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Background: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs., Methods: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively., Results: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively., Conclusion: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted., Trial Registration: NCT04507906 August 11, 2020., (© 2024. The Author(s).)

Patients diagnosed with non-small cell lung cancer (NSCLC) have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for antitumor immunity. This study aims to develop an immunotherapy response evaluation model for NSCLC patients based on transcription. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy are downloaded from the POPLAR and OAK projects. Immune cell infiltration in NSCLC patients is examined, and thereafter, different coexpressed genes are identified. Next, the impact of M1 macrophage-related genes on the prognosis of NSCLC patients is investigated. Six M1 macrophage coexpressed genes, namely, NKX2-1 , CD8A , SFTA3 , IL2RB , IDO1 , and CXCL9 , exhibit a strong association with the prognosis of NSCLC and serve as effective predictors for immunotherapy response. A response model is constructed using a Cox regression model and Lasso Cox regression analysis. The M1 genes are validated in our TD-FOREKNOW NSCLC clinical trial by RT-qPCR. The response model shows excellent immunotherapy response prediction and prognosis evaluation value in advanced-stage NSCLC. This model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs.

Background: Non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancers. Early detection is crucial to reduce lung cancer-related mortality. Aberrant DNA methylation occurs early during carcinogenesis and can be detected in blood. It is essential to investigate the dysregulated blood methylation markers for early diagnosis of NSCLC., Methods: NSCLC-associated methylation gene folate receptor gamma (FOLR3) was selected from an Illumina 850K array analysis of peripheral blood samples. Mass spectrometry was used for validation in two independent case-control studies (validation I: n = 2548; validation II: n = 3866). Patients with lung squamous carcinoma (LUSC) or lung adenocarcinoma (LUAD), normal controls (NCs) and benign pulmonary nodule (BPN) cases were included. FOLR3 methylations were compared among different populations. Their associations with NSCLC clinical features were investigated. Receiver operating characteristic analyses, Kruskal-Wallis test, Wilcoxon test, logistics regression analysis and nomogram analysis were performed., Results: Two CpG sites (CpG_1 and CpG_2) of FOLR3 was significantly lower methylated in NSCLC patients than NCs in the discovery round. In the two validations, both LUSC and LUAD patients presented significant FOLR3 hypomethylations. LUSC patients were highlighted to have significantly lower methylation levels of CpG_1 and CpG_2 than BPN cases and LUAD patients. Both in the two validations, CpG_1 methylation and CpG_2 methylation could discriminate LUSC from NCs well, with areas under the curve (AUCs) of 0.818 and 0.832 in validation I, and 0.789 and 0.780 in validation II. They could also differentiate LUAD from NCs, but with lower efficiency. CpG_1 and CpG_2 methylations could also discriminate LUSC from BPNs well individually in the two validations. With the combined dataset of two validations, the independent associations of age, gender, and FOLR3 methylation with LUSC and LUAD risk were shown and the age-gender-CpG_1 signature could discriminate LUSC and LUAD from NCs and BPNs, with higher efficiency for LUSC., Conclusions: Blood-based FOLR3 hypomethylation was shown in LUSC and LUAD. FOLR3 methylation heterogeneity between LUSC and LUAD highlighted its stronger associations with LUSC. FOLR3 methylation and the age-gender-CpG_1 signature might be novel diagnostic markers for the early detection of NSCLC, especially for LUSC., (© 2024. The Author(s).)

Early detection of lung cancer (LC) is vital for reducing LC-related mortality. However, noninvasive diagnostic tools remain a great challenge. We aim to identify blood-based biomarkers for the early detection of LC. Here, LC-associated hypomethylation in alpha-1,3-fucosyltransferase VII (FUT7) is identified via the Illumina 850K array in a discovery study and validated by mass spectrometry in two independent case-control studies with blood samples from 1720 LC patients (86.8% LC at stage I, blood is collected before surgery and treatment) and 3143 healthy controls. Compared to the controls, blood-based FUT7 hypomethylation is identified in LC patients at stage I, and even in LC patients with malignant nodules ≤ 1 cm and in patients with adenocarcinoma in situ. Gender plays a role in the LC-associated FUT7 hypomethylation in blood, which is more significant in males than in females. We also reveal that FUT7 hypomethylation in LC could be enhanced by the advanced stage of cancer, involvement of lymph nodes, and larger tumor size. Based on a large sample size and semi-quantitative methods, our study reveals a strong association between blood-based FUT7 hypomethylation and LC, suggesting that methylation signatures in blood may be a group of potential biomarkers for detection of early-stage LC., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Ltd.)

