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Background Video-assisted thoracoscopic surgery ( VATS) lobectomy has emerged as a safe and effective technique for treating early-stage lung cancer. Novel three-dimensional, high-definition ( 3D HD) imaging has removed this technical obstacle and is increasingly used in laparoscopic surgery. We compared our initial experience of 3D HD VATS with standard two-dimensional ( 2D) HD VATS to identify the advantages and disadvantages of 3D HD visualization in VATS. Methods The data of consecutive patients diagnosed with lung cancer who underwent 2D or 3D thoracoscopic lobectomy or bilobectomy at the Guangdong Lung Cancer Institute from July 2013 to October 2014 were retrospectively analyzed. Operation duration, estimated blood loss, length of postoperative stay, major complications, and mortality were recorded for each patient. Results In total, 359 patients were enrolled in the study. Lobectomy was performed in 339 patients and bilobectomy in 20; the 3D HD system was used for 178 of the 359 patients, and the 2D HD system for 181. Tumor size, distribution of the resected lobes, and the demographic characteristics of the patients were matched between the two groups. The mean operative time for 3D VATS was 163 minutes (range 60-330), whereas 2D VATS required 184 minutes (range 75-360; P < 0.001). The volume of blood loss was 109 and 144 mL in the 3D and 2D VATS groups, respectively ( P = 0.064). Conclusions The new-generation 3D HD imaging system is feasible and safe for thoracic lobectomy. The 3D system required a shorter operative duration. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR and cytochrome P450, family 1, member A1 (CYP1A1) genes were associated with clinical outcome in NSCLC patients treated with EGFR-TKI. Methods: Genotypes for the intron 1 (CA)n repeat and R497K polymorphisms in the EGFR gene and the *2A (3801 T→C) and *2C (2455 A→G) polymorphisms in CYP1A1 gene were evaluated in 115 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs. From a subgroup of patients whose tumour tissues were available, associations between somatic EGFR mutations, EGFR expression, and genomic polymorphisms were also analysed. Results: EGFR intron 1 (CA)n and CYP1A1*2A polymorphisms were independent predictive factors (p =0.046, p =0.011, respectively) and the latter was also a prognostic factor (p =0.001) for patients treated with EGFR-TKIs. We also observed a strong synergistic effect from two genotypes. Specifically, patients with both the T/T allele of the CYP1A1 gene and shorter intron 1 CA repeats (⩽16 CA) of the EGFR gene showed an improved response (p =0.002) compared with patients with the T/C or C/C allele and longer intron 1 CA repeats (both alleles >16 CA). In contrast, for R497K and CYP1A1*2C, no relationship was observed with clinical outcome for patients treated with EGFR-TKIs (p= 0.573; p =0.629, respectively). Both SNPs in the CYP1A1 gene showed a correlation with EGFR somatic mutations. Conclusions: The findings of this study suggest that the CYP1A1*2A polymorphism is a predictor for clinical outcome in NSCLC patients treated with EGFR-TKI therapy, and combining analysis of both CYP1A1*2A and EGFR intron 1 (CA)n polymorphisms may be useful for predicting treatment outcome in NSCLC patients treated with EGFR-TKIs. [Copyright &y& Elsevier]

Objectives: Primary pulmonary lymphoepithelioma‐like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB‐treated PLELC. Viral EBNA‐1 and BamHI‐W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression‐free survival (PFS) was significantly longer in EBNA‐1 high or BamHI‐W high groups. A longer PFS was also observed in patients with both high plasma EBNA‐1 or BamHI‐W and PD‐L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA‐1 and BamHI‐W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy‐to‐use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P  =   0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P  <   0.000 vs P  <   0.000) and overall survival (P  =   0.003 vs P  =   0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P  =   0.189). CONCLUSIONS Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional. [ABSTRACT FROM AUTHOR]

