Electromagnetic navigational bronchoscopy-directed dye marking for locating pulmonary nodules.

BACKGROUND: Small peripheral pulmonary nodules, which are usually deep-seated with no visual markers on the pleural surface, are often difficult to locate during surgery. At present, CT-guided percutaneous techniques are used to locate pulmonary nodules, but this method has many limitations. Thus, we aimed to evaluate the accuracy and feasibility of electromagnetic navigational bronchoscopy (ENB) with pleural dye to locate small peripheral pulmonary nodules before video-associated thoracic surgery (VATS). METHODS: The ENB localisation procedure was performed under general anaesthesia in an operating room. Once the locatable guide wire, covered with a sheath, reached the ideal location, it was withdrawn and 0.2-1.0 mL of methylene blue/indocyanine green was injected through the guide sheath. Thereafter, 20-60 mL of air was instilled to disperse the dye to the pleura near the nodules. VATS was then performed immediately. RESULTS: Study subjects included 25 patients with 28 nodules. The mean largest diameter of the pulmonary nodules was 11.8 mm (range, 6.0-24.0 mm), and the mean distance from the nearest pleural surface was 13.4 mm (range, 2.5-34.9 mm). After the ENB-guided localisation procedure was completed, the dye was visualised in 23 nodules (82.1%) using VATS. The average duration of the ENB-guided pleural dye marking procedure was 12.6 min (range, 4-30 min). The resection margins were negative in all malignant nodules. Complications unrelated to the ENB-guided localisation procedure occurred in two patients, including one case of haemorrhage and one case of slow intraoperative heart rate. CONCLUSION: ENB can be used to safely and accurately locate small peripheral pulmonary nodules and guide surgical resection. TRIAL REGISTRATION NUMBER: ChiCTR1900021963.

Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study.

BACKGROUND: Supraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression. RESULTS: Two hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7-13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3-13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71-4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40-0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25-0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS. CONCLUSIONS: SCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.

Potential biomarker for checkpoint blockade immunotherapy and treatment strategy.

Programmed cell death protein-1 (PD-1) and ligand (PD-L1) provide an important escape mechanism from immune attack, and blockade therapy of these proteins show promising clinical benefits in many types of cancer. PD-L1 can be induced by interferon-gamma (IFN-γ), hypoxia, or toll-like receptor (TLR)-mediated pathways that confer adaptive immune resistance, or upregulated by oncogenic signals leading to constitutive expression and resulting in intrinsic immune resistance. The PD-1/PD-L1 checkpoint blockade, which targets regulatory pathways in T cells to overcome immune resistance, is correlated to PD-L1 expression pattern and the presence of tumor-infiltrating lymphocytes (TILs). Meanwhile, immunogenic mutation loads show significant response to checkpoint blockade, which is probably due to PD-1/L1 status and TIL content. Finally, the clinical strategies to design effective checkpoint-targeting immunotherapies are based on the classification of inducible/constitutive expression of PD-L1 and the presence of TILs.

A lobe-specific lymphadenectomy protocol for solitary pulmonary nodules in non-small cell lung cancer.

BACKGROUND: We want to establish a lobe-specific mediastinal lymphadenectomy protocol for solitary pulmonary nodules (SPNs) in non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed 401 patients with pathological diagnoses of NSCLC who underwent lobectomy, bilobectomy, or pneumonectomy with systematic lymphadenectomy from March 2004 to June 2011 in our hospital. All of the patients enrolled had a SPN preoperatively. Information about the primary tumor location, lymph node metastasis, and other baseline data were collected. Stepwise logistic regression was used to identify the key factors indicating non-regional mediastinal lymph node metastases (NRM). RESULTS: Of the primary tumors, 117, 39, 74, 104, and 67 were in the right upper lung (RUL), right middle lung (RML), right lower lung (RLL), left upper lung (LUL), and left lower lung (LLL), respectively. Stepwise regression showed that #2,4, #10,11, and #10,11 as well as #7 was the key lymph node station for RUL, LUL, and lower lobes: #2,4 [odds ratio (OR)=28.000, 95% confidence interval (CI): 2.917-268.790, P=0.004] for RUL, #10,11 (OR=31.667, 95% CI: 2.502-400.833, P=0.008) for LUL, #10,11 (OR=19.540, 95% CI: 4.217-90.541, P<0.001) and #7 (OR=7.395, 95% CI: 1.586-34.484, P=0.011) for lower lobes, respectively. Patients with tumors >2 cm rarely had NRM without primary regional mediastinal involvement. CONCLUSIONS: With rigid consideration, a lobe-specific lymphadenectomy is feasible in practice. This protocol can be used when the lobe-specific key nodes are negative in intraoperative frozen sections, especially for NSCLC diagnosed as SPN <2 cm preoperatively.