Treatments for NSCLC patients with EGFR-TKI resistance are limited. Given that immunotherapy and antiangiogenic agents may have synergistic antitumor effects, we aimed to analyze the effect of multi-target angiogenesis inhibitor anlotinib and immune checkpoint inhibitors (ICIs) combination therapy in NSCLC patients who failed EGFR-TKI. The medical records of lung adenocarcinoma (LUAD) patients with EGFR-TKI resistance were reviewed. After EGFR-TKI resistance, patients who simultaneously received anlotinib and ICIs were enrolled in the observation group, and those who received platinum-pemetrexed chemotherapy were included in the control group. A total of 80 LUAD patients were reviewed and allocated to the anlotinib and ICIs combination therapy (n = 38) and chemotherapy (n = 42) groups. A re-biopsy was performed in all patients in the observation group before the administration of anlotinib and ICIs. The median follow-up was 15.63 months (95% CI: 12.19-19.08). Combination therapy exhibited better PFS (median PFS: 4.33 months [95% CI: 2.62-6.05] vs 3.60 months [95% CI: 2.48-4.73], P = .005), and better OS (median OS: 14.17 months [95% CI: 10.17-18.17] vs 9.00 months [95% CI: 6.92-11.08], P = .029) than chemotherapy. Most patients (73.7%) received combination therapy as fourth and later lines of therapy, with a median PFS of 4.03 months (95% CI: 2.05-6.02) and a median OS of 13.80 months (95% CI: 8.25-19.36). The disease control rate was 92.1%. Four patients discontinued the combination therapy due to adverse events, but the other adverse reactions were manageable and reversible. The combination of anlotinib and PD-1 inhibitors is a promising regimen for the late-line treatment of LUAD patients with EGFR-TKI resistance., (© 2023 UICC.)

