Characterization of Lung and Oral Microbiomes in Lung Cancer Patients Using Culturomics and 16S rRNA Gene Sequencing.

Recently, microbiota dysbiosis in lung cancer has attracted immense attention. Studies on lung microbes are mostly based on sequencing, which has left the potentially functional bacteria with extremely low abundance uncovered. In this study, we characterized and compared the lung and oral cavity microbiotas using culturomics and 16S rRNA gene sequencing. Of the 198 bacteria identified at the species level from bronchoalveolar lavage fluid (BALF) samples, Firmicutes was predominant (39.90%). Twenty bacterial species isolated from BALF samples were present in at least half of the patients and were also highly abundant in oral samples. Of all isolated strains, Streptococcus and Veillonella were highly dominant. The abundance of Prevotella and Veillonella decreased from the oral cavity to the lung, whereas that of Pseudomonas increased. Linear discriminant analysis effect size demonstrated that Prevotella was more abundant in the healthy samples than in the cancerous ones, which is in accordance with the isolation of Prevotella oralis only from the healthy group using culturomics. Moreover, Gemella sanguinis and Streptococcus intermedius were isolated only from the non-small-cell lung cancer (NSCLC) group, and 16S rRNA gene sequencing showed that they were higher in the NSCLC than in the small-cell lung cancer group. Furthermore, while Bacillus and Castellaniella were enriched in lung adenocarcinoma, Brucella was enriched in lung squamous cell carcinoma. Overall, alterations were observed in the microbial community of patients with lung cancer, whose diversity might be site and pathology dependent. Using culturomics and 16S rRNA gene amplicon sequencing, this study has provided insights into pulmonary and oral microbiota alterations in patients with lung cancer. IMPORTANCE The relationship between lung microbiota and cancer has been explored based on DNA sequencing; however, culture-dependent approaches are indispensable for further studies on the lung microbiota. In this study, we applied a comprehensive approach combining culturomics and 16S rRNA gene amplicon sequencing to detect members of the microbiotas in saliva and BALF samples from patients with unilateral lobar masses. We found alterations in the microbial community of patients with lung cancer, whose diversity might be site and pathology dependent. These features may be potential bacterial biomarkers and new targets for lung cancer diagnosis and treatment. In addition, a lung and oral microbial biobank from lung cancer patients was established, which represents a useful resource for studies of host-microbe interactions.

Secreted proteins MDK, WFDC2, and CXCL14 as candidate biomarkers for early diagnosis of lung adenocarcinoma.

BACKGROUND: Early diagnosis of lung adenocarcinoma (LUAD), one of the most common types of lung cancer, is very important to improve the prognosis of patients. The current methods can't meet the requirements of early diagnosis. There is a pressing need to identify novel diagnostic biomarkers. Secretory proteins are the richest source for biomarker research. This study aimed to identify candidate secretory protein biomarkers for early diagnosis of LUAD by integrated bioinformatics analysis and clinical validation. METHODS: Differentially expressed genes (DEGs) of GSE31210, gene expression data of early stage of LUAD, were analyzed by GEO2R. Upregulated DEGs predicted to encode secreted proteins were obtained by taking the intersection of the DEGs list with the list of genes encoding secreted proteins predicted by the majority decision-based method (MDSEC). The expressions of the identified secreted proteins in the lung tissues of early-stage LUAD patients were further compared with the healthy control group in mRNA and protein levels by using the UALCAN database (TCGA and CPTAC). The selected proteins expressed in plasma were further validated by using Luminex technology. The diagnostic value of the screened proteins was evaluated by receiver operating characteristic (ROC) analysis. Cell counting kit-8 assay was carried out to investigate the proliferative effects of these screened proteins. RESULTS: A total of 2183 DEGs, including 1240 downregulated genes and 943 upregulated genes, were identified in the GSE31210. Of the upregulated genes, 199 genes were predicted to encode secreted proteins. After analysis using the UALCAN database, 16 molecules were selected for further clinical validation. Plasma concentrations of three proteins, Midkine (MDK), WAP four-disulfide core domain 2 (WFDC2), and C-X-C motif chemokine ligand 14 (CXCL14), were significantly higher in LUAD patients than in healthy donors. The area under the curve values was 0.944, 0.881, and 0.809 for MDK, WFDC2, and CXCL14, 0.962 when combined them. Overexpression of the three proteins enhanced the proliferation activity of A549 cells. CONCLUSIONS: MDK, WFDC2, and CXCL14 were identified as candidate diagnostic biomarkers for early-stage LUAD and might also play vital roles in tumorigenesis.

