This study aimed to analyze the predictive value of the neutrophil-to-lymphocyte ratio (NLR) to better clarify which patients with advanced non-small cell lung cancer (NSCLC) would benefit most from apatinib after multiline treatment for drug resistance. This observational cohort study involved patients with advanced NSCLC who were treated with apatinib between May 2016 to May 2018. The participants in this study had previously been treated with at least two treatment regimens. Multivariate logistic regression and Cox proportional risk models were used to evaluate the overall survival (OS) and progression-free survival (PFS) of the pretreatment NLR. A total of 125 patients were reviewed. The median age was 64 years (range, 33–92); and 32.8% of the patients were female. Only 0.8% of the patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score ≥ 2. In multivariate analysis, pretreatment NLR ≥ 5 had an independent correlation with inferior OS (median 2.07 vs 3.40 months; HR 1.493, 95% CI 1.022–2.182; P = .038) and inferior PFS (median 1.83 vs 2.76 months; HR 1.478, 95% CI 1.015–2.153; P = .042). Elevated pretreatment NLR is associated with shorter OS and PFS in patients with advanced NSCLC treated with apatinib after multiline treatment for drug resistance.
Triboelectric nanogenerator (TENG) and its self-powered sensor based on the principles of contact electricity generation and electrostatic induction have important application prospects in the fields of new energy and internet of things (IoT). In the contact separation process of polymer materials with different electronegativity values, due to the transfer of electrons, a changing electrostatic field will be generated in the space around the polymer. In the existing TENG research, the field strength perpendicular to the plane of the friction layer and the electrode layer is mainly used to generate electrostatic induction, and the electric field effect around the polymer is ignored. According to the principle of electrostatic induction, the internal charge of the conductor in the electric field will be redistributed, which provides a way for the conductor to generate an induced electrical signal on the surface of the conductor without contacting the friction material. In this paper, we design a non-contact triboelectric nanogenerator (NC-TENG) based on changing electrostatic field. The influence of the distance between the conductor and the friction material, the induction area of the conductor and the position of the conductor relative to the friction material on the induced electrical output performance are studied when silicone rubber and nitrile rubber are used as a friction material. The results show that the NC-TENG can produce a stable electrical signal output when the conductor is completely separated from the friction material. The induced voltage of NC-TENG decreases with the increase of the distance between the conductor and the friction material, and gradually increases with the increase of the conductor's induction area. For the friction material with a size of 30 mm × 30 mm, the electrical output of NC-TENG tends to be stable when its conductor area is 60 mm × 45 mm. In addition, the different orientation of the conductor relative to the friction material also has a significant effect on the induced electrical output. The NC-TENG designed in this paper provides a novel electrical output generation mode, which provides a higher possibility for the subsequent research on TENG and the application of self-powered sensors.
This publication has been retracted by the Editor due to concerns regarding the originality of the figure images. Reference: Min Xu, Weiguang Gu, Zhou Shen, Fang Wang. Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway. Med Sci Monit, 2018; 24: 6551-6558. DOI: 10.12659/MSM.910542.
Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.