Stability is crucial for the clinical applicable biomarker such as DNA methylation profiles. However, the influence of various blood processing on the DNA methylation signatures have been barely studied. Here, we systematically evaluated the impact of temporary storage and frozen and thaw on the levels of DNA methylation. The methylation intensities of 13 CpG loci from 53 individuals (42 healthy participants and 11 lung cancer patients) whose blood samples were processed by up to 14 various protocols were quantitatively determined by the mass spectrometry, obtaining more than 8,000 quantitative data. We disclosed a trend of accumulatively increased DNA methylation along with time when the blood from healthy people were stored for up to 96 h at room temperature (RT), whereas the storage at 4°C had much weaker effects or no impact. On the contrary, the methylation patterns in the blood of lung cancer patients were more stable at both RT and 4°C even for 96 h. Multiple cycles of frozen and thaw could result in demethylation, but was more significant to the blood than to the extracted DNA. Our study indicated that the blood processing in vitro could influence the DNA methylation signatures and introduce unexpected biases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objectives: Treatments for advanced small-cell lung cancer (SCLC) patients who are resistant to first-line chemotherapy are limited. Given that antiangiogenic agents and immune-checkpoint inhibitors (ICIs) can confer synergistic therapeutic benefits, combination therapy should be considered. We explored the efficacy and safety of combination therapy with anlotinib and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors as second-line and subsequent therapy for advanced SCLC., Materials and Methods: We reviewed advanced SCLC patients at Shanghai Chest Hospital who had received anlotinib in combination with ICIs from November 2016 to November 2020 as second- and subsequent-line treatment. Patients with advanced SCLC who had received paclitaxel monotherapy as second-line treatment were included as the control group., Results: A total of 141 patients were included in the final analysis (40 in the combination therapy group and 101 in the paclitaxel monotherapy group). The median progression-free survival (PFS) times for the combination therapy and paclitaxel monotherapy groups were 3.40 and 2.83 months (p = 0.022), respectively, while the median overall survival (OS) times for the combination therapy and paclitaxel monotherapy groups were 8.20 and 5.87 months (p = 0.048), respectively. Hypertension and hepatic dysfunction were the most pronounced adverse events of combination therapy and two patients changed regimens due to severe fatigue and anorexia., Conclusion: The combination of anlotinib and PD-1/PD-L1 blockade has promising efficacy and safety as a second-line or subsequent therapy for SCLC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Surgery is controversial in limited-stage small-cell lung cancer (LS-SCLC) (except for T1-2, N0M0). This study aimed to analyze the survival of LS-SCLC patients with proximal lobe (N1) lymph node metastases after surgery and appropriate postoperative adjuvant treatment., Patients and Methods: We reviewed and followed up medical history and survival data of LS-SCLC patients from June 2007 to June 2016, and a total of 68 pathological stage N1 (p-N1) patients who underwent surgical resection and 71 clinical-stage N1 (c-N1) patients who received chemoradiotherapy were included in the final analysis., Results: The median follow-up of all the patients was 99.30 months. The median disease-free survival (DFS) of the surgery group was 13.567 months, and the median overall survival (OS) of the surgery and chemoradiotherapy groups were 29.600 months and 21.133 months (P-value < .001), respectively. The 2- and 5-year survival rates of the surgery group were 55.9% and 33.7%, and the 2- and 5-year survival rates of the chemoradiotherapy group were 39.8% and 9.4%, respectively. Meanwhile, postoperative thoracic radiotherapy appeared to be associated with a good prognosis (median OS 36.400 vs. 21.333 months, P-value .048), as did prophylactic cranial irradiation (median OS 50.867 vs. 22.600 months, P-value .007) in the surgery group., Conclusions: Surgery may benefit patients with p-N1 SCLC, and in combination with appropriate postoperative adjuvant treatment, surgery may be a new therapeutic modality for SCLC., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Novel biomarkers for LC detection are urgently needed. Here we aimed to investigate the association between RPTOR methylation in peripheral blood and LC., Methods: The methylation levels were measured by mass spectrometry in two independent case-control studies (159 LC cases vs. 188 controls in Study I, 413 LC cases vs. 687 controls in Study II). Logistic regression and Bonferroni correction were conducted to analyze the association., Results: RPTOR hypomethylation was discovered in Study I and validated in Study II. Combining the two studies, RPTOR&#95;CpG&#95;2 and RPTOR&#95;CpG&#95;8 showed significantly lower methylation levels in stage I cases (ORs per -10% methylation = 1.22 and 1.27, respectively, both P-values < 0.005). The significance kept between RPTOR&#95;CpG&#95;8 and LC cases with tumor length ≤ 1 cm (OR per -10% methylation = 1.39, P = 0.001). Moreover, methylation levels of all CpG sites were lower in cases at stage II & III than in those at stage I (all P-values less than 0.017)., Conclusion: Our study disclosed the association between RPTOR hypomethylation in peripheral blood and LC even in very early stage, suggesting the feasibility of blood-based DNA methylation for LC early detection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Tumor mutational burden (TMB) is an emerging predictive marker of response to immune checkpoint inhibitor therapies. We evaluated the correlation between clinical indicators and high-throughput sequencing results and TMB in lung adenocarcinoma patients, with the aim of finding simpler and more economical factors as surrogate markers for TMB. The medical records, next-generation sequencing data, and immunohistochemistry results of 340 lung adenocarcinoma patients who were admitted to the First Affiliated Hospital of Zhengzhou University between 2019 and 2020 were collected. The mutated genes were screened for, and the obtained mutated genes were subjected to functional enrichment analysis using R software. A protein-protein interaction (PPI) network was also constructed, and significant modules in the network were identified. Gene Ontology (GO) analyses were performed for the core genes. Univariate and multivariate correlation analyses were performed to judge the correlation between gene mutations and TMB. Genes with a junction mutation rate >1 were selected to construct PPI network and 13 high-connection core genes were screened. The results of GO enrichment analysis showed that the biological processes related to mutant core genes mainly included mitotic cell cycle and cell aging. Subsequently, ATM (p = 0.006) and PIK3CA (p = 0.008) mutation positivity were identified by univariate and multivariate correlation analysis, while TP53 (p = 0.003) and EGFR (p = 0.008) mutation negativity were significantly associated with elevated TMB. The results of this study demonstrate that ATM- and PIK3CA-positive and EGFR-negative mutation status are strongly associated with high levels of TMB and have the potential to be predictive biomarkers of response to immune checkpoint inhibitors in lung adenocarcinoma patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Early detection is essential to improve the survival of lung cancer (LC). The quantitative measurement of specific DNA methylation changes in the peripheral blood could provide an efficient strategy for the detection of early cancer., Objective: We applied a candidate approach and assess the association between blood-based SH3BP5 methylation and the risk of lung adenocarcinoma (LUAD) in a case-control cohort., Methods: The methylation level of four CpG sites in the promoter of SH3BP5 gene was quantitatively determined by mass spectrometry in 171 very early-stage LUAD patients (93.6% LUAD at stage I) and 190 age and gender-matched controls. The logistic regression and non-parametric tests were used for the statistical analyses., Results: We observed a significant association between decreased methylation of SH3BP5&#95;CpG&#95;4 in the peripheral blood and increased risk of LUAD (odds ratio (OR) per-10% methylation = 1.51, P = 0.006, FDR = 0.024), and even for the LUAD at stage I (OR per-10% methylation = 1.53, P = 0.006, FDR = 0.024). Moreover, the lower quartile of SH3BP5&#95;CpG&#95;4 methylation was correlated with increased risk for LUAD with a P trend of 0.011. Further investigation disclosed that the hypomethylation of SH3BP5&#95;CpG&#95;4 was mostly associated with LUAD in younger subjects (OR per-10% methylation = 2.02, P = 0.010, age < 55 years old) and probably could be enhanced by advance stage., Conclusion: Our study revealed an association between blood-based SH3BP5 hypomethylation and very early-stage LUAD, which provides a novel support for the blood-based methylation signatures as a potential marker for the evaluation of cancer risk., (© 2021. The Genetics Society of Korea.)

