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Background: Small cell lung cancer (SCLC) is a highly aggressive disease characterized by early metastasis. Aneuploid CD31- disseminated tumor cells (DTCs) and CD31+ disseminated tumor endothelial cells (DTECs) residing in the bone marrow are generally considered as the initiators of metastatic process. However, the clinical significance of DTCs and DTECs in SCLC remains poorly understood. The aim of this study is to investigate the clinical implications of diverse subtypes of highly heterogeneous DTCs and DTECs in SCLC patients. Methods: Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) was applied to enrich and perform comprehensive morphologic, karyotypic, and phenotypic characterization of aneuploid DTCs and DTECs in 30 patients. Additionally, co-detection of circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) was conducted on 24 of the enrolled patients. Proof-of-concept of the whole exon sequencings (WES) on precisely selected different subtypes of CTCs or DTCs, longitudinally detected from a representative case with pathologically confirmed bone marrow metastasis, was validated to feasibly reveal genetic mutations in these cells. Results: DTCs, DTECs and their subtypes were readily detectable in SCLC patients. Comparative analysis revealed that the number of DTCs and DTECs was significantly higher than that of their corresponding CTCs and CTECs (P < 0.001 for both). Positive detection of disseminated tumor microemboli (DTM) or disseminated tumor endothelial microemboli (DTEM) was associated with inferior survival outcomes (P = 0.046 and P = 0.048). Patients with EpCAM+ DTCs detectable displayed significantly lower disease control rate (DCR) (16.67% vs 73.33%, P = 0.019), reduced median progression-free survival (mPFS) and median overall survival (mOS) compared with those with EpCAM- DTCs (P = 0.028 and P = 0.002, respectively). WES analysis indicated that post-treatment DTCs isolated from bone marrow at the time of disease progression shared more homologous somatic gene mutations with pre-treatment CTCs compared with post-treatment CTCs. Conclusions: Our findings suggest that bone marrow sampling and characterization of DTC subtypes provided a valuable tool for predicting treatment response and the prognosis in SCLC. Moreover, DTCs inherit a greater amount of homologous somatic information from pre-treatment CTCs, indicating their potential role in disease progression and treatment resistance.

Abstract Background Selective RET inhibitors have been approved by the Chinese government for the treatment of RET-rearranged non-small cell lung cancer. This study aimed to illustrate the efficacy and safety of selective RET inhibitors in a real-world clinical context in China. Methods Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring RET rearrangement and receiving RET tyrosine kinase inhibitors (RET-TKI) in the real world were enrolled in this retrospective study. Clinical data, including baseline clinicopathological information, efficacy parameters such as objective response rate (ORR) and progression-free survival (PFS), and adverse events (AEs), were collected from the electronic medical record system. The pattern of treatment failure of first-line RET-TKI was also described. Results Fifty-one patients were enrolled in this study. RET-TKI induced an ORR of 73.1% and a median PFS (mPFS) of 22.7 months (95%CI, 11.7–33.7) in the first-line setting. The ORR and mPFS were 58.3% and 17.7 months (95%CI, 9.1–26.2), 55.6% and 14.7 months (95%CI, 12.6–16.8) in the second-line and later-line settings, respectively. No significant difference was observed among different application lines with respect to the ORR (P = 0.534) or PFS (P = 0.795). In the first-line setting, RET-TKI significantly prolonged PFS compared to other regimens including chemotherapy-based regimens, multikinase inhibitors and other systemic regimens without chemotherapy (P

Abstract Small-cell lung cancer (SCLC) transformation accounts for 3–14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.

Abstract Background SUZ12 is one of the core members of the polycomb repressive complex 2 (PRC2), but its expression and role in lung adenocarcinoma (LUAD) are unclear. We aimed to explore the expression, prognosis, biological functions and roles of SUZ12 in LUAD. Methods The expression of SUZ12 was detected by immunohistochemical staining, qRT‐PCR, and western blotting in LUAD tissues and cells. The biological functions and molecular mechanisms of SUZ12 were characterized by a range of in vitro and in vivo experiments. Results SUZ12 was overexpressed in LUAD tissues, and high SUZ12 expression was correlated with worse clinicopathological features and a poorer prognosis. Knockdown of SUZ12 significantly inhibited cell growth, colony formation, invasion, and migration, and induced apoptosis and G1/S phase arrest, while overexpression of SUZ12 had the opposite effects. Knockdown of SUZ12 decreased the tumorigenic capacity of A549 cells in vivo. The expression of key signaling molecules related to the cell cycle, apoptosis, migration, and immunity were altered by the knockdown or overexpression of SUZ12. SUZ12 can directly bind to the Bax promoter region, EZH2 and H3K27me3 levels dependents on SUZ12. The expression levels of SUZ12 and Bax were negatively correlated in LUAD tissues. Conclusions SUZ12 is a new oncogene related to the poor prognosis of LUAD. SUZ12 regulates LUAD progression by regulating the expression of related signaling molecules, and as a part of the PRC2 complex, it may bind to the Bax promoter to silence Bax expression.

Abstract Background The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non‐small cell lung cancer (NSCLC). Methods Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L‐) and subsequent lines (2L‐) of ICIs were defined as 1L‐ICI and 2L‐ICI, respectively. Results A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression‐free survival (mPFS), and median overall survival (mOS) for 2L‐ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L‐ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L‐ICIs were discontinued following clinical decision (the mPFS of 2L‐ICIs was not reach) achieved a more prolonged mPFS of 2L‐ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p

Abstract Background Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. Methods This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. Results A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. Conclusions Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. Trial registration Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Abstract Background As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Methods/design In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). Results Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1–13.8%) and 42.1% (16/38, 95% CI 26.3–59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4–99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9–3.7) and 10.3 months (95% CI 7.3–not evaluable [NE]), respectively. Conclusion BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. Trial registration Clinicaltrials.gov NCT02929290 (11/10/2016).