Abstract Background: Immune checkpoint inhibitors have provided remarkable antitumor effects in non-small cell lung cancer (NSCLC), while their efficacy in patients harboring driver mutations is still controversial and the correlation between driver gene mutations and PD-L1 expression remains unclear. In this study, we explored the association of PD-L1 expression, tumor mutation burden (TMB) and genomic mutation in NSCLC patients. Methods: FFPE tumor and matched blood samples of 244 NSCLC patients were collected for NGS-based targeted panel sequencing from July 2017 to July 2018. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. PD-L1 expression, TMB and microsatellite instability status (MSI) were assessed in 244 (100%), 188 (77%) and 198 (81%) patients, respectively. Results: There were 145 males (59.4%) and 99 females (40.6%) with a median age of 62 (31-84) years were involved, including 183 adenocarcinomas and 61 squamous carcinomas. PD-L1 expression of negative, 1-49% and ≥50% were 63.5%, 20.9% and 15.6%, respectively. The median value of TMB was 9.2 (0.8-68.9) muts/Mb and TMB≥10 muts/Mb was seen in 30.9% tumors. All the tumors but one were MSS status. The demographic features were comparable among different PD-L1 expression and TMB level (cutoff is 10 muts/Mb) group. We found recurrent mutations (>10%) in 6 genes, including TP53 (67.6%), EGFR (60.7%), CDKN2A (15.2%), KRAS (13.9%), PI3KCA (11.1%) and LRP1B (10.7%). AKT2 (2.5%) amplification was associated with higher TMB (p=0.011). For the relationship between driver genes and immunotherapeutic biomarkers, TP53 were positively associated with higher PD-L1 expression (p<0.001), while BRAF associated with lower PD-L1 (p<0.001); TP53 and BRAF mutations were correlated with higher TMB (p<0.001, p<0.001; respectively), while EGFR, KRAS, ERBB2 and ALK correlated with lower TMB (p<0.001, p<0.001, p<0.001,p=0.046; respectively). Interestingly, in terms of double mutants, NSCLC patients with EGFR and NOTCH1 co-mutations had lower level of TMB than either single mutant alone. EGFR and RBM10 double mutant was associated with lower PD-L1 expression than either single mutant. Conclusion: This study revealed the impact of genomic mutational status on immunotherapeutic biomarkers in NSCLC. TP53 mutation was associated with higher PD-L while TP53, BRAF mutations and AKT2 amplification correlated with higher TMB. EGFR with NOTCH1 or RBM10 co-mutation is associated with lower TMB or PD-L1, which needs further investigation in their impact on immunotherapy. Our study indicated that NGS panel sequencing and co-mutation analysis could provide potentially insights to precise immunotherapy. Citation Format: Qing Zhou, Weiguang Gu, WenFan Fu, Shijie Mai, Daren Lin, Shiyue Zhang, Wenjing Wang, Peng Zhang. The impact of genomic mutational status on PD-L1 expression and tumor mutation burden in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1691.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a standard treatment for patients with advanced non-small-cell lung cancer (NSCLC) harboring classic EGFR mutations. However, resistance to TKIs remains a major clinical challenge. The transformation from adenocarcinoma to small-cell lung cancer (SCLC) is a rare resistance mechanism to EGFR-TKIs. In this article, we report on 2 lung adenocarcinoma patients with EGFR mutations who developed EGFR-TKI resistance. In case one, the patient was initially diagnosed as lung adenocarcinoma with EGFR L858R, RB1 R445*, and TP53 Y205C mutations. EGFR-TKI failed to bring satisfactory curative effect with the emergence of EGFR T790M mutation and MET amplification and finally passed away. In case two, the patient was diagnosed with lung cancer harboring EGFR L747 and TP53 R342* mutations, and EGFR-TKIs brought a progression-free survival for nine months. However, EGFR-TKI resistance was acquired, and adenocarcinoma transformed into a complex of neuroendocrine carcinoma, SCLC, and lung adenocarcinoma, with the emergence of the EGFR L747, TP53 R342*, and RB1 mutations. Follow-up treatments failed to prevent tumor progression, and the patient died These 2 cases expand our understanding of EGFR-TKI resistance, SCLC transformation, and highlight the importance of histopathology and molecular characteristics for therapeutic strategies for transformed SCLC patients.
Cholangiocarcinoma (CCA) is a diverse group of malignancies arising from the intra- or extrahepatic biliary epithelium and characterized by its late diagnosis and fatal outcome. Extrahepatic cholangiocarcinoma (ECC) accounts for 90% of CCA. However, little is known about the comprehensive genomic alterations of ECC in Chinese population for providing clinical managements especially targeted therapy.Comprehensive genomic profiling (CGP) was performed with next generation sequencing panel on paraffin-embedded tumor from a cohort of 80 Chinese ECC patients.The most frequently altered genes were TP53 (68%), KRAS (46%), SMAD4 (22%), ARID1A (20%) and CDKN2A (19%). Mutual exclusivity was observed between multiple genes including ARID1A:TP53, KRAS:LRP1B and NF2:TP53. Genetic alterations with potential therapeutic implications were identified in 43% of patients. The top three actionable alterations include CDKN2A (n=11), BRAF (n=5) and ERBB2 (n=4). Potentially actionable alterations were mainly enriched in the G1-S transition, homologous recombination repair, MAPK/ERK pathway.This is the largest data set of ECC cases providing a comprehensive view on genetic alterations in Chinese population which differs significantly from a US cohort, and indicates the potential clinical implications for targeted therapies.