Background: Lung cancer (LC) is the leading cause of cancer-related morbidity and mortality in China. Exploring novel biomarkers for the early detection of LC is important., Materials and Methods: We quantified DNA methylation levels of three CpG sites of FYB gene in peripheral blood in 163 early-stage LC cases (88.3% at stage I) and 187 age- and gender-matched healthy controls. Covariates-adjusted odds ratios (ORs) for -10% methylation were calculated by binary logistic regression., Results: With multiple testing corrections, hypomethylation of FYB&#95;CpG&#95;4 was significantly associated with LC (OR = 2.04, p  = 4.50E-04) even with LC at stage I (OR = 1.41, p  = 0.003) without obvious bias between genders, but it mainly affected the subjects older than 55 years (OR = 2.04, p  = 0.015). Hypomethylation of FYB&#95;CpG&#95;2 was also associated with LC, but only for the males (OR = 1.76, p  = 0.018). FYB&#95;CpG&#95;3 methylation had no association with LC, but interestingly its methylation level in the males was only half of that in the females., Discussion and Conclusions: We proposed a novel association between blood-based abnormal FYB methylation and very early-stage LC. The age- and gender-related DNA methylation patterns also revealed the diversity and precision of epigenetic regulations.

Aims: This study aimed to characterize the functions of pseudogene-derived long non-coding RNA (lncRNA) FAM207BP in lung adenocarcinoma (LUAD)., Materials and Methods: Through the Cancer Genome Atlas (TCGA)-Genotype Tissue Expression (GTEx) database, FAM207BP expression was detected in LUAD and normal tissues. Overall survival (OS) and disease-free survival (DFS) analysis was presented using log-rank test or univariate Cox regression analysis. The relationships between FAM207BP expression and clinical features were analyzed. FAM207BP expression was validated in LUAD tissues and cells using RT-qPCR. Cell viability of LUAD cells was evaluated after silencing or overexpressing FAM207BP. Furthermore, migrated and invasive abilities were examined by Transwell and scratch assays. The correlation between FAM207BP expression and the immune infiltration levels was analyzed. Gene Set Enrichment Analysis (GSEA) was performed for high- and low-expression of FAM207BP using C2 collection in the Molecular Signatures Database (MSigDB) database., Key Findings: FAM207BP expression was distinctly higher in LUAD than normal tissues. Patients with its high expression indicated worse OS and DFS time. FAM207BP expression was significantly related to gender. RT-qPCR results confirmed that FAM207BP was significantly highly expressed in LUAD tissues and cells. Knockdown of FAM207BP distinctly suppressed cellular viability, migration and invasion for LUAD cells. Also, its expression was negatively related to B cell infiltration levels. GSEA results indicated that high FAM207BP expression was involved in regulation of gene expression. Its low expression was related to immune response., Significance: Pseudogene-derived lncRNA FAM207BP could induce proliferation and migration of LUAD cells, which could act as an immune-related prognostic factor., (Copyright © 2021. Published by Elsevier Inc.)

Background: It has previously been demonstrated that surgically resected small-cell lung cancer (SCLC) patients could benefit from prophylactic cranial irradiation (PCI). However, PCI in patients without lymph node involvement remains controversial. This study includes a larger sample size to evaluate the benefit of PCI therapy in this specific population., Methods: The records of surgically resected SCLC patients without lymph node involvement (N0M0) in Shanghai Chest Hospital were retrospectively reviewed., Results: Between January 2006 and May 2017, a total of 146 cases of surgically resected SCLC without lymph node involvement were included. A total of 46 patients received PCI therapy and 100 patients received no therapy. During the observation period, 12.0% (12/100) of the patients who did not receive PCI therapy developed brain metastases while 10.9% (5/46) of patients who received PCI therapy developed brain metastases. With regard to time to recurrence, no significant difference was observed among the groups (P = 0.798). Moreover, there was no significant difference in either the overall survival benefit (hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.49-1.45, P = 0.532) or disease-free survival rate (HR = 0.95, 95% CI: 0.52-1.75, P = 0.864)., Conclusions: The evidence obtained does not support PCI therapy in the management of surgically resected SCLC with no lymph node involvement., Key Points: Prophylactic cranial irradiation (PCI) remains controversial for resected small-cell lung cancer (SCLC) without lymph node involvement. In this study, the results indicated that PCI does not reduce the risk of cerebral recurrence of resected p-T1-2N0M0 SCLC. This is the largest sample size study focused on PCI in resected p-T1-2N0M0 SCLC. Future revised versions of the guidelines should address this issue., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment., Patients and Methods: Patients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected., Results: Among the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54)., Conclusion: Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy., (Copyright © 2019. Published by Elsevier Inc.)

Chronic arsenic exposure through water intake is a worldwide issue, which has caused many diseases. Lungs are the first target organ of arsenic and lung inflammation, autophagy, and even the onset of tumors can be induced by arsenic exposure. Here, we tested the outcome of low-concentration arsenic exposure in rat lungs. Tissue changes, inflammation, autophagy, and other physiological responses were observed in this study. Results showed that low-concentration exposure of arsenite through water intake could initiate autophagy and inflammation in lungs but high concentration exposure produced a weak autophagy response and accentuated inflammation with the possibility of a chronic inflammation environment emerging followed by tumorigenesis., (© 2019 Wiley Periodicals, Inc.)