Abstract Objective To retrospectively analyze the efficacy and safety of osimertinib combined with anlotinib in the treatment of advanced non‐small‐cell lung cancer (NSCLC) after drug resistance, and to explore the related factors affecting the efficacy. Methods The clinical data of 34 patients with advanced NSCLC who received osimertinib combined with anlotinib as three or more lines of treatment in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from June 2019 to March 2022 were collected, and the therapeutic efficacy and safety were analyzed. Results A total of 34 advanced NSCLC patients met the inclusion criteria. The objective response rate was 20.6%, the disease response rate was 88.2%, the median overall survival was 19.0 months, and the median progression‐free survival was 6.0 months. The common adverse events were mainly grade 1–2, and only three cases (11.1%) of adverse events were grade 3, including hypertension, proteinuria, and vomiting. No grade 4 or above adverse events were observed. Multivariate Cox regression analysis showed that the Eastern Cooperative Oncology Group Performance Status score and bone metastasis were independent prognostic factors for osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC. Conclusions Osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC was effective and adverse events were tolerable.

ObjectiveThis study sought to assess the efficacy and safety of immunotherapy combined with single-agent chemotherapy as a second- or later-line setting for metastatic non-small cell lung cancer (NSCLC) and to provide clinical evidence for this treatment regimen. The predictive value of extracellular vesicle (EV) membrane proteins was explored in patients who underwent this treatment.MethodsClinical data from patients diagnosed with metastatic NSCLC who received immunotherapy plus single-agent chemotherapy as a second- or later-line setting were retrospectively collected between March 2019 and January 2022. A total of 30 patients met the inclusion criteria, and all were pathologically confirmed to have NSCLC. Short-term efficacy, progression-free survival (PFS), EV markers for response prediction, and adverse events were assessed.ResultsEfficacy data were available for all 30 patients and included a partial response in 5 patients, stable disease in 18 patients, and disease progression in 7 patients. The objective response rate was 16.7%, the disease control rate was 76.7%, and the median PFS was 3.2 months. Univariate analysis showed that PFS was not associated with sex, age, smoking status, treatment lines, prior use of immunotherapy, or prior use of antiangiogenic drugs. The EV membrane proteins MET proto-oncogene, receptor tyrosine kinase (c-MET), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor 2 (VEGFR2) at baseline were associated with poor prognosis and correlated with the efficacy of immunotherapy plus chemotherapy. According to the receiver operating characteristics and Kaplan–Meier curve analyses, patients with high c-MET, EGFR, and VEGFR2 expression at baseline had significantly shorter PFS than those with low expression. In addition, VEGFR2 expression was increased after combined immunotherapy in responders, which was decreased in non-responders. The most common grade 2 or higher adverse events were neutropenia, gastrointestinal reactions, and thyroid dysfunction, all of which were tolerated.ConclusionsImmunotherapy plus single-agent chemotherapy as a second- or later-line treatment is safe, effective, and tolerable for metastatic NSCLC. EV markers can be used as predictive markers of efficacy in patients with metastatic NSCLC treated with immunotherapy plus chemotherapy to help monitor treatment efficacy and guide treatment decisions.

Abstract Background Real‐world application of osimertinib with antiangiogenic agents in non‐small cell lung cancer (NSCLC) is common, but the efficacy data are rarely reported. Methods To obtain an objective efficacy report of different real‐world treatment models of osimertinib and antiangiogenic agents. Results A total of 54 patients with NSCLC were enrolled into the study. Twelve (22.2%) who received a combination of antiangiogenic agents, when there was a trend of osimertinib resistance but did not reach imageology progressive disease (PD), were assigned to Group A, with a median overall survival (OS) and progression‐free survival (PFS) of 48.0 (95% CI, not reached) and 21.0 (95% CI: 16.7–25.3) months, respectively. Thirty (55.6%) who received a combination of antiangiogenic agents when there was imageology PD during treatment with osimertinib were assigned to Group B, with a median OS and PFS of 31.8 (95% CI: 26.6–37.1) and 9.2 (95% CI: 5.9–12.6) months, respectively. Twelve (22.2%) who received a combination of antiangiogenic agents at the initial treatment with osimertinib were assigned to Group C, with a median OS and PFS of 28.5 (95% CI: 15.2–41.8) and 15.3 (95% CI: 7.9–22.7) months, respectively. Patients in Group A achieved a significant prolonged median PFS (p

Abstract Background Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients. Methods HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR). Results Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported. Conclusions Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 .

IntroductionThe treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics.MethodsA total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis.ResultsThe radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable.DiscussionThe constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC.

BackgroundNeoadjuvant chemoimmunotherapy (NCIO) is more effective than neoadjuvant immunotherapy alone for pathological response in non-small cell lung cancer (NSCLC) patients, but the processes for determining patient suitability for its implementation are not clear. We aimed to identify the most relevant factors and build a convenient model to select NSCLC patients who would benefit most from NCIO.Methods We retrospectively collected the clinical data of patients with locally advanced NSCLC who received NCIO followed by surgery at our institution between January 2019 and July 2022.ResultsA total of 101 eligible stage IIB-IIIC NSCLC patients were included. After NCIO, all patients successfully underwent surgical resection. A total of 46.53% (47/101) of patients achieved pathological complete response (pCR), and 70.30% (71/101) achieved major pathologic response (MPR). Tumor regression rate (adjusted odds ratio OR = 12.33), PD-L1 expression (adjusted odds ratio (OR) = 9.66), pembrolizumab/nab-paclitaxel–based regimens (adjusted OR = 4.92), and comorbidities (adjusted OR = 0.16) were independently associated with pCR rate (all P < 0.05). Tumor regression rate (adjusted OR = 8.45), PD-L1 expression (adjusted OR = 5.35), and presence of squamous cell carcinoma (adjusted OR = 7.02) were independently associated with MPR rate (all P < 0.05). We established and validated an easy-to-use clinical model to predict pCR (with an area under the curve [AUC] of 0.848) and MPR (with an AUC of 0.847). Of note, the present study showed that CD4+ T-cell count/rate and total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels in the peripheral blood of pre-NCIO patients were also significantly correlated with pathological response in univariate analyses.ConclusionsThe tumor regression rate, PD-L1 expression, pembrolizumab/nab-paclitaxel–based regimens, presence of squamous cell carcinoma, and comorbidities were the main influential factors for incidence of pCR/MPR in patients with stage IIB-IIIC NSCLC in the present study. Through predictive models, we can predict who will benefit most from NCIO prior to the emergence of clinical outcomes in locally advanced NSCLC.

Abstract Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of TKIs for nonclassical EGFR mutation is unclear, especially for patients with rare uncommon mutations. Methods A retrospective study based on electronic medical records was conducted to collect data on the effectiveness of afatinib in patients with stage IIIB/IV lung adenocarcinoma (LUAD) bearing uncommon mutations between January 2017 and January 2021. Results Forty‐two patients with uncommon mutations treated with afatinib were enrolled. The objective response rate (ORR) was 50.0% (10 of 20 patients). The median time to treatment failure (TTF) was 11.7 months (95% confidence interval = 8.5–18.3 months). Of the 42 patients, the median TTF was 15.0, 11.7, and 16.6 months in patients with Gly719Xaa (G719X), Ser768Ile (S768I), and Leu861Gln (L861Q) mutations, respectively. In patients with the rare uncommon mutation, the median TTF was 10.0 months, and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare uncommon mutations, including EGFR L747P, A767_V769dup, and L833V/H835L, with a case having a TTF of more than 1 year. Molecular profiling reports of 16 afatinib‐resistant biopsy samples were available, and the secondary T790M mutation was detected in one patient with L833V/H835L mutation and one harboring S768I/L858R mutation. Conclusions Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.

Objective: Immune checkpoint inhibitors have revolutionized cancer therapy for multiple types of solid tumors, but as expected, a large percentage of patients do not show durable responses. Biomarkers that can predict clinical responses to immunotherapies at diagnosis are therefore urgently needed. Herein, we determined the associations between baseline gut commensal microbes and the clinical treatment efficiencies of patients with thoracic neoplasms during anti-programmed death protein 1 (PD-1) therapy. Methods: Forty-two patients with advanced thoracic carcinoma who received anti-PD-1 treatment were enrolled in the study. Baseline and time-serial stool samples were analyzed using 16S ribosomal RNA gene sequencing. Tumor responses, patient progression-free survival, and overall survival were used to measure clinical outcomes. Results: The diversities of the baseline gut microbiota were similar between responders (n = 23) and nonresponders (n = 19). The relative abundances of the Akkermansiaceae, Enterococcaceae, Enterobacteriaceae, Carnobacteriaceae and Clostridiales Family XI bacterial families were significantly higher in the responder group. These 5 bacterial families acted as a commensal consortium and better stratified patients according to clinical responses (P = 0.014). Patients with a higher abundance of commensal microbes had prolonged PFS (P = 0.00016). Using multivariable analysis, the abundance of the commensal consortium was identified as an independent predictor of anti-PD-1 immunotherapy in thoracic neoplasms (hazard ratio: 0.17; 95% confidence interval: 0.05–0.55; P = 0.003). Conclusions: Baseline gut microbiota may have a critical impact on anti-PD-1 treatment in thoracic neoplasms. The abundance of gut commensal microbes at diagnosis might be useful for the early prediction of anti-PD-1 immunotherapy responses.

Abstract Background Transformation to small cell lung cancer (SCLC) is a resistance mechanism of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (LADC) patients treated with EGFR tyrosine kinase inhibitors (TKIs). Here, we describe the clinical characteristics and prognosis of these patients and explore the treatment modes after transformation. Methods EGFR‐mutant LADC patients with SCLC transformation were retrospectively included in the study. Demographic and clinical data were collected. Survival outcomes and corresponding influential factors were analyzed. Results Twenty‐nine patients were included in the study. The median progression‐free survival (PFS) of patients who received first‐line EGFR‐TKIs was 13.1 months. The median time to SCLC transformation was 27.5 months. After transformation, the objective response rates of patients who received first‐line chemotherapy with or without EGFR‐TKIs were 43.8% and 37.5%, respectively. The median PFS of patients reveiving chemotherapy with EGFR‐TKIs was significantly longer than that of patients receiving chemotherapy without EGFR‐TKIs (5.2 vs. 3.0 months; HR, 0.19; 95% CI: 0.05–0.72; p = 0.014). However, there was no significant difference in median overall survival (OS) between patients who received chemotherapy with or without EGFR‐TKIs (14.8 vs. 13.0 months; p = 0.474). In the multivariate Cox proportional hazards regression analysis, both anti‐angiogenic treatment (HR, 0.04; 95% CI: 0.01–0.29; p = 0.001) and local radiotherapy (HR, 0.28; 95% CI: 0.08–0.97; p = 0.044) were significantly associated with better patient OS after transformation. Conclusions Compared with chemotherapy alone, the combination of chemotherapy and EGFR‐TKIs as first‐line treatment after SCLC transformation can benefit patients in PFS but not in OS. However, anti‐angiogenic therapies and local radiotherapy can significantly prolong OS after transformation.

Abstract Background Previous studies have demonstrated that PD‐1 inhibitors are effective in the treatment of advanced or metastatic non‐small cell lung cancer (NSCLC). However, whether the combination of PD‐1 inhibitors and antiangiogenic agents benefit advanced NSCLC patients as subsequent therapy remains unknown. In this study, we retrospectively reviewed the efficacy and safety profile of this combination strategy as subsequent therapy for NSCLC patients in a real‐world setting. Methods A total of 30 patients with advanced NSCLC, who progressed after at least two cycles of platinum‐based chemotherapy or targeted therapy and subsequently received combination therapy with a PD‐1 inhibitor and antiangiogenic agent, were included in this study. The safety profile and efficacy were also investigated. Results At the time of a median follow‐up period of 10.7 months, 28 patients had experienced progression of disease and 16 patients had died. The median progression‐free survial (mPFS) was 5.0 months (95% confidence interval [CI]: 3.179–6.821), and the median overall survival (mOS) was 14.3 months (95% CI: 8.912–19.659). The objective response rate (ORR) and the disease control rate (DCR) were 10.3% and 72.4%, respectively (0 complete remission, three partial responses and 18 stable disease in 29 patients with measurable lesions). Patients with PD‐L1 expression of at least 1% of tumor cells (n = 5) had relatively longer mPFS compared to those with PD‐L1‐negative tumors (n = 14), (11.6 months vs. 3.7 months). Treatment was suspended in two patients due to grade 3 immune‐related pneumonia and pancreatitis, respectively. No novel adverse events (AEs) or grade 4 AEs were observed. Conclusions A combination of PD‐1 inhibitors and antiangiogenic targeting agents may be beneficial for patients with advanced or metastatic NSCLC as subsequent treatment, especially for patients with PD‐L1 protein expression positive, and treatment is well tolerated.

The cobalt−carbonate (CoCi)/NiFeOOH double-layer co-catalyst was prepared on bismuth vanadate (BiVO4). Compared with the same type of electrode (Co−Pi/NiFeOOH/BiVO4 and Co−Sil/NiFeOOH/BiVO4), the photoelectrochemical (PEC) performance of the composite electrode presents the most excellent performance. The Co−Ci/NiFeOOH/BiVO4 electrode prepared by photoelectric deposition (PED) achieves a photocurrent density of 4.1 ​mA/cm2 at 1.23 ​V vs RHE, and the applied bias photon-current efficiency (ABPE) is up to 0.95%. In addition, with the help of the equivalent circuit fitting in electrochemical impedance spectroscopy (EIS), the charge transfer resistance (Rct) of Co−Ci/NiFeOOH/BiVO4 is only 108.9 ​Ω, which is 16% that of BiVO4. The enhanced PEC performance of Co−Ci/NiFeOOH/BiVO4 in the double-layer cocatalyst system is attributed to the outstanding advantages of Co−Ci cocatalyst in oxygen vacancy defects, superior to other cobalt-based catalysts in promoting charge transfer and improving the kinetics of water oxidation. This makes Co−Ci co-catalyst become one of the favorable competitors in the field of photoelectric catalysis.

Abstract Introduction Local recurrence (LR) is clinical challenge in the treatment of esophageal squamous cell carcinoma (ESCC). The current study aimed to determine the optimal re-irradiation dose for local recurrent esophageal squamous cell carcinoma (LRESCC) following radical (chemo) radiotherapy. Methods We retrospectively analyzed 125 patients with LRESCC after receiving initial radiotherapy. For radiotherapy treatment, 58 patients were assigned to low-dose (LD) group (50–54 Gy) and 67 were assigned to the high-dose (HD) group (55–60 Gy). The response rate (complete + partial response), 1-, 2- and 3-year survival rate, and toxicity were recorded. We then analyzed the impact of different radiotherapy doses and combination chemotherapy on the survival of patients with LRESCC. Results After re-irradiation, the 1-, 2- and 3-year survival rates in the LD and HD groups were 48.3%, 24.1% and 10.3% and 61.2%, 34.3% and 19.4% in the HD group, respectively, and the difference in overall survival rate between the two groups were significant (P

Abstract Background BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC). Methods Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28 days). Standard “3 + 3” dose escalations were performed. Results Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to C max ranged from 2.0 to 3.5 h, and the plasma concentration of BPI-9016M declined rapidly after T max fitting a single-compartment model. The mean AUC0–72 h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8–6.6 folds and 4.1–9.8 folds higher than that of BPI-9016M, respectively. Exposure to BPI-9016M, M1, and M2-2 reached moderate saturation at 600 mg. Among 19 evaluable patients, 1 had a partial response and 10 patients had stable disease. Conclusion BPI-9016M showed favorable safety and pharmacokinetic profiles, and no DLT was observed at doses up to 800 mg once daily. The promising antitumor activity in Chinese NSCLC patients supports further development of this tyrosine kinase inhibitor. Trial registration Clinical Trial ID: NCT02478866, registered May 21, 2015.

BackgroundHyaluronan (HA) is one of the essential elements of the extracellular matrix (ECM), involved in the onset of metastasis in various tumors. The interaction and binding of the ligand–receptor HA/cluster of differentiation-44 (CD44) regulate the physical and biochemical properties of the ECM, which correlates with an increased propensity toward metastasis and poor survival outcome. Our study aimed to explore HA for predicting metastasis and survival rate in patients with small-cell lung cancer (SCLC).Materials and MethodsThis prospective cohort study recruited 72 patients with SCLC. Plasma HA and CD44 levels were assayed by enzyme-linked immunosorbent assay (ELISA) for 72 cases before initial systematic treatment (baseline samples), and plasma HA was detected via after-2-cycle-chemotherapy (A-2-C-CT) in 48 samples. Logistic regression analysis and the Cox proportional risk model were used to determine the independent predictors of distant metastasis and survival rate of patients.ResultsBaseline plasma HA was notably associated with bone metastasis (BM) [OR (95% CI = 1.015 (1.006–1.024), p = 0.001]. Multivariate logistic regression analysis showed that baseline plasma HA was chosen as an independent predictor of BM. Either baseline HA or CD44 or both were associated with BM. Dynamic alteration of HA was notably associated with A-2-C-CT clinical efficacy. Multivariate Cox regression analysis in forward likelihood ratio showed that A-2-C-CT HA was an independent predictor of progression-free survival (PFS) and overall survival (OS).ConclusionsHA appears to be used as an independent predictive factor for BM, and the dynamic detection of HA can predict prognosis in SCLC patients. The mechanism of the HA/CD44 axis in BM of SCLC deserves further exploration.

Objective Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline BRCA mutations (gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients.Methods A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations.Results Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic gBRCAm, with BRCA2 mutations being the most predominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry gBRCAm (P = 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent gBRCAm were significantly younger than those harboring the wild-type gBRCA (P = 0.029). By contrast, the age of patients with or without concurrent gBRCAm was comparable to those of patients without the driver mutations (P = 0.972). In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival (P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA.Conclusions Overall, our study is the largest survey of the prevalence of pathogenic gBRCAm in advanced Chinese NSCLC patients. Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic gBRCAm and an early onset of NSCLC.

PurposePaclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure–safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).MethodsData from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.ResultsThe PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m–2, the estimated clearance of total plasma paclitaxel was 21.55 L h–1. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure–safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.ConclusionThis PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure–safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.

Objective: To investigate clinical efficacy and safety of convalescent plasma (CP) therapy in coronavirus disease 2019 (COVID-19) patients. Methods: We included 4 severe patients and 3 critical patients. The date of admission to hospital ranged from January 30 to February 19, 2020. We retrospectively collected clinical and outcome data. Relative parameters were compared. Results: After CP therapy, the symptoms and respiratory functions were improved. Median PaO 2 /FIO 2 increased from 254 (142-331) to 326 (163–364), and dependence of oxygen supply decreased. Median time to lesion’s first absorption was 5 (2–7) days, undetectable viral RNA was 11 (3.5–15.7) days. Median lymphocyte count (0.77 × 10 9 /L vs 0.85 × 10 9 /L) and albumin level (31g/L vs 36 g/L) were elevated, C-reactive protein (44 mg/L vs 18 mg/L), D-dimer (5.9 mg/L vs 4 mg/L) and lactate dehydrogenase (263 U/L vs 245 U/L) decreased. No obvious adverse reactions were observed. At the follow-up on June 14, 2020, 6 patients had completely recovered and one died from terminal disease. Conclusion: CP therapy for COVID-19 was effective and safe. Three patients who did not combine with antiviral therapy after CP also obtained viral clearance and clinical improvement. However, CP therapy failed to save the life of a terminally ill patient.

Aim: To investigate clinical characteristics and identify risk factors for severity of coronavirus disease 2019 (COVID-19) pneumonia outside of Wuhan, China. Materials and methods: We included 213 patients with confirmed COVID-19 who had been discharged or died by 15 March 2020. We retrospectively collected epidemiological, clinical, laboratory, computed tomography imaging and outcome data. Clinical characteristics were described and relative risk factors were compared. Results: Most clinical characteristics of this study were similar to those from studies in Wuhan, but there were lower mortality rate and milder severity. The median time from onset of symptoms to confirmation and hospitalization was 4 and 5 days, respectively. The median virus clearance and shedding times were 10 and 15 days, respectively. When the severe/critical group was compared with the mild/moderate group, significant risk factors included: older age; dyspnea; hypertension; poor appetite; fatigue; higher white cell count, neutrophil count, prothrombin time, creatine kinase, creatine kinase-MB, D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and C-reactive protein; and lower lymphocyte count and albumin ( p

Objective: To compare the efficacy of 3/4-drugs’ group with 1-drug’s or 2-drugs’ groups in coronavirus disease 2019 (COVID-19). Methods: We included 207 patients confirmed with COVID-19. We compared the viral clearance rate and discharge rate at day 7, 14, 21 and 28, and median time of viral clearance and length of hospitalization in patients treated with 3/4, 1 or 2 drugs. Results: The viral clearance rates of the 3/4-drugs group at day 7, 14 and 21 were significantly lower than those in the 1-drug’s or 2-drugs’ groups (P < 0.05). The median viral clearance days in 3/4-drugs group (13.5 days) were longer than 1-drug’s or 2-drugs’ groups (both were 9 days) (P < 0.001). The patients’ discharge rates in the 3/4-drugs group at day 14 and 21 were significantly lower than that in the 1-drug’s or 2 drugs’ group (P < 0.05). The median length of hospitalization in the 3/4-drugs group was 17 days, which was significantly longer than 11 days in the 1-drug group and 13 days in the 2-drug group (P < 0.05). Conclusion: The efficacy of 1 or 2 antiviral drugs was similar in COVID-19, and 3/4-drug regimens were not associated with clinical improvement. Corticosteroid treatment and more serious disease were also risk factors for viral clearance and patients’discharge.