Tumor response T cells, which have specific T cell receptor (TCR) rearrangements in tumor-infiltrating lymphocytes, determine their ability to interact with the mutation-derived neoantigens presented by antigen-presenting cells. Little is known about the genetic alterations related to specific TCR clones in non-small cell lung cancer (NSCLC) patients who have an epidermal growth factor receptor (EGFR) mutation. In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial for high-throughput TCRβ V region and exome sequencing. Ten clonal TCRs were associated with EGFR exon 19 deletion (del), EGFR exon 21 mutation (L858R), RB1 alteration, TP53 exon 4/5 missense mutation, TP53 nonsense mutation, or copy number gains in NKX2-1 and CDK4. Among the TCRs, there was frequent use of Vβ20-1Jβ2-3 specifically for EGFR exon 19 del or Vβ9Jβ2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting. Moreover, in comparison with the chemotherapy-preferable (CP) group, higher frequencies of Vβ20-1Jβ2-3 and Vβ9Jβ2-1 were found in the highly TKI-preferable (HTP) or TKI-preferable (TP) groups. Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vβ20-1Jβ2-3 or Vβ9Jβ2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R. [ABSTRACT FROM AUTHOR]

Background: Sublobectomy for early‐stage non‐small cell lung cancer (NSCLC) remains a matter of debate. This study aimed to discuss the feasibility of sublobectomy in patients with pathological‐stage IA1‐2 confirmed as pathologically invasive but radiologically noninvasive adenocarcinoma. Methods: From 2011 to 2019, we screened clinical stage IA1–IA2 lung cancer patients who underwent surgery at the Guangdong Provincial People's Hospital (GDPH). Inclusion criteria were maximum tumor diameter of 2.0 cm or less, consolidation tumor ratio (CTR) ≤ 0.25, and pathologically confirmed invasive adenocarcinoma. Sublobectomy (segmentectomy and wedge resection) and lobectomy groups were created, and propensity scores were computed. The primary endpoints were lung cancer‐specific overall survival (LCSS) and LCS‐ relapse‐free survival (LCS‐RFS) after adjusting propensity scores. Results: A total of 1731 patients were screened, and 100 patients were enrolled. The lobectomy group had 51 patients and the limited resection group had 49. No cases relapsed, and two patients died from nontumor causes. For the entire cohort, the 5‐year LCSS and 5‐year LCS‐RFS were 100% in the lobectomy and limited resection groups. When propensity scores matched, there were no differences in LCSS and LCS‐RFS between the two groups (LCSS:100%, LCS‐RFS 100% in lobectomy and limited resection, respectively). Discussion: Sublobectomy may be curative for pathologically invasive but radiologically noninvasive adenocarcinoma at pathological stage IA1‐2. [ABSTRACT FROM AUTHOR]

Objective: In recent years, the lung cancer incidence has grown and the population is younger. We intend to find out the true detection rate of pulmonary nodules and the incidence of lung cancer in the population and search for the risk factors. Method: Hospital employees ≥40 years old who underwent low‐dose computed tomography (CT) lung cancer screening from January 2019 to March 2022 were selected to record CT‐imaging characteristics, pathology, staging, and questionnaires to investigate past history, smoking history, diet, mental health, etc. PM2.5 and radiation intake in radiation‐related occupation received monitoring in hospital. Result: The detection rate of suspicious pulmonary nodules was 9.1% (233/2552), and the incidence rate of lung cancer (including adenocarcinoma in situ) was 4.0% (103/2552). Morbidity among doctors, nurses, technicians, administers, and logistics was no difference (p = 0.184), but higher in women than in men (4.7% vs 2.4% p = 0.002). The invasiveness increased with age and CT density of nodules (p = 0.018). The relationship between lung cancer morbidity and PM2.5 was not clear (p = 0.543); and no lung cancer has been found in employees related ionizing radiation. Conclusion: The high screening rate has brought about a high incidence of lung cancer. At present, the risk factor analysis of lung cancer based on small samples cannot find the direct cause. Most of the ground glass opacity (GGO)s detected by LDCT screening are indolent, but there are also rapidly progressive lung cancer. A predictive model to identify active and indolent GGO is necessary. [ABSTRACT FROM AUTHOR]

Background: Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non‐small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs. Methods: Whole‐exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls. Results: In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division‐related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles. Conclusions: Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability. [ABSTRACT FROM AUTHOR]

(D) Association between V 6-6J 1-3 and V 6-6J 1-6 combination based risk score and OS or disease-free survival (DFS) in EGFR-mutant non-small-cell lung cancer (NSCLC) patients. When patients carried high frequency of V 6-6J 1-3 or V 6-6J 1-6, the application of V 6-6 antibody or other treatment options should be considered. Overall, the results indicated both V 6-6J 1-3 and V 6-6J 1-6 associated with poor OS of I EGFR i -mutant NSCLC patients. These results not only show that specific TCR rearrangements (V 6-6J 1-3 and V 6-6J 1-6) are prognostic on their own, but the optimal model with a combination of these TCRs have the greatest predictive potential for prognosis of I EGFR i -mutant NSCLC patients. [Extracted from the article]