Background: At present there is a significant lack of clinical data for patients with surgically resected stage I squamous lung cancer. The purpose of this study was to investigate the impact of postoperative chemotherapy in this specific population., Methods: We retrospectively identified patients who had undergone complete squamous lung cancer resection at the Shanghai Chest Hospital between January 2008 and January 2014., Results: A total of 596 patients (236 stage IA, 360 stage IB) were included in this study. Results demonstrated that adjuvant chemotherapy (ACT) could provide longer overall survival for patients with p-stage IB disease (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.34-0.90; p = 0.017). Among p-stage IB patients the ACT-treated cohort trended toward a benefit (HR, 0.69; 95% CI, 0.45-1.04) in recurrence-free survival but failed to reach statistical significance (p = 0.076). After propensity score matching the HRs of recurrence-free survival and overall survival were 0.58 (95% CI, 0.35-0.96; p = 0.033) and 0.49 (95% CI, 0.27-0.88; p = 0.017), respectively. With regards to patients with p-stage IA disease, neither overall survival (HR, 0.87; 95% CI, 0.34-2.27; p = 0.783) nor recurrence-free survival (HR, 0.79; 95% CI, 0.38-1.65; p = 0.534) was significantly different when compared between patients receiving ACT and those who did not. Similar results were also achieved after propensity score matching., Conclusions: The data presented herein demonstrated that ACT might provide survival benefits for squamous lung cancer patients with p-stage IB disease., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Primary epidermal growth factor receptor (EGFR) T790M mutation can be occasionally identified in previous untreated nonsmall cell lung cancer (NSCLC) patients. To compare clinical characteristics and outcomes in patients with primary and acquired EGFR T790M mutation, we collected the data of patients diagnosed with EGFR mutation from 2012 to 2017 in Shanghai Chest Hospital. Primary EGFR T790M mutation was identified in 61 patients (1.1%; 95% confidence interval (CI): 0.8%-1.3%) of 5685 TKI-naive EGFR mutant patients. Acquired T790M mutation was detected in 98 patients (50.3%; 95%CI: 43.2%-57.3%) of 195 TKI-treated patients. T790M mutation always coexisted with sensitizing EGFR mutations. Primary EGFR T790M always coexisted with 21L858R (46/61) whereas acquired T790M coexisted with 19del (68/98), (p < 0.001). Among them, 18 patients with primary T790M mutation received osimertinib and 72 patients with acquired T790M mutation received osimertinib. The median progression-free survival (PFS) of osimertinib was significantly longer in primary T790M group (17.0 months, 95%CI:14.0-20.0 months) compared to acquired T790M group (10.0 months, 95%CI:8.6-11.4 months, p = 0.022). However, the median overall survival (OS) of acquired T790M mutation patients was significantly longer compared to that of primary T790M mutation patients who received osimertinib (50.4 months vs. 29.9 months, p = 0.016). Our findings suggest that primary T790M mutation likely coexists with 21L858R while acquired mutation likely coexists with 19del. Both mutations showed good response to osimertinib. Patients with primary T790M mutation experienced greater benefits from osimertinib. However, patients with acquired T790M mutation had a better overall survival during the entire clinical treatment., (© 2018 UICC.)

Background: Patients harboring concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) arrangements constitute a small subgroup of non-small-cell lung cancer (NSCLC) patients. The efficacy of EGFR tyrosine kinase inhibitors (TKIs) and the ALK-specific TKI crizotinib in these patients has not been well-established., Objective: This study investigated the efficacy of targeted therapies in these patients compared with patients with EGFR or ALK alterations alone., Methods: Patients were screened for EGFR mutation and ALK rearrangement at the Shanghai Chest Hospital (2011-2017). Progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) were retrospectively analyzed., Results: A total of 5816 patients were screened, and 26 patients were identified as having concomitant EGFR mutations and ALK rearrangements; 22 patients were eligible for survival analysis. Additionally, 95 EGFR-mutant patients and 60 ALK-rearranged patients were randomly selected for analysis. The ORR to EGFR TKIs was 63.2% (12/19) for EGFR/ALK co-altered patients and 62.1% (59/95) for EGFR-mutant patients (p = 0.93) with a median PFS of 10.3 and 11.4 months, respectively (hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.59-1.57; p = 0.87). The ORR to crizotinib was 66.7% (8/12) for double-positive patients and 65.0% (39/60) for ALK-rearranged patients (p = 1.00), with a median PFS of 11.1 and 12.5 months, respectively (HR 1.39; 95% CI 0.69-2.80; p = 0.28). OS was 27.1, 36.2, and 36.8 months for EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered patients, respectively, and the EGFR/ALK co-existing subgroup tended to have a longer survival period than EGFR-mutant cohorts, though no statistical difference was found (p = 0.12). The median PFS of crizotinib as a sequential therapy after failure of EGFR TKIs was 15.0 months, which exhibited no statistically significant difference compared with the median PFS of ALK-altered patients who received crizotinib (p = 0.80)., Conclusions: Both first-generation EGFR TKIs and the ALK TKI crizotinib were effective in these patients. Sequential treatment with EGFR TKIs and crizotinib should be considered as a management option.

