PSM) was performed to minimize the effect of confounders. Univariable and multivariable cox regressions were analyzed to discover the independent risk factors of recurrence-free survival (RFS) and overall survival (OS). Subgroup analysis and Kaplan-Meier survival curves were performed if necessary., Results: The 5-year RFS (86.1 vs 91.5%, p = 0.001 for unmatched group; 84 v 92%, p < 0.001 for PSM group) and OS (83.6 vs 91.7%, p < 0.001 for unmatched group; 81.6 vs 88.2%, p < 0.001 for PSM group) all indicated a better prognosis when conducting CL. Subgroup analysis suggested that WR was appropriate for non-invasive ADC. Three prognostic factors (sex, surgical approach and pleural invasion) were correlated with RFS and two (sex and surgical approach) corresponded with OS in invasive ADC through multivariable analysis. Non-lepidic-predominant component showed a better RFS and OS when CL was operated after WR in the subgroup of invasive ADC., Conclusion: CL was an appropriate remediation to WR when the existence of invasive ADC, especially non-lepidic-predominant one. While WR could be applied if non-invasive ADC was confirmed. Whether lepidic-predominant adenocarcinoma was fit for WR needed further study.

Purpose: This study was designed to investigate the risk factors of recurrence and survival of clinical stage I lung adenocarcinoma underwent wedge resection by the use of Shanghai Chest Hospital Lung Cancer Database., Patients and Methods: A total of 746 patients with clinical stage I adenocarcinoma underwent wedge resection from 2010 to 2015 in our database were included in this study. Univariable and multivariable Cox proportional hazards regression were performed successively to select significant risk factors and then nomograms as well as the concordance indexes for RFS, OS and LCSS were developed, respectively. Kaplan-Meier survival curves were performed if necessary, with the identification of log-rank test., Results: The 5-year RFS, OS and LCSS of clinical stage I adenocarcinoma underwent wedge resection were 86.1, 83.6 and 85.2%, respectively. There were three independent risk factors related with RFS (sex, pathology, pleural invasion), two related with OS (sex, volume ratio) and two with LCSS (sex, volume ratio) with the analysis of Cox regression and were selected to develop nomograms. The C-indexes of RFS, OS and LCSS were 0.767 (95% CI 0.667-0.867), 0.782 (95% CI 0.660-0.904) and 0.794 (95% CI 0.669-0.919), respectively. Lymphadenectomy did not show differences statistically but had tendencies of better RFS, OS and LCSS among the subgroup of invasive adenocarcinoma., Conclusion: Sex, pathology and pleural invasion could be recommended as criteria for clinical stage I adenocarcinoma undergoing wedge resection. And the larger the wedge volume and/or the smaller the tumor volume was, the better OS and LCSS were. If the volume ratio reached 10:1 or more, the survival rate was approximately 90% for both OS and LCSS. Whether lymphadenectomy was necessary for WR, especially in invasive adenocarcinoma, needed further research.

Introduction: This study investigated the correlation between histologic predominant pattern and postrecurrence survival (PRS), and identified the clinicopathologic factors influencing PRS in patients with completely resected stage I lung adenocarcinoma., Methods: A total of 136 stage I lung adenocarcinoma patients who experienced tumor recurrence after completely resection were included in this study. To analysis the association between histologic predominant pattern and PRS, invasive adenocarcinomas with mixed histologic components were divided into 2 groups: solid and nonsolid group (including lepidic, acinar, papillary, micropapillary) based on the histologic predominant pattern. PRS was analyzed to identify the prognostic predictors using the Kaplan-Meier approach and multivariable Cox models., Results: For all stage I invasive adenocarcinoma patients, the majority of postsurgical recurrences occurred within 2 years. Patients with solid predominant histological pattern were associated with unfavorable PRS (HR, 2.40; 95%CI 1.13-5.08, p=.022). There was a significant difference for poor PRS for patients who diagnosed tumor recurrence shorter than 12 months after surgery (HR, 2.34; 95%CI 1.12-4.90, p=.024). Extrathoracic metastasis was associated with poor media PRS in univariable analysis (p =.011), however, there was no significant PRS difference in multivariable analysis (HR, 1.56; 95%CI 0.65-3.73, p=.322) compared with intrathoracic metastasis., Conclusions: Solid predominant histologic subtype and recurrence free interval less than 12 months predict worse PRS in patients with stage I lung adenocarcinoma.