Background: Src homology region 2 domain‐containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non‐small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME). Methods: Sixty‐one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next‐generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho‐SHP2 (pSHP2), and programmed death ligand 1 (PD‐L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME. Results: SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H‐score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s‐SHP2) was higher in tumors with PD‐L1 ≥50% versus PD‐L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s‐SHP2 had positive correlation with CD8, CD4, CD68, and PD‐L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression‐free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD‐L1 had longer PFS (p < 0.001). Conclusion: High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME. [ABSTRACT FROM AUTHOR]

Leptomeningeal metastases (LM) occur in up to 5% of non–small cell lung cancer (NSCLC) patients and often develop after previous systemic treatments. In this article, we explored whether immune checkpoint inhibitors (ICIs) enhanced the dismal survival of patients with LM. Data on NSCLC patients with LM prescribed ICIs were collected at the Guangdong Lung Cancer Institute. Furthermore, relevant literature was reviewed. A total of 255 NSCLC patients diagnosed with LM were screened from January 2015 to March 2020 at our institute. Cases reported by literature were also included. Finally, 32 NSCLC patients received ICIs after LM diagnosis; their median age was 55 years. Druggable genes were detected in 37.5% of all patients. The ICI regimens included nivolumab (n = 21), pembrolizumab (n = 9), and atezolizumab (n = 2). Ultimately, 62.5% of patients evidenced neurological symptom controlled. Two patients exhibited both intracranial and extracranial complete tumour response; one patient showed both intracranial and extracranial partial response (PR), one patient indicated intracranial PR and a systemic PR, and one patient showed central nervous system PR without extracranial response reported. The median progression-free survival (PFS) in the single-agent subgroup was 2.1 months (95% confidence interval [CI]: 1.4–2.9 months), and the median overall survival (OS) was 4.0 months (95% CI: 0.1–13.3 months). In the combined subgroup, the median PFS and OS were 3.0 months (95% CI: 1.1–4.9 months) and 5.4 months (95% CI: 0.5–10.3 months), respectively. Three patients exhibited remarkable PFS of over 20 months: all patients had ICI single agent, received cranial radiotherapy before ICI prescription, and took ICIs as second-line therapy, and two patients were EGFR / ALK wild type. Multivariate analysis showed that a better Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was associated with prolonged PFS (P = 0.04). No difference in survival was seen between monotherapy and combination therapy groups. NSCLC patients with LM may benefit from ICIs of both monotherapy and combination with other therapies, especially those with good ECOG-PS scores. Further work in this regard is required. • Selected NSCLC patients with leptomeningeal metastases might benefit from ICIs. • ECOG-PS score is related with outcome of ICIs in leptomeningeal metastases. • Our study support ICIs as one of the options for some leptomeningeal metastases. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related death worldwide [[1]], with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases [[2]], and lung adenocarcinoma and squamous cell carcinoma representing the most common NSCLC subtypes [[3]]. Herein, we describe the case of a patient with pleural-disseminated I EGFR i mutation-positive stage IV lung adenocarcinoma, who achieved long-term clinical benefit of more than 6 years with sequential EGFR TKI treatment. There were no further standard treatments for the patient, so from January 2015, the patient began treatment with osimertinib, which he obtained himself; it had not been approved in China at the time. 10.1038/bjc.2015.356 25 Hochmair MJ, Buder A, Schwab S, Burghuber OC, Prosch H, Hilbe W. Liquid-biopsy-based identification of EGFR T790M mutation-mediated resistance to afatinib treatment in patients with advanced EGFR mutation-positive NSCLC, and subsequent response to osimertinib. [Extracted from the article]

A 48‐year‐old woman presented to our department and chest computed tomography (CT) revealed five pulmonary nodules, two of which were in the left upper lobe of the lung and three in the superior segment of the left lower lobe., All the lesions were resected for comprehensive histological assessment in order to distinguish synchronous multiple primary lung cancers (SMPLCs) from intrapulmonary metastases. The nodules were all successfully removed by minimally invasive surgery under the guidance of three dimensional (3D) reconstruction, in order to preserve as much lung function for the patient as possible. Postoperative histopathological examination demonstrated the presence of SMPLC. The patient was discharged from hospital on postoperative day 4 without any complications. [ABSTRACT FROM AUTHOR]