Single nucleotide polymorphisms of MAGE-A3 gene and its clinical implications in Chinese patients with non-small cell lung cancer (NSCLC).

BACKGROUND: Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism (SNP) loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors. METHODS: Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR mRNA expression were detected by qRT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors. RESULTS: Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC (0.681)/CT (0.319), CC (0.660)/CG (0.340), CC (0.681)/CA (0.319), AA (0.984)/AT (0.016) and GG (1.000)/GA (0.000), respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mRNA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients. CONCLUSIONS: Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR mRNA expression levels and helpful to the selection of patients for epidermal growth factor receptor (EGFR) targeted immunotherapy.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. Conclusions and Relevance: The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial.

EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously; 2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase). Objective response rate (ORR), complete pathologic response (pCR), PFS, and overall survival (OS) were assessed along with safety. Post hoc analysis was performed for subsequent treatments after disease recurrence. Among investigated 72 patients (erlotinib, n = 37; GC, n = 35), the median follow-up was 62.5 months. The median OS was 42.2 months (erlotinib) and 36.9 months (GC) (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.47-1.47; p = 0.513). The 3- and 5-year OS rates were 58.6% and 40.8% with erlotinib and 55.9% and 27.6% with GC (p3-y = 0.819, p5-y = 0.252). Subsequent treatment was administered in 71.9% and 81.8% of patients receiving erlotinib and GC, respectively; targeted therapy contributed mostly to OS (HR, 0.35; 95% CI, 0.18-0.70). After disease progression, the ORR was 53.3%, and the median PFS was 10.9 months during the EGFR-TKI rechallenge. During postoperative therapy, grade 3 or 4 adverse events (AEs) were 13.5% in the erlotinib group and 29.4% in the GC group. No serious adverse events were observed. Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study.

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab-chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA-IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9-81.0%). For patients with ctDNA- vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Nedaplatin/Gemcitabine Versus Carboplatin/Gemcitabine in Treatment of Advanced Non-small Cell Lung Cancer: A Randomized Clinical Trial.

OBJECTIVE: To evaluate the efficacy and safety of nedaplatin/gemcitabine (NG) and carboplatin/gemcitabine (CG) in the management of untreated advanced non-small cell lung cancer (NSCLC). METHODS: Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm (n=30) and the CG arm (n=32). Only patients (24 and 25 in the NG and CG arms, respectively) who completed ≥2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate (ORR). The secondary outcome measures included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: There were no statistically significant differences in the efficacy measures (ORR, P=0.305; median PFS, P=0.198; median OS, P=0.961) or in the major adverse events (grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.212) between the two treatment arms. However, there was a trend towards higher ORR (37.5% vs. 24.0%), longer PFS (6.0 vs. 5.0 months), and less adverse events in the NG arm. CONCLUSION: NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.

Genetic Profiling of Cell-Free DNA From Pleural Effusion in Advanced Lung Cancer as a Surrogate for Tumor Tissue and Revealed Additional Clinical Actionable Targets.

BACKGROUND: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. METHOD: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1PE-sDNA. RESULT: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. CONCLUSION: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.

PD-1/PD-L1 combined with LAG3 is associated with clinical activity of immune checkpoint inhibitors in metastatic primary pulmonary lymphoepithelioma-like carcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is an Epstein-Barr virus (EBV)-related, rare subtype of non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) show durable responses in advanced NSCLC. However, their effects and predictive biomarkers in PLELC remain poorly understood. We retrospectively analyzed the data of 48 metastatic PLELC patients treated with ICI. Pretreated paraffin-embedded specimens (n = 19) were stained for PD-1, PD-L1, LAG3, TIM3, CD3, CD4, CD8, CD68, FOXP3, and cytokeratin (CK) by multiple immunohistochemistry (mIHC). Next-generation sequencing was performed for 33 PLELC samples. Among patients treated with ICI monotherapy (n = 30), the objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and overall survival (mOS) were 13.3%, 80.0%, 7.7 months, and 24.9 months, respectively. Patients with PD-L1 ≥1% showed a longer PFS (8.4 vs. 2.1 months, p = 0.015) relative to those with PD-L1 <1%. Among patients treated with ICI combination therapy (n = 18), ORR, DCR, mPFS, and mOS were 27.8%, 100.0%, 10.1 months, and 19.7 months, respectively. Patients with PD-L1 ≥1% showed a significantly superior OS than those with PD-L1 <1% (NA versus 11.7 months, p = 0.001). Among the 19 mIHC patients, those with high PD-1/PD-L1 and LAG3 expression showed a longer PFS (19.0 vs. 3.9 months, p = 0.003). ICI also showed promising efficacy for treating metastatic PLELC. PD-L1 may be both predictive of ICI treatment efficacy and prognostic for survival in PLELC. PD-1/PD-L1 combined with LAG3 may serve as a predictor of ICI treatment effectiveness in PLELC. Larger and prospective trials are warranted to validate both ICI activity and predictive biomarkers in PLELC. This study was partly presented as a poster at the IASLC 20th World Conference on Lung Cancer 2019, 7-10 September 2019, Barcelona, Spain.