Background: The purpose of this study was to identify the technical aspects and short-term results of robotic sleeve resection for lung cancer patients., Methods: Twenty-one consecutive cases of robotic sleeve resection from September 2014 to September 2015 were reviewed., Results: There were 17 single sleeve resection (bronchial) and 4 double sleeve resection (bronchial and vascular) cases. Nineteen of 21 cases (90.5%) achieved R0 resection. The mean console time was 120.4 ± 37.3 minutes. The mean operation time was 158.4 ± 42.0 minutes. There was no massive bleeding (800 mL or more) during operation. The mean intraoperative blood loss was 157.1 ± 97.8 mL. One case (4.8%) was converted to thoracotomy owing to severe calcification of lymph node. There was no intraoperative death. The overall complication rate was 19.0%. The major complications were subcutaneous emphysema (14.4%), cardiac arrhythmia (9.6%), pneumonia (9.6%), pyothorax (9.6%), bronchial anastomosis bleeding (4.8%), bronchial anastomosis leakage (4.8%), and multiple organ failure (4.8%). The 30-day mortality rate was 4.8%. The mean postoperative length of stay was 10.7 ± 7.6 days., Conclusions: Robotic sleeve resection is technically feasible and can be carried out with acceptable short-term results., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Controversy remains exist for the effect of adjuvant chemotherapy (ACT) among stage IB lung adenocarcinoma patients. This study aimed to investigate the predictive value of the current lung adenocarcinoma classification system on benefit of ACT among patients with stage IB lung adenocarcinoma., Methods: A total of 928 pathological stage IB invasive adenocarcinoma patients with R0 resection were included in this study. Based on the predominant growth pattern present in the tumor, invasive adenocarcinomas with mixed histologic components were classified into five subtypes: lepidic (LEP), acinar (ACN), papillary (PAP), micropapillary (MIP) and solid (SOL). These five histologic subtypes were collapsed into three groups (LEP, ACN/PAP and SOL/MIP). Disease-free survival (DFS) and overall survival (OS) were analyzed to evaluate benefit from ACT in patients with different histologic patterns using the Kaplan-Meier approach and multivariable Cox models., Results: For all stage IB invasive adenocarcinoma patients, SOL/MIP subgroup presented the worst prognosis, and LEP subgroup showed approximately 100 % 5-year survival. ACT was associated with a better DFS (HR, 0.70; 95 % CI 0.51-0.96, p = .026) for all stage IB patients. In SOL/MIP subgroup, patients could benefit from ACT for a significant improved DFS (HR, 0.81; 95 % CI 0.49-1.35; p = .030), but not for OS (HR, 0.39; 95 % CI 0.12-1.30, p = .111). In ACN/PAP subgroup, there was no significant benefit from ACT for both DFS (HR, 0.76; 95 % CI 0.54-1.08, p = .125) and OS (HR, 0.81; 95 % CI 0.49-1.35, p = .421)., Conclusions: SOL/MIP predominant pattern was predictive for ACT benefit for DFS among invasive lung adenocarcinoma patients in stage IB.

Purpose: The correlations between histological, clinical features and prognosis of stage I invasive mucinous adenocarcinoma (IMA) have not been thoroughly studied for its rare incidence. This study aimed to compare the prognosis among IMA with different percentage of mucinous component and the effect of adjuvant chemotherapy on IMA patients., Methods: A total of 145 stage I IMA and 3536 invasive nonmucinous adenocarcinoma patients with R0 resection were included. Based on the percentage of mucinous pattern presented in tumor, IMA were classified into two subgroups: pure mucinous (>90 % invasive mucinous pattern) and mixed mucinous/nonmucinous (≥10 % of each histologic component). Invasive nonmucinous adenocarcinomas were classified into three subgroups: lepidic (LEP), acinar/papillary (ACN/PAP) and solid/micropapillary (SOL/MIP). Disease-free survival (DFS) and overall survival (OS) were assessed and compared among IMA and invasive nonmucinous patients., Results: For IMA patients, DFS (p = 0.003) was worse for mixed mucinous/nonmucinous compared with pure mucinous subgroup, OS (p = 0.514) was not prognostically different between two groups. There were no significant difference for DFS (p = 0.428) and OS (p = 0.232) between IMA and invasive nonmucinous adenocarcinoma. However, statistical significance were seen for DFS (p < 0.001) and OS (p < 0.001) between 5 major histological subgroups: LEP and pure IMA showed excellent prognosis, mixed mucinous/nonmucinous IMA and SOL/MIP subtypes presented the worst prognosis. No significant survival benefit from adjuvant chemotherapy for IMA patients., Conclusions: Mixed mucinous/nonmucinous IMA had a worse DFS compared with pure mucinous. Early stage IMA could not benefit from adjuvant chemotherapy.