Background: The aim of this study was to determine the prognostic value of lymph node status in patients with pathologic N2 (pN2) stage IIIA small cell lung cancer (SCLC)., Methods: A total of 163 consecutive pN2 stage IIIA SCLC patients who underwent pulmonary resections and systematic lymphadenectomies at Shanghai Chest Hospital between January 2006 and June 2014 were enrolled. We retrospectively analyzed the potential clinicopathologic factors that influenced survival, including the node levels (single or multiple-station) and the node-spreading patterns (skip N2 or non-skip N2). The prognostic significance was examined by Cox regression analysis., Results: The median overall survival (OS) was 23.7 months. Multiple-station lymph node metastasis indicated a poorer prognosis than single-station involvement (p = 0.003). Skip metastasis did not appear to influence survival (p = 0.099). With respect to the station of lymph node metastasis, the OS was only related to the involvement of the subcarinal node, regardless of tumor location (p < 0.05). Multivariate analysis showed two statistically significant risk factors for survival, including multiple-station lymph node and subcarinal node metastasis (hazard ratio [HR] = 1.76, 95% confidence interval [CI]:1.11-2.78, p = 0.015; HR = 1.61, 95% CI: 1.03-2.50, p = 0.036, respectively)., Conclusions: Multiple-station N2 metastasis and involvement of the subcarinal node predicted poor prognosis in pN2 stage IIIA SCLC patients, which may profoundly influence therapeutic decisions.

Objectives: This study explored the prognostic significance and adjuvant chemotherapy benefits in resected patients with stage I non-small cell lung cancer with lymphovascular invasion., Methods: A total of 2633 patients who received complete resection with pathologic stage I non-small cell lung cancer in the Shanghai Chest Hospital (2008-2012) were enrolled in the study, of whom 222 were diagnosed with lymphovascular invasion. By using the Kaplan-Meier method and Cox proportional hazard regression model, we explored the impact of lymphovascular invasion on prognosis and determined if the use of adjuvant chemotherapy is associated with improved outcomes in patients with lymphovascular invasion. A propensity score-matched analysis was implemented to reduce the selection bias., Results: Patients with lymphovascular invasion had an unfavorable overall survival and recurrence-free survival in stage I non-small cell lung cancer. Multivariate Cox analysis indicated that lymphovascular invasion was an independent poor prognostic factor for recurrence-free survival (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.58-2.71; P < .001) and overall survival (HR, 2.04; 95% CI, 1.45-2.87; P < .001) in patients with stage I. After using propensity score-matched pairs, analysis of 65 pairs of patients with lymphovascular invasion indicated a beneficial recurrence-free survival (HR, 0.33; 95% CI, 0.16-0.67; P = .002) and overall survival (HR, 0.30; 95% CI, 0.12-0.74; P = .009) from adjuvant chemotherapy., Conclusions: Lymphovascular invasion was correlated with poor prognosis in patients with stage I non-small cell lung cancer. For such patients, adjuvant chemotherapy was associated with improved survival. Our study suggests that adjuvant chemotherapy might be an appropriate option for patients with stage I non-small cell lung cancer with lymphovascular invasion., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Lymphovascular invasion (LVI) and Visceral Pleural Invasion (VPI) have been reported to be risk factors for stage I Non-Small Cell Lung Cancer (NSCLC). However, only VPI was incorporated into the current 8th Tumor-Node-Metastasis (TNM) classification. This study aimed to explore the prognostic effect of LVI and VPI on TNM staging in pathological stage I NSCLC., Method: We retrospectively reviewed 2633 consecutive p-stage I NSCLC patients in the Shanghai Chest Hospital (2008-2012). By using the Kaplan-Meier method and Cox proportional hazard regression model, we identified the correlations between LVI, VPI, and clinical outcomes in p-stage 1 NSCLC., Results: Of all 2633 p-stage I NSCLC patients, 222 were pathologically diagnosed with LVI and 836 pathologically with VPI. The 5-year recurrence free survival (RFS) and overall survival (OS) rates of patients with LVI was significantly worse compared to those without LVI (61.2% vs 82.0%, p < 0.001; 73.3% vs 88.1%, p < 0.001). The same results emerged for patients with VPI (70.1% vs 85.9%, p < 0.001; 82.3% vs 90.0%, p < 0.001). Using the univariable and multivariable analysis, we found that when tumor diameter was 3 cm or smaller, LVI (RFS: hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.86-3.50; p < .001; OS: HR, 2.53; 95% CI, 1.72-3.71; p < .001) and VPI (RFS: HR, 2.14; 95% CI, 1.71-2.67; p < .001; OS: HR, 1.56; 95% CI, 1.12-2.04; p = 0.01) were significant prognostic factors for RFS and OS. When tumor size was between 3-4 cm, LVI (HR, 1.84; 95% CI, 1.03-3.29; p = 0.039) and VPI (HR, 2.56; 95% CI, 1.61-4.07; p < .001) were associated with inferior OS., Conclusions: The presence of LVI significantly affected OS and RFS in stage I NSCLC patients. Our results suggested that it might be better to incorporate LVI as a T descriptor as VPI in the further TNM classification., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Oncogenic fusion genes consisting of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) can be detected in 5-7% of lung adenocarcinoma cases. The prevalence of ALK rearrangement in non-adenocarcinoma, non-small cell lung cancers (NA-NSCLC) is currently unknown. In addition, the efficacy of crizotinib in these patients has not been well established., Objectives: The aim of this study was to investigate the prevalence of ALK rearrangement in NA-NSCLC patients and the therapeutic efficacy of crizotinib in these patients., Methods: We included NA-NSCLC patients who were tested for the presence of ALK rearrangement in our institution from January 2013 to May 2018. The effectiveness of crizotinib in ALK-positive patients was retrospectively analyzed. A literature review was performed and eligible previously published cases were analyzed in combination with our data., Results: A total of 4662 patients were screened and 1696 NA-NSCLC patients were tested for the presence of ALK rearrangement during the study period. Thirty-two positive patients were identified (1.9%, 95% CI, 1.2-2.5%). A statistically higher percentage of younger (58.0 vs. 63.0, p = 0.01), female patients (53.1% vs. 10.8%, p < 0.01) who were non-smokers (71.9% vs. 40.6%, p < 0.01) and whose tumors contained adenocarcinoma components (34.4% vs. 6.1%, p < 0.01) were observed in the ALK-positive group. Eighteen patients were excluded from the study and 14 eligible patients were included for survival analysis. The median duration of crizotinib treatment (MDT) as a proxy for progression-free survival of the 14 eligible patients in our institution was 6.0 months (95% CI, 1.2-10.8 months). We combined our data with sporadic cases from 16 previous publications (total n = 37) and found that the MDT was 7.0 months (95% CI, 6.0-8.0 months)., Conclusions: Our study suggests the opportunity to test ALK rearrangement in NA-NSCLC patients, especially in younger, female, non-smoking patients containing adenocarcinoma components. Crizotinib provides an option for the treatment of NA-NSCLC patients who have an ALK rearrangement.

Background: Two or more different epidermal growth factor receptor (EGFR) mutations can be detected within a single tumor sample, which represents complex mutations. However, the frequency and efficacy of tyrosine kinase inhibitor (TKI) treatments for patients harboring these mutations are unknown., Methods: From January 2011 to January 2017, patients diagnosed with EGFR mutations were screened. The effectiveness of TKIs in patients with complex mutations was retrospectively analyzed., Results: A total of 16,840 subjects were screened, and there were 5898 positive patients. One hundred eighty-seven patients (3.2% of all patients with EGFR mutations) had complex EGFR mutations, and 51 of the patients with advanced adenocarcinoma were treated with TKIs as a first-line treatment. The objective response rates for patients who had Del-19+21L858R mutations (n = 15), Del-19/21L858R+atypical mutations (n = 16), double atypical mutations (n = 8), and complex mutations with a primary drug-resistant pattern (n = 12) were 75.0%, 60.0%, 71.0%, and 8.3%, respectively. The median progression-free survival times for the 4 groups were 18.2 months (95% confidence interval [CI], 10.6-25.9 months), 9.7 months (95% CI, 3.3-15.8 months), 9.6 months (95% CI, 3.3-19.0 months), and 1.4 months (95% CI, 0.4-2.3 months), respectively., Conclusions: These results from the largest sample size suggest that EGFR-TKI therapy is effective in patients with Del-19+21L858R mutations, Del-19/21L858R+atypical mutations, and double atypical mutations but is less effective in patients with a primary drug-resistant pattern. Patients with the Del-19+21L858R mutations may, therefore, benefit more from treatment with first-generation TKIs. Cancer 2018;124:2399-406. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Objectives: Occasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients., Materials and Methods: From January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed., Results: 16,842 individuals were screened during the study period with 5900 positive patients identified. Sixty-one patients were confirmed to have primary 20 T790M/insertion plus sensitive mutations (1% of all EGFR-mutant patients, 95% CI, 0.8%-1.3%). Among them, 31 eligible patients were included for survival analyses. The median progression-free survival (PFS) of the 15 osimertinib-treated patients was 18.0 months (95% CI, 15.1-20.9 months), which was greatly longer than the 16 patients who were treated with first generation TKIs (1.2 months, 95% CI, 0.9-1.6, P < 0.001). Similar results were also observed in overall survival (OS) with 25.1 months (95% CI, not calculable) in the osimertinib group and 17.3 months (95% CI, 9.3-25.4 months) in the first generation TKI group (P = 0.02)., Conclusions: For patients harboring primary resistant and sensitive mutations detected by routine clinical methods, first generation TKIs are ineffective even with the presence of sensitive mutations. However, osimertinib shows great survival benefit, and thus, should be considered during the whole clinical management., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Despite its great promise in non-invasive treatment of cancers, magnetic resonance-guided focused ultrasound surgery (MRgFUS) is currently limited by the insensitivity of magnetic resonance imaging (MRI) for visualization of small tumors, low efficiency of in vivo ultrasonic energy deposition, and damage to surrounding tissues. We hereby report the development of an active targeting nano-sized theranostic superparamagnetic iron oxide (SPIO) platform for significantly increasing the imaging sensitivity and energy deposition efficiency using a clinical MRgFUS system. The surfaces of these PEGylated SPIO nanoparticles (NPs) were decorated with anti-EGFR (epidermal growth factor receptor) monoclonal antibodies (mAb) for targeted delivery to lung cancer with EGFR overexpression. The potential of these targeted nano-theranostic agents for MRI and MRgFUS ablation was evaluated in vitro and in vivo in a rat xenograft model of human lung cancer (H460). Compared with nontargeting PEGylated SPIO NPs, the anti-EGFR mAb targeted PEGylated SPIO NPs demonstrated better targeting capability to H460 tumor cells and greatly improved the MRI contrast at the tumor site. Meanwhile, this study showed that the targeting NPs, as synergistic agents, could significantly enhance the efficiency for in vivo ultrasonic energy deposition in MRgFUS. Moreover, we demonstrated that a series of MR methods including T2-weighted image (T2WI), T1-weighted image (T1WI), diffusion-weighted imaging (DWI) and contrast-enhanced T1WI imaging, could be utilized to noninvasively and conveniently monitor the therapeutic efficacy in rat models by MRgFUS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Rs11614913 is a polymorphism in hsa-miR-196a2 reported to alter mature microRNA expression and function. This single-nucleotide polymorphism (SNP) was reported to be associated with susceptibility and prognosis of lung cancer., Methods: In this article, association study was performed to reveal the relation between SNP and response rate or severe toxicity after platinum-based regimen in advanced nonsmall cell lung cancer patients., Results: By screening this polymorphism in 442 Chinese patients with MALDI-TOF Mass Spectrometer, significantly higher occurrence of grade 3 or 4 overall toxicity (P = 0.02) in response to treatment was found in patients with homozygous CC. After stratified analyses, association between rs11614912 and overall toxicity existed, especially in individuals treated with gemcitabine (P = 0.006) or cisplatin (P = 0.008), and in male patients (P = 0.02) or younger patients (P = 0.01)., Conclusion: Our study confirmed that rs11614913 in hsa-miR-196a2 was associated with severe toxicity in lung cancer patients, and might help to improve individualized therapy in the future., (© 2012 Wiley Periodicals, Inc.)