• Adjuvant gefitinib provides favourable HRQoL in resected, early-stage, EGFR m + NSCLC. • Adjuvant gefitinib was associated with higher HRQoL scores than chemotherapy. • Adjuvant gefitinib delayed deterioration in HRQoL compared with chemotherapy. Health-related quality of life (HRQoL) data complement conventional clinical endpoints when comparing adjuvant gefitinib with chemotherapy in patients with early-stage non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations. This study aimed to assess changes in HRQoL with adjuvant gefitinib vs chemotherapy in this patient group. In the phase III ADJUVANT trial, patients with completely resected, stage II–IIIA (N1–N2), EGFR -mutant NSCLC were randomized (1:1) to receive either gefitinib for 24 months or vinorelbine plus cisplatin (VP) every 3 weeks for four cycles. HRQoL was assessed as a secondary endpoint using the Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L), Lung Cancer Symptom Scale (LCSS) questionnaires, and Trial Outcome Index (TOI) composite score. HRQoL dynamics, improvements, and time to deterioration were compared between groups. At baseline, 104 of 106, and 80 of 87 patients receiving gefitinib and VP, respectively, completed two questionnaires (FACT-L and LCSS). Baseline scores were balanced between groups. Although HRQoL fluctuated and gradually improved in both groups, longitudinally higher scores were reported with gefitinib than VP (FACT-L, odds ratio 418.16, 95 % confidence interval [CI] 2.75–63509.05, p = 0.019; LCSS, 1.13, 1.04–1.22, p = 0.003; TOI, 88.39, 4.40–1775.05, p = 0.003). Time to deterioration in HRQoL was delayed with gefitinib compared with VP (FACT-L, median 69 vs 6 weeks, hazard ratio 0.62, 95 % CI 0.42–0.90, p = 0.013; LCSS, median 45 vs 6 weeks, 0.63, 0.43–0.93, p = 0.020; TOI, median 164 vs 9 weeks, 0.51, 0.33–0.77, p = 0.001). Adjuvant gefitinib is associated with improved HRQoL over VP, supporting its use in patients with stage II–IIIA (N1–N2), EGFR -mutant NSCLC. [ABSTRACT FROM AUTHOR]

Background: Localization of small pulmonary nodules is an inevitable challenge for the thoracic surgeon. This study aimed to investigate the accuracy of three‐dimensional (3D) printing technology for localizing small pulmonary nodules, especially ground‐glass nodules (GGNs). Methods: This study enrolled patients with peripheral small pulmonary nodules (≤ 2 cm) who required preoperative localization. In the comparison period, patients underwent both computed tomography‐guided (CT‐G) and 3D‐printing template guided (3D‐G) localization to compare the accuracies of the two methods. In the testing period, the 3D‐printing technique was implemented alone. The 3D‐printing physical navigational template was designed based on data from perioperative CT images. Clinical data, imaging data, surgical data, and evaluation index were collected for further analysis. The learning curve of the 3D‐printing localization technique was assessed using cumulative sum (CUSUM) analysis and multiple linear regression analysis. Results: In the comparison period (n = 14), the success rates of CT‐G and 3D‐G were 100% and 92.9% (P = 0.31), respectively; in the testing period (n = 23), the success rate of 3D‐G was 95.6%. The localization times of CT‐G, 3D‐G (comparison), and 3D‐G (testing) were 23.6 ± 5.3, 19.3 ± 6.8, and 9.8 ± 4.6 minutes, respectively. The CUSUM learning curve was modeled using the equation: Y = 0.48X2− 0.013X − 0.454 (R2 = 0.89). The learning curve was composed of two phases, phase 1 (the initial 20 patients) and phase 2 (the remaining 17 patients). Conclusions: 3D printing localization has adequate accuracy and is a feasible and accessible strategy for use in localizing small pulmonary nodules, especially in right upper lobe. The use of this technique could facilitate lung nodule localization prior to surgery. [ABSTRACT FROM AUTHOR]

