This study aims to identify patient subgroups who benefit more from perioperative immunotherapy combined with chemotherapy (IO-CT) based on clinical and molecular characteristics in resectable non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on perioperative IO-CT were searched. Beneficial differences of IO-CT regimens across different patient subgroups were assessed by pooling trial-specific ratios in event-free survival (EFS), overall survival (OS), pathological complete response (pCR), and major pathological response (MPR). Six studies (n = 3003) involving five IO-CT regimens were included. Compared to CT alone, all IO-CT regimens significantly improved EFS, OS, MPR, and pCR, but increased toxicity. Toripa-chemo showed the best EFS and nivo-chemo showed the best OS. Patients with PD-L1 ≥ 1

Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC.

BACKGROUND:This study was aimed to establish a prediction model for spread through air spaces (STAS) in early-stage non-small cell lung cancer based on imaging and genomic features. METHODS:We retrospectively collected 204 patients (47 STAS+ and 157 STAS-) with non-small cell lung cancer who underwent surgical treatment in the Jinling Hospital from January 2021 to December 2021. Their preoperative CT images, genetic testing data (including next-generation sequencing data from other hospitals), and clinical data were collected. Patients were randomly divided into training and testing cohorts (7:3). RESULTS:The study included a total of 204 eligible patients. STAS were found in 47 (23.0%) patients, and no STAS were found in 157 (77.0%) patients. The receiver operating characteristic curve showed that radiomics model, clinical genomics model, and mixed model had good predictive performance (area under the curve [AUC] = 0.85; AUC = 0.70; AUC = 0.85). CONCLUSIONS:The prediction model based on radiomics and genomics features has a good prediction performance for STAS.

Objectives: Several randomized controlled trials (RCTs) indicated that first-line programmed cell death protein-1/death-ligand 1 inhibitors plus chemotherapy (PD-1/PD-L1 + chemo) led to survival benefits in extensive-stage small-cell lung cancer (ES-SCLC) compared with platinum-based chemotherapy. This study aims to identify the optimal PD-1/PD-L1 + chemo combination strategy. Methods: We included RCTs comparing PD-1/ PD-L1 + chemo versus chemo alone in ES-SCLC. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ⩾3 treatment-related adverse events were considered. Odds ratios (ORs), hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted. Results: Six RCTs with 2600 patients were analyzed in this Bayesian network meta-analysis. Results showed that adding PD-1/PD-L1 inhibitors to chemotherapy led to significant benefits in OS (HR = 0.72, 95% CI: 0.66–0.79), PFS (HR = 0.69, 95% CI: 0.63–0.75), and ORR (OR = 1.32, 95% CI: 1.12–1.56), and no differences in toxicity were found (OR = 1.09, 95% CI: 0.92–1.30). Serplulimab plus chemotherapy was found to provide the best OS (HR = 0.63, 95% CI: 0.49–0.82), the best PFS (HR = 0.47, 95% CI: 0.38–0.59), and the best ORR (OR = 1.7, 95% CI: 1.15–2.53). Moreover, although there were no difference between PD-L1 + chemo and PD-1 + chemo regarding OS (HR = 0.99, 95% CI: 0.91–1.08) and ORR (OR = 1.27, 95% CI: 0.91–1.78), PD-1 + chemo showed a significant benefit in PFS (HR = 0.82, 95% CI: 0.68–0.98) compared with PD-L1 + chemo. Conclusions: Serplulimab plus chemotherapy seems to be superior first-line immunotherapy combination for patients with ES-SCLC. PD-1 + chemo seems to outperform PD-L1 + chemo in PFS.

In view of the success of targeted therapy in the field of advanced lung cancer, it is gradually pushed further to neoadjuvant therapy. Alectinib has been recommended for advanced anaplastic lymphoma kinase (ALK) + non-small cell lung cancer (NSCLC) in first-line therapy. Here, we report two cases of neoadjuvant alectinib in locally advanced lung adenocarcinoma with ALK rearrangement. Case 1 was a 64-year-old man with no history of smoking who was diagnosed with the clinical stage as IIIB, with ALK fusion-positive. Chest-enhanced computed tomography (CT) revealed marked regression and achieved partial response (PR) incorporated with grade 3 interstitial pneumonia after 44 days of alectinib neoadjuvant therapy. Interstitial pneumonia improved after methylprednisolone therapy, then thoracoscopic lobe resection with lymph node dissection was performed with blood loss. The pathological assessment was a pathologic complete response(pCR). Case 2 was a 66-year-old man who had a routine physical examination and then diagnosed with a clinical-stage IIIB by CT-guided percutaneous cutting needle biopsy (PCNB). Chemotherapy with 1 cycle of pemetrexed combined with nedaplatin was performed in the interval waiting for next-generation sequencing (NGS) results. NGS testing revealed an EML4-ALK fusion mutation. After 109 days of alectinib treatment, radiographic evaluation was classified as PR and then he underwent thoracoscopic upper lobectomy smoothly with pathological assessment as a major pathological response (MPR). To date, neoadjuvant alectinib has only been reported in a few cases in locally advanced lung adenocarcinoma with ALK-rearranged. Neoadjuvant alectinib may be feasible in locally advanced disease for complete resection. The duration and safety of neoadjuvant therapy with alectinib still need further study.

Two-sided p-values were used, and statistical significance was defined as p < 0.05.Subgroup analysis Subgroup analyses were conducted based on predetermined factors, including PD-L1 expression level, disease stage at baseline, and histology. Sensitivity analysis Sensitivity analysis wasperformed by sequentially excluding one study at a time to validate the results of the meta-analysis.Country(ies) involved China.

BACKGROUND:Despite major advances in cancer therapeutics, the therapeutic options of Lung Squamous Cell Carcinoma (LSCC)-specific remain limited. Furthermore, the current staging system is imperfect for defining a prognosis and guiding treatment due to its simplicity and heterogeneity. We sought to develop prognostic decision tools for individualized survival prediction and treatment optimization in elderly patients with LSCC.METHODS:Clinical data of 4564 patients (stageIB-IIIB) diagnosed from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database for prognostic nomograms development. The proposed models were externally validated using a separate group consisting of 1299 patients (stage IB-IIIB) diagnosed from 2012-2015 in China. The prognostic performance was measured using the concordance index (C-index), calibration curves, the average time-dependent area under the receiver operator characteristic curves (AUC), and decision curve analysis.RESULTS:Eleven candidate prognostic variables were identified by the univariable and multivariable Cox regression analysis. The calibration curves showed satisfactory agreement between the actual and nomogram-estimated Lung Cancer-Specific Survival (LCSS) rates. By calculating the c-indices and average AUC, our nomograms presented a higher prognostic accuracy than the current staging system. Clinical usefulness was revealed by the decision curve analysis. User-friendly online decision tools integrating proposed nomograms were created to estimate survival for patients with different treatment regimens.CONCLUSIONS:The decision tools for individualized survival prediction and treatment optimization might facilitate clinicians with decision-making, medical teaching, and experimental design. Online tools are expected to be integrated into clinical practice by using the freely available website ( https://loyal-brand-611803.framer.app/ ).

Distinguishing between N6-methyladenosine (m6A)-associated long noncoding RNAs (lncRNAs) is crucial in non-small-cell lung cancer (NSCLC) patients. In this research, the prognosis and immunotherapeutic response of lncRNAs and m6A in NSCLC were examined. lncRNAs related to m6A were identified using co-expression analyses, and their prognostic impact on patients with NSCLC was assessed using univariate Cox regression analysis. Sixty-three m6A-associated lncRNAs were determined as prognostic lncRNAs, and on this basis, 25 m6A-associated lncRNAs were screened by least absolute shrinkage and selection operator (lasso) Cox regression. Multivariable Cox analysis obtained 14 m6A-associated lncRNAs for the construction of risk model. The NSCLC patients were grouped into different risk subgroups in accordance with the median of the risk fraction in each data, and we evaluated the differences of potential immunotherapeutic characteristics and drug sensitivity prediction between the two subgroups. By using this model to recombine patients, they can be effectively distinguished in terms of the immunotherapy response. Furthermore, candidate compounds for the differentiation of NSCLC subtypes were identified. The model based on 14 m6A-associated lncRNAs is a promising prognostic biomarker, which may help to predict the efficacy of immunotherapy in NSCLC patients and provide a theoretical basis for improving the outcome of patients.

Background Currently, immunotherapy is widely used in the treatment of various stages of non-small cell lung cancer. According to clinical experience and results of previous studies, immunotherapy as neoadjuvant therapy seems to exhibit better efficacy against early resectable non-small cell lung cancer as compared to advanced lung cancer, which is often defined as unresectable non-small cell lung cancer. However, this observation has not been established in clinical studies. This systematic review aimed to evaluate the efficacy of immunotherapy in early and late lung cancer, wherein objective response rate (ORR) and disease control rate (DCR) were used as evaluation indexes. The present study also evaluated the safety of immunotherapy in early and late lung cancer, wherein the rate of treatment-related adverse reactions (TRAEs) was used as an indicator. Methods Electronica databases, including PubMed, Cochrane Library, Embase, and other databases, were searched to identify relevant studies. Besides this, all the available reviews, abstracts, and meeting reports from the main international lung cancer meetings were searched manually. ORR, DCR, and TRAEs were extracted as the primary outcomes. Results A total of 52 randomized controlled trials involving 13,660 patients were shortlisted. It was observed that immunotherapy alone significantly improved DCR in early lung cancer in comparison to advanced lung cancer. Importantly, the improvement in ORR was not to the same extent as reported in the case of advanced lung cancer. The combination of immunotherapy with other therapies, especially immunochemotherapy, significantly improved ORR and DCR in early lung cancer. In terms of safety, immunotherapy either alone or in combination with other therapies exhibited a better safety profile in early lung cancer than in advanced lung cancer. Conclusions Altogether, the benefits of immunotherapy in early lung cancer appeared to be better than those observed in advanced lung cancer, especially with the regard to the regimen of immunotherapy in combination with chemotherapy. In terms of safety, both immunotherapy alone and its combination with chemotherapy were found to be safer in early lung cancer as compared to advanced lung cancer.

Background Immune checkpoint inhibitor (ICI)-based immunotherapy has improved the clinical outcome of non-small cell lung cancer (NSCLC). However, current indicators, such as programmed cell death-ligand 1 (PD-L1) expression in tumors or tumor mutational burden (TMB), are not considered ideal biomarkers for prognosis. Thus, there is an urgent requirement for a comprehensive risk scoring system. Methods In this study, we enrolled 464 NSCLC patients who received ICIs between March 2017 and January 2020 at four clinical centers. Univariate and multivariate (the logistic and the Cox regression) analyses were conducted to screen clinically relevant variables. Significant parameters (P<0.05) including absolute lymphocyte count (ALC, L), Eastern Cooperative Oncology Group Performance Status (ECOG PS, E) and lung/pleural metastasis (M) were selected for LEM score. Weighted values based on odds ratio and hazard ratio of multiple analyses were assigned to each parameter. LEM score was the sum of weighted values of each variable (Good, 0-1; Intermediate, 2-3; Poor, 4-6). Kaplan-Meier curves were used to evaluate the association between LEM score and progression-free survival (PFS). Results In total, 258 patients were pooled and stratified into three risk categories based on the LEM score. Objective response rate (ORR) was significantly higher in the good-risk group compared with the poor-risk group [55.9% vs. 7.3%, odds ratio (OR), 0.023; 95% confidence interval (CI), 0.005–0.099; P<0.001]. Patients with good risk [hazard ratio (HR), 0.130; 95% CI, 0.084–0.203; median PFS, 12.5 months; P<0.001] or intermediate risk (HR, 0.330; 95% CI, 0.222–0.490; median PFS, 4.2 months; P<0.001) had longer PFS than those with poor risk (median PFS, 2.1 months). DNA sequencing was performed in 41 patients [no durable benefit (NDB): n=29; durable clinical benefit (DCB): n=12] and epidermal growth factor receptor (EGFR) mutations were enriched in samples of the NDB group vs. the DCB group (11/29 vs. 1/12; Fisher’s exact P=0.073; OR, 6.722; 95% CI, 0.760–59.479). Additionally, patients with EGFR mutations had higher LEM scores than those with wild-type EGFR. Conclusions In conclusion, the LEM score provided a potential prognostic biomarker for NSCLC patients treated with ICIs.

Abstract Immunotherapy has dramatically altered the treatment of non-small cell lung cancer. Currently, the emergence of combination strategies in immunotherapy has brightened the prospects of improved clinical outcomes and manageable safety profiles in the first/second-line settings. However, sub-optimal response rates are still observed in several clinical trials. Hence, alternative combination models and candidate selection strategies need to be explored. Herein, we have critically reviewed and commented on the published data from several clinical trials, including combined immunotherapy and chemotherapy, anti-angiogenic agents, epidermal growth factor receptor/anaplastic lymphoma kinase tyrosine kinase inhibitors, radiotherapy, and other immune checkpoint inhibitors.

Acute respiratory distress syndrome (ARDS) is characterized by an uncontrollable cytokine storm, which is associated with high mortality due to lack of effective treatment. Regulatory T cells (Tregs) play an indispensable role in maintaining immune homeostasis and CD39 is considered as a functional cell marker of Tregs. In this study, we aimed to evaluate the effect of CD39 + Tregs on acute lung injury (ALI) and investigate the frequency of CD39 + Tregs in ARDS patients. We found that after lipopolysaccharide (LPS) treatment, CD39 −/− mice exhibited more severe inflammation and wild type (WT) mice exhibited a decreased frequency of CD39 + Tregs in the peripheral blood. Furthermore, CD39 + Tregs had a protective effect on LPS-induced inflammation in vitro and the adoptive transfer of CD39 + Tregs had a therapeutic effect on ALI in vivo . We further sought to explore the mechanisms that affect CD39 expression on Tregs. LPS-induced inflammation in the lung impaired the immunosuppressive effect of Tregs via the autophagy-mediated downregulation of CD39. In addition, CD39 induced the expression of itself in Tregs via activating the ERK1/2-FOS pathway. Consistent with this finding, the frequency of CD39 + Tregs was also decreased in the peripheral blood of ARDS patients and was positively correlated with disease severity. Our results suggested that the adoptive transfer of CD39 + Tregs may provide a novel method for the clinical prevention and treatment of ARDS.

Human epidermal growth factor receptor 2 (HER2), as a receptor tyrosine kinase of EGF receptor family, whose mutation is often associated with even if less frequency but poor prognosis and shorter survival in pulmonary malignant tumor. HER2 status include mutation, overexpression, amplification and also some rare genotypes, detected by next generation sequencing (NGS), immunohistochemistry (IHC), and also fluorescence in situ hybridization (FISH). Different genotypes represent different therapeutic targets and indicate different clinical prognosis concluded by previous studies. Unfortunately, no standard guidelines for first-line treatment are widely recognized, and current therapeutic schedules include chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Especially for patients with advanced metastasis, chemotherapy is based as a systemic therapy using studies of breast cancer or EGFR-positive lung adenocarcinoma as a template. Studies already explored treatment including EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and afatinib, and also trastuzumab and its conjugation like HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) and conjugate trastuzumab deruxtecan (T-DXd). Also, he researches explored combination therapy with chemotherapy and TKIs or monoclonal antibodies. This review describes commonly used therapies for HER2-positive/HER2-overexpression patients and general relationship between genotypes of HER2, drug selection and final prognosis in order to provide suggestions for future diagnosis and treatment.

Background: Hemorrhage is the second most common complication of percutaneous transthoracic needle biopsy (PTNB), and at present, there is no effective prevention strategy. Contrast-enhanced computed tomography (CECT) has the advantage of clearly visualizing blood supply within the lesion and aiding in the imaging of blood vessels, which can reduce hemorrhage complicating PTNB. As no large-sample studies were evaluating whether CECT could reduce hemorrhage, we conducted the present retrospective study. Methods: From November 2011 to February 2016, 1,282 biopsies at Jinling Hospital were retrospectively reviewed; 555 underwent CECT, and 727 underwent non-contrast computed tomography (CT). Factors associated with hemorrhage were defined, and hemorrhage rates were compared between the 2 groups. Results: We found that pre-biopsy CECT was associated with a reduced incidence of biopsy-related hemorrhage compared to non-contrast CT (16.4% vs. 23.1%, P=0.003). Propensity score matching (PSM) analysis also showed that the incidence of hemorrhage in the CECT group was lower than that of the non contrast CT group at a ratio of 1:1 (P=0.039), 1:2 (P=0.028), or 1:3 (P=0.013). In the multivariate analysis, CECT before PTNB was found to be significantly associated with a reduced risk of hemorrhage [odds ratio (OR): 0.671, 95% confidence interval (CI): 0.499-0.902, P=0.008]. Puncture position, lesion size, depth of needle tract, and the number of punctures were also found to be associated with hemorrhage (all P<0.05). Conclusions: Compared with non-contrast CT, CECT significantly reduced the risk of post-biopsy pulmonary hemorrhage, which suggests that CECT should be performed before PTNB.

Background Pleural effusion is a common presentation in clinical practice. About 40% of exudative pleural effusion is unable to be diagnosed through thoracentesis, and closed pleural biopsy (CPB) is needed. This study was designed to investigate the diagnostic yield of CPB in exudative pleural effusion. Methods This was a retrospective 10-year study of patients with unexplained exudative pleural effusion who underwent CPB in two centers. Malignant pleural effusion (MPE) was diagnosed when there was histopathological evidence of pleural tissue, pulmonary tissue, or pleural fluid. Tuberculous pleural effusion (TPE) was confirmed when granuloma or coagulative necrosis was observed in pleural tissue, Ziehl-Neelsen acid-fast staining was positive, or adenosine deaminase (ADA) in pleural effusion was higher than 35IU with clinical symptoms of TB orγ-interferon increased with symptoms of TB. Results A total of 644 patients were enrolled, of which 479 were specifically diagnosed (217 patients with TPE and 262 patients with MPE). The sensitivity of CPB in the diagnosis of MPE was 51.5%. Among the pathological types of MPE, lung adenocarcinoma accounted for 77.9% (204/262) of cases, making up the largest proportion. The sensitivity of CPB for diagnosing TPE was 68.7%. Conclusions CPB has a relatively high sensitivity in the diagnosis of exudative pleural fluid, especially in relation to tuberculous lesions. CPB could provide an alternative technique in clinical practice, especially for basic hospital units without thoracoscopy.

Small cell lung cancer (SCLC) is one of the malignant cancers of lung tumors, and hyponatremia, defined as serum sodium concentration (Na+) lower than 135 mmol/L, is the most common complication of solid tumors, with an incidence of up to 18.9% and a negative impact on quality of life in SCLC. As a prognostic index of SCLC, timely monitoring and correcting of hyponatremia is of great clinical significance for prolonging the survival period of patients. In the explore of new drugs for small cell lung cancer, it is necessary to include hyponatremia as an evaluation index in clinical studies. As the occurrence of hyponatremia is sometimes unavoidable owing to SCLC specific neurological characteristics, early monitoring to detect the presence of hyponatremia and timely correction are helpful to improve the prognosis of patients. There are many predisposing factors for hyponatremia, including heterotopia of antidiuretic hormone (ADH), use of platinum-based chemotherapy drugs, and intracranial metastasis, among others. Patients with small cell lung cancer are usually asymptomatic in the early stage, while it is of great significance to find a suitable clinical index to judge whether it is a malignant inducement or not. In the clinical setting, due to different electrolyte levels and therapeutic scheduling for the primary disease, an individualized plan is often made, mainly comprising water restriction, infusion, and medications. This review includes related clinical studies and describes the common symptoms and predisposing factors of hyponatremia in patients with SCLC, and their impact on quality of life and prognosis.

BACKGROUND:Anastomotic leakage (AL), a serious complication after esophagectomy, might impair patient quality of life, prolong hospital stay, and even lead to surgery-related death. The aim of this study was to show a novel decision model based on classification and regression tree (CART) analysis for the prediction of postoperative AL among patients who have undergone esophagectomy. METHODS:A total of 450 patients (training set: 356; test set: 94) with perioperative information were included. A decision tree model was established to identify the predictors of AL in the training set, which was validated in the test set. A receiver operating characteristic curve was also created to illustrate the diagnostic ability of the decision model. RESULTS:A total of 12.2% (55/450) of the 450 patients suffered AL, which was diagnosed at median postoperative day 7 (range: 6-16). The decision tree model, containing surgical duration, postoperative lymphocyte count, and postoperative C-reactive protein to albumin ratio, was established by CART analysis. Among the three variables, the postoperative C-reactive protein to albumin ratio was identified as the most important indicator in the CART model with normalized importance of 100%. According to the results validated in the test set, the sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy of the prediction model were 80%, 98.8%, 88.9%, 97.6%, and 96.8%, respectively. Moreover, the area under the receiver operating characteristic curve was 0.95. CONCLUSION:The decision model based on CART analysis presented good performance for predicting AL, and might allow the early identification of patients at high risk.

Background: Several studies have reported an increased prevalence of Parkinson disease (PD) amongst patients with inflammatory bowel disease (IBD) with conflicting results. We aimed to evaluate the risk of PD in the IBD population by conducting a meta-analysis (MA). Methods: A systematic review with MA of the existing literature was conducted. The main outcome of interest was the incidence of developing PD in patients previously diagnosed with IBD. Results: Four studies were included in this MA. The overall risk of PD in IBD was significantly higher than controls (RR 1.41, 95% c.i. 1.19-1.66). Crohn's disease had a 28% increased risk of PD and ulcerative colitis had a 30% increased risk of PD compared to controls (CD: RR 1.28, 95% c.i. 1.08-1.52, UC: RR 1.30, 95% c.i. 1.15-1.47). Conclusion: The MA detected an increased risk of PD in the IBD population and CD/UC subgroup. These results merit further clinical validation in future studies. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Abstract Background Exosomes are 50–150 nm endocytic vesicles secreted by almost all type of cells that carry bioactive molecules from host. These small vesicles are considered to be novel cross-talk circuits established by tumor cells and tumor microenvironment. Previous studies have shown certain biological influence of exosomal programmed cell-death ligand 1 (Exo-PD-L1) on immune suppression and dysfunction. The aim of the current study was to investigate the impact of Exo-PD-L1 and soluble PD-L1 (sPD-L1) on non-small cell lung cancer (NSCLC) and explore the concordance between Exo-PD-L1 and PD-L1 expression in matched tumor tissues in NSCLC patients. Methods 85 consecutive patients from April 2017 to December 2017 at General Hospital of Eastern Command Theatre who were primarily diagnosed with NSCLC and 27 healthy individuals were enrolled in this study. Two milliliters of whole blood samples were collected from each participant and further centrifuged. Exosomes were derived from serum using the commercial kit (Total Exosome Isolation Kit), which was further identified by Western blotting analysis (CD63/TSG101), transmission electron microscope analysis (TEM) and nanoparticle tracking analysis (NTA). Exosomes were next solubilized for Exo-PD-L1 detection by enzyme-linked immuno-sorbent assay (ELISA). PD-L1 expression in matched tissue were assessed by PD-L1 immunohistochemistry (IHC) (clone 28-8) assay. Tumor proportion score (TPS) ≥ 1% was deemed as “positive” in this study and TPS < 1% was deemed as “negative”. Written informed consent were obtained before acquisition of all data and biological sample. Data were analyzed using SPSS 20.0 and Graphpad Prism 5 software. Chi square test was conducted to estimate the correlation between Exo-PD-L1 levels, sPD-L1 levels, PD-L1 IHC profiles and clinicopathological features. For all analysis, a two-sided p < 0.05 was considered significant statistically. Results Exo-PD-L1 levels were higher in NSCLC patients with advanced tumor stage, larger tumor size (> 2.5 cm) (p < 0.001), positive lymph node status (p < 0.05) and distant metastasis (p < 0.05). In contrast, sPD-L1 levels were not different between NSCLC patients and healthy donors, it was not correlated with any clinicopathologic features except for tumor size (> 2.5 cm) (p < 0.05). In addition, Exo-PD-L1 levels showed slight correlation with sPD-L1 levels (Spearman’s correlation at r = 0.3, p = 0.0027) while no correlation with PD-L1 IHC profiles was detected. Conclusions In conclusion, Exo-PD-L1, but not sPD-L1, was correlated with NSCLC disease progression, including tumor size, lymph node status, metastasis and TNM stage. However, Exo-PD-L1 was not associated with PD-L1 IHC status.

Sensitizing mutations in epidermal growth factor receptor (EGFR) are associated with positive responses to anti-EGFR-targeted therapy, leading to a new era of treatment for non-small cell lung cancer (NSCLC). Exon 19 deletions and exon 21 L858R substitutions are the most common mutations, accounting for approximately 90% mutations in NSCLC; these are termed classic mutations and result in high sensitivity to tyrosine kinase inhibitors (TKIs). Other EGFR mutations are termed uncommon EGFR mutations, of which G719X, S768I, L861Q, exon 20 insertions, and complex mutations are the most frequent. G719X, S768I, and L861Q are point mutations and those that exist with complex mutations are sensitive to first-generation TKIs. A prospective analysis demonstrated that afatinib, a second-generation TKI, led to a better prognosis in some patients with NSCLC compared to first-generation TKIs. Chemotherapy used to be the traditional choice for patients carrying exon 20 insertions; however, with the development of novel targeted drugs, the role of chemotherapy is changing. Tremendous progress has also been made in clinical trials on immunotherapy treatment of uncommon EGFR mutations. The treatment for patients with NSCLC harboring uncommon EGFR mutations remains a subject of debate and the sensitivity of uncommon EGFR mutations to TKIs is still unclear. Here, we summarized recent data in the literature and provide an overview of the clinical characteristics, incidence, and outcomes of patients harboring G719X, S768I, L861Q, exon 20 insertions, and complex mutations who were treated with TKIs, chemotherapy, or immunotherapy.