Analysis of spatial distribution characteristics and main influencing factors of heavy metals in road dust of Tianjin based on land use regression models.

Land use regression (LUR) models are mainly used for the simulation and prediction of conventional atmospheric pollutants. Whether the LUR models can be expanded to study more toxic and hazardous pollutants (such as heavy metals) remains to be verified. Combined with the factors of road, land use type, population, pollution enterprise, meteorology, and terrain, the LUR models were used to simulate the spatial distribution characteristics of heavy metals in road dust and determine the main influencing factors. Samples of road surface dust were collected from 144 evenly distributed points in Tianjin, China, with 108 modelling points and 36 verification points. The R2 values of the LUR models of Cd, Cr, Cu, Ni, and Pb contents were 0.301, 0.412, 0.399, 0.496, and 0.377, and their error rates were 2.72%, 4.96%, 4.64%, 8.91%, and 4.94%, respectively. The error rates of the kriging interpolation models were 3.33%, 6.50%, 5.14%, 18.30%, and 22.87%, which were all greater than those of the LUR models. The estimation effect of the LUR models was more refined than that of the kriging interpolation models. The contents of most heavy metals (except Ni) in road dust of the central area in Tianjin were generally higher than those of the surrounding areas. The heavy metal contents in road dust of Tianjin were mainly affected by road variables and meteorological variables. The LUR models were suitable for small-scale spatial prediction of heavy metals in urban road dust within urban areas.

The prevalence and real-world therapeutic analysis of Chinese patients with KRAS-Mutant Non-Small Cell lung cancer.

OBJECTIVE: Kirsten rat sarcoma viral oncogene homolog (KRAS) is an important driver gene of non-small cell lung cancer (NSCLC). Despite a rapid progress achieved in the targeted therapy, chemotherapy remains the standard treatment option for patients with KRAS-mutant NSCLC. This study aimed to assess real-world data of Chinese patients with KRAS-mutant NSCLC undergoing chemotherapy and/or immunotherapy. METHODS: KRAS mutational status was analyzed using next-generation sequencing of 150,327 NSCLC patients from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) project (Cohort I). Treatment data were collected and analyzed retrospectively from 4348 NSCLC patients who were admitted to the Peking University Cancer Hospital and Institute between January 2009 and October 2020 (Cohort II). RESULTS: In Cohort I, 18,224 patients were detected with KRAS mutations (12.1%) of whom G12C (29.6%) was the most frequent subtype, followed by G12D (18.1%) and G12V (17.5%). In case of concomitant mutations, TP53 had the highest incidence of 33.6%, followed by EGFR (11.6%), STK11 (10.4%), KEAP1(6.2%), and CDKN2A (6.0%). Cohort II included 497 patients (11.4%) with KRAS mutations. In the first-line chemotherapeutic analysis of Cohort II, patients benefited more from the pemetrexed/platinum (PP) regimen than the gemcitabine/platinum (GP) or taxanes/platinum (TP) regimen (median progression-free survival [PFS], 6.4 vs. 4.9 vs. 5.6 months, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.48-0.88, p = 0.033 and HR = 0.69, 95% CI 0.47-1.00, p = 0.05, respectively), with no significant difference when combined with bevacizumab. Regarding patients who received immune checkpoint inhibitors (ICIs), the objective response rate was 26% for a median PFS of 9.6 months (95% CI 6.16-13.03). Patients who received ICIs combined with chemotherapy had a significantly longer survival than monotherapy (median PFS, 13.9 vs. 5.2 months, HR = 0.59, 95% CI 0.35-0.99, p = 0.049). CONCLUSION: KRAS is an important driver gene in NSCLC, compromising 12.1% in this study, and G12C was noted as the most common subtype. Patients with KRAS-mutant NSCLC could benefit from pemetrexed-based chemotherapy and ICIs.

Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells.

Lung cancer is the second most common cancer worldwide and the leading cause of cancer death in the world. Therefore, there is an urgent need to develop new and effective biomarkers for diagnosis and treatment. Under this circumstance, human endogenous retroviruses (HERVs) were recently introduced as novel biomarkers for cancer diagnosis. This study focused on the correlation between lung cancer and HERV-K (HML-2) transcription levels. At the cellular level, different types of lung cancer cells and human normal lung epithelial cells were used to analyze the transcription levels of the HERV-K (HML-2) gag, pol, and env genes by RT-qPCR. At the level of lung cancer patients, blood samples with background information from 734 lung cancer patients and 96 healthy persons were collected to analyze the transcription levels of HERV-K (HML-2) gag, pol, and env genes. The results showed that the transcriptional levels of the HERV-K (HML-2) gag, pol, and env genes in lung cancer cells and lung cancer patient blood samples were significantly higher than those in the healthy controls, which was also verified by RNAScope ISH technology. In addition, we also found that there was a correlation between the abnormal transcription levels of HERV-K (HML-2) genes in lung cancer patients and the clinicopathological parameters of lung cancer. We also identified the distribution locations of the gag, pol, and env primer sequences on each chromosome and analyzed the function of these loci. In conclusion, HERV-K (HML-2) genes may be a potential biomarker for the diagnosis of lung cancer.

A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non-Small Cell Lung Cancer: a Multicenter Phase I/II Study.

PURPOSE: To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non-small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II. PATIENTS AND METHODS: This multicenter, open-label study included 367 adult Chinese patients. Abivertinib at doses of 50 mg twice a day to 350 mg twice a day was evaluated in phase I in continual 28-day cycles, and the RP2D of 300 mg twice a day was used in phase II in continual 21-day cycles. Primary endpoints include RP2D in phase I and objective response rate (ORR) at RP2D in phase II. RESULTS: The RP2D of 300 mg twice a day for abivertinib was established based on pharmacokinetics, efficacy, and safety profiles across doses in phase I. In phase II, 227 patients received RP2D for a median treatment duration of 24.6 weeks (0.43-129). Among 209 response-evaluable patients, confirmed ORR was 52.2% [109/209; 95% confidence interval (CI): 45.2-59.1]. Disease control rate (DCR) was 88.0% (184/209; 95% CI: 82.9-92.1). The median duration of response (DoR) and progression-free survival (PFS) was 8.5 months (95% CI: 6.1-9.2) and 7.5 months (95% CI: 6.0-8.8), respectively. The median overall survival (OS) was 24.9 months [95% CI: 22.4-not reachable (NR)]. All (227/227) patients reported at least 1 adverse event (AE), with 96.9% (220/227) of treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed as treatment-related. CONCLUSIONS: Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy with manageable side effects in patients with EGFR T790M+ NSCLC.

Toripalimab in an advanced non-small cell lung cancer patient with poor general condition after multiline treatment: a case report.

Several clinical trials have proven that immunotherapy can improve survival and benefit non-small cell lung cancer (NSCLC) patients. In patients who progress after chemotherapy, immune checkpoint inhibitor (ICI) monotherapy can prolong overall survival compared with patients receiving single-agent chemotherapy. A 61-year-old man diagnosed with advanced NSCLC and without driver variants received first-line chemotherapy but experienced recurrence. During subsequent treatment, the disease progressed rapidly, and his general condition deteriorated; therefore, toripalimab monotherapy was initiated. Surprisingly, he responded well, and symptoms were relieved after several treatment cycles despite pseudoprogression, shown in chest images. For driver gene-negative NSCLC patients who progress after chemotherapy and who develop poor performance status (PS), ICIs are an option to alleviate symptoms and improve survival. Furthermore, immunotherapy in patients with pseudoprogression may also provide a survival benefit.

Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma-A Retrospective Analysis of a Multicenter Clinical Study.

Currently, there are limited treatment options for patients who developed resistance to osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor. Resistance to EGFR inhibitors is frequently associated with enhanced vascular endothelial growth factor (VEGF) levels. This multicenter, retrospective study aimed to evaluate the efficacy of the combination treatment with apatinib and osimertinib in 39 patients with EGFR-mutant non-small cell lung carcinoma (NSCLC) who developed osimertinib resistance. The patients received the combination of oral apatinib 250 mg qd and osimertinib 80 mg qd. The efficacy was evaluated after the first month then every 2 months thereafter. The primary endpoint was progression-free survival (PFS). The overall response rate (ORR) and the disease control rate (DCR) of the combination of apatinib and osimertinib was 12.8% (5/39) and 79.5% (31/39), respectively. The median PFS was 4 months [95% confidence interval (CI): 3.5-4.5 months]. Fourteen patients were administered with at least 6 months of combination therapy, and 11 of them remained on treatment programs. The 6-month PFS rate was 38%. Nine patients underwent biopsies after failing osimertinib treatment, and five of six patients with TP53 mutations had PFS of less than 3 months. The spectrum of resistance to osimertinib mechanisms included c-mesenchymal-epithelial transition factor (c-Met) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gain-of-function mutation, phosphatase and tensin homolog (PTEN) loss-of-function mutation, Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, and insulin-like growth factor 1 receptor (IGF1R) mutation. The most common adverse events were hypertension (30.7%, 12/39), diarrhea (15.4%, 6/39), and proteinuria (12.8%, 5/39). The combination of apatinib and osimertinib improved the ORR and the DCR of patients with osimertinib-refractory EGFR-positive NSCLC, thus making it a reasonable treatment choice after the development of osimertinib resistance.

Evaluation of different treatment strategies between right-sided and left-sided pneumonectomy for stage I-IIIA non-small cell lung cancer patients.

BACKGROUND: This study aimed to assess the different survival outcomes of stage I-IIIA non-small cell lung cancer (NSCLC) patients who received right-sided and left-sided pneumonectomy, and to further develop the most appropriate treatment strategies. METHODS: We accessed data from the Surveillance, Epidemiology, and End Results database from the United States for the present study. An innovative propensity score matching analysis was used to minimize the variance between groups. RESULTS: For 2,683 patients who received pneumonectomy, cancer-specific survival [hazard ratio (HR) =0.863, 95% confidence interval (CI): 0.771 to 0.965, P=0.010] and overall survival (OS; HR =0.875, 95% CI: 0.793 to 0.967, P=0.008) were significantly superior in left-sided pneumonectomy patients compared with right-sided pneumonectomy patients. Cancer-specific survival (HR =0.847, 95% CI: 0.745 to 0.963, P=0.011) and OS (HR =0.858, 95% CI: 0.768 to 0.959, P=0.007) were also significantly longer with left-sided compared to right-sided pneumonectomy after matching analysis of 2,050 patients. Adjuvant therapy could significantly prolong cancer-specific survival (67 versus 51 months, HR =1.314, 95% CI: 1.093 to 1.579, P=0.004) and OS (46 versus 30 months, HR =1.458, 95% CI: 1.239 to 1.715, P<0.001) among left-sided pneumonectomy patients after the matching procedure, while adjuvant therapy did not increase cancer-specific survival for right-sided pneumonectomy patients (46 versus 42 months, HR =1.112, 95% CI: 0.933 to 1.325, P=0.236). Subgroup analysis showed that adjuvant chemotherapy could significantly improve cancer-specific survival and OS for all pneumonectomy patients. However, radiotherapy was associated with worse survival for patients with right-sided pneumonectomy. CONCLUSIONS: Pneumonectomy side can be deemed as an important factor when physicians determine the most optimal treatment strategies.

Efficacy and safety of pemetrexed maintenance chemotherapy for advanced non-small cell lung cancer in a real-world setting.

BACKGROUND: Pemetrexed maintenance therapy offers a survival benefit in patients with nonprogressive advanced nonsquamous non-small cell lung cancer (NSCLC) with good tolerability. This study was designed to analyze the efficacy and safety of pemetrexed maintenance chemotherapy in advanced nonsquamous NSCLC patients in a real-world setting. METHODS: The response rate (RR) and adverse events in 71 nonsquamous NSCLC patients treated with pemetrexed-based chemotherapy were observed until disease progression or unacceptable toxicities. Measures of survival were analyzed during follow-up. RESULTS: Of 69 efficacy-evaluable patients, the objective response rate (ORR) was 46.4% and the disease control rate (DCR) was 98.6%. ORR showed no significant difference between patients who received pemetrexed as first-line therapy and those who received pemetrexed as second-line or higher treatment. The median treatment cycle for all patients was 8. The median progression-free survival (PFS) was 9.5 months (m) and median overall survival (OS) was 30.5 m. The univariate and multivariate analyses showed that the number of chemotherapy cycles was an independent factor for PFS. The most common adverse reactions were grade 1 to 2 hematologic toxicities, gastrointestinal reactions, and liver enzyme abnormalities. Only 1 patient experienced a grade 3 gastrointestinal event. CONCLUSIONS: Pemetrexed maintenance chemotherapy can improve PFS in patients with advanced nonsquamous NSCLC with good tolerability.

Identification of serum biomarkers to predict pemetrexed/platinum chemotherapy efficacy for advanced lung adenocarcinoma patients by data-independent acquisition (DIA) mass spectrometry analysis with parallel reaction monitoring (PRM) verification.

BACKGROUND: Pemetrexed/platinum chemotherapy has been the standard chemotherapy regimen for lung adenocarcinoma patients, but the efficacy varies considerably. METHODS: To discover new serum biomarkers to predict the efficacy of pemetrexed/platinum chemotherapy, we analyzed 20 serum samples from advanced lung adenocarcinoma patients who received pemetrexed/platinum chemotherapy with the data-independent acquisition (DIA) quantitative mass spectrometry (MS). RESULTS: The 20 patients were categorized as "good response" [12 patients achieving partial response (PR)] and "poor response" [8 patients with progressive disease (PD)] groups. Altogether 23 significantly different expressed proteins were identified, which had relative ratios higher than 1.2 or lower than -0.83, with 7 proteins having an area under the curve (AUC) above 0.8. To further validate the DIA results, we used the parallel reaction monitoring (PRM) method to examine 16 candidate serum biomarkers in the study cohort of 20 patients and another cohort of 22 advanced lung adenocarcinoma patients (16 PR and 6 PD). Quantitative validation using PRM correlated well with the DIA results, and 10 promising proteins exhibited a similar up- or downregulation. It is worth noting that glutathione peroxidase 3 (GPX3) exhibits significant upregulation in the poor response group compared with the good response group, which was validated by both DIA and PRM methods. CONCLUSIONS: Our study confirmed that combined DIA MS and PRM approaches were effective in identifying serum predictive biomarkers for advanced lung adenocarcinoma patients. Further studies are needed to explore the potential biological mechanism underlying these biomarkers.

Plasma cytokines interleukin-18 and C-X-C motif chemokine ligand 10 are indicative of the anti-programmed cell death protein-1 treatment response in lung cancer patients.

BACKGROUND: Although programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors have shown prominent efficacy for treatment of advanced lung cancer, the outcomes of metastatic lung cancer remain poor throughout the world. Although progression-free survival (PFS) and overall survival (OS) have improved in the first- and second-line therapy settings for advanced lung cancer, the response rates to PD-1/PD-L1 inhibition range from 20% to 40%. Furthermore, patients may be at risk for immune-related adverse events (irAEs); hence, appropriate patient selection is crucial. This study aimed to identify a panel of plasma cytokines representing prognostic and predictive biomarkers of the response to anti-PD-1/PD-L1 treatment. METHODS: We prospectively studied 32 lung cancer patients who received anti-PD-1/PD-L1 antibody immunotherapy. Plasma cytokines in peripheral blood samples were evaluated and analyzed using flow cytometry at the time of diagnosis and at 2 months after the initiation of PD-1/PD-L1 inhibition. RESULTS: The baseline plasma concentrations of interleukin-18 (IL-18) and C-X-C motif chemokine ligand 10 (CXCL10) were correlated with the degree of tumor response. Moreover, the magnitude of plasma IL-18 and CXCL10 level fluctuations were correlated significantly with the objective tumor response to anti-PD-1/PD-L1 immunotherapy, and patients with high CXCL10 expression had significantly shorter PFS than those with low CXCL10 expression. A strong positive correlation between the fluctuation of IL-18 and interleukin-8 (IL-8) levels was detected, as was a negative correlation between the fluctuation of IL-18 and CXCL10 levels. The level of plasma C-C motif chemokine ligand 5 (CCL5) was significantly higher in patients with irAEs than in those without irAEs. CONCLUSIONS: Plasma cytokines are related to the clinical efficacy of PD-1/PD-L1 inhibitors. IL-18 and CXCL10 are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.

Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients.

BACKGROUND: Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. METHODS: This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. RESULTS: Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P < 0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs. 25.0%, P = 0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab. CONCLUSIONS: Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment.

INTRODUCTION: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking. METHODS: ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel. RESULTS: Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment. CONCLUSIONS: The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.

Characterization of Microbiota in Cancerous Lung and the Contralateral Non-Cancerous Lung Within Lung Cancer Patients.

BACKGROUND: The functional role of lung microbiota has attracted an accumulating attention recently, but the profile and functional role of the lung microbiota in patients with lung cancer remained largely unknown. METHODS: To evaluate the association of the microbiota with lung cancer, we performed comparative analysis of the lung microbiota using 16S rRNA amplicon sequencing approach in the paired bronchoalveolar lavage fluid (BALF) samples (paired samples from cancerous lung and the contralateral non-cancerous lung) from 50 cancer patients with unilateral lobar masses. RESULTS: We found that the relative abundance of phylum Tenericutes, its class Mollicutes, its order Entomoplasmatales, its family Spiroplasmataceae, and its genus Spiroplasma was significantly increased in cancerous lung, but the relative abundance of phylum Bacteroidetes, its class Bacteroidia, and its order Bacteroidales was significantly decreased in cancerous lung. In addition, the relative abundance of family Leuconostocaceae and its genus Weissella was significantly increased in cancerous lung. CONCLUSION: Our findings provide insights into a change of lung microbiota community associated with the development of lung cancer.

Clinical Characteristics and Outcomes of Patients With Primary Mediastinal Germ Cell Tumors: A Single-Center Experience.

Purpose: Primary mediastinal germ cell tumors (PMGCTs) are rare. The natural history and optimal treatment strategies still need to be defined. The aim of the study was to summarize the clinical characteristics, treatment outcomes, and prognostic factors of PMGCTs. Methods: Twenty-four patients with PMGCTs who were treated from December 2008 to January 2019 were evaluated retrospectively. The Kaplan-Meier method and Cox regression analysis were used to evaluate factors associated with prognosis. Results: The study population consisted of 23 male patients and 1 female patient. Five patients were diagnosed with seminoma and 19 patients were diagnosed with nonseminoma. The median follow-up time for all patients was 15.8 (3.9-114.5) months. The 5-year overall survival (OS) and progression free survival (PFS) rates for all patients were 65.2 and 44.3%. For nonseminoma and seminoma, the 5-year OS rates were 54.1 and 100% (P = 0.093), respectively, and the 5-year PFS rates were 28.7 and 100%, respectively (P = 0.044). In patients with nonseminoma, first-line radiotherapy indicated superior OS and PFS (P = 0.037 and 0.027, respectively). The median survival time after recurrence was 4.3 months and the 1-year survival rate after recurrence was 23.4%. Conclusion: These results indicated that in PMGCTs, the prognosis of seminoma is superior to that of nonseminoma. Radiotherapy may be an essential treatment in patients with nonseminoma. Patients with relapse have unfavorable prognosis.

Nomogram model for predicting cause-specific mortality in patients with stage I small-cell lung cancer: a competing risk analysis.

BACKGROUND: The five-year cumulative incidence rate in patients diagnosed with stage I small-cell lung cancer (SCLC) who were instructed to undergo surgery was from 40 to 60%.The death competition influence the accuracy of the classical survival analyses. The aim of the study is to investigate the mortality of stage I small-cell lung cancer (SCLC) patients in the presence of competing risks according to a proportional hazards model, and to establish a competing risk nomogram to predict probabilities of both cause-specific death and death resulting from other causes. METHODS: The study subjects were patients diagnosed with stage I SCLC according to ICD-O-3. First, the cumulative incidence functions (CIFs) of cause-specific death, as well as of death resulting from other causes, were calculated. Then, a proportional hazards model for the sub-distribution of competing risks and a monogram were constructed to evaluate the probability of mortality in stage I SCLC patients. RESULTS: 1811 patients were included in this study. The five-year probabilities of death due to specific causes and other causes were 61.5 and 13.6%, respectively. Tumor size, extent of tumor, surgery, and radiotherapy were identified as the predictors of death resulting from specific causes in stage I SCLC. The results showed that surgery could effectively reduce the cancer-specific death, and the one-year cumulative incidence dropped from 34.5 to 11.2%. Like surgery, chemotherapy and radiotherapy improved the one-year survival rate. CONCLUSIONS: We constructed a predictive model for stage I SCLC using the data from the SEER database. The proportional sub-distribution models of competing risks revealed the predictors of death resulting from both specific causes and other causes. The competing risk nomogram that we built to predict the prognosis showed good reliability and could provide beneficial and individualized predictive information for stage I SCLC patients.