Background: Primary pulmonary lymphoepithelioma‐like carcinoma (PLELC) is a rare and unique subtype of lung cancer. However, the prevalence of driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, and the response of tyrosine kinase inhibitor (TKIs) in PLELC has not been thoroughly investigated. Method: We retrospectively reviewed the genetic profiles and treatment course of 330 PLELC patients at the Guangdong Lung Cancer Institute (GLCI) from 1st January, 2008 to 30th December, 2018. We searched and analyzed related literature published in PubMed and Web of Science from 1st January, 2000 and 31th August, 2019 based on their mention of "driver mutations" and "the response of TKIs to mutant PLELC". Results: Genetic alterations of EGFR/ALK were tested in 203 patients (203/330, 61.5%). Five patients (5/175, 2.9%) had EGFR mutation and three patients (3/140, 2.1%) had ALK alteration. From the total of 15 articles identified from electronic searches, 1071 PLELC cases mentioned the driver mutations. EGFR mutation and ALK rearrangement were detected in 15 patients and one patient, respectively. In total, there were four EGFR/ALK mutant PLELC patients who received targeted therapy as palliative treatment at the GLCI and in the literature. However, there was disease progression in all cases one month after use of TKIs. Conclusion: The mutation rates of EGFR and ALK were low in PLELC. EGFR and ALK TKIs showed limited response in EGFR/ALK mutant PLELC. Further studies are needed to explore other molecular targets to optimize the therapeutic strategy for PLELC. [ABSTRACT FROM AUTHOR]

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 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. [ABSTRACT FROM AUTHOR]

• This was the first and largest study focusing on prognosis model in LM of lung cancer patients. • EGFR/ALK positivity, KPS score≥60 and absence of ECM independently predict better OS in LM of lung cancer patients. • A novel LM molGPA model was established and internally validated to classify the heterogeneous patients. Leptomeningeal metastases (LM) had increased in advanced non-small-cell lung cancer (NSCLC) over the last 10 years. The survival outcome remained overall poor, heterogeneous and was reported in association with genotypes in lung cancer patients with LM. Graded prognostic assessment model integrated with molecular alterations (molGPA) might be accurate for outcome prediction of LM patients, but needs to be established. We retrospectively screened 8921 consecutive lung cancer patients from January 2011 to March 2018. A total of 301 patients diagnosed as LM were enrolled, and randomly divided into training and validation sets after stratified by gender and age. A molGPA score for each patient was calculated based on the weighted significant parameters including gene mutations. The median OS for the 301 patients was 9.2 months (95%CI: 7.9–10.5). In the training set, EGFR/ALK positivity, Karnofsky performance score (KPS) score≥60 and absence of extracranial metastasis (ECM) independently predicted better OS. We developed a molGPA model based on above significant prognostic factors. This molGPA model classified LM patients into three prognosis groups of high, intermediate and low risk (molGPA score of 0, 0.5–1.0 and 1.5–2.0, respectively. The median OS of high, intermediate and low risk LM patients in the training set was 0.3, 3.5 and 15.9 months, respectively (p < 0.001). In the validation set, the median OS was 0.9, 5.8 and 17.7 months in the three molGPA subgroups, accordingly (p < 0.001). The C-index of this model in training and validation sets was 0.70 (95%CI: 0.66-0.73) and 0.64 (95%CI: 0.58-0.70) respectively. The LM molGPA model with integration of gene status, KPS and ECM can accurately classify lung cancer patients with LM into diverse prognosis. [ABSTRACT FROM AUTHOR]