Deep learning-based growth prediction for sub-solid pulmonary nodules on CT images.

Background: Estimating the growth of pulmonary sub-solid nodules (SSNs) is crucial to the successful management of them during follow-up periods. The purpose of this study is to (1) investigate the measurement sensitivity of diameter, volume, and mass of SSNs for identifying growth and (2) seek to establish a deep learning-based model to predict the growth of SSNs. Methods: A total of 2,523 patients underwent at least 2-year examination records retrospectively collected with sub-solid nodules. A total of 2,358 patients with 3,120 SSNs from the NLST dataset were randomly divided into training and validation sets. Patients from the Yibicom Health Management Center and Guangdong Provincial People's Hospital were collected as an external test set (165 patients with 213 SSN). Trained models based on LUNA16 and Lndb19 datasets were employed to automatically obtain the diameter, volume, and mass of SSNs. Then, the increase rate in measurements between cancer and non-cancer groups was studied to evaluate the most appropriate way to identify growth-associated lung cancer. Further, according to the selected measurement, all SSNs were classified into two groups: growth and non-growth. Based on the data, the deep learning-based model (SiamModel) and radiomics model were developed and verified. Results: The double time of diameter, volume, and mass were 711 vs. 963 days (P = 0.20), 552 vs. 621 days (P = 0.04) and 488 vs. 623 days (P< 0.001) in the cancer and non-cancer groups, respectively. Our proposed SiamModel performed better than the radiomics model in both the NLST validation set and external test set, with an AUC of 0.858 (95% CI 0.786-0.921) and 0.760 (95% CI 0.646-0.857) in the validation set and 0.862 (95% CI 0.789-0.927) and 0.681 (95% CI 0.506-0.841) in the external test set, respectively. Furthermore, our SiamModel could use the data from first-time CT to predict the growth of SSNs, with an AUC of 0.855 (95% CI 0.793-0.908) in the NLST validation set and 0.821 (95% CI 0.725-0.904) in the external test set. Conclusion: Mass increase rate can reflect more sensitively the growth of SSNs associated with lung cancer than diameter and volume increase rates. A deep learning-based model has a great potential to predict the growth of SSNs.

Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer.

The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. SIGNIFICANCE: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599.

Randomized Trial of an Improved Drainage Strategy Versus Routine Chest Tube After Lung Wedge Resection.

BACKGROUND: Patients undergoing thoracic lung wedge resection could benefit from tubeless strategies. However, postoperative pneumothorax is a primary limiting factor for such strategies. Accordingly, we evaluated the safety and efficacy of the prophylactic use of an air-extraction catheter as an improved drainage strategy and compared the findings with those for chest tube drainage in patients undergoing thoracic wedge resection. METHODS: Patients undergoing thoracic wedge resection between August 2017 and October 2018 were enrolled in this single-center, randomized, open-label, noninferiority trial. Patients who received an improved drainage strategy involving the use of a prophylactic air-extraction catheter were randomized to the intervention group, whereas those who underwent routine chest tube drainage were assigned to the control group. Analysis was based on the per-protocol population. The primary outcome was the incidence of pneumothorax on postoperative day 1. Secondary outcomes included patient recovery and related complications, including pleural effusion, lung infection, numeric rating scale score for pain, postoperative chest tube or catheter removal, postoperative hospitalization, and chest tube reinsertion. RESULTS: A total of 96 patients were randomized. Baseline demographic and clinical characteristics were similar between groups. The incidence of pneumothorax in the intervention and control groups was 10.0% and 9.1%, respectively (noninferiority, P = 1.00). In addition, there were no significant between-group differences in secondary outcomes. A significantly lower pain score was observed in the intervention group (P = .001). CONCLUSIONS: The improved drainage strategy is not inferior to standard chest tube drainage after thoracic wedge resection and should be popularized.

Plasma extracellular vesicle microRNAs for pulmonary ground-glass nodules.