The currently adopted staging system for lung cancer is the seventh edition of the TNM staging edited by Union for International Cancer Control (UICC) in January, 2009. In recent years, with the advances of techniques in lung cancer diagnosis and the treatment trends towards precision treatment modalities such as individualized therapy and molecular targeted therapy, the survival and prognosis of lung cancer has been significantly improved. The old staging standard is difficult to satisfy the currentrapidly developing clinical needs. Therefore, the International Lung Cancer Research Society (International Association for the Study of Lung Cancer, IASLC) updated the stage of lung cancer in 2015, and the forthcoming eighth edition of the TNM Classification for Lung Cancer, which will be formally adopted in Jan. 2017, has been published in Journal of Thoracic Oncology. The new staging system has adopted 35 databases from 16 countries, including 94,708 cases treated between 1999 and 2010. The advantages of the new staging lies in its higher prognosis prediction and clinical guidance value.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

Objectives: Primary adenosquamous carcinoma (ASC) of the lung is rare. The current study was a retrospective two-institutional analysis of surgical therapy with respect to the clinicopathological characteristics and prognostic factors associated with ASC of the lung., Methods: The clinical records of patients with pathologically confirmed ASC of the lung treated surgically in two centres between January 2008 and December 2014 were retrospectively reviewed., Results: One hundred and four patients with ASC of the lung after surgical intervention, including 68 males and 36 females were identified. The 5-year overall survival (OS) and disease-free survival (DFS) of all ASC stages were 38.3 and 16.9%, respectively. Patients with N0, N1 and N2 ASC [N0 vs N1 (P = 0.047) and N1 vs N2 (P = 0.028), respectively], or Stage I, II and IIIA ASC [Stage I vs Stage II (P = 0.005) and Stage II vs Stage IIIA (P = 0.016), respectively] had significant differences with respect to OS. Multivariate analysis using a Cox proportional hazards model indicated that the level of serum carbohydrate antigen 12-5 (CA 12-5) (normal vs high level, P = 0.029), TNM stage [Stage I vs Stage IIIA (P < 0.001), Stage II vs Stage IIIA (P = 0.001)] and adjuvant chemotherapy (P = 0.027) were significant factors associated with OS in ASC patients, and TNM stage [Stage I vs Stage IIIA (P < 0.001), Stage II vs Stage IIIA (P = 0.003)] and adjuvant chemotherapy (P < 0.001) were the significant prognostic variables for DFS., Conclusions: Serum CA 12-5 level and TNM status predict the long-term prognosis of resected primary ASC of the lung. Postoperative platinum-based chemotherapy improved survival in patients with ASC., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: With the development of diagnostic techniques, the incidence of multiple pulmonary nodules has increased. The management of multiple primary lung cancer patients based on currently established criteria, however, remains controversial., Methods: Patients who underwent curative operations for bilateral multiple primary lung cancer (BMPLC) based on the Martini-Melamed criterion between January 2001 and June 2014 were reviewed retrospectively., Results: Bilateral lobectomies and lobectomies with contralateral sublobar resections were performed in 39 and 49 patients, respectively. Bilateral sublobar resections were performed in the remaining 13 cases. Overall survival at 3 and 5 years was 84.5% and 75.0%, respectively. The use of a limited resection procedure for the contralateral second nodule in cases with stage I BMPLC did not have a negative effect on the 5-year overall survival (p = 0.752). Postoperative pathologic diagnosis classified by the most advanced TNM stage appeared to present a good correlation with prognosis in patients with BMPLC. Cox multivariate analysis identified the most advanced TNM stage (p = 0.018) and the number of lesions (p = 0.001) as significant predictors of overall survival., Conclusions: The prognosis of patients after bilateral surgical treatment with curative intent for BMPLC was shown to be promising. The use of a limited resection procedure for the contralateral second nodule in cases with stage I BMPLC did not have a negative effect on the 5-year overall survival. Postoperative pathologic diagnosis classified by the most advanced TNM had a good correlation with prognosis in patients with BMPLC., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A 61-year-old man had experienced an irritating cough for 1 month. He received a diagnosis of lung adenocarcinoma by bronchoscopy. Computed tomography showed a mass in the left hilum and mediastinal lymph node enlargement. After two cycles of neoadjuvant chemotherapy, the patient underwent a robotic assisted atypical sleeve lobectomy (left lower lobe + S4+5). The patient's postoperative course was uneventful, and he was discharged on the tenth postoperative day. This is the first description of the feasibility of robotic extended sleeve lobectomy for a lung cancer patient receiving neoadjuvant chemotherapy., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignancies. In this study, we analyzed the global expression profile of miR-181 in non-small cell lung cancer (NSCLC), as its participation in some other types of cancer has been suggested by previous reports. We found that miR-181 was downregulated both in NSCLC tissues and cell lines. Overexpression of miR-181 evidently inhibited A549 cell proliferation, migration, and invasion and promotes cell apoptosis. Moreover, we also found miR-181 reduction was associated with increased Bcl-2 levels and miR-181 was further suggested to exert its pro-apoptotic function mainly through targeting Bcl-2 expression. Taken together, our study implicates important roles of miR-181 in lung cancer pathogenesis and implicates its potential application in cancer therapy.

Lung cancer is a leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) constitutes ~85% of lung cancers. However, the mechanisms underlying the progression of NSCLC remain unclear. In this study, we found the mRNA and protein expression levels of integrin αv are both increased in NSCLC tissues compared to healthy ones, which indicates that integrin αv may play an important role in NSCLC progression. To further investigate the roles of integrin αv in NSCLC, we overexpressed the integrin αv gene in the NSCLC cell line A549, and found that the cell proliferative ability increased. The apoptosis of A549 cells was inhibited with overexpression of integrin αv. To elucidate the molecular mechanism underlying the role of integrin αv in promoting NSCLC progression, we studied the expression of proteins from a number of important pathways associated with tumorigenesis, and found that the extracellular signal regulated protein kinase (ERK)1/2 signaling pathway may be involved in the mediation of the observed integrin αv effects. component of an important pathway for tumorigenesis, the ERK 1/2. Following inhibition of ERK 1/2 signaling, the proliferation of A549 cells induced by integrin αv was reduced, while the inhibition of apoptosis was attenuated. Our findings demonstrate that integrin αv promotes the proliferation of the human lung cancer cell line A549 by activating the ERK 1/2 signaling pathway, which suggests that this pathway may be a promising target for the treatment of human lung cancer.

Mediator complex subunit MED23 has been reported to facilitate the transformation induced by oncogenic Ras in non-small-cell lung carcinoma (NSCLC). However, the expression pattern and biological functions of MED23 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of MED23 was significantly upregulated in NSCLC samples compared to their adjacent normal tissues. Moreover, in the biological function studies, overexpression of MED23 was further validated to promote the growth, migration, and metastasis of NSCLC cells, while knockdown of the expression of MED23 inhibited the growth, migration, and metastasis of NSCLC cells in vitro and in vivo. Mechanistically, MED23 was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that MED23 played an oncogenic role in the progression of NSCLC and that MED23 might be a promising target for the treatment of NSCLC.

Biomarker discovery is of great importance in diagnosis and treatment of diseases. In present study, a number of differentially expressed genes (DEGs) were identified for lung adenocarcinoma via comparative analysis of gene expression data. A gene expression core signature was generated for four types of lung adenocarcinoma (EGFR-mutated, KRAS-mutated, ALK-mutated and triple-negative adenocarcinoma). Functional enrichment analysis with DAVID tools revealed that up-regulated genes were mainly associated with cell cycle while down-regulated genes were mainly involved in vasculature development and cell adhesion. Then it was used to retrieve relevant small molecule drugs with Connectivity map and trichostatin A was predicted to be the top candidate drug for treatment of lung cancer. Network clustering was performed with MCL in cytoscape to identify sub-networks and several hub genes were obtained: CDC25C, ICT1, TK1 and EZH2. These genes play important roles in the progression of lung cancer and some have been suggested as potential biomarkers. Therefore, our findings are beneficial in deepening the understandings about the pathogenesis and providing directions for future researches.

Objectives: The aim of this study was to analyse the early and long-term results of completion pneumonectomy (CP)., Methods: A retrospective review of consecutive patients who underwent CP in the Shanghai Chest Hospital., Results: Fifty-six CP were performed between January 2003 and July 2013. There were 45 conventional CP (CCP) and 11 rescue CP (RCP) cases. CCP was defined as resection of the remaining lung because of the occurrence of new lesions in patients with previous lung resection. RCP was defined as resection of the remaining lung because of severe complication after primary lung surgery. The mortality and morbidity rates of CCP were 4.4 and 33.3%, respectively. For CCP, the morbidity was significantly higher in benign cases than in malignant cases (80.0 vs 27.5%, P = 0.04). The mortality and morbidity rates of RCP were 27.3 and 90.9%, respectively. For RCP, advanced age (P = 0.046) and preoperative mechanical ventilation (P = 0.03) were related to higher postoperative mortality. The overall 5-year survival rate was 80% for benign cases, whereas for lung malignancy cases, it was 30%. Survival varied (median 60.0 vs 35.0 vs 10.0 months, I vs II vs III, P < 0.01) for different TNM stages and was better for a time interval (between primary surgery and occurrence of lesion) of >2 years (median 60.0 vs 18.0 months, P < 0.01)., Conclusions: CP was an operation with high risk, especially for RCP. Advanced age and mechanical ventilation before the operation were related to higher mortality in RCP. CCP of benign cases was related to higher postoperative risk, but with good survival. For lung malignancy, survival was better for a time interval (between primary surgery and occurrence of lesion) of >2 years., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

PHF8 is a JmjC domain-containing protein and erases repressive histone marks including H4K20me1 and H3K9me1/2. It binds to H3K4me3, an active histone mark usually located at transcription start sites (TSSs), through its plant homeo-domain, and is thus recruited and enriched in gene promoters. PHF8 is involved in the development of several types of cancer, including leukemia, prostate cancer, and esophageal squamous cell carcinoma. Herein we report that PHF8 is an oncogenic protein in human non-small cell lung cancer (NSCLC). PHF8 is up-regulated in human NSCLC tissues, and high PHF8 expression predicts poor survival. Our in vitro and in vivo evidence demonstrate that PHF8 regulates lung cancer cell proliferation and cellular transformation. We found that PHF8 knockdown induces DNA damage and apoptosis in lung cancer cells. PHF8 promotes miR-21 expression in human lung cancer, and miR-21 knockdown blocks the effects of PHF8 on proliferation and apoptosis of lung cancer cells. In summary, PHF8 promotes lung cancer cell growth and survival by regulating miR-21., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pulmonary benign metastasizing leiomyoma (PBML) is a rare and often to be misdiagnosed disease. In this study, we want to investigate the diseased of the clinicopathological characteristics, diagnosis, treatment and prognosis. The retrospective analysis were performed on the clinicopathological data of 5 patients with PBML. All 5 cases were female, mean age 46.8 years old, and were found with single nodule. One case was found with left kidney metastasis. Surgical procedures includes: VATS biopsy (3 cases), resection of superior lobe of left lung (1 case), resection of superior lobe of right lung and wedge resection of middle and inferior lobe of right lung (1 case). The residual nodules in lung were stable in all cases with followup 3-48 mo. PBML is dominated occurring in females with history of uterine leiomyoma, preferential to metastasize to lung, and surgery is the primary therapy. Since it is hormone dependent, hormonal therapy may be suggested in these patients.

Lung cancer is the most common cause of death from cancer worldwide and recent studies have revealed that microRNAs play critical roles to regulate lung carcinogenesis. Here we present evidence to show the role of miR-198 in lung cancer development. Our results showed that ectopic expression of miR-198 inhibits the viability and induces the apoptosis of human non-small cell lung cancer cells A549 and NCI-H460, while miR-198 inhibition resulted in opposite changes. In nude mice miR-198 inhibits A549 growth of tumor graft. We further demonstrated that miR-198 directly targets fibroblast growth factor receptor 1 (FGFR1) in lung cancer cells. Restoring FGFR1 expression blocked the inhibitory function of miR-198, while FGFR1 inhibition achieved the similar phenotypes of miR-198 overexpression. Hence, our data delineates the molecular pathway by which miR-198 inhibits lung cancer cellular proliferation and induces apoptosis, and may have important implication for the treatment of lung carcinogenesis., (© 2013 Wiley Periodicals, Inc.)

