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Lung cancer is currently the leading cause of cancer-related death in worldwide, non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Surgery, platinum-based chemotherapy, molecular targeted agents and radiotherapy are the main treatment of NSCLC. With the strategies of treatment constantly improving, the prognosis of NSCLC patients is not as good as before, new sort of treatments are needed to be exploited. Programmed death 1 (PD-1) and its ligand PD-L1 play a key role in tumor immune escape and the formation of tumor microenvironment, closely related with tumor generation and development. Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses. Utilizing the PD-1 and/or PD-L1 inhibitors has shown benefits in clinical trials of NSCLC. In this review, we discuss the basic principle of PD-1/PD-L1 pathway and its role in the tumorigenesis and development of NSCLC. The clinical development of PD-1/PD-L1 pathway inhibitors and the main problems in the present studies and the research direction in the future will also be discussed.

VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18–75 years with locally advanced or metastatic NSCLC and EGFRmut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4–13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0–9.3] vs 4·3 months [4·1–5·4]; hazard ratio 0·46 [0·34–0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. Innovent Biologics and the National Natural Science Foundation of China. For the Chinese translation of the abstract see Supplementary Materials section.

The eastern/western Taijinar Salt Lake in Qaidam Basin is rich in lithium and boron resources. Chemical speciation of boron and lithium is conducive to identify the migration way and enrichment of heavy metals which might cause certain effects on the environment of salt-lake area. A total of 28 surface sediment samples were collected from the Taijinar Salt Lake in June of 2020 to investigate the distribution, speciation and sources of boron and lithium in salt-lake sediments. The results showed that the average content of boron/lithium was low with value of 1.6/3.4 µg kg−1, while that of the other elements in sediments ranging from 0.035 µg kg−1 (Cd) to 48.20 mg kg−1 (As) by following the order of As > Pb > Hg > Zn > Cr > Cd. Boron and lithium in sediments were mainly bound to Fe–Mn oxide and residual fractions with the average proportion of 29.87% and 35.36% for boron as well as 32.18% and 31.43% for lithium. Pb mainly existed in carbonate and residual fraction, while Zn mainly existed in the Fe–Mn oxide and residual bound with average value of 40.56% and 43.32%, respectively. Hg/Cr mainly existed in the residual with the average value of 58.68%/84.18%, while Cd mainly existed in the Fe–Mn oxide and residual fraction with an average proportion of 26.52% and 30.89%, respectively. As mainly existed in Fe–Mn oxide, residual, and organic fraction with an average proportion of 30.20%, 32.61% and 21.92%, respectively. Elements including Zn, Cr and Pb had a certain influence on the speciation of boron and lithium based on the correlation analysis. The enrichment of Cd, Cr and Pb might be mainly caused by anthropogenic sources. The findings of this study will provide some basic information on the important elements including lithium and boron in the salt-lake areas.

No information is currently available on potential environmental impact of boric acid solvent extraction from salt-lake brine although boron production is important for industry, agriculture, and human well-beings. Life cycle assessment (LCA) was firstly used by this study to evaluate the environmental impact of boron production using extraction method with the functional unit of 1-ton boric acid. CO2 was the pollutant with the highest emission amount among the target pollutants, while both extraction and reverse extraction stages contributed to 61.6% of total emission amount for the boron extraction technique. Global warming potential (GWP) and acidification potential (AP) of producing 1-ton boric acid by extraction technique reached 5.52 × 103 kg CO2 eq and 28.0 kg SO2 eq, respectively. Extraction/dry stage contributed to the highest/lowest percentage of environmental impact indices by following the order of extraction > reverse extraction > acidification > dry. Life cycle cost for 1 ton of boric acid was estimated as $1054.83 with 67.5% of internal cost. Approximately 1.59 ton of indirect water and 6010 kWh of electricity were consumed to produce 1 ton of boric acid. The emission amounts of pollutants for nanofiltration boron-production technique were 1.4–1.7 times those for extraction technique. GWP and AP of boron extraction production were comparable with those of the other production processes. The findings of this study will provide the theoretical basis and quantitative data for the sustainable development and cleaner production of boron industry.Graphic abstract