In this study, we evaluated the diagnostic value and molecular characteristics of plasma extracellular vesicles (EVs)-derived miRNAs for patients with solitary pulmonary nodules (SPNs), particularly ground-glass nodules (GGNs). This study was registered at www.clinicaltrials.gov under registration number NCT03230019. Small RNA sequencing was performed to assess plasma EVs miRNAs in 59 patients, including 12 patients with benign nodules (2017, training set). MiRNA profiles of 40 an additional individuals were sequenced (2018, validation set). Overall, 16 pure GGNs, 21 mixed GGNs, and 42 solid nodules were included, with paired post-operative plasma samples available for 20 patients. The target miRNA/reference miRNA ratio was used to construct a support vector machine (SVM) model. The SVM model with the best specificity showed 100% specificity in both the training and validation sets independently. The model with the best sensitivity showed 100% and 96.9% sensitivity in the training and validation sets, respectively. Principal component analysis revealed that pure GGN distributions were distinct from those of solid nodules, and mixed GGNs had a diffuse distribution. Among differentially expressed miRNAs, miR-500a-3p, miR-501-3p, and miR-502-3p were upregulated in tumor tissues and enhanced overall survival. The SVM classifier accurately distinguished malignant GGNs and benign nodules. The distinct profile characteristics of miRNAs provided insights into the feasibility of EVs miRNAs as prognostic factors in lung cancer.

Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study.

PURPOSE: To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non-small-cell lung cancer. PATIENTS AND METHODS: This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non-small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS: Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments. CONCLUSION: The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

[Clinicopathologic study of pulmonary adenocarcinoma with features of bronchioloalveolar carcinoma].

OBJECTIVE: Further investigation on the incidence and clinicopathologic features of bronchioloalveolar carcinomas (BAC) including: (1) BAC of strictly defined, (2) adenocarcinoma with bronchioloalveolar features, (3) other different histologic subtypes of lung adenocarcinomas. METHODS: Surgical specimens from 348 lung adenocarcinoma patients admitted in that hospital between 1998 - 2005 were included. And clinical data were collected at the same time. Patients of strictly defined BAC, BAC with focal invasion (BWFI), and adenomas with bronchioloalveolar features (AWBF) were followed-up. Data were analyzed using SPSS statistics software and Kaplan-Meier survival curves were constructed. RESULTS: The resected lung adenocarcinomas consisted of different histologic subtypes. The most frequent one was adenocarcinoma of mixed subtypes (78.2%, 272/348), followed by the acinar type (8.1%, 28/348), the papillary type (4.0%, 14/348), the BAC (3.7%, 13/348), the mucinous (colloid) type (3.4%, 12/348) and the solid types (2.3%, 8/348). The fetal adenocarcinoma was the least component detected. There was no significant difference on the survival curves between groups BAC and BWFI. The survival rate of patients with AWBF was poorer than that of BAC and BWFI. CONCLUSIONS: Since patients with strictly defined (simple) BAC, BWFI, and AWBF have their own distinct clinicopathologic features and prognosis respectively, they should be strictly distinguished from other types of pulmonary adenocarcinomas.

Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells Define the Response of Different Subsets of Non-Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy.

INTRODUCTION: Inhibition of programmed cell death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1 expression in tumor cells with treatment outcomes has been reported in many pivotal trials; however, the relationship remains unclear. Here, we demonstrate that those patients with both high density of PD-1-positive CD8 and PD-L1-positive CD4-positive CD25-positive (PD-1hi PD-L1hi) regulatory T cells (Tregs) have a better response to PD1/PD-L1 blockade. METHODS: In our study between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood samples and fresh tumor specimens were collected for study. Of these, 42 large (10-mm3) fresh tumor specimens were obtained from surgical procedures and checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4, and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small biopsy specimens from patients who received immunotherapy (pembrolizumab or nivolumab) were analyzed by immunohistochemistry and IF. The correlation between flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank correlation test; the primary end point was progression-free survival. For the PD-1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells were cultured (1×105 per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by anti-PD-1 and anti-PD-L1 was measured by a conventional 51Cr release assay. RESULTS: We first identified a population of high-PD-L1-expressing CD25-positive CD4-positive T cells (PD-L1hi Tregs) in the tumor microenvironment. The frequency of PD-L1hi Tregs was higher in tumor tissue (mean 48.6 ± 14.3% in CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 ± 10.2% in CD25-positive CD3-positive CD4-positive T cells) and normal tissue (mean 38.6 ± 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as determined by flow cytometry. The frequency of PD-L1hi Tregs was positively correlated with PD-1-positive CD8 in Tregs. In addition, the TILs from these patients (PD-1hi PD-L1hi) showed PD-1/PD-L1 pathway dependence and could induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The patients with PD-L1-positive NSCLC with PD-1hi PD-L1hi TILs showed a better clinical outcome than those with a low frequency of PD-1hi CD8 or PD-L1hi Tregs (median progression-free survival not reached versus 2 months). CONCLUSIONS: Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC.