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The combination of antiangiogenic agents with epidermal growth factor receptor inhibitors (EGFR-TKIs) and chemotherapy with EGFR-TKIs are the most common combination treatment options in epidermal growth factor receptor (EGFR) positive non-small cell lung cancer (NSCLC). This network meta-analysis was performed to evaluate the differences between them.We searched the PubMed, EMBASE and the Cochrane Controlled Trials Register up to August 2022. The primary outcomes were progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS), disease control rate (DCR) and adverse events (AEs). The data of hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were extracted in the studies. A network meta-analysis (NMA) was used to indirectly compare the efficacy and safety of antiangiogenic agents plus EGFR-TKIs and chemotherapy plus EGFR-TKIs.Pooled data of included studies were demonstrated that chemotherapy plus EGFR-TKIs had a benefit in ORR compared to antiangiogenic agents plus EGFR-TKIs in patients with EGFR mutated NSCLC (RR = 1.1, 95% CI: 1.0-1.2). However, there were no significant differences in PFS, OS and DCR between in the two group (PFS: HR = 1.0, 95% CI: 0.74-1.6; OS: HR = 0.78, 95% CI: 0.45-1.5; DCR: RR = 1.0, 95% CI: 0.94-1.1). The common treatment-related AEs in the two groups were relatively manageable.Based on the efficacy and safety, the combination of chemotherapy with EGFR-TKIs is considered the best combination treatment options in advanced NSCLC with EGFR mutation.

Background Acquired resistance development is a major challenge in the epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR–TKI) treatment of non–small cell lung cancer (NSCLC). Here, we investigated the potential effects of the concurrent use of anlotinib and EGFR‐TKI to overcome acquired resistance. Methods We conducted a preclinical study to evaluate the antitumor effects of gefitinib + anlotinib in gefitinib‐resistant lung adenocarcinoma models in vitro and in vivo. We then investigated the treatment effect of EGFR–TKI + anlotinib therapy in 24 advanced EGFR‐mutant NSCLC patients after EGFR‐TKI acquired resistance between January 2018 and August 2020. Results Anlotinib reversed gefitinib resistance in gefitinib‐resistant lung adenocarcinoma models by enhancing the antiproliferative and proapoptotic effects of gefitinib. The gefitinib + anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR–TKI + anlotinib therapy exhibited an objective response rate of 20.8% and a disease control rate of 95.8%. Median progression‐free survival (PFS) was 11.53 ± 2.41 months, but median overall survival was not reached. The median PFS was longer in patients experiencing gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (6.80 ± 1.75 months, p = 0.017). One grade 3 adverse event was noted (diarrhea, n = 2, 8.3%), and grade 4 or 5 adverse events were absent. Conclusions EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and in vivo. Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in advanced EGFR‐mutant NSCLC patients., Gefitinib and anlotinib synergistically promoted PC9/GR cells proliferation and inhibited PC9/GR cells apoptosis through the inhibition of EGFR phosphorylation, VEGFR2 phosphorylation and the downregulation of ERK and Akt signaling.

The mechanism(s) of immune checkpoint inhibitor (ICI)-induced myasthenia gravis (MG), an immune-related adverse event (irAE) that is fatal and limits subsequent ICI use, remain unexplored. Here, through comparative genomic analysis, we identified a pathogenic p.S467C germline variant inSLC22A5in a thymoma case with ICI-induced MG, which was found to be associated with fatty acid oxidation through its regulation on L-carnitine levels. Remarkably, ICI rechallenge with L-carnitine pretreatment led to durable response without MG-related symptoms. Thus, we provide the first clinical evidence of genetic test-directed irAE management, which integrates individualized ICI treatment into the evolving paradigm of cancer management.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are strongly recommended for non-small cell lung carcinoma (NSCLC) patients harboring active EGFR mutations, while drug resistance inevitably makes exploring the resistance mechanisms and seeking effective therapeutic strategies urgent endeavors. Thymidylate synthetase (TYMS or TS) is a dominant enzyme in thymidylate nucleotide metabolism. In this study, based on public database analysis and examination of gene sets from 140 NSCLC patients that received EGFR-TKI therapy, we found a significantly positive correlation between TS expression and overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma. Twenty-four tissue specimens from NSCLC patients exhibited upregulated TS mRNA expression in NSCLC patients resistant to gefitinib. The human NSCLC cell line PC9, which is sensitive to gefitinib, and relatively resistant PC9/GR cells were used to demonstrate that knockdown of TS restored the sensitivity of resistant cells to gefitinib. Furthermore, pemetrexed effectively suppressed TS-mediated thymidylate metabolism and induced ROS generation and cellular senescence, thereby hampering carcinogenesis and restoring cell sensitivity to gefitinib. The combination of pemetrexed and gefitinib damaged the proliferation, migration and invasion capabilities of gefitinib-resistant cells, exhibiting a synergistic anticancer effect. Our findings illuminate the potential mechanism of TS-triggered gefitinib resistance and indicate that inhibition of TS by pemetrexed can potentiate the effect of gefitinib in NSCLC cells resistant to gefitinib. Pemetrexed combined with gefitinib has potent anti-progression potential in gefitinib-resistant NSCLC. This suggests that NSCLC patients with both high TS expression and EGFR-driving mutations might benefit more from a combination strategy of EGFR-TKIs and pemetrexed-based chemotherapy than EGFR-TKI monotherapy, which has profound clinical implications and considerable therapeutic value.

Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting. Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity. Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.67–23.33] vs. 11.70 months [95% CI, 10.81–12.59], p p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

Purpose: EGFR-TKIs are the first-line therapy for advanced NSCLC harboring EGFR-sensitive mutations. A robust immunity is an essential foundation for patients to tolerate continuous drug treatments. Lienal polypeptide (LP) is an immunomodulator widely applied to regulate immunity in clinical practice. Nevertheless, its potential impact on EGFR-TKIs therapy has not been illustrated. This study aimed to explore the immunomodulatory and antitumor efficacy of LP in combination with EGFR-TKIs threapy in advanced NSCLC.Patients and methods: Retrospective analysis on variation of lymphocytes in 106 NSCLC patients after EGFR-TKIs combined with LP treatment was performed. Proliferation experiment, transwell and wound healing assays were performed in PC9-GR cells to estimate influence of LP on tumor proliferation, invasion and migrati n in vitro . Flow cytometry was performed to detect cell apoptosis and cell cycle. The expression of p-EGFR and EGFR were detected by Western blot to investigate antitumor effect of LP.Results: The levels of CD3 + , CD4 + T cells and the CD4 + /CD8 + ratio were higher in NSCLC patients treated with Gefitinib in conjunction with LP. Gefitinib combined with LP inhibited tumor invasion and migration, triggered G0/G1 phase arrest to block cellular proliferation and promote cell apoptosis in vitro. Furthermore, the expression of p-EGFR was decreased after Gefitinib-combining-LP treatment.Conclusions: LP had a synergistic anticancer effect with EGFR-TKIs in NSCLC. LP in combination with EGFR-TKIs therapy has clinical curative effect in treatment of advanced NSCLC with EGFR driving mutations, can effectively enhance physical immunity and resensitize drug-resistant cells to EGFR-TKIs, which has a certain clinical application value.

Background Checkpoint inhibitor pneumonitis (CIP) may be accompanied by lung cancer in patients treated with immune checkpoint inhibitors (ICI). This study aimed to test the risk factors, genetic and clinical characteristics of CIP in a cohort of Chinese patients with lung cancer. Methods We retrospectively reviewed the medical records of eligible patients who received ICI treatment from December 2017 to September 2020 in our hospital. Patient characteristics, ICI protocols, and mutation frequencies of related genes are compared between the CIP group and the non-CIP group. Results A total of 94 patients were recruited. Of them, 16 (17.0%) patients developed CIP. Multivariate logistic regression analysis suggested Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 [odds ratio (OR) =6.53; 95% confidence interval (CI), 1.74-24.46; P=0.005] and previous pulmonary fibrosis (OR =20.13; 95% CI, 3.64-111.44; P=0.001) were independently associated with a higher incidence of CIP. There was an increasing trend, although not statistically significant, in the risk of CIP in patients with TP53 mutation (P=0.280). Most CIP patients were managed successfully following the current guideline. However, serious events (including one death) were still observed. Conclusions ECOG PS ≥2 and earlier pulmonary fibrosis were closely correlated to the occurrence of CIP in Chinese lung cancer patients after ICI treatment. Early screening and prompt intervention are necessary for the management of CIP.

The underlying molecular mechanisms of tumorigenesis and progression of non-small cell lung cancer (NSCLC) are not yet fully elucidated. In the present study, in vitro functional dissections suggest that siRNA-mediated silencing of CCNE2 profoundly attenuated the proliferative and colony-formative abilities of NSCLC PC9 and HCC827 cells, while forced overexpression of CCNE2 significantly strengthened the proliferative and colony-formative capabilities of these cells. Intriguingly, by ChIP and luciferase reporter gene assays, we observed that CARM1 is recruited to the promoter regions of CCNE2 gene and acts as a transcriptional activator. Mechanically, the asymmetric di-methylation of H3R17me2a and H3R26me2a, as the catalytic substrates of CARM1, were highly enriched at the core promoter regions of CCNE2 gene, thereby activating the expression of CCNE2. In vitro and in vivo rescue experiments demonstrated that restoration of CCNE2 expression significantly abolished the CARM1 shRNA-mediated inhibition of cell proliferation, indicating that the oncogenic function of CARM1, at least partially, depended on the activation of CCNE2. Inhibition of CARM1 enzymatic activity could significantly repress CCNE2 expression in NSCLC cells. In addition, the expression of CARM1 was significantly elevated and positively correlated with CCNE2 levels in 20 cases of NSCLC patients. Both CARM1 and CCNE2 are highly associated with shorter 10-year overall survival of at a large cohort of 461 cases of NSCLC patients from the Kaplan-Meier plotter database. To summarize, these findings provide compelling evidence that CARM1 could promote NSCLC progression via activation of CCNE2, paving the way for future therapeutic strategies in NSCLC.

Lung cancer leads to the highest mortality among all cancer types in the world, and non–small‐cell lung cancer (NSCLC) occupies over 80% of the lung cancer cases. Numerous studies have demonstrated that long non‐coding RNA (lncRNA) is involved in various human diseases including cancer. LncRNA FTX was firstly identified in Xist gene locus and was dysregulated in many human cancers. However, the function of FTX in NSCLC is still unclear. Here, we report that long non‐coding RNA FTX expression level is down‐regulated in NSCLC clinical tissue samples and cell lines. Ectopic expression of FTX inhibits proliferation and metastasis of lung cancer cells in vitro and in vivo. Furthermore, we find that FTX overexpression activates the expression of transcription factor FOXA2, an important regulator in lung cancer progression, and we reveal a novel FTX/miR‐200a‐3p/FOXA2 competing endogenous RNA regulatory axis in lung cancer cells. Our results provide new insights and directions for exploring the function of FTX in lung cancer progression.

Background MiRNAs have been reported to induce certain drug resistance in multiple solid tumors via various mechanisms. Our study aimed to investigate whether miRNA-1269b was involved in the chemoresistance and the progression of non-small cell lung cancer (NSCLC). Methods MTT and colony formation assay were conducted to determine cell proliferation and cell apoptosis was analyzed by flow cytometry with annexin V/PI. Luciferase reporter assay was performed to validate miRNA-targeting sequences. The function of miR-1269b in cisplatin-resistant was evaluated in vivo in a mouse tumor model. Results We found that miR-1269b expression was up-regulated in cisplatin-resistant NSCLC specimens and NSCLC cell lines, which resulted in the promotion of chemoresistance and tumorigenicity. miR-1269b overexpression enhanced drug resistance and promoted cell proliferation in vitro and tumor growth in vivo, with reduced apoptosis rate of A549 cells inin vitro cell culture. Mechanistically, we identified PTEN as the direct target of miR-1269b, and the PTEN level was negatively correlated with miR-1269b in NSCLC specimens. Further study demonstrated that miR-1269b targeted PTEN to modulate PI3K/AKT signaling pathway. Conclusion In conclusion, these findings suggest that the miR-1269b/PTEN/PI3K/AKT-mediated network might promote cisplatin resistance in NSCLC, and that miR-1269b can be a potential therapeutic target for chemoresistance in NSCLC patients.

Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.

Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. Such exchange results in tumor‐educated platelets with altered RNA expression profiles. Multiple lines of evidence indicate that platelet RNA profiles may be suitable as diagnostic biomarkers for cancer‐related biological processes. In this study, we characterized the gene expression signatures of platelets in breast cancer (BC) by high‐throughput sequencing and quantitative real‐time RT‐PCR. Our results indicate that the expression of TPM3 (tropomyosin 3) mRNA is significantly elevated in platelets from patients with BC compared with age‐matched healthy control subjects. Furthermore, up‐regulation of TPM3 mRNA in platelets was found to be significantly correlated with metastasis in patients with BC. Finally, we report that platelet TPM3 mRNA is delivered into BC cells through microvesicles and leads to enhanced migrative phenotype of BC cells. In summary, our findings suggest that the transfer of platelet TPM3 mRNA into cancer cells via microvesicles promotes cancer cell migration, and thus platelet‐derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic BC., Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. In this study, we found that platelet TPM3 (tropomyosin 3) mRNA can be delivered into cancer cells via microvesicles to promote cancer cell migration. Platelet‐derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic breast cancer.

Wen Gao,1,* Jing He,1,* Shi-Dai Jin,1,* Jing Xu,1 Tong-Fu Yu,2 Wei Wang,3 Quan Zhu,2 Hui Dai,4 Hao Wu,1 Yi-Qian Liu,1 Yong-Qian Shu,1 Ren-Hua Guo1 1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 4Medical Records Statistics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ren-Hua Guo; Yong-Qian ShuDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, People’s Republic of ChinaEmail rhguo@njmu.edu.cn; shuyongqian@csco.org.cnBackground: The present study analyzed the relationship between clinical features and the T790M mutation in non-small cell lung cancer (NSCLC) patients resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment.Methods: NSCLC patients with resistance to first-generation EGFR-TKIs in which the disease control time was more than 6 months after initial TKI treatment were enrolled. T790M mutation analysis was performed using one of the following methods according to each manufacturer’s protocols: Cobas EGFR mutation test (41/105, 39.0%), digital PCR (42/105, 40.0%) or Scorpion amplification refractory mutation system (ARMS) (22/105, 21.0%). Sample type of T790M was from tissue only (53/105, 50.5%), plasma only (46/105, 43.8%), tissue and plasma (6/105, 5.7%).Results: Of 105 patients, 57 were T790M-positive and 48 were T790M-negative. T790M-positive patients had longer progression-free survival (PFS) after initial EGFR-TKI treatment (p = 0.019). T790M positivity was more frequent in patients treated with gefitinib than in those treated with icotinib (65% vs 40.54%, p = 0.018). The rate of T790M positivity was lower in patients with EGFR L858R (44.44%, 12/27) before TKI treatment than in those with EGFR 19del (72.0%, 36/50, p = 0.036). Patients who achieved PR after initial EGFR-TKI treatment had a higher rate of T790M positivity than those with SD (75.76% vs 50%, p = 0.023). There was no relationship between T790M status and age, gender, primary site, metastasis site, or treatment before TKI.Conclusion: Progression-free survival (PFS), drug type, response to initial EGFR-TKI treatment, and EGFR status before initial EGFR treatment were associated with the frequency of T790M mutation.Keywords: lung cancer, EGFR, T790M, gefitinib, icotinib

The inflammatory state of tumor microenvironment play an important role in non-small cell lung cancer (NSCLC) drug resistance. As the key signal pathway connecting inflammation and tumor, activated signal transduction and transcriptional activation factor 3 (STAT3) leads togenetic abnormal expression, gene silencing, genomic instability, etc. in tumor cells, and induces therapeutic resistance. STAT3 has thepotential to be a new target for reversal of resistance. In this review, we summarize the progress of STAT3 in acquired drug resistance of NSCLC, explore the possibility of STAT3 as a new target to reverse drug resistance, and provide basic theories for the new clinical treatment strategy of acquired drug resistance in NSCLC.

Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor, has been used as the first choice of treatment for advanced non-small-cell lung cancer. However, during the course of treatment, cancer cells often develop resistance to gefitinib without fully understood mechanisms. In this study, we aimed to elucidate an important role of long intergenic non-coding RNA 00665 in developing resistance to gefitinib in non-small-cell lung cancer. We showed that long intergenic non-coding RNA 00665 expression was significantly upregulated in lung cancer tissues and cells with acquired gefitinib resistance. Long intergenic non-coding RNA 00665 knockdown restored gefitinib sensitivity both in vitro and in vivo by suppressing cell proliferation and inducing apoptosis. Moreover, knockdown of long intergenic non-coding RNA 00665 markedly reduced activation of EGFR and its downstream event protein kinase B (AKT). Moreover, LINC00665 could interact with EZH2 and regulate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Thus, our study suggests that long intergenic non-coding RNA 00665 is important for non-small-cell lung cancer to develop drug resistance and might be a potential biomarker for drug resistance and a therapeutic target for non-small-cell lung cancer. Keywords: lncRNA, LINC00665, acquired resistance, EGFR-TKIs, NSCLC

EphB3 is a member of the EPH family of receptors and has been found to play a role in the carcinogenesis of some human cancers. However, its expression and clinical significance in gastric cancer (GC) have not been well documented. In the present study, we detected the expression of EphB3 in GC and adjacent noncancerous tissues and explored its relationships with the clinicopathological features and prognosis of GC patients. It was found that EphB3 silenced GC cells epigenetically by direct transcriptional repression of GC cells via polycomb group protein EZH2 mediation. EphB3 was downregulated in GC cells and tissues, and EphB3 depletion promoted GC cell growth and invasion, while ectopic overexpression of EphB3 produced a significant anti-tumor effect. EphB3 was found to be involved in epithelial-mesenchymal transition by regulating E-cadherin and vimentin expression. In addition, patients with reduced EphB3 expression had shorter disease-free survival (DFS), indicating that EphB3 may prove to be a biomarker for prognosis of GC. These results demonstrated that EphB3 functioned as a tumor-suppressor and prognostic biomarker in GC.

Background The incidence of brain metastasis (BM) in patients suffering from lung squamous cell carcinoma (LUSC) is lower than that in patients suffering from non-squamous cell carcinoma (NSCC) and there are few studies on BM of LUSC. The purpose of this investigation was to ascertain the risk factors of LUSC, as well as to establish a nomogram prognostic model to predict the incidence of BM in patients with LUSC. Methods Patients diagnosed with LUSC between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database and the patient data were collated. All patients diagnosed from 2010-2012 were allocated into the training cohort, and the remaining patients diagnosed from 2013-2015 formed the test cohort. Using factors that were screened out through logistic regression analyses, the nomogram in the training cohort was established. It was then evaluated for discrimination and calibration using the test cohort. The performance of the nomogram was assessed by quantifying the area under the receiver operating characteristic (ROC) curve and evaluating the calibration curve. Results A total of 26,154 LUSC patients were included in the study. The training cohort consisted of 16,543 patients and there were 8611 patients in the test cohort. Age, marital status, insurance status, histological grade, tumor location, laterality, stage of the cancer, number of metastatic organs, chemotherapy, surgery, and radiotherapy were highly correlated with the incidence of BM. The area under the ROC curve (AUC) of the nomogram for the training cohort and the test cohort were 0.810 [95% confidence interval (CI): 0.796 to 0.823] and 0.805 (95% CI: 0.784 to 0.825), respectively. The slope of the calibration curve was close to 1. Conclusions The nomogram was able to accurately predict the incidence of BM. This may be beneficial for the early identification of high-risk LUSC patients and the establishment of individualized treatments.

Additional file 1: Fig. S1. Best response time in different subgroups. T + C, EGFR-TKI combined with chemotherapy; T, EGFR-TKI monotherapy. Fig. S2. 1-year survival (a) (start the Y-axis with 90%) and 2-year survival (b) (start the Y-axis with 70%) in two groups; (c) 1-year and 2-year OS rates in two groups. T + C, EGFR-TKI combined with chemotherapy; T, EGFR-TKI monotherapy; OS, overall survival. Fig. S3. The site of progression in two groups. T + C, EGFR-TKI combined with chemotherapy; T, EGFR-TKI monotherapy. Table S1. Tumor response.

BackgroundThe incidence of brain metastasis (BM) in patients suffering from lung squamous cell carcinoma (LUSC) is lower than that in those suffering from non squamous cell carcinoma (NSCC). The purpose of this investigation is to ascertain the risk factors of LUSC as well as to establish a nomogram prognostic model to predict the incidence of BM.MethodsData about the patients diagnosed with LUSC between 2010 and 2015 were collected from Surveillance, Epidemiology, and End Results (SEER) database. The patients diagnosed during 2010-2012 were divided into the training cohort, and the remaining diagnosed during 2013-2015 into the test cohort. Using factors screened out through logistic regression analyses, we established the nomogram in the training cohort and then evaluated the discrimination and calibration in the test cohort. The prediction performance of nomogram was quantified by AUC（area under ROC(receiver operating characteristic curve)）and evaluated by calibration curve.Results26154 LUSU patients were included: 16543 in the training cohort and 8611 in the test cohort. Age, marital status, insurance status, histological grade, tumor location, laterality, stage, number of metastatic organs, chemotherapy, surgery and radiotherapy were highly related to the incidence of BM. The AUC of nomogram was 0.810 (95% confidence interval (CI): 0.796-0.823) and 0.805 (95%CI: 0.784-0.825) in the training cohort and the test cohort, respectively. The slope of calibration curve was closed to 1. ConclusionsThe nomogram can accurately predict the incidence of BM, which is helpful for the early identification of high-risk LUSU patients and the establishment of individualized treatment.

Background: Early stages of lung cancer have a better prognosis than later stages. The accuracy of current lung cancer early detection methods is relatively poor. We firstly try to use circRNAs of platelets enable blood-based early detection of lung cancer. Methods: We did a three-stage study that included healthy controls, benign lung nodule, and patients with diagnosed lung cancer from two hospitals in China. We used High-throughput Illumina sequencing analysis to profile circRNAs expression in the 8 patients with lung cancer and 8 non-cancer controls (including healthy controls and benign lung nodule patients). Using a training cohort of patients with lung cancer and non-cancer controls, we built a circRNAs classifier to detect lung cancer. Then, the classifiers’ ability was validated in two independent cohorts of patients and non-cancer controls. We used the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to evaluate diagnostic performance. Findings: Between Aug 1, 2018, and September 31, 2019, we recruited 88 participants to the training cohort, and 694 and 605 participants to the two independent validation cohorts. A signature comprising 23 circRNAs was identified by RNA-Seq analysis in the discovery stage. Then, four circRNAs (CD274, TIMP1, FLNA, ITGA2B) was found to have the possibility to serve as biomarkers for LC detection in the training stage by qRT-PCR. These selected four circRNAs from platelets was identified and subsequently assessed in the two independent validation cohorts. The area under the curve (AUC) for the five circRNAs from platelets (Pcs) were 0.975 in the validation cohort. In the following blinded test including the platelets from benign pulmonary nodule, LC patients and LC patients after surgery, Pcs correctly discriminated the patients with 90.6% sensitivity and 96.3% specificity. Interpretation: CircRNAs from platelets are very promising biomarkers for early stages of lung cancer diagnosis with very high sensitivity and specificity. This novel technology could serve as a Non-invasive, highly accurate diagnostic tool for lung nodule carriers that difficult to distinguish malignance from benign ones. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81572262), Jiangsu Province’s Key provincial Talents Program (ZDRCA2016028), 333 high class Talented Man Project (BRA2016516) and The Natural Science Foundation of the Jiangsu Higher Education Institution of China (18KJB320006). Declaration of Interests: None declared. Ethics Approval Statement: The study was approved by institutional ethics committee in each study center.

BACKGROUND The five-year survival rate of non-small cell lung cancer (NSCLC) patients is very low. MiR-873 is involved in the growth, metastasis, and differentiation of tumors. Herein, we determined the target gene and influence of miR-873 in NSCLC. METHODS MiRanda and Targetscan websites were used to predict the target gene of miR-873 in NSCLC. Luciferase activity was examined using a dual luciferase reporter gene assay kit. The viability, tube formation, and proliferation of cells were analyzed by cell counting kit-8, angiogenic analysis, and flow cytometry, respectively. The levels of miR-873 and GLI1 were evaluated using quantitative real-time PCR and Western blot assays. RESULTS Low levels of GLI1 and high levels of miR-873 were observed in an NSCLC cell line (PC9) highly sensitive to EGFR-tyrosine kinase inhibitors. There was a negative correlation between miR-873 and GLI1 expression in PC9 and PC9/GR cells. The inhibition of miR-873 enhanced GLI1 levels. MiR-873 expression was inhibited by gefitinib. Gefitinib markedly reduced the viability, tube formation, and cell number in PC9 cells. However, suppression of miR-873 enhanced the resistance and knockdown of GLI1 enhanced the sensitivity of PC9 cells to gefitinib. CONCLUSIONS GLI1 is a target gene of miR-873 in NSCLC. The inhibition of miR-873 increased gefitinib resistance of NSCLC cells via the upregulation of GLI1. These results indicate that miR-873-GLI1 signaling is involved in gefitinib resistance in NSCLC.

Background: Lung cancer is the most common cause of cancer-related deaths in men and women worldwide. Novel diagnostic biomarkers are urgently required to enable the early detection and treatment of lung cancer, and using novel methods to explore tumor-related biomarkers is a hot topic in lung cancer research. The purpose of this study was to use ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics analysis technology combined with multivariate data processing methods to identify potential plasma biomarkers for non-small cell lung cancer (NSCLC). Methods: Plasma samples from 99 NSCLC patients and 112 healthy controls were randomly divided into the screening group and the validation group, respectively. UPLC-MS metabolomics analysis technology combined with multivariate data processing methods were used to identify potential plasma biomarkers for NSCLC. Results: A total of 254 metabolites were detected and validated in plasma. Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) modeling indicated that 28 endogenous metabolites were present at significantly different levels in patients with NSCLC than healthy controls (variable importance in projection (VIP)>1 and PConclusions: Metabolomics has the potential to distinguish between NSCLC patients and healthy controls, and may reveal new plasma biomarkers for the early detection of NSCLC.

Background/Aims: Most of estrogen receptor positive breast cancer patients respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. Thus, it is necessary to further elucidate the function and mechanism of miRNAs in tamoxifen resistance. Methods: Tamoxifen sensitivity was validated by using Cell Counting Kit-8 in tamoxifen-sensitive breast cancer cells (MCF-7, T47D) and tamoxifen-resistant cells (MCF-7/TAM, T47D/ TAM). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of miR-449a in tamoxifen-sensitive/-resistant cells and patient serums. Dual-luciferase assay was used to identify the binding of miR-449a and predicted gene ADAM22. The expression level of ADAM22 was determined by qRT-PCR and western blotting in miR-449a +/- breast cancer cells. Subsequently, rescue experiments were carried out to identify the function of ADAM22 in miR-449a-reduced tamoxifen resistance. Finally, Gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of ADAM22 in regulating tamoxifen resistance. Results: MiR-449a levels were downregulated significantly in tamoxifen-resistant breast cancer cells when compared with their parental cells, as well as in clinical breast cancer serum samples. Overexpression of miR-449a re-sensitized the tamoxifen-resistant breast cancer cells, while inhibition of miR-449a conferred tamoxifen resistance in parental cells. Luciferase assay identified ADAM22 as a direct target gene of miR-449a. Additionally, silencing of ADAM22 could reverse tamoxifen resistance induced by miR-449a inhibition in ER-positive breast cancer cells. GO analysis results showed ADAM22 was mainly enriched in the biological processes of cell adhesion, cell differentiation, gliogenesis and so on. Protein-protein interaction analyses appeared that ADAM22 might regulate tamoxifen resistance through PPARG, LGI1, KRAS and LYN. Conclusion: Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells. These results suggest that miR-449a, functioning by targeting ADAM22, contributes to the mechanisms underlying breast cancer endocrine resistance, which may provide a potential therapeutic strategy in ER-positive breast cancers.

Breast cancer is one of the most common malignancies and bone is the commonest site of distant metastases. Evidences indicate that adequate supply of vitamin D will decrease the morbidity and mortality of breast cancer. However, the main role of vitamin D deficiency in breast cancer bone metastases remains unclear. In this study, the relationship between vitamin D and breast cancer bone metastases were evaluated. Results showed that 1,25(OH)2D3 can not only inhibit the proliferation, migration and invasion of breast cancer cell TM40D in vitro, but also attenuate the breast cancer cell TM40D-induced bone destruction in vivo, whose underlying mechanism was at least partially through decreasing the number of the osteoclasts. To our knowledge, this is the first to use 1-alpha-hydroxylase [1α(OH)ase] knockout mice which characterized vitamin D deficiency to establish the breast cancer bone metastases model. Based on this model, we also found that vitamin D deficiency will accelerate the osteolytic lesions, and 1,25(OH)2D3 supplement will restrain osteolytic lesions. Therefore, these findings suggest that vitamin D has the potential capacity to be a therapeutic agent for the breast cancer bone metastases.

Jun Li,1,* Ruitong Xu,2,* Xiao Lu,3 Jing He,1 Shidai Jin1 1Department of Medical Oncology, 2Department of General Practice, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 3Department of Medical Oncology, Changshu No 1 People’s Hospital, Changshu, People’s Republic of China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR) is one of the major obstacles in successful chemotherapy. The combination of chemotherapy drugs and multidrug-resistant reversing agents for treating MDR tumor is a good strategy to overcome MDR. In this work, we prepared the simple redox-responsive micelles based on mPEG-SS-C18 as a co-delivery system to load the paclitaxel (PTX) and dasatinib (DAS) for treatment of MCF-7/ADR cells. The co-loaded micelles had a good dispersity and a spherical shape with a uniform size distribution, and they could quickly disassemble and rapidly release drugs under the reduction environment. Compared with MCF-7 cells, the DAS and PTX co-loaded redox-sensitive micelle (SS-PDNPs) showed stronger cytotoxicity and a more improving intracellular drug concentration than other drug formulations in MCF-7/ADR cells. In summary, the results suggested that the simple co-delivery micelles of PTX and DAS possessed significant potential to overcome drug resistance in cancer therapy. Keywords: redox responsive, overcoming multidrug resistant, co-delivery, paclitaxel, dasatinib&nbsp

// Yue Sun 1, * , Shi-Dai Jin 2, * , Quan Zhu 3, * , Liang Han 4, 6, * , Jing Feng 1, 5 , Xi-Yi Lu 2 , Wei Wang 3 , Feng Wang 3 , Ren-Hua Guo 2 1 Department of Oncology, Yancheng Third People’s Hospital, The Affiliated Yanchen Hospital of Southeast University Medicine College, Yancheng, Jiangsu, China 2 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 3 Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 4 Department of Oncology, Xuzhou Central Hospital, Affiliated Xuzhou Hospital, College of Medicine, Southeast University, Xuzhou, Jiangsu, China 5 Department of Oncology, Jiangsu Shengze Hospital, Suzhou, Jiangsu, China 6 Department of Oncology, Yancheng Third People’s Hospital, The Affiliated Yanchen Hospital of Southeast University Medicine College, Yancheng, Jiangsu, China * These authors contributed equally to this work and should be regarded as joint first authors Correspondence to: Ren-Hua Guo, email: rhguo@njmu.edu.cn Keywords: LncRNAs, LUCAT1, p21, p57, non-small cell lung cancer (NSCLC) Received: June 09, 2016 Accepted: February 27, 2017 Published: March 09, 2017 ABSTRACT Recently, long non-coding RNAs (lncRNAs) have been recognized as playing key roles in regulating cellular processes, such as proliferation, invasion, and metastasis. These lncRNAs have been shown to be abnormally expressed in tumorigenic processes. However, the role and clinical relevance of LUCAT1 in non-small-cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of LUCAT1 was significantly up-regulated in NSCLC tissues compared to non-tumor tissues, and its expression was associated with tumor size, tumor–node–metastasis (TNM) stage and overall survival (OS). Further experiments showed that LUCAT1 knockdown inhibited cell proliferation both in vitro and in vivo . Mechanistic investigations showed that LUCAT1 plays a key role in G0/G1 arrest. We further demonstrated that LUCAT1 was associated with polycomb repressor complexes (PRC2) and that this association was required for epigenetically repression of p21 and p57, thus contributing to the regulation of NSCLC cell cycle and proliferation. In summary, our results show that LUCAT1 could regulate tumorigenesis of NSCLC and be biomarker for poor prognosis in NSCLC.

Background: The efficacy of an EGFR-targeted treatment strategy for non-small cell lung cancer (NSCLC) is reduced by drug resistance. IL-22 enhances tumor growth and induces chemotherapy resistance in human lung cancer cells. The present study elucidated the IL-22-induced mechanism underlying EGFR-tyrosine kinase inhibitor (TKI) resistance in NSCLC. Methods: The plasma and tissues of patients who received EGFR-TKIs were utilized to determine the association between IL-22 expression and gefitinib efficacy. The IL-22 effect on the EGFR/ERK/AKT pathways in NSCLC HCC827 and PC-9 cells was determined using the CCK-8 assay, western blot, and flow cytometric analysis. A PC-9 xenograft model of IL-22 exposure was established. Gefitinib was administered to mice in combination with IL-22 or vehicle. Results: We showed that IL-22 expression was higher in the EGFR-TKI-resistant group compared to EGFR-TKI-sensitive group. IL-22 expression was associated with EGFR-TKI efficacy in plasma. Additional treatment of IL-22 induced gefitinib resistance and reduced apoptosis in PC-9 and HCC827 cell lines. Furthermore, we showed that the effects of IL-22 attributed to p-ERK, p-EGFR, and p-AKT up-regulation. IL-22 neutralizing antibody completely abrogated the effects of IL-22 on apoptosis and AKT/EGFR/ERK signaling. Finally, we showed that IL-22 enhanced tumor growth and induced gefitinib resistance in the PC-9 xenograft model. Moreover, compared with gefitinib alone, the combination of IL-22 and gefitinib led to an increase in Ki67-positive staining and a reduction in TUNEL staining. Conclusions: Our findings indicate that IL-22 plays a role in tumor progression and EGFR-TKI resistance in NSCLC. Thus, IL-22 might serve as a novel biomarker to overcome resistance of EGFR-TKI.

Background MiRNAs have been reported to induce certain drug resistance in multiple solid tumors via various mechanisms. Our study aimed to investigate whether miRNA-1269b was involved in the chemoresistance and the progression of non-small cell lung cancer (NSCLC). Methods MTT and colony formation assay were conducted to determine cell proliferation and cell apoptosis was analyzed by flow cytometry with annexin V/PI. Luciferase reporter assay was performed to validate miRNA-targeting sequences. The function of miR-1269b in cisplatin-resistant was evaluated in vivo in a mouse tumor model. Results We found that miR-1269b expression was up-regulated in cisplatin-resistant NSCLC specimens and NSCLC cell lines, which resulted in the promotion of chemoresistance and tumorigenicity. miR-1269b overexpression enhanced drug resistance and promoted cell proliferation in vitro and tumor growth in vivo, with reduced apoptosis rate of A549 cells inin vitro cell culture. Mechanistically, we identified PTEN as the direct target of miR-1269b, and the PTEN level was negatively correlated with miR-1269b in NSCLC specimens. Further study demonstrated that miR-1269b targeted PTEN to modulate PI3K/AKT signaling pathway. Conclusion In conclusion, these findings suggest that the miR-1269b/PTEN/PI3K/AKT-mediated network might promote cisplatin resistance in NSCLC, and that miR-1269b can be a potential therapeutic target for chemoresistance in NSCLC patients.

Background: Paired tumor-normal targeted next-generation sequencing (NGS) is primarily used to identify actionable somatic mutations, but can also detect germline variants including pathogenic germline mutations in DNA mismatch repair (MMR) genes that underlie Lynch syndrome. In the present study we examined paired NGS data from lung cancer patients to identify germline mutations in MMR genes. As lung cancer is not one of the recognized Lynch syndrome-associated neoplasms, we also investigated whether these lung cancer cases are due to Lynch syndrome or are instead sporadic cancers occurring in Lynch syndrome patients. Methods: A retrospective study of 1,179 lung cancer patients with available paired NGS data was performed to identify germline mutations in the MMR genes MLH1, MSH2, MSH6, and PMS2, and evaluate tumor mutation burden (TMB). Microsatellite instability (MSI) testing was done on select cases with MMR gene mutations by either NGS or PCR/capillary electrophoresis approach. Immunohistochemistry (IHC) for MMR proteins was performed in select patients. Results: Pathogenic or likely-pathogenic germline mutations in PMS2, MSH2, or MSH6 were detected in 0.5% (6/1,179) of lung cancer patients; three of the patients had a family history of colon or gastric cancer. The median age at diagnosis of these cases was 68.5 years old. None of these six patients exhibited MSI or loss of MMR protein expression. Among them, no second hit somatic mutations in MMR genes (including single-nucleotide variants, small insertions or deletions and copy number alterations) were detected, and the median TMB was 4.5 muts/MB. Subsequent genetic testing of family members identified new Lynch syndrome cases in two first-degree relatives. Conclusion: These data imply that lung cancers in Lynch syndrome patients are unrelated to the underlying Lynch syndrome diagnosis and occur spontaneously. Nonetheless, paired tumor-normal NGS can identify germline mutations to help reveal Lynch syndrome in cancer patients. This has important implications for cancer screening and risk reduction in these patients and their families.

The molecular mechanism responsible for Helicobacter pylori infection-mediated gastritis and carcinogenesis is not yet clear. Increased evidence suggests that chronic gastritis and elevated gastric epithelial cell (GEC) apoptosis are crucial events during stomach carcinoma transformation. PUMA is a potent proapoptotic Bcl-2 protein and mediates acute tissue injury. In this study, we aimed to investigate the role of PUMA in GEC apoptosis and inflammation induced by H. pylori infection. As a result, we found that PUMA expression was elevated in gastritis tissues compared with uninvolved tissues, and it was correlated with the severity of apoptosis and gastritis. In mice, PUMA mRNA and protein were markedly induced in GECs upon induction of gastritis by H. pylori. PUMA-deficient mice were highly resistant to apoptosis and gastritis induced by H. pylori. Furthermore, the transcription factor NF-κB p65 binds to PUMA promoter to activate PUMA transcription after H. pylori infection. In addition, NF-κB inhibitor could rescue H. pylori-induced apoptosis and gastritis. Finally, H. pylori-induced activation of p-p65 and PUMA was mediated via Toll-like receptor 2 (TLR2) and blocked in TLR2 knockout mice. Taken together, these results verified the pro-inflammatory effect of PUMA in H. pylori-infected gastric tissue. Moreover, TLR2/NF-κB-mediated transcriptional regulation of PUMA contributes to the pathogenesis of H. pylori-infected gastritis.

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation inevitably have a relapse due to the occurrence of acquired resistance, resulting in treatment failure. However, little is known about the mechanisms of acquired resistance of NSCLC patients. Here, we elucidated the expression pattern of LOC554202 and miR-31, and their biological functions and mechanisms in NSCLC with acquired EGFR TKI resistance to gefitinib. In the present study, we observed that LOC554202 and miR-31 promoted proliferation and clonogenic growth of gefitinib-resistant NSCLC cells in vitro. LOC554202 upregulated miR-31 expression and they both reduced sensitivity of NSCLC cells to gefitinib. In a xenograft mice model, we found that knockdown of miR-31 significantly repressed gefitinib-resistant NSCLC cells growth in vivo. Furthermore, both LOC554202 and miR-31 levels were significantly increased in NSCLC patients acquiring resistance to gefitinib, and the expression of LOC554202 was positively correlated with the expression of miR-31. By luciferase reporter assays, we identified RAS P21 Protein Activator 1 (RASA1) and Hypoxia Inducible Factor 1 Subunit Alpha Inhibitor (FIH-1) as direct targets of miR-31 in NSCLC cells. Mechanistically, miR-31 directly repressed RASA1 and FIH-1 expression, and thus, at least partially activated the RAF-MEK-ERK and PI3K-AKT signaling pathways in NSCLC with acquired resistance to gefitinib. In conclusion, these data will help us develop potential therapeutic targets for the diagnosis and treatment of acquired EGFR TKI resistance in EGFR-mutant NSCLC.

Supplemental material, supplementary_fig_S1_and_table_S1 for Cortisol, cortisone, and 4-methoxyphenylacetic acid as potential plasma biomarkers for early detection of non-small cell lung cancer by Chengcheng Xiang, Shidai Jin, Juan Zhang, Minjian Chen, Yankai Xia, Yongqian Shu and Renhua Guo in The International Journal of Biological Markers

Dysregulation of microRNAs in various types of human cancer promote or suppress oncogenesis. MicroRNA (miR)-1 was previously revealed to function as a tumor suppressor in prostate cancer cells, and its expression was associated with reduced metastatic potential in lung cancer. The present study investigated the role of miR-1 and its association with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) in the pathophysiology of esophageal squamous cell carcinoma (ESCC), and analyzed the effects of miR-1 inhibitor or mimics on sensitivity to epidermal growth factor receptor-tyrosine kinase inhibitors, the alterations of cell cycle distribution and apoptosis in ESCC cells. Compared with normal tissues, the level of miR-1 expression was significantly lower and PIK3CA expression was higher in ESCC tissues. The level of miR-1 expression was also inversely associated with the level of PIK3CA mRNA expression. Low miR-1 and high PIK3CA expression levels were strongly associated with lymph node metastasis, and the level of miR-1 expression was negatively associated with clinical Tumor-Node-Metastasis stage. Furthermore, exogenous expression of miR-1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIK3CA protein expression levels. Furthermore, overexpression of miR-1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib. A possible mechanism for this increased sensitivity to gefitinib may be inactivation of the PIK3CA signaling pathway. To the best of our knowledge, this is the first time that the results of the present study demonstrated that miR-1 upregulation may be a potential strategy for the treatment of human ESCC.