Background: Increasing identification of small pulmonary nodules promotes sublobar resection, but localization and surgical margins of non‐palpable pulmonary nodules through sublobar resection are challenging. Our aim was explicate the feasibility of applying indocyanine green (ICG) fluorescence to localized nodules, and to carry out surgical resection. Methods: A total of 46 patients with subpleural pulmonary nodules <3 cm were enrolled, including 35 for wedge resection and 11 for segmentectomy. For wedge resection, patients underwent computed tomography‐guided percutaneous injection of ICG preoperatively. Wedge resection was carried out after confirmation of the fluorescence using fluoroscopy. For segmentectomy, ICG was injected through the peripheral vein during surgery and resection of the segmental plain was carried out. Detailed measurements were taken and information was collected for the whole procedure. Results: A total of 33 out of 35 patients underwent successful wedge resection using ICG fluorescence. Segmentectomy was successfully carried out for all 11 patients who underwent the procedure. For two patiens, the nodules failed to be localized with unclear fluorescence, and one patient with an undetected nodule was altered to perform lobectomy. For wedge resection, the mean tumor size and depth from the pleural surface were 7.8 ± 0.5 mm and 10.5 ± 1.6 mm, respectively. The median time taken for preoperative computed tomography‐guided percutaneous injection was 28 min (range 18–40 min), and 25 min (range 16–30 min) for wedge resection. For segmentectomy, the ICG fluorescence occurred 14 s after injecting ICG through the peripheral vein, and the median duration was 15 min. All surgical margins were negative based on pathological evaluation. Conclusions: The implementation of ICG fluorescence could provide surgeons carrying out precision sublobar resection with a time‐saving surgical technique with less unnecessary intraoperative damage. [ABSTRACT FROM AUTHOR]

Highlights • PD-L1 and CD8 co-expression is scarce in EGFR -mutant or ALK -rearranged lung cancer. • Such co-expression predicts shorter OS in EGFR -mutant or ALK -rearranged lung cancer. • PD-L1 combined with CD8+ T cells could be better prognostic markers than PD-L1 alone. Abstract Objectives EGFR -mutated or ALK -rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8+ T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS). Materials and methods Tumor samples from 715 patients with lung cancer were retrospectively collected at Guangdong Lung Cancer Institute. Tumoral PD-L1 expression (N = 715) and CD8+ T cells infiltration (N = 658) was determined by immunohistochemistry (IHC), based on which TME was categorized into four different subtypes: PD-L1+/CD8+, PD-L1-/CD8+, PD-L1+/CD8-, PD-L1-/CD8-. Proportion of four TME subtypes was determined, and overall survival with PD-L1 expression and TME was analyzed. Results In patients with EGFR mutations or ALK rearrangements, proportion of PD-L1+/CD8+ tumors was the lowest (5.0%, 17/342), and that of PD-L1-/CD8- tumors was the highest (63.5%, 217/342). In patients with wild-type EGFR and ALK , 14.2% (45/316) tumors were PD-L1+/CD8+ and 50.3% (159/316) tumors were PD-L1-/CD8- (P < 0.001). Median OS of EGFR -mutated or ALK -rearranged lung cancer was 78.6 months in PD-L1 positive group and 93.4 months in PD-L1 negative group (HR 0.47, 95%CI 0.23-0.76, P = 0.005). PD-L1+/CD8+ group exhibited the shortest OS, with 44.3 months, but is likely to respond to CPIs. The PD-L1-/CD8+ group exhibited the longest OS but is unlikely to respond to CPIs. Conclusion Patients with EGFR mutations or ALK rearrangements exhibited lower PD-L1 and CD8 co-expression level in TME, which could be responsible for poor response to CPIs. PD-L1 and CD8 co-expression in EGFR -mutated or ALK -rearranged lung cancer is a biomarker for poor prognosis with shorter OS. [ABSTRACT FROM AUTHOR]

Background: Since the conception of enhanced recovery after surgery protocols, tubeless strategies have become popular. Herein, we introduce a previously unreported alternative air‐extraction strategy for patients who have undergone thoracoscopic wedge resection and explore its feasibility and safety. Methods: Between January 2015 and June 2017, 264 consecutive patients underwent thoracoscopic wedge resection with different drainage strategies. Patients were divided according to the postoperative drainage strategies used: routine chest tube drainage (RT group), complete omission of chest tube drainage (OT group), and prophylactic air‐extraction catheter insertion procedure (PC group). Using the propensity score matching method, clinical parameters and objective operative qualities were compared among the three groups. Results: Optimal 1:1 matching was used to form pairs of RT (n =36) and PC (n =36) groups and balance baseline characteristics among the three groups. The incidence rates of pneumothorax were 5.6% (2/36), 9.8% (5/51), and 19.4% (7/36) in the RT, OT, and PC groups, respectively (P = 0.07). Chest tube reinsertion incidence for postoperative pneumothorax was 19.4% (1/7) in the PC group and 60% (3/5) in the OT group. Other postoperative complications were comparable among these groups. Conclusions: The prophylactic air‐extraction strategy may be an alternative procedure for selected patients. Remedial air extraction may reduce the occurrence of chest tube reinsertion for pneumothorax patients, but further investigation is required. [ABSTRACT FROM AUTHOR]

Background: ALK‐tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK‐positive non‐small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Methods: Targeted next‐generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. Results: ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK ‐positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post‐treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK‐TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Conclusions: Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes. [ABSTRACT FROM AUTHOR]

The goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN IHC showed that 108 TMA samples and 105 whole-section samples qualified for PD-L1 IHC. With a clinically relevant cutoff, 41.7% of the TMA samples were PD-L1 positive. PD-L1 level was much lower in EGFR-mutant patients and seemed to be a favorable prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). These findings were confirmed in the whole-section samples except that their survival data were not mature enough for correlation analysis. In summary, PD-L1 expression was detected in approximately 40% of PTEN-qualified Chinese NSCLC samples, negatively correlated with EGFR mutation and seemed to be a favorable prognostic factor for both OS and RFS. Notably, the different results from PTEN-qualified and PTEN-disqualified samples underscore the importance of tissue quality control prior to biomarker testing. [ABSTRACT FROM AUTHOR]

Objectives Most lung adenocarcinomas consist of mixtures of histological subtypes harboring different frequencies of driver gene mutations. However, little is known about intratumoral heterogeneity(ITH) within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to personalized treatment. Methods Morphologically different areas within the same surgically resected adenocarcinomas were extracted from tissues to analyze gene status in each growth pattern. Driver genes, epidermal growth factor receptor ( EGFR ), KRAS and EML4-ALK , were assessed by assays with different sensitivities. Results Seventy-nine consecutive eligible patients harboring a driver gene ( EGFR = 65; KRAS = 10; EML4-ALK = 4) were enrolled. For EGFR mutations, ITH occurred in 13.3% (8/60) by direct sequencing (DS) and 1.7% (1/60) by amplification refractory mutation system (ARMS) ( P = 0.016) among adenocarcinomas, but consistent within five adeno-squamous cell carcinomas by both methods. ITH among KRAS mutations were detected in 20% (2/10) by DS, whereas consistent (10/10) by high resolution melting. No discrepancies in EML4-ALK rearrangements existed according to fluorescence in situ hybridization. Conclusion Rare ITHs of EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas existed by methods with higher sensitivity. Discrepancies might be due to abundance of mutant tumor cells and detection assays. [ABSTRACT FROM AUTHOR]

Objective Some population-based studies involving lung cancer patients have reported that inherited susceptibility is responsible for the familial aggregation observed in non-smoking lung cancer patients; however, it has been found that the false-negative rates in clinic-ascertained probands are significantly lower than population-ascertained probands. In this clinic-based study, we sought to determine the relationship between a family history of cancer and lung cancer risk in Chinese never-smokers. Methods In this clinic-based case–control study, all 318 probands and 509 controls were Chinese. The data on demographic characteristics, age, gender, race, lung disease history, living environment, occupational exposure, and smoking history were collected from a structured questionnaire. Multiple conditional logistic regression was used to estimate adjusted odds ratios (aOR) and 95% CIs after adjusting for possible confounders. Results The risk of lung cancer was increased in individuals with a family history of lung (aOR, 3.21; p < 0.001) or any other cancer (aOR, 1.79; p < 0.001). Analyses were carried out using stratified relative gender; first-degree female relatives tended to have a higher risk than first-degree male relatives. Similarly, the aOR for a female developing a malignant tumor was two times greater than controls. Conclusions Our analysis provides further evidence of the importance of genetic factors underlying lung cancer in patients who are never-smokers, especially in patients with a maternal history of cancer. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is no published overview of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure modes in advanced non-small-cell lung cancer (NSCLC). This study aimed to classify the diversity of EGFR-TKI failure, and to investigate the usefulness of clinical modes in subsequent management and prognosis. Methods: One-hundred and twenty consecutive clinical trial patients with EGFR-TKI failure were enrolled as the training set to establish a clinical model based on clinical factors. Another 107 routine patients were enrolled as the validating set according to a Bayes discriminant analysis. EGFR mutations and c-MET amplification were analyzed. Kaplan–Meier survival analysis was used to test the differences among three clinical modes and subsequent management. Results: The duration of disease control, evolution of tumor burden, and clinical symptom were verified as feasible grouping variables. A correct grouping rate achieved 87.9%. The cohort was classified into three groups, as follows: 130 patients with dramatic progression, 42 with gradual progression, and 55 with local progression. Progression-free survivals (PFSs) for the dramatic progression, gradual progression, and local progression groups were 9.3, 12.9, and 9.2 months, respectively (P =0.007). Overall survivals for the groups (OSs) were 17.1, 39.4, and 23.1 months, respectively (P <0.001). TKI continuation was superior to switching chemotherapy in a subsequent setting for gradual progression (39.4 months vs. 17.8 months; P =0.02). The difference of EGFR or c-MET among the three groups was not significant. Conclusions: Clinical modes of EGFR-TKI failure could favor strategies for subsequent treatment and predicting a survival benefit in advanced NSCLC. [Copyright &y& Elsevier]