Background: Lung adenocarcinoma (LUAD) possesses a poor prognosis with a low 5-year survival rate even for stages I-III resected patients, it is thus critical to understand the determinants that affect the survival and discover new potentially prognostic biomarkers. Somatic copy number alterations (CNAs) are major source of genomic variations driving tumor evolution, CNAs screening may identify prognostic biomarkers.Methods: Oncoscan MIP array was used to analyze the patterns of CNAs on formalin fixed paraffin embedded(FFPE) tumor specimens from 163 consecutive stage I-III resected LUAD patients, 145 out of which received platinum-based adjuvant chemotherapy.Results: Of the 163 patients, 91(55.8%) were recurred within 3 years after surgery. The most common aberrations in our cohort were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q, 18q for losses. The GISTIC2 analysis produced 45 amplification peaks and 40 deletion peaks, involving some reported genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, and CDKN2A, most of which were consistent with TCGA database. The amplifications of 12p12.1 (CMAS, GOLT1B, YS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS) and KDM5A were correlated with worse prognosis in our cohort, this result was further validated in 506 LUAD patients from TCGA. In addition, 163 patients could be well-classified into five groups, and the clinical outcomes were significantly different based on threshold copy number at reoccurring alteration peaks. Among the 145 patients who received adjuvant chemotherapy, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients, this result was validated in an independent group of Imielinski et al., demonstrating these two CNAs may contribute to resected LUAD recurrence after adjuvant chemotherapy.Conclusion: This study suggests that CNAs profiling may be a potential prognostic classifier in resected LAUD patients. Amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for LUAD, and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after adjuvant chemotherapy. These novel findings may provide implication for better implementation of precision therapy for lung cancer patients.

Background and objective Small cell lung cancer (SCLC) is a rapidly growing tumor with characteristic of neuroendocrine cellular function. Neuron specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP) and lactic dehydrogenase (LDH) are valuable in diagnosis and treatment of SCLC. By analyzing the variation of NSE, ProGRP and LDH before and after treatment, the aim of this study is to investigate the efficacy of tumor markers in diagnostic staging, therapeutic evaluation and prediction of disease relapsing. Methods Patients with SCLC who receiving the first line chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled and retrospectively analyzed. Clinical characteristic (includes NSE, ProGRP and LDH level before and after 2 cycles chemotherapy), efficacy evaluation, progression-free survival (PFS) were analyzed. Results Before treatment, Serum NSE, ProGRP and LDH in patients with extensive disease (ED) were significantly higher than those with limited disease (LD)(all P4 cycles chemotherapy and with obvious decrease of ProGRP than those who accepted ≤4 cycles chemotherapy and with less obvious decrease of ProGRP in LD group; ED patients with no more than 2 distant metastasis, normal LDH level before treatment and obvious decrease of ProGRP after chemotherapy had lower short term relapse risk. In addition, the types of relapse (sensitive relapse, drug resistance relapse and refractory relapse) were negatively correlated with decrease of ProGRP (P=0.044). By multivariate analysis, numbers of chemotherapy cycle was independent prognostic factor for PFS in LD SCLC; numbers of distant metastasis and decrease of ProGRP were independent prognostic factors for PFS in ED SCLC. Conclusion Increase level of serum tumor markers is related to tumor burden. Decrease level of ProGRP after treatment may prognose efficacy and relapse risk.

Background and objective Cetuximab is a monoclonal antibody directed against epidermal growth factor receptor. Emerging evidence showed improved efficacy with the addition of cetuximab to chemotherapy in advanced non-small cell lung cancer (NSCLC), but the data in oriental population are limited. The aim of this study is to investigate the efficacy of cetuximab in combination with chemotherapy in Chinese patients with advanced NSCLC. Methods NSCLC patients receiving cetuximab in combination with chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College were enrolled and retrospectively analyzed. Clinical characteristic, efficacy, outcome and toxicity data were analyzed. Results A total of 40 patients were enrolled into this study in which 29 were male, 36 with adenocarcinoma. In the 23 patients who had received palliative chemotherapy previously (with a median of 2 prior chemotherapy regimens), the median progression-free survival (PFS) after the last prior chemotherapy regimen was 2.3 months. For the overall population, 13 (32.5%) patients achieved partial response after cetuximab in combination with chemotherapy. Response rate were 52.9% (9/17) and 17.4% (4/23) in chemotherapy-naive patients and chemotherapy-treated patients, respectively (P=0.018). The median PFS was 4.8 months for the overall population. In chemotherapy-naive patients and chemotherapy-treated patients, the median PFS was 8.4 months and 4.1 months, respectively (P=0.062). The estimated median overall survival was 17.1 months. Toxicities were generally manageable and no treatment-related deaths occurred. Conclusion Cetuximab in addition to chemotherapy appears to be associated with promising efficacy and acceptable toxicity profile in Chinese patients with advanced NSCLC. Further validation is needed.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status is crucial in treatment selection for non–small cell lung cancer (NSCLC) patients; however, the detection materials’ availability remains challenging in clinical practice. In this study, we collected surgical resection tissues, lymph node biopsy, and cytological samples for EGFR mutation testing and investigated the associations between gene mutation and clinical characteristics. METHODS: Two hundred and seventy-six NSCLC adenocarcinoma specimens were collected, and highly sensitive amplification refractory mutation system method was implemented for EGFR mutation detection, with clinicopathologic characteristics involved in the final analysis. RESULTS: In the total of 276 samples, 96% (265/276) of tumors obtained evaluable EGFR mutation status, the frequency of mutation was 55.8% (148/265) in all specimens, and three different type samples shared a comparable successful testing rate: 97.4% (38/39) in surgical tumor tissues, 100% (108/108) in lymph node biopsy samples, and 92.2% (119/129) in cytological samples. EGFR mutation was significantly associated with sex, smoking history, lymph node metastasis status (N stage), primary tumor size, testing tissues origin, and sample type (P < .05). Multivariate analysis reconfirmed that smoking history and primary tumor size shared significant correlation with EGFR mutation after adjustment. CONCLUSIONS: Both lymph node biopsy and cytological samples were suitable surrogates for EGFR mutation detection in NSCLC compared with tumor tissues, gene status should be detected widely considering the high EGFR mutation rate, and nonsmoking history together with smaller primary tumor size was an independent indicator of EGFR mutation status.