Purpose: Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy., Experimental Design: 353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg(156)Arg, Asp(312)Asn, Asp(711)Asp and Lys(751)Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing., Results: Variant genotypes of XPD Asp(312)Asn, Asp(711)Asp and Lys(751)Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp(312)Asn, Asp(711)Asp and Lys(751)Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10(-4), log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0-1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS., Conclusions: Our study provides evidence for the predictive role of XPD Asp(312)Asn, Asp(711)Asp and Lys(751)Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.

Platinum-based chemotherapy is the most common treatment for non-small cell lung cancer (NSCLC), and expression levels of drug metabolism and transport proteins are correlated with its efficacy and toxicity. In this study, we investigated the association of three putative functional polymorphisms of ABCC2 (C-24T, G1249A, and C3972T) with tumor response and occurrence of the grade 3 or 4 toxicity in 445 patients with stage III and IV NSCLC treated with platinum-based chemotherapy. We determined the genotypes of these three polymorphisms by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MassArray) method. We found that the common homozygotes of -24C was associated with a better treatment response (adjusted odds ratios [ORs], 1.84; 95% confidence interval [CI], 1.05-3.23; P=0.032). Furthermore, patients with 3972T had increased risk of severe thrombocytopenia toxicity (adjusted OR, 2.43; 95% CI, 1.06-5.56; P=0.034); and in female subgroup analyses, this variant was associated with significantly increased risk of overall toxicity (adjusted OR, 2.63; 95% CI, 1.17-5.95; P=0.02), particularly of hematologic toxicity (adjusted OR, 3.80; 95% CI, 1.62-8.87; P=0.002). Moreover, -24T/3972T haplotype was also associated with significantly increased risk of hematologic toxicity. Our results suggested that C-24T variants had an effect on treatment response and that C3972T had an effect on severe toxicities among platinum-treated non-small cell lung cancer patients., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer patients., Experimental Design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non-small cell lung cancer patients treated with platinum-based chemotherapy., Results: The variant homozygotes of XPD p.Arg(156)Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype "CG" (in the order of p.Arg(156)Arg-p.Asp(312)Asn) on the risk of grade 3 or 4 hematologic toxicity., Conclusions: This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg(156)Arg polymorphism on severe toxicity variability among platinum-treated non-small cell lung cancer patients.