Patient-derived tumor-like cell clusters for personalized chemo- and immunotherapies in non-small cell lung cancer.

Many patient-derived tumor models have emerged recently. However, their potential to guide personalized drug selection remains unclear. Here, we report patient-derived tumor-like cell clusters (PTCs) for non-small cell lung cancer (NSCLC), capable of conducting 100-5,000 drug tests within 10 days. We have established 283 PTC models with an 81% success rate. PTCs contain primary tumor epithelium self-assembled with endogenous stromal and immune cells and show a high degree of similarity to the original tumors in phenotypic and genotypic features. Utilizing standardized culture and drug-response assessment protocols, PTC drug-testing assays reveal 89% overall consistency in prospectively predicting clinical outcomes, with 98.1% accuracy distinguishing complete/partial response from progressive disease. Notably, PTCs enable accurate prediction of clinical outcomes for patients undergoing anti-PD1 therapy by combining cell viability and IFN-γ value assessments. These findings suggest that PTCs could serve as a valuable preclinical model for personalized medicine and basic research in NSCLC.

Synthesis of Fe-N doped porous carbon/silicate composites regulated by minerals in coal gasification fine slag for synergistic electrocatalytic treatment of phenolic wastewater.

Coal gasification fine slag (CGFS), as a difficult-to-dispose solid waste in the coal chemical industry, consists of minerals and residual carbon. Due to the aggregate structure of minerals blocking pores and encapsulating active substances, the high-value utilization of CGFS still remains a challenge. Based on the intrinsic characteristics of CGFS, this study synthesized Fe-N doped porous carbon/silicate composites (Fe-NC) by alkali activation and pyrolysis for electrocatalytic degradation of phenolic wastewater. Meanwhile, minerals were utilized to regulate the surface chemical and pore structure, turning their disadvantages into advantages, which caused a sharp increase in m-cresol mineralization. The positive effect of minerals on composite properties was investigated by characterization techniques, electrochemical analyses and density functional theory (DFT) calculations. It was found that the mesoporous structure of the mineral-regulated composites was further developed, with more carbon defects and reactive substances on its surface. Most importantly, silicate mediated iron conversion through strong interaction with H2O2, high work function gradient with electroactive iron, and excellent superoxide radical (•O2-) production capacity. It effectively improved the reversibility and kinetics of the entire electrocatalytic reaction. Within the Fe-NC311 electrocatalytic system, the m-cresol removal rate reached 99.55 ± 1.24%, surpassing most reported Fe-N-doped electrocatalysts. In addition, the adsorption and electrooxidation experiment confirmed that the synergistic effect of Fe-N doped porous carbon and silicate simultaneously promoted the capture of pollutants and the transformation of electroactive molecules, and hence effectively shortened the diffusion path of short-lived radicals, which was further supported by molecular dynamics simulation. Therefore, this research provides new insights into the problem of mineral limitations and opens an innovative approach for CGFS recycling and environmental remediation.

Preparation of macroporous ion-exchange resin organic amine composite material by using waste plastics and its application in CO2 capture.

Two new types of solid adsorption material (macroporous cation exchange resin (MCER) and macroporous ion-exchange resin organic amine composite material (MCER-DEA)) were prepared from waste television plastics outer shell (WTPS) and used to capture CO2 in flue gas from coal-fired power plants. The results showed that the CO2 adsorption capacity of MCER-DEA was 2.87 mmol/g, while MCER was 1.87 mmol/g. The preparation mechanism and action mechanism of MCER and MCER-DEA was studied by Fourier transform infrared and quantum chemical calculations. The results showed that the electrophilic substitution occurs in between an H atom of meta position on the benzene ring and H2SO4. The electron energy of MCER-DEA was calculated to be 1.14 ev, indicating these MCERs formed acid-base coordination with diethanolamine (DEA). Besides, the electron energy of between MCER and CO2 was 0.27 ev, and the interaction force was dominated by hydrogen bonds. The electron energy of the MCER-DEA and CO2 was 3.02 ev, and the interaction force was mainly controlled by coordination bonds. It indicated that MCER and CO2 were primarily based on physical adsorption, while MCER-DEA and CO2 were mainly based on chemisorption adsorption. Adsorption kinetics studies showed that internal diffusion was a rate-controlling step.

Prognosis of different extrathoracic metastasis patterns in patients with M1c lung adenocarcinoma receiving immunotherapy.

INTRODUCTION: Lung cancer with extrathoracic metastases is classified as M1c. However, extrathoracic metastases can be further classified into different patterns. The purpose of this study was to analyze the survival differences between different patterns of extrathoracic metastases in patients with stage M1c lung adenocarcinoma after receiving immunotherapy. MATERIALS AND METHODS: This study included 160 stage M1c lung adenocarcinoma patients and treated with immunotherapy. The enrolled patients were divided into two groups: those with multiple extrathoracic metastases alone (EM group) and those with simultaneous multiple extrathoracic and intrathoracic metastases (EIM group). Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: The median PFS and OS in the whole group were 7.7 months and 25.4 months, respectively. The patients in the EM group show better PFS (13.0 months vs. 5.0 months; hazard ratio [HR] = 0.462, 95% confidence interval [CI] 0.317-0.673, P < 0.0001) and OS (35.0 months vs. 18.9 months; HR 0.592, 95% CI 0.380-0.922, P = 0.019) compared with the EIM group. Furthermore, in patients with lung adenocarcinoma with simultaneous extrathoracic and intrathoracic metastases who received immunotherapy, immunotherapy combined with chemotherapy has better PFS and OS than immunotherapy alone. There was no difference between immunotherapy alone or combined with chemotherapy in patients with lung adenocarcinoma with extrathoracic metastasis alone. CONCLUSION: The different patterns of extrathoracic metastasis were related to the efficacy and prognosis of immunotherapy in M1c cohort. In addition, patients with simultaneous extrathoracic and intrathoracic metastases were more recommended to choose immunotherapy in combination with chemotherapy rather than immunotherapy alone.

Clinical predictors of treatment efficacy and a prognostic nomogram in patients with lung adenocarcinoma receiving immune checkpoint inhibitors: a retrospective study.

Background: At present, there is no accurate biomarker for immune checkpoint inhibitors (ICIs). Since the efficacy of ICIs is associated with a variety of indicators, establishing a model to predict its efficacy is more clinically significant and in line with clinical needs. Methods: We collected and retrospectively analyzed the relationship between immunotherapy efficacy and clinicopathologic features in lung adenocarcinoma patients treated with ICIs. Progression-free survival (PFS) and overall survival (OS) were analyzed. Univariate and multivariate Cox proportional hazards regression analyses were conducted to identify prognostic factors associated with PFS. Besides, a clinical prediction model was established based on the results of the multivariate Cox regression analyses to predict PFS. Results: A total of 201 lung adenocarcinoma patients treated with ICIs were assessed. Univariate analysis showed that male gender [hazard ratio (HR) =0.521, 95% confidence interval (CI): 0.356-0.761, P=0.001], smoking (HR =0.595, 95% CI: 0.420-0.843, P=0.003), epidermal growth factor receptor (EGFR) wild type (HR =2.766, 95% CI: 1.719-4.452, P<0.001), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (HR =0.449, 95% CI: 0.271-0.743, P=0.001), positive programmed death ligand 1 (PD-L1) expression (HR =0.527, 95% CI: 0.336-0.825, P=0.004), early tumor node metastasis (TNM) stage (HR =0.581, 95% CI: 0.344-0.983, P=0.039), no liver metastasis (HR =1.801, 95% CI: 1.046-3.102, P=0.031), ICIs combined with chemotherapy (HR =0.560, 95% CI: 0.384-0.815, P=0.002), having immune-related adverse effects (HR =0.354, 95% CI: 0.228-0.511, P<0.001) and first-line immunotherapy (HR =0.596, 95% CI: 0.420-0.845, P=0.003) were significantly associated with better PFS in patients with lung adenocarcinoma receiving immunotherapy. Multivariate analysis showed that smoking status, KRAS mutation, PD-L1 expression, line of immunotherapy and immune-related adverse effects were independent prognostic factors affecting PFS. A clinical prediction model was established to predict the PFS of lung adenocarcinoma patients treated with ICIs. The model showed good predictive ability via C-index, calibration curve and receiver operating characteristic (ROC) curve validation. Conclusions: The clinical prediction model developed in this study can be used to some extent to predict PFS after immunotherapy in lung adenocarcinoma patients. However, the model still needs to be validated in studies with large sample size.

Distribution modes of residual carbon and ash in coal gasification fine slag and its feasibility analysis as particle electrodes.

From the perspective of environmental protection and resource utilization, the feasibility of treating m-cresol wastewater with coal gasification fine slag (GFS) as particle electrodes in an electrocatalytic system was evaluated to achieve the purpose of treating waste with waste. Characterization by scanning electron microscope (SEM), Brunauer-Emmett-Teller (BET), Raman, and fourier transform infrared spectroscopy (FTIR) confirmed that the GFS featured a diverse inorganic framework, large specific surface area (as large as above 155 m2 g-1), hierarchical porous structure, and plenty of catalytic sites. The Venn diagram method was used to systematically propose the following distribution modes of residual carbon (RC) and ash in GFS: discrete distribution, embedded distribution, crosslinked distribution, and association and bonding. Only 8 g L-1 of GFS particle electrodes prevented the formation of a yellow sticky passivation film on the anode. Compared to the two-dimensional electrocatalytic system (47.89%), the wastewater treatment efficiency was increased by 108.81%. Zero-order kinetic results showed that the reaction rate constant was the highest (2.1106 mg L-1·min-1) when the secondary flotation RC was adopted as particle electrodes. It was indicated that GFS in discrete mode played either no role or at most a minor role. Last but not least, the synergy of RC and ash was revealed from a molecular perspective. The RC exhibited hierarchical microporous/mesoporous/macroporous structure, which facilitated the entry of H2O2 into the catalytic sites of ash. Abundant catalytic sites in ash accelerated adsorption and oxidation processes on RC surfaces.

Serum NSE is Early Marker of Transformed Neuroendocrine Tumor After EGFR-TKI Treatment of Lung Adenocarcinoma.

Background: Transformation to a lung neuroendocrine tumor (LNET) is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). Serum neuron-specific enolase (NSE) is a useful marker in the detection of LNET. Therefore, we explored the clinical significance of serum NSE levels in the detection of transformed neuroendocrine tumors after EGFR-TKI therapy. Methods: We report a cohort of 5 cases in our treatment group. The characteristics of the patients, pathological diagnoses, immunohistochemistry with molecular detection, laboratory examination, and treatment histories are analyzed. The tumor markers of serum NSE were analyzed. Additionally, we reviewed the publications reporting the tumor markers before and after LNET transformation during EGFR-TKI therapy. Results: Most patients are female (3/5), aged <60 years old (4/5), nonsmokers (4/5) and harbor the EGFR 19 exon deletion (4/5). The median time of LNET transformation was 19 months (range: 12-31 months). The clinical characteristics were similar to those reported in previous studies. Laboratory examination revealed an increased NSE level before the LNET is defined. Sixteen publications were reviewed. Of those, 86.67% (13/15) publications showed an increased level of NSE when the LNET transformation was defined. Conclusion: Adenocarcinoma tumors in non-smokers, young patients harboring the EGFR 19 exon deletion tended to transform to LNETs after EGFR-TKI therapy. Combining our findings and a review of the literature, we suggest that serum NSE may be a useful tumor marker to predict neuroendocrine tumor transformation.

Study on the mechanism of anaerobic fluidized bed microbial fuel cell for coal chemical wastewater treatment.

The coal chemical wastewater (CCW) was treated by anaerobic fluidized bed microbial fuel cell (AFB-MFC) with macroporous adsorptive resin (MAR) as fluidized particle. Isosteric heat calculation and molecular dynamics simulation (MDS) have been performed to study the interaction between organics of CCW and MAR. The isosteric heat of MAR to m-cresol was the largest at 65.4961 kJ/mol, followed by phenol. Similarly, the diffusion coefficient of m-cresol on MAR was the largest, which was 0.04350 Å2/ps, and the results were verified by the kinetic adsorption experiments. Microbial community analysis showed that the dominant bacteria in activated sludge of MFC fed with CCW were acinetobacter, aeromonas, pseudomonas and sulfurospirillum. The synergistic cooperation of bacteria contributed to improving CCW degradation and the power generation of MFC. Headspace-gas chromatography-mass spectrometry (HS-GC-MS) was used to detect intermediate of organics in CCW. It was proved that the intermediate of m-cresol degradation was 4-methyl-2-pentanone and acetic acid, and the intermediate of phenol degradation included cyclohexanone, hydroxyhexanedither and hydroxyacetic acid. Combined with the highest occupied molecular orbital (HOMO) analysis results of organic matter obtained by molecular simulation, the degradation pathway of organic matter in CCW was predicted. The energy of organics degradation pathway was analyzed by Materials Studio (MS) software, and the control step of organics degradation was determined.

Main Controlling Factors and Models of Organic Matter Accumulation in Lower Carboniferous Dawuba Formation Shale in Southern Guizhou, China.

A set of high-quality marine facies organic-rich shales developed in the Lower Carboniferous Dawuba Formation, which is considered to be the main target of shale gas exploration and development in Guizhou Province. In this paper, 53 samples from Well ZY1 are selected, and the core observation data, field-emission scanning electron microscopy (FE-SEM) images, and geochemical data of these samples are analyzed. On the basis of these data, the main influencing factors of organic matter enrichment in the Dawuba Formation shale were identified and an organic matter accumulation model was established. The results show that total organic carbon (TOC) values of the Dawuba Formation in the ZY1 well vary between 1.97 and 4.11%, with high values appearing at the depths of 2796-2814 m (3.00-4.11) and 2877-2894 m (1.97-3.49). The redox-sensitive element enrichments are generally low, indicating that these samples were deposited under oxic-suboxic conditions. The micronutrients (Zn, Cu, and Ni), biological Ba (BaXS), and P/Al also show low values, indicating low primary productivity. The chemical index of alteration (CIA) and terrigenous clastic input index (Ti/Al) showed two obvious high-value zones, indicating that shale in the study area was affected by terrigenous inputs. Similarly, the calculation results show that Fe/Mn and Rb/K values have two abnormal data segments at the same depth. The anomaly of these data at the same depth section further suggests that the shale was affected by terrigenous input during deposition. Moreover, the terrigenous input reaches the maximum in the above TOC high-value region, and it is inferred by combining with the core observation results that the gravity flow occurs in this depth. The carbon isotope of kerogen (δ13Corg) ranges from -26.84 to -24.36%, indicating that the source of organic matter is likely to be terrestrial plants. This is further supported by the widespread presence of filamentous organic matter using FE-SEM, despite the low productivity and poor preservation conditions during deposition of the Dawuba Formation; the enhanced terrigenous input may have provided additional sources of organic matter for the Dawuba shale.

tsRNA-5001a promotes proliferation of lung adenocarcinoma cells and is associated with postoperative recurrence in lung adenocarcinoma patients.

BACKGROUND: The biological role and clinical significance of transfer RNA-derived small RNAs (tsRNAs) remain largely unclear. The purpose of this study was to investigate the biological function, molecular mechanism, and clinical significance of tsRNA-5001a in lung adenocarcinoma. METHODS: The function of tsRNA-5001a on the growth of tumor cells was accessed by cell function experiments. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of tsRNA-5001a in paired samples of lung adenocarcinoma. Cell localization of tsRNA-5001a was performed by nuclear-cytoplasmic separation assay. Transcriptome sequencing was used to screen the molecules involved in the regulatory network of tsRNA-5001a. Independent samples t-test was used to compare the two groups. Prism software (Prism 7.0) was used to analyze the statistical results. P<0.05 was considered statistically significant. RESULTS: tsRNA-5001a was significantly upregulated in lung adenocarcinoma tissues. Upregulation of tsRNA-5001a was found to increase the risk of postoperative recurrences in patients with lung adenocarcinoma and was associated with poor prognosis. Function assay showed that overexpression tsRNA-5001a could significantly promote cell proliferation. In contrast, knockdown of tsRNA-5001a significantly inhibited the proliferation of lung adenocarcinoma cells. In addition, nucleoplasmic isolation assay indicated that tsRNA-5001a was located mainly in the cytoplasm. According to the results of RNA sequencing and The Cancer Genome Atlas database (TCGA database) analysis, growth arrest and DNA damage 45G (GADD45G) was screened and may be the target gene of tsRNA-5001a. CONCLUSIONS: tsRNA-5001a promotes the proliferation of lung adenocarcinoma cells and increases the risk of postoperative recurrences in lung adenocarcinoma patients.

A Prediction Model for Postoperative Pulmonary Complication in Pulmonary Function-Impaired Patients Following Lung Resection.

PURPOSE: Most patients with lung cancer have impaired pulmonary function. Single pulmonary function parameters have been suggested as good indices for predicting postoperative pulmonary complications (PPC). The purpose of this retrospective study was to construct a prediction model, including more than one pulmonary function parameter, for better prediction of PPC in patients with lung cancer and impaired pulmonary function. PATIENTS AND METHODS: Our database of patients who underwent lung resection for non-small cell lung cancer was reviewed and those with impaired pulmonary function were enrolled. Clinical data, including PPC, were recorded. Univariate and logistic regression analyses were applied to explore potential predictors and a prediction model constructed based on the results of logistic regression. RESULTS: Patients with impaired pulmonary function (n = 124) were enrolled. Most patients were male, current smokers, >60 years old, and had adenocarcinoma and mild ventilatory dysfunction or diffusion dysfunction. In univariate analysis, we identified six pulmonary function parameters that differed significantly between the PPC and non-PPC groups. Receiver operating characteristic curves were used to determine the best cutoff values. In logistic regression, only forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC%), peak expiratory flow (PEF%), and post predictive operation (ppo)-FEV1% remained significant. Based on these results, we constructed a prediction model for PPC including FEV1/FVC%, PEF%, and ppo-FEV1%, which had an good diagnostic performance of, with 76.7% sensitivity and 67.6% specificity. CONCLUSION: Our prediction model, including the pulmonary function parameters, FEV1/FVC%, PEF%, and ppo-FEV1%, shows excellent performance for predicting PPC in patients with lung cancer and impaired pulmonary function following resection, and has potential for wide application in clinical practice.

The Clinical Value of Pulmonary Rehabilitation in Reducing Postoperative Complications and Mortality of Lung Cancer Resection: A Systematic Review and Meta-Analysis.

Background: Pulmonary rehabilitation is one meaningful way of improving exercise tolerance and pulmonary function. Thus, it may reduce the postoperative complications and mortality of pulmonary resection. Hence, we refreshed the data and conducted this systemic analysis. Method: We searched Pubmed, Web of Science, and EMBASE using "lung OR pulmonary" AND "operation OR resection OR surgery" AND "rehabilitation or exercise." The cut-off date was September 30, 2020. The publications were filtrated, and data were extracted from all selected studies by two reviewers. Review Manger 5.1 and the fixed or random regression model were used for calculating the pooled odds ratio (OR). Result: Finally, 13 publications were enrolled in this study. Among them, five publications reported mortality, nine reported postoperative complications, and seven reported postoperative pulmonary complications. The pooled OR of mortality was 1.32 [95% confidence interval (CI): 0.54-3.23] for the pulmonary rehabilitation group, the pooled OR of postoperative complications was 0.62 (95% CI: 0.49-0.79) for the pulmonary rehabilitation group, and the pooled OR of postoperative pulmonary complications was 0.39 (95% CI: 0.27-0.56) for the pulmonary rehabilitation group. Subgroup analysis revealed the perioperative pulmonary rehabilitation was the most important part. Conclusion: Pulmonary rehabilitation may not affect the mortality of pulmonary resection patients, however, it could decrease the number of postoperative complications, especially pulmonary complications. Perioperative pulmonary rehabilitation was the most important part of the program.

Using T stage and tumor thrombosis as predictive factors for patients with resected I-IIA small cell lung cancer: a retrospective study.