Background: To identify patients in whom systematic lymph node dissection would be suitable, preoperative diagnosis of the biological invasiveness of lung adenocarcinomas through the classification of these T1aN0M0 lung adenocarcinomas into several subgroups may be warranted. In this retrospective study, we sought to determine predictive factors of lymph node status in clinical stage T1aN0M0 lung adenocarcinomas., Methods: We retrospectively reviewed the records of 273 consecutive patients undergone surgical resection of clinical stage T1aN0M0 lung adenocarcinomas at Shanghai Chest Hospital, from January 2011 to December 2012. Preoperative computed tomography findings of all 273 patients were reviewed and their tumors categorized as pure GGO, GGO with minimal solid components (<5 mm), part-solid (solid parts >5 mm), or purely solid. Relevant clinicopathologic features were investigated to identify predictors of hilar or mediastinal lymph node metastasis using univariate or multiple variable analysis., Results: Among the 273 eligible clinical stage T1aN0M0 lung adenocarcinomas examined on thin-section CT, 103 (37.7%) were pure GGO, 118 (43.2%) GGO with minimal solid components, 13 (4.8%) part-solid (solid parts >5 mm, five GGO predominant and eight solid predominant), and 39 (14.3%) pure solid. There were 18 (6.6%) patients with lymph node metastasis. Incidence of N1 and N2 nodal involvement was 11 (6.6%) and seven (2.6%) patients, respectively. All patients with pure GGO and GGO with minimal solid components (<5 mm) tumors were pathologically staged N0. Multivariate analyses showed that the following factors significantly predicted lymph node metastasis for T1a lung adenocarcinomas: symptoms at presentation, GGO status, and abnormal carcinoembryonic antigen (CEA) titer. Multivariate analyses also showed that the following factors significantly predicted lymph node metastasis for pure solid tumors: air bronchogram sign, tumor size, symptoms at presentation, and abnormal CEA titer., Conclusions: The patients of clinical stage T1aN0M0 lung adenocarcinomas with pure GGO and GGO with minimal solid components tumors were pathologically staged N0 and systematic lymph node dissection should be avoided. But systematic lymph node dissection should be performed for pure solid tumors or part-solid, especially in patients with CEA greater than 5 ng/mL or symptoms at presentation, because of the high possibility of lymph node involvement.

Genome-wide association studies have identified 6p21 as a new lung cancer susceptibility locus in populations of European descent. Since then, the relationship between common variations on 6p21 and lung cancer has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 11 studies involving a total of 36,890 cases and 52,767 controls for three widely studies polymorphisms (rs4324798, rs3117582, and rs9295740) to evaluate its effect on genetic susceptibility for lung cancer. An overall random-effects per-allele odds ratio (OR) of 1.11 (95% confidence interval (CI) 1.04–1.19; P = 0.002) and 1.20 (95% CI 1.14–1.26; P < 10(−5)) was found for the rs4324798 and rs3117582 polymorphism, respectively. Marginal significant associations were also detected for rs9295740 with per-allele OR of 1.09 (95% CI 1.01–1.18; P = 0.03). In the subgroup analysis by ethnicity, significantly increased risks were found for the three polymorphisms among Caucasians. Similar results were also observed using dominant or recessive genetic models. This meta-analysis demonstrated that the three common variations (rs4324798, rs3117582, and rs9295740) on 6p21 are risk factors associated with increased lung cancer susceptibility, but these associations vary in different ethnic populations.

Background: Elderly patients with severe cardiopulmonary and other system dysfunctions are unable to tolerate pulmonary lobectomy. This study aimed to evaluate the risk and efficacy of wedge resection under video-assisted thoracoscopic surgery (VATS) on elderly high-risk patients with stage I peripheral non-small-cell lung cancer (PNSCLC)., Methods: Elderly patients (≥70 years) with suspected PNSCLC were divided into high-risk group and conventional risk group. The high-risk patients confirmed in stage I by the examination of positron emission tomography computed tomography (PET-CT) and the postoperative patients in stage I PNSCLC with negative incisal margin were treated with VATS wedge resection. The conventional risk patients were treated with VATS radical resection and systematic lymphadenectomy. The clinical and pathological data were recorded. The total survival, tumor-free survival, recurrence time and style of patients were followed up., Results: The operative time and blood loss of the VATS wedge resection group (69.4 ± 15.5 min, 52.1 ± 11.2 ml) were significantly less than those of the VATS radical resection group (128 ± 35.5 min, 217.9 ± 87.1 ml). Neither groups had postoperative death. The overall and tumor-free survival rate of the VATS wedge resection group within three years were 66.7% and 60.0%, and those of the VATS radical resection group were 93.8% and 94.1%, without significant difference (P > 0.05). The recurrence rates of the VATS wedge resection group and VATS radical resection group were 14.3% and 3.0%, without significant difference (P > 0.05)., Conclusion: It is safe, minimally invasive and meaningful to perform VATS wedge resection on the elderly high-risk patients with stage I PNSCLC.