Basic fibroblast growth factor (bFGF) is known to stimulate angiogenesis and thus to influence the proliferation, migration and survival of tumor cells. Many studies examined the relationship between human bFGF overexpression and survival in lung cancer patients, but the results have been mixed. To systematically summarize the clinical prognostic function of bFGF in lung cancer, we performed this systematic review with meta-analysis. Studies were identified by an electronic search of PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang databases, including publications prior to August 2014. Pooled hazard ratios (HR) for overall survival (OS) were aggregated and quantitatively analyzed by meta-analysis. Twenty-two studies (n = 2154) were evaluated in the meta-analysis. Combined HR suggested that bFGF overexpression had an adverse impact on survival of patients with lung cancer(HR = 1.202,95%CI, 1.022-1.382). Our subgroup analysis revealed that the combined HR evaluating bFGF expression on OS in operable non-small cell lung cancer (NSCLC) was 1.553 (95%CI, 1.120-1.986); the combined HR in small cell lung cancer (SCLC) was 1.667 (95%CI, 1.035-2.299). There was no significant impact of bFGF expression on survival in advanced NSCLC. This meta-analysis showed that bFGF overexpression is a potential indicator of worse prognosis for patients with operable NSCLC and SCLC, but is not associated with outcome in advanced NSCLC. The data suggests that high bFGF expression is highly related to poor prognosis. Nevertheless,more high-quality studies should be performed in order to provide additional evidence for the prognostic value of bFGF in lung cancer.

Background Immune checkpoint inhibitors (ICIs) had modest advances in the treatment of extensive-stage small cell lung cancer (ES-SCLC) in clinical trials, but there is a lack of biomarkers for prognosis in clinical practice. Methods We retrospectively collected data from ES-SCLC patients who received ICIs combined chemotherapy from two centers in China, integrated clinical and blood parameters, and constructed risk prognostication for immunochemotherapy. The population was divided into high- and low-risk groups, and the performance of the model was assessed separately in the training and validation cohorts. Results Two hundred and twenty and 43 patients were included in the training and validation groups, respectively. The important predictors were screened including body mass index, liver metastases, coefficient variation of red blood cell distribution width, lactate dehydrogenase, albumin, and C-reactive protein. Predicting 1-year overall survival (OS), the AUC values under ROC for the model under training, internal validation, and external validation were 0.760, 0.732, and 0.722, respectively, and the calibration curve and clinical decision curve performed well. Applied the model to divide patients into low-risk and high-risk groups, and the median OS was 23.7 months and 9.1 months, and the median progression-free survival was 8.2 months and 4.8 months, respectively; furthermore, this ability to discriminate survival was also observed in the validation cohort. Conclusions We constructed a novel prognostic model for ES-SCLC to predict survival employing baseline tumor burden, nutritional and inflammatory parameters, it is easily measured to screen high-risk patient populations.

Purpose For the first-line treatment of KRAS mutant non-small cell lung cancer (NSCLC) patients, immunotherapy or platinum-based chemotherapy are the main treatment method. Here, we investigated the clinical efficacy and prognosis those two regimens as first-line treatment in real-world practice. Methods KRAS mutant NSCLC patients received chemotherapy or immunotherapy as first-line treatment from September 2014 to March 2022 were enrolled. Clinical characteristics, treatment scheme, clinical curative effect and follow-up data of enrolled patients were collected for analysis. Results Fifty patients received immunotherapy and 115 patients received chemotherapy were enrolled. Patients who received immunotherapy (HR = 0.350, 95%CI 0.156–0.781, P  = 0.010), or pemetrexed-based regimen (HR = 0.486, 95%CI 0.255–0.928, P  = 0.029), or antiangiogenic therapy (HR = 0.355, 95%CI 0.159–0.790, P  = 0.011) were at a low risk of disease progression. And patients received antiangiogenic therapy had lower risk of death than those not (HR = 0.333, 95%CI 0.120–0.926, P  = 0.035). Subgroup analysis revealed the immunotherapy compared to chemotherapy alone had lower risk of disease progression (HR = 0.377, 95%CI 0.166–0.856, P  = 0.020) in PD-L1 expression ≥1% subgroup. And in non-G12C KRAS subgroup, but not in G12C KRAS subgroup, patients who received antiangiogenic therapy had lower risk of disease progression (HR = 0.254, 95%CI 0.098–0.656, P  = 0.005) and death than those not (HR = 0.197, 95%CI 0.056–0.692, P  = 0.011). In terms of different chemotherapy regimen, platinum-paclitaxel combined with antiangiogenic therapy achieved the highest ORR and DCR ( P  < 0.05), while the platinum-pemetrexed combined with antiangiogenic therapy had the longest PFS and OS ( P  < 0.001). Conclusion For the first-line treatment of KRAS mutant NSCLC patients, immunotherapy, antiangiogenic therapy, and pemetrexed-based regimen could obtain more benefits. Subgroup analysis revealed the benefits of immunotherapy compared to chemotherapy were applicable in PD-L1 expression≥1% subgroup, and antiangiogenic therapy could benefit non-G12C KRAS subgroup, but not G12C KRAS subgroup. In terms of different chemotherapy regimen, platinum-pemetrexed combined with antiangiogenic therapy may be the preferred chemotherapy regimen.

Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)– CTCs and CD31+ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM+/Vim+ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM–/Vim– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post‐therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients. Aneuploid CD31− CTCs and CD31+ CTECs, a pair of mutually related and interacting cellular circulating tumor biomarkers, play a critical role in tumorigenesis, neovascularization, and cancer metastasis. Longitudinally comprehensive co‐detection of diverse subtypes of CTCs and CTECs during therapy by iFISH may effectively prognosticate and real‐time monitor therapeutic efficacy or emerging resistance in cancer patients subjected to anti‐angiogenic combination regimens.

Background Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine, which is overexpressed and/or activated in multiple malignancies and is reported to be associated with tumor development and inferior survival. At present, the role of HGF in small cell lung cancer (SCLC) has not been fully explored yet. Materials and methods The expression of HGF and its value in predicting survival in SCLC were explored from GEO database and in pan-cancer analysis. Furthermore, we detected the expression of HGF using tumor tissue and paired plasma samples from a validation cohort of 71 SCLC patients at our institute. Correlation between tumor and plasma HGF expression and the prognostic values were analyzed. Results GEO database analysis revealed that tumor tissue had lower HGF expression than paired normal tissue in SCLC. At our institute, immunohistochemical staining showed negative expression of HGF in tumor tissue of SCLC at our institute (47/47, 100%). The average baseline plasma HGF was 1.28 (range,0.42–4.35) ng/ml. However, plasma HGF was higher in SCLC patients with patients with N 3, M 1 , liver metastasis (LM) and bone metastasis (BM) disease compared with those N 0 − 2 (1.25 vs. 1.75 ng/mL, P  = 0.000), M 0 (1.26 vs. 1.63 ng/mL, P  = 0.003), non-LM (1.32 vs. 2.06 ng/mL, P  = 0.009), and non-BM (1.35 vs. 1.77 ng/mL, P  = 0.047), respectively. Multivariate analysis revealed plasma HGF was an independent predictor for LM and prognostic factor of OS. Conclusion Our results revealed that plasma HGF rather than tumor HGF exhibited a potential role in predicting metastasis and survival in SCLC. Plasma HGF might be used as a non-invasive detecting and monitoring tool for SCLC.

Purpose This study aimed to investigate the clinical utility of diverse aneuploid circulating tumor cell (CTC) subtypes and particularly CTC-associated white blood cell (CTC-WBC) clusters in predicting treatment response, prognosis and real-time monitoring disease progression in advanced driver gene-negative non-small lung cancer (NSCLC) patients. Materials and methods A total of 74 eligible patients were prospectively enrolled and serial blood samples were collected at pre-treatment(t 0 ), after two cycles of therapy (t 1 ) and at post-four-to-six treatment cycles (t 2 ). Co-detection of diverse subtypes of aneuploid CTCs and CTC-WBC clusters was conducted in advanced NSCLC patients receiving first-line treatment. Results At baseline, CTCs were detected in 69 (93.24%) patients and CTC-WBC clusters were detected in 23 (31.08%) patients. Patients with CTCs < 5/6ml or with CTC-WBC clusters undetectable exhibited a better treatment response than patients with pre-therapeutic aneuploid CTCs ≥ 5/6ml or harboring CTC-WBC clusters ( p  = 0.034 and p  = 0.012, respectively). Before treatment, patients bearing tetraploid CTCs ≥ 1/6ml showed significantly inferior progression-free survival (PFS) [hazard ratio (HR):2.420, 95% confidence interval (CI): 1.426–4.106; p  = 0.001] and overall survival (OS) compared to patients with tetraploid CTCs < 1/6ml (HR:1.907, 95%CI: 1.119–3.251; p  = 0.018). A longitudinal study demonstrated that post-therapeutic patients harboring CTC-WBC clusters displayed the reduced PFS and OS compared with those without CTC-WBC clusters, and subgroup analysis showed that the presence of CTC-WBC clusters indicated a worse prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. After adjusting for multiple significant factors, post-therapeutic CTC-WBC clusters were the only independent predictor of both PFS (HR:2.872, 95% CI: 1.539–5.368; p  = 0.001) and OS (HR:2.162, 95% CI: 1.168–4.003; p  = 0.014). Conclusions In addition to CTCs, longitudinal detection of CTC-WBC clusters provided a feasible tool to indicate initial treatment response, dynamically monitor disease progression and predict survival in driver gene-negative advanced NSCLC patients.