Apatinib, an oral small-molecule angiogenesis inhibitor, selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which inhibits vascular endothelial growth factor (VEGF) stimulated endothelial cell migration and proliferation and decreases tumour growth and metastasis. Recently, the efficacy of multi-target angiogenic drugs has been demonstrated for many cancers, including non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the clinical efficacy of apatinib in patients with advanced NSCLC.We conducted a retrospective analysis of 70 patients with advanced NSCLC who received second-line and later treatment from November 2015 to July 2017 with poor results. Out of the 70 patients, 36 patients received apatinib treatment after second-line or later treatment, whereas 34 patients in the control group did not receive further treatment. The patients were treated with oral apatinib 500 mg once a day every day for 4 weeks per cycle. Treatment was continued in responding and stable patients until disease progression or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed.ORR, DCR, PFS, and OS were evaluated in 36 patients receiving apatinib and 34 patients in the control group. The ORR and DCR in patients receiving apatinib therapy were 22.2% and 77.8%, respectively. The median PFS and OS in the treatment group were 5.6 and 9.6 months, respectively. The median OS in the apatinib group was significantly longer than that in the control group (9.6 versus 3.8 months; p < 0.0001). In contrast, there were no differences in adverse reactions between the patients in the treatment and control groups.Apatinib showed favourable efficacy and safety and can thus be used as a treatment option for patients with advanced NSCLC.
Concurrent chemotherapy and radiation is the standard treatment for unresectable stage III Lung adenocarcinoma. However, no optimal concurrent chemotherapeutic regimen has been described. This study aimed to assess concurrent pemetrexed, nedaplatin and thoracic intensity-modulated radiotherapy followed by consolidation pemetrexed/nedaplatin for unresectable Stage IIIA/B lung adenocarcinoma. Patients with unresectable stage III lung adenocarcinoma received thoracic intensity-modulated radiotherapy at 60–64 Gy in 30–32 fractions, concurrently with two cycles of 500 mg/m2 pemetrexed, with nedaplatin doses escalating from 60 mg/m2 (level 1) to 70 mg/m2 (level 2) and 80 mg/m2 (level 3). Consolidation consisted of three pemetrexed/nedaplatin (500 mg/m2, 60 mg/m2) cycles every 3 weeks after concurrent therapy. The primary objective of the safety was to determine the maximum-tolerated dose (MTD). The secondary endpoints included response rate, PFS and OS. Fifteen patients were enrolled, including 3, 6 and 6 individuals in the first, second, and third dose levels, respectively. Three cases of dose-limiting toxicities (grade 3 hepatitis, pneumonitis, and grade 4 thrombocytopenia), including one and two patients at levels 2 and 3, respectively, were observed and resulted in discontinued/delayed treatment. Response rates were 86.7 % (95 % confidence interval [CI], 64.2–97.8 %) and 64.3 % (95 % CI, 38.3–85.4 %) at chemoradiation and treatment completions, respectively. Median OS was 30.0 months (95 % CI, 16.4–43.6 months); 2-year OS was 44.0 % (95 % CI, 18.7–69.2 %). Median PFS was 12.0 months (95 % CI, 6.9–17.0 months), and the 2-year PFS 27.0 % (95 % CI, 4.7–49.3 %). Full dose 500 mg/m2 of pemetrexed and nedaplatin 70 mg/m2 could be used safely with thoracic intensity-modulated radiotherapy for inoperable stage III lung adenocarcinoma. Further evaluation of stage III lung adenocarcinoma management is warranted. This study was retrospectively registered at Chinese Clinical Trial Registry ( ChiCTR-OPN-16008316 , April 2016).
To compare the 2 analytical methds, CIA(chemiluminescent immunoassay) and RIA, serum T 3 and T 4 concentrations were analyzed by IMMULITE Ⅰ chemiluminescent immunoassay system and RIA respectively. The intra-and inter-assay CV of CIA were smaller than 5%. The serum containing 432ng/dL and 377ng/dL T 3 was performed in the recovery test. The recovery rate was 103.2% to 116.9%. The analytical results of the two methods were highly correlated. The correlation coefficient was 0.91, and the regression equation is Y=1.06X+0.159. IMMULITE Ⅰ analysis system needs 25 min to have the first result and then every 35 seconds for one of the following sample results, but the RIA needs several hours to have the results. IMMULITE Ⅰ analysis system is based on CIA, its results are highly comparable with the RIA. Its stable, simple to operate and can be extensively used for clinical applications.
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