A nomogram model to predict death rate among non-small cell lung cancer (NSCLC) patients with surgery in surveillance, epidemiology, and end results (SEER) database.

BACKGROUND: This study aimed to establish a novel nomogram prognostic model to predict death probability for non-small cell lung cancer (NSCLC) patients who received surgery.. METHODS: We collected data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict mortality of NSCLC patients who received surgery. RESULTS: A total of 44,880 NSCLC patients who received surgery from 2004 to 2014 were included in this study. Gender, ethnicity, tumor anatomic sites, histologic subtype, tumor differentiation, clinical stage, tumor size, tumor extent, lymph node stage, examined lymph node, positive lymph node, type of surgery showed significant associations with lung cancer related death rate (P < 0.001). Patients who received chemotherapy and radiotherapy had significant higher lung cancer related death rate but were associated with significant lower non-cancer related mortality (P<0.001). A nomogram model was established based on multivariate models of training data set. In the validation cohort, the unadjusted C-index was 0.73 (95% CI, 0.72-0.74), 0.71 (95% CI, 0.66-0.75) and 0.69 (95% CI, 0.68-0.70) for lung cancer related death, other cancer related death and non-cancer related death. CONCLUSIONS: A prognostic nomogram model was constructed to give information about the risk of death for NSCLC patients who received surgery.

Effects of Surgery on Survival of Early-Stage Patients With SCLC: Propensity Score Analysis and Nomogram Construction in SEER Database.

Purpose: We aimed to assess the survival benefit of surgery for patients with stage IA-IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS). Methods: Patients who had been diagnosed with stage IA-IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram. Results: We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557-0.740; P < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's C-index = 0.645). Conclusion: Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.

Retrospective analysis of the effectiveness and tolerability of nab-paclitaxel in Chinese elderly patients with advanced non-small-cell lung carcinoma.

BACKGROUND: Previous trials have suggested that elderly patients with non-small-cell lung cancer (NSCLC) could benefit from nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Real-world data on the elderly Chinese population are lacking. This study aimed to analyze the effectiveness and tolerability of nab-paclitaxel in Chinese elderly patients (≥65 years) with advanced NSCLC. METHODS: This study included 76 patients with a primary diagnosis of IIIB-IV NSCLC from January 2010 to December 2017 at Peking University Cancer Hospital, who received nab-paclitaxel (125 or 130 mg/m2 i.v.) every three weeks. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. RESULTS: There were 12 patients who received nab-paclitaxel as the first-line treatment (seven also received carboplatin), and 64 received nab-paclitaxel as the latter-line treatment. The overall ORR, DCR, median PFS, and median OS were 14.5%, 69.7%, 5.2 months, and 12.2 months, respectively. The Eastern Cooperative Oncology Group performance status of one and the age of 70-74 years were independently associated with longer OS, while early treatment line of nab-paclitaxel and age of 70-74 years were independently associated with longer PFS. The most common AEs were anemia, leukopenia, gastrointestinal reaction, fatigue, and peripheral neuropathy, which were all manageable. Dose adjustment or treatment discontinuation was encountered in 10 patients because of AEs. The incidence of AEs was not different among age subgroups. CONCLUSIONS: Nab-paclitaxel has a good clinical response profile in Chinese elderly patients with stage IIIB-IV NSCLC. Prospective clinical trials are needed to confirm these results. KEY POINTS: Significant findings of the study Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has a good clinical response profile in Chinese elderly (≥65 years) patients with stage IIIB-IV non-small-cell lung cancer (NSCLC), with acceptable and manageable adverse events. What this study adds Preliminary evidence shows a good clinical response from treatment with nab-paclitaxel in Chinese elderly patients with advanced NSCLC.