Purpose: We conducted a randomized trial to investigate whether systematic nodal dissection (SND) is superior to mediastinal lymph nodal sampling (MLS) in surgical treatment of non-small cell lung cancer (NSCLC). Methods: The patients resectable clinical Stage I–IIIA NSCLC were randomly assigned to lung resection combined with SND or lung resection combined with MLS. After postoperative pathological re-staging, eligible cases were followed up until 30 November 2000. The Kaplan–Meier method was used for survival analysis. COX proportional hazards model was used for prognostic analysis. Results: Of the 532 patients who were enrolled in the study, 268 patients were assigned to lung resection combined with SND and 264 were assigned to lung resection combined with MLS. After surgical restaging only 471 cases were eligible for follow-up. The median survival was 59 months in the group given SND and 34 months in the group given MLS (P=0.0000 by the log rank test). There was significant difference in survival in Stage I (5-year survival 82.16 vs. 57.49%) and Stage IIIA (26.98 vs. 6.18%) by the log rank test and Breslow test. There was no significant yet marginal difference in survival by log rank test (10-year survival 32.04 vs. 26.92%, P=0.0523) but significant difference in survival by Breslow test (5-year survival 50.42 vs. 34.05%, P=0.0284) in Stage II. Types of mediastinal lymph node dissection, pTNM stage, tumor size and number of lymph node metastasis were four factors that influenced long-term survival rate by multivariate analysis. Conclusions: As compared with MLS, lobectomy (pneumonectomy) combined with SND can improve survival in resectable NSCLC. [Copyright &y& Elsevier]

Background: Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years. However, patient-derived non-small cell lung cancer (NSCLC) xenograft mouse models are relatively few in number and are limited in their degree of genetic characterization and validation. In this study, we aimed to establish a variety of patient-derived NSCLC models and characterize these for common genetic aberrations to provide more informative models for preclinical drug efficacy testing.Methods: NSCLC tissues from thirty-one patients were collected and implanted into immunodeficient mice. Established xenograft models were characterized for common genetic aberrations, including detection of gene mutations within EGFR and KRAS, and genetic amplification of FGFR1 and cMET. Finally, gefitinib anti-tumor efficacy was tested in these patient-derived NSCLC xenograft models.Results: Ten passable patient-derived NSCLC xenograft models were established by implantation of NSCLC specimens of thirty-one patients into immunodeficient mice. Genetic aberrations were detected in six of the models, including one model with an EGFR activating mutation (Exon19 Del), one model with KRAS mutation, one model with both KRAS mutation and cMET gene amplification, and three models with FGFR1 amplification. Anti-tumor efficacy studies using gefitinib demonstrated that the EGFR activating mutation model had superior sensitivity and that the KRAS mutation models were resistant to gefitinib. The range of gefitinib responses in the patient-derived NSCLC xenograft models were consistent with the results reported from clinical trials. Furthermore, we observed that patient-derived NSCLC models with FGFR1 gene amplification were insensitive to gefitinib treatment.Conclusions: Ten patient-derived NSCLC xenograft models were established containing a variety of genetic aberrations including EGFR activating mutation, KRAS mutation, and FGFR1 and cMET amplification. Gefitinib anti-tumor efficacy in these patient-derived NSCLC xenografts containing EGFR and KRAS mutation was consistent with the reported results from previous clinical trials. Thus, data from our panel of patient-derived NSCLC xenograft models confirms the utility of these models in furthering our understanding of this disease and aiding the development of personalized therapies for NSCLC patients. [ABSTRACT FROM AUTHOR]