Background and objective Lung cancer in young patients (less or equal to 45 years) is relatively rare. We explored the efficacy and survival of Gefitinib for young patients with unknown epidermal growth factor receptor (EGFR) gene mutation of advanced lung adenocarcinoma. Methods The clinical data of 55 young patients with unknown EGFR gene mutation in advanced lung adenocarcinoma referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from Jan 2006 through Dec 2010 were analyzed retrospectively. Results Of 55 young patients enrolled, the median age was 41 years. The objective response rate and disease control rate were 43.6% and 90.9%, respectively.. The median progression-free survival (PFS) was 9.0 months. Among the factors analyzed, brain metastasis had significant effect on PFS (P=0.017). The median overall survival (OS) was 24.0 months. The independent prognostic factors to significantly improve OS included non-smoking history (P=0.028) and receiving other anti-cancer treatment after Gefitinib therapy (P

Background and objective Subsequent chemotherapy were needed in patients with advanced pulmonary adenocarcinoma experiencing disease progression after epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. The study is to explore factors potentially influencing efficacy of subsequent chemotherapy. Methods One hundred and ninety-one patients with advanced lung adenocarcinoma, who were resistant from EGFR-TKIs and then received subsequent chemotherapy, were identified. Data of patient’s characteristics, responses to chemotherapy and survival time were analyzed retrospectively. Results The overall response rate of the pemetrexed-based chemotherapy (9.3%) was higher than non-pemetrexed-based regimen (1.1%), P=0.011. Furthermore, the response in the second-line was more obvisous [objective response rate (ORR) 14.3% vs 3.7%, P=0.041]. The patients who achieved response of partial response (PR) showed longer progression-free survival (PFS) than those who achieved non-PR (PFS 10.1 months and 2.3 months, P=0.012). The patients treated with platinum-based chemotherapy had longer PFS and OS than those with non-platinum-based chemotherapy, therefore platinum-based regimen was independent prognosis factors for PFS and OS (PFS: RR=0.634, 95%CI: 0.466-0.832, P=0.004; OS: RR=0.666, 95%CI: 0.460-0.960, P=0.030), especially the pateients who were aquired EGFR-TKIs resistance and who got drmatic progression from EGFR-TKIs treatment might got more benefits from platinum-based chemotherapy. However there was no significant difference in ORR, PFS or OS between patients with TKIs primary resistance and acquired resistance, or between dramtic progression and gradual/local progression. Conclusion The patients with advanced lung adenocarcinoma might get benefits from pemetrexed-based or platinum-based chemotherapy after they were EGFR-TKIs resistace.

Background and objective At present no standard second-line combination has been established for recurrent small cell lung cancer (SCLC). Therefore we evaluate the efficacy and safety of irinotecan in combination with nedaplatin/cisplatin against refractory or relapsed small cell lung cancer. Methods In this retrospective study, we analyzed the data of 1,140 patients who diagnosed small cell lung cancer at our hospital from April 2009 to April 2012. Of all the patients, 34 patients were treated with irinotecan and nedaplatin (irinotecan 60 mg/m2 on days 1, 8 nedaplatin 85 mg/m2 day 1, every 3 weeks) , and 20 patients were treated with irinotecan and cisplatin (irinotecan 60 mg/m2 on days 1, 8 cisplatin 75 mg/m2 day 1, every 3 weeks) as the second-line treatment. Prognostic factors of overall survival (OS) were estimated by Kaplan-Meier and Cox's Regression-proportional hazards model. Results Of all the 54 eligible patients, median progression free survival (PFS) was 4.9 months, and median OS was 13.3 months. Median PFS was 5.4 months for irinotecan plus nedaplatin (IN) and 4.9 months for irinotecan plus cisplatin (IC), respectively (P=0.465). Median OS was 14.3 months and 13.3 months, respectively (P=0.704). In multivariate analysis, ECOG PS, number of metastases and cycles of chemotherapy were independent prognostic factors. The toxicities were mild, while toxicity profile was slightly different for each of the arms: hematologic toxicity was higher in IN group, and diarrhea was higher in IC group. Conclusion Irinotecan plus platinum is effective and tolerable for refractory and relapsed small cell lung cancer. Irinotecan plus nedaplatin is non-inferior to irinotecan plus cisplatin in terms of efficacy and safety.