BACKGROUND: Surgery is recognized as an important part of treating stage I-IIA small cell lung cancer (SCLC), but few studies have explored the predictive factors for overall survival (OS) or time to tumor progression (TTP). This paper aims to explore the predictive factors related to improved overall and relapse-free survival. METHODS: Patients with stage I-IIA SCLC were reviewed between January 1st, 2014, and December 30th, 2016, at the Shanghai Chest Hospital. Basic patient characteristics and clinical data were collected, including age, sex, tumor (T) stage, pathological characteristics, and treatment. Patient follow-ups were conducted by checking medical records or phoning the patient, with survival data and instances of recurrence and/or metastasis being collected and recorded. Univariate and multivariate analyses were used to identify the predictive factors. RESULTS: A total of 59 patients were enrolled in this study, and the median follow-up duration was 53.7 months. The 3-year disease free and 3-year OS rates were 62.5% and 75.0%, respectively. The 5-year disease free and 5-year OS rates were not reached. Univariate and multivariate analyses revealed that a higher T stage [hazard ratio (HR) 3.210, P=0.048], the presence of tumor thrombosis (HR 6.021, P=0.043), and the absence of adjuvant chemotherapy (HR 3.425, P=0.059) were more reflective of shorter TTP than other factors, with the presence of adjuvant chemotherapy also correlating with improved OS. CONCLUSIONS: A patient having a T1 stage with no tumor thrombus and receiving adjuvant chemotherapy were observed as positive factors for longer periods of TTP, and adjuvant chemotherapy was a favorable predictor for the OS of patients with resected stage I-IIA SCLC.

Treatment of isopropanol wastewater in an anaerobic fluidized bed microbial fuel cell filled with macroporous adsorptive resin as multifunctional biocarrier.

The isopropanol (IPA) wastewater was treated in an anaerobic fluidized bed microbial fuel cell (AFB-MFC) filled with macroporous adsorptive resin (MAR) particles as multifunctional biocarrier. MAR was used as a biological carriers and adsorbent. MAR was characterized by scanning electron microscope. The diffusion of isopropanol in MAR was studied by Materials Studio (MS) software, and diffusion coefficients were analyzed and calculated by molecular dynamics simulation. The simulation results were qualitatively consistent with the available experimental data. The diffusivity of IPA in MAR increased firstly, with the increasing IPA weight, and then decreased. The maximum diffusivity was resulted to be 0.3722 Å2/ps. In addition, the response surface methodology (RSM) and Box-Behnken design were used to study the effects of initial IPA concentration, flow rate and external resistance on performance of power output and pollutant degradation. The optimal experimental condition was observed as initial IPA concentration of 483.49 mg/L, a flow rate of 57.70 mL/min, and external resistance of 5225.78 Ω. After 21 h of operation under the optimized conditions, the maximum power density was 135.73 ± 0.17 mW/m2 and the COD removal was 68.21 ± 0.24%, which increased by 65.85% and 9.29%, respectively.

Racial differences in characteristics and prognoses between Asian and white patients with nonsmall cell lung cancer receiving atezolizumab: An ancillary analysis of the POPLAR and OAK studies.

This study aimed to compare the differences in characteristics and prognoses between Asian and white patients receiving immunotherapy for nonsmall cell lung cancer (NSCLC). We studied 390 patients who received atezolizumab as part of the POPLAR or OAK trial, and analyzed the differences in baseline characteristics, outcomes and genetic mutations in blood samples between Asian and white patients. Overall survival (OS) was longer in Asian compared to white patients (median OS: 18.7 vs. 11.1 months; p = 0.005). Race was identified as an independent prognostic factor for OS (Asian vs. white: hazard ratio 0.647, 95% confidence interval 0.447-0.936, p = 0.021), together with performance status, histology, baseline sum of the longest tumor diameters (BLSLD) and number of metastatic sites. The two groups also differed in terms of characteristics including smoking history, BLSLD, epidermal growth factor receptor (EGFR) mutation frequency, programmed death-ligand 1 expression and blood-based tumor-mutation burden. Blood mutations of STK11, EGFR, KEAP1, POLE, GRM3, ATM and STAG2 were associated with treatment response, and TP53, KEAP1, APC, RB1, CREBBP, EPHA5 and STAG2 mutations were associated with OS. The blood-based mutation profiles differentiated between Asian and white patients, especially in relation to EGFR (23.8 vs. 8.5%), TP53 (30.2 vs. 46.9%) and STK11 (1.6 vs. 12.3%) mutations (all p < 0.05). The different clinicopathological features and mutation profiles in Asian and white patients may explain the superior outcome following atezolizumab treatment in Asian patients with NSCLC. The results of this study have important implications for further studies on racial disparities in relation to immunotherapy.

Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial.

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3-19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2-6.3) or gefitinib (11.9 months, 95% CI, 9.1-14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09-0.29, p < 0.001) and 0.48 (95% CI, 0.29-0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.

[Clinical Experience with First-generation Epidermal Growth Factor Receptor 
Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients 
with Brain Metastasis].

BACKGROUND: A survival analysis and the influencing factors for non-small cell lung cancer (NSCLC) patients with brain metastases accepting first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) treatment have not yet been elucidated to date. In this study, we collected and analyzed the survival data of NSCLC patients with brain metastasis to obtain evidence and to provide guidance in clinical practice. METHODS: NSCLC patients with brain metastases who were treated with first-generation EGFR-TKIs were retrospectively collected in 2012-2013 from Shanghai Chest Hospital, Shanghai Jiao Tong University. The Kaplan-Meier method and Cox regression were performed for univariate and multivariate analyses, respectively, to explore the independent predictors influencing the survival of patients with NSCLC brain metastases. RESULTS: The median progression-free survival (PFS) and median overall survival (OS) of all patients treated with first-generation EGFR-TKIs were 10.0 months (95%CI: 8.3-11.7) and 28.0 months (95%CI: 22.9-33.1), respectively. Pathological subtypes were the independent predictors of PFS (P=0.001), and tumor differentiations were the independent predictors of OS (P=0.050). CONCLUSIONS: First-generation EGFR-TKIs showed promising efficacy in NSCLC patients with brain metastases. PFS was longer in patients with adenocarcinoma than in those with a non-adenocarcinoma subtype. OS was longer in patients with differentiated tumors than in those who developed poorly differentiated tumors.
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Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

Capture-based next-generation sequencing (NGS) is a potentially useful diagnostic method to measure tumor tissue DNA in blood as it can identify concordant mutations between cell-free DNA (cfDNA) and primary tumor DNA in lung cancer patients. In this study, the sensitivity, specificity and accuracy of capture-based NGS for detecting ALK fusion in plasma cfDNA was assessed. 24 patients with tissue ALK-positivity and 15 who did not harbor ALK fusion were enrolled. 13 ALK-positive samples were identified by capture-based NGS among the 24 samples with tissue ALK-positivity. In addition to EML4-ALK, 2 rare fusion types (FAM179A-ALK and COL25A1-ALK) were also identified. The overall sensitivity, specificity and accuracy for all cases were 54.2%, 100% and 71.8%, respectively. For patients without distant metastasis (M0-M1a) and patients with distant metastasis (M1b), the sensitivities were 28.6% and 64.7%, respectively. In the 15 patients who received crizotinib, the estimated median PFS was 9.93 months. Thus, captured-based NGS has acceptable sensitivity and excellent specificity for the detection of ALK fusion in plasma cfDNA, especially for patients with distant metastasis. This non-invasive method is clinically feasible for detecting ALK fusion in patients with advanced-stage NSCLC who cannot undergo traumatic examinations or have insufficient tissue samples for molecular tests.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors combined with chemotherapy in first-line treatment in an advanced non-small cell lung cancer patient with EGFR sensitive mutation.

This article demonstrates a case of a lung adenocarcinoma patient in stage IV harboring an epidermal growth factor receptor (EGFR) 19 exon deletion mutation treated with 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin on day 1, sequenced with 250 mg gefitinib on prescription on days 4-28 for six cycles as first-line, then by gefitinib combined with pemetrexed as maintenance therapy. The patient achieved a partial response. Performance status increased from grade 2 to 1. The progression-free survival period was 17 months. Overall survival is now over three years. Side effects of grade two liver dysfunction and dermal toxicity were tolerable. Combined gefitinib with platinum-based chemotherapy as first-line treatment probably benefits non-small cell cancer patients in stage IV harboring sensitive EGFR gene mutations with a better local control rate, longer survival, and tolerable side effects.

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.