Breast cancer is one of the most common malignancies and bone is the commonest site of distant metastases. Evidences indicate that adequate supply of vitamin D will decrease the morbidity and mortality of breast cancer. However, the main role of vitamin D deficiency in breast cancer bone metastases remains unclear. In this study, the relationship between vitamin D and breast cancer bone metastases were evaluated. Results showed that 1,25(OH)

Gastric cancer is the second leading cause of cancer-related deaths worldwide, and is characterized by invasion and metastasis. Increasing attention is being focused on discovering molecular markers for diagnosis and prognosis. Our objective was to evaluate PI3K, Akt and survivin protein expression in gastric cancer, and their correlations with clinicohistological features and prognosis in patients with gastric cancer.Tissue samples were obtained from 70 patients with gastric cancer patients and 20 patients with normal gastric mucosa. The protein levels of PI3K, Akt and survivin were evaluated by immunohistochemistry. Statistical analyses were performed to establish the correlations between their expressions and patients' clinicopathologic characteristics.The positive expression rates of PI3K, Akt and survivin were significantly higher in the gastric cancer tissues compared to normal gastric mucosa (P0.05). Expression levels of PI3K, Akt and survivin proteins were significantly correlated with TNM stage, differentiation grade, lymph node metastasis and metastases to other organs (P0.05). Cooperative relationships were identified between PI3K and Akt, and PI3K and survivin (P0.01), suggesting the involvement of the PI3K/Akt/survivin signaling pathway in the tumorigenesis of gastric cancer.Protein expression of PI3K, Akt and survivin were significantly associated with the development, progression and metastasis of gastric cancer and may have value as diagnostic and prognostic markers in gastric cancer.

BACKGROUND The aim of this study was to investigate the expression level of maspin mRNA in pulmonary adenocarcinoma and to clarify its clinical significance in prediction of prognosis. MATERIAL/METHODS RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks of 30 pairs of pulmonary adenocarcinoma (AC) tissues and adjacent noncancerous tissues (ANT) and in another 81 AC tissues. Expression of maspin mRNA was tested by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and the potential relationship between maspin mRNA expression and clinic pathological features of AC patients was analyzed. RESULTS The expression of maspin mRNA was upregulated in AC samples compared with the ANT (p

Rationale: Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Patient concerns: Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. Diagnoses: We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. Interventions: In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. Outcomes: A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. Lessons: To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC.

We report a case of 43-year-old male with advanced malignant mesothelioma (MM) with a large amount of fluid in the pleural and peritoneal cavity. The addition of endostar to the gemcitabine-cisplatin regimen gave a prompt and significant improvement of clinical symptoms and disappearance of ascites. The patient is still progression free after 27 months. Endostar, in combination with chemotherapy should be explored in the treatment of MM, especially its effect on pleural and ascitic fluid.

The aim of our study is to investigate the relationship between lymphatic vessel density (LVD) marked by D2-40 and E-cadherin expression and the clinicopathological characteristics of patients with non-small-cell lung cancer (NSCLC). Immunohistochemical analysis was used to detect the expression of D2-40 and E-cadherin in 46 archival surgical specimens of human NSCLC and 10 cases of benign pulmonary disease. The LVD positively stained with D2-40 was observed and counted. The LVD was mainly distributed in the tumor borderline. The LVD in NSCLC tissues was significantly higher than in benign lesions (p < 0.001), and the LVD marked by D2-40 was significantly associated with lymph node metastasis (p < 0.001). The reduced expression of E-cadherin was present in NSCLC tissues. The positive rate of E-cadherin expression was negatively correlated with TNM stage (p = 0.027), pathological grade (p = 0.032), and lymph node metastasis (p = 0.014), and not significantly correlated with histologic classification (p = 0.714) in NSCLC tissues. A correlation analysis showed that high LVD marked by D2-40 was correlated with reduced E-cadherin expression in NSCLC tissues (t = 36.476, p < 0.001). The new monoclonal antibody D2-40 can specifically recognize lymphatic endothelial cells in NSCLC tissue. The relationship between LVD marked by D2-40 and the reduced expression of E-cadherin and lymph node metastasis in NSCLC was demonstrated. The detection of D2-40 and E-cadherin may be used as an indicator of lymph node metastasis in NSCLC.

Background: The regimen of weekly irinotecan plus cisplatin (IP) is used for treatment of small cell lung cancer (SCLC). We conducted a phase II trial to evaluate the efficacy and toxicity of weekly IP in patients with previously untreated extensive-stage extrapulmonary small cell carcinoma (EPSCC). Patients and Methods: 15 patients with previously untreated extensive-stage EPSCC were enrolled. They received 60 mg/m2 of irinotecan on days 1, 8 and 15, and 25 mg/m2 of cisplatin days 1–3. This regimen was given every 28 days, and efficacy was evaluated after 2 cycles. Results: Objective responses were observed in 10 patients (66.7%), including 3 complete responses (20%) and 7 partial responses (46.7%). The median time to tumor progression was 4.5 months, the median survival time was 11.4 months, and the 1-year survival rate was 46.7%. Toxicities were relatively mild, and there were no treatment-related deaths. Conclusions: Weekly IP has significant activity in extensive-stage EPSCC. The regimen was well tolerated, with acceptable myelosuppression and treatment-related diarrhea.