Background and objective Squamous cell carcinoma (SCC) is a common pathological type of non-small cell lung cancer, and advanced lung SCC is incurable. Chemotherapy combined with anti-angiogenesis agents can prolong the patients’ survival time. The aim of the study was to analyze the efficacy and safety of recombinant human endostatin (Endostar) in treating advanced lung SCC. Methods We retrospectively analyzed the short-term efficacy and toxicity of recombinant human endostatin combined with traditional chemotherapy regimens in treating 15 advanced lung squamous cell carcinoma patients in Department of Medical Oncology retrospectively, Cancer Hospital, Chinese Academy of Medical Sciences from November 2011 to May 2015. Treatment-related survival was also analyzed. Results Among the evaluble 14 patients, the best overall response was partial response in 5 patients (35.7%), stable disease in 7 patients (50.0%), and progressive disease in 2 patients (14.3%). The objective response rate (ORR) was 35.7%, and disease control rate (DCR) was 85.7%. The median progression-free survival (PFS) was 9.3 months. The main grade 3 toxicity was neutropenia (2/15, 13.3%) and vomitting (1/15, 6.7%). Conclusion Chemotherapy combined with recombinant human endostatin enabled good objective response in advanced SCC patients and had well security.

BACKGROUND:Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC). METHODS:We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration's risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software. RESULTS:Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW". CONCLUSIONS:Gemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation.

INTRODUCTION:There are no adequate data to determine whether intensity-modulated radiotherapy (IMRT) is superior to three-dimensional conformal radiotherapy (3DCRT) in the treatment of non-small cell lung cancer (NSCLC). This meta-analysis was conducted to compare the clinical outcomes of IMRT and 3DCRT in the treatment of NSCLC. METHODS:No exclusions were made based on types of study design. We performed a literature search in PubMed, EMBASE and the Cochrane library databases from their inceptions to April 30, 2015. The overall survival (OS) and relative risk (RR) of radiation pneumonitis and radiation oesophagitis were evaluated. Two authors independently assessed the methodological quality and extracted data. Publication bias was evaluated by funnel plot using Egger's test results. RESULTS:From the literature search, 10 retrospective studies were collected, and of those, 5 (12,896 patients) were selected for OS analysis, 4 (981 patients) were selected for radiation pneumonitis analysis, and 4 (1339 patients) were selected for radiation oesophagitis analysis. Cox multivariate proportional hazards models revealed that 3DCRT and IMRT had similar OS (HR = 0.96, P = 0.477) but that IMRT reduced the incidence of grade 2 radiation pneumonitis (RR = 0.74, P = 0.009) and increased the incidence of grade 3 radiation oesophagitis (RR = 2.47, P = 0.000). CONCLUSIONS:OS of IMRT for NSCLC is not inferior to that of 3DCRT, but IMRT significantly reduces the risk of radiation pneumonitis and increases the risk of radiation oesophagitis compared to 3DCRT.

Background and objective Due to the various inter-individual differences in the biological characteristics of tumor cells, as well as issues on the efficacy, adverse reactions, and defects of existing drugs, we compared the clinical efficacy and toxicity of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced non-small cell lung cancer (NSCLC). Methods 251 patients were randomly divided into pemetrexed combined with cisplatin group (PP group) with 127 cases and gemcitabine combined with cisplatin group (GP group) with 124 cases. PP group received pemetrexed 500 mg/m2 iv infusion d1 and cisplatin 75 mg/m2 iv infusion d1, whereas GP group received gemcitabine 1,000 mg/m2 iv infusion d1,8 and cisplatin 75 mg/m2 iv infusion d1. The treatment cycle was once every three weeks. In addition, folic acid, vitamin B12, and dexamethasone were administered in both groups. Results The total clinical effective rates in PP group and GP group were 25.20% and 17.74%, respectively. The total efficiencies of non-squamous cell carcinoma were 27.62% and 16.00%. The tumor progression duration in these two groups was 6.5 and 5.6 months, respectively. The median survival time in the two groups was 16.9 and 17.0 months, respectively, with 59.62% and 65.87% survival rates of 1 year and 27.28% and 27.93% survival rates of 2 years, respectively. The total efficacy of non-squamous cell carcinoma in the PP group was significantly higher than that in GP group. The results were statistically significant. However, there were no significant differences in total response rates, tumor progression duration, and median survival rates of 1 and 2 years. The rate of adverse reactions, including white blood cell reduction, lower platelet count, lower hemoglobin, and hair loss in the PP group was significantly lower than that in the GP group. The results were statistically significant. Conclusion The clinical efficacy of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced NSCLC was roughly the same, but the adverse reactions decreased significantly in the PP group compared with those in the GP group. Therefore, pemetrexed combined with cisplatin can be used as a safe and effective drug for clinical first-line treatment for previously untreated NSCLC.

Background and objective It has been proven that metastasis-associated in colon cancer 1 (MACC1) is a new gene that is related to the invasion and metastasis of tumors. MACC1 also regulates c-met expression. The aim of this study is to explore the expressions of MACC1 and hepatocyte growth factor receptor (c-met), and its relationship with invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC). Methods MACC1 and c-met expressions were detected in 103 cases of NSCLC and 40 cases of neighboring normal lung cancer tissue using immunohistochemistry. Results MACC1 and c-met expressions were significantly higher in lung cancer tissues than that in neighboring normal tissue (P0.05). In addition, a positive correlation between MACC1 and c-met expressions was observed (r=0.403, P

Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125 mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety.From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9-6.6 m) and 5.4 months (95%CI 3.1-7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127).In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy.ClinicalTrials.gov NCT02486354.