Showing papers in "Thoracic Cancer in 2018"

ALK‐rearrangement in non‐small‐cell lung cancer (NSCLC)

Abstract: The ALK gene encodes a transmembrane tyrosine kinase receptor. ALK is physiologically expressed in the nervous system during embryogenesis, but its expression decreases postnatally. ALK first emerged in the field of oncology in 1994 when it was identified to fuse to NPM1 in anaplastic large-cell lymphoma. Since then, ALK has been associated with other types of cancers, including non-small-cell lung cancer (NSCLC). More than 19 different ALK fusion partners have been discovered in NSCLC, including EML4, KIF5B, KLC1, and TPR. Most of these ALK fusions in NSCLC patients respond well to the ALK inhibitor, crizotinib. In this paper, we reviewed fusion partner genes with ALK, detection methods for ALK-rearrangement (ALK-R), and the ALK-tyrosine kinase inhibitor, crizotinib, used in NSCLC patients.

Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease.

Abstract: Background The risk of developing lung cancer is high in patients with interstitial lung disease (ILD), as few treatment options are available. Immune checkpoint inhibitors (ICI) are used for the treatment of non-small cell lung cancer (NSCLC) in clinical practice; however, in patients with preexisting ILD, the risk of ICI-related pneumonitis is unknown. We evaluated the efficacy and lung toxicity of nivolumab in patients with NSCLC and ILD. Methods We retrospectively reviewed the medical records of 216 NSCLC patients who had received nivolumab therapy. The existence of ILD in these patients was determined by lung computed tomography findings; 26 patients had ILD. We evaluated the efficacy of nivolumab by measuring the response rate (RR), progression-free survival (PFS) duration, and lung toxicity by incidence, severity, and outcome of nivolumab-related ILD. Results The RR and median PFS of the ILD and non-ILD groups were 27% versus 13% (P = 0.078) and 2.7 (95% confidence interval [CI], 1.7-5.3) versus 2.9 months (95% CI 2.1-3.4; P = 0.919), respectively. The incidences of total and severe nivolumab-related pneumonitis were significantly higher in the ILD group than in the non-ILD group (31% vs. 12%, P = 0.014 and 19% vs. 5%, P = 0.022, respectively). No death from nivolumab-related pneumonitis occurred. Over 50% of the patients in both groups with nivolumab-related pneumonitis showed improvement over time. Conclusion Relative to the non-ILD group, nivolumab-related pneumonitis was observed more frequently in the ILD group; however, most cases were manageable.

Dielectric properties for non-invasive detection of normal, benign, and malignant breast tissues using microwave theories.

Abstract: Background Despite the high incidence of breast cancer worldwide, methods for early non-invasive diagnosis and sensitive and specific prognostic evaluation remain difficult. In this study, we investigated microwave parameters as a potential non-invasive approach to detect breast cancer. Methods Samples of freshly excised breast tissues (n = 509) from 98 patients were identified as normal, benign tumor, or malignant cancer via histology. Further samples were prepared and the microwave effective dielectric permittivity and effective conductivity were measured every 0.0375 GHz from 0.5 GHz to 8 GHz. These parameters were compared among the breast tissue types. Results The effective relative permittivity and effective conductivity at each frequency was significantly higher in breast cancer tissues compared with benign tumors, which in turn was significantly higher than in normal breast tissue. The standard deviation of each parameter was narrowest at ~2.5 GHz in both normal and malignant breast tissues. Conclusions The effective dielectric permittivity and effective conductivity, measured via microwave technology, could differentiate breast cancer from normal and benign tumor tissues.

Long non-coding RNA OIP5-AS1 promotes proliferation of lung cancer cells and leads to poor prognosis by targeting miR-378a-3p

Abstract: Background The antisense of the OIP5-AS1 gene is a long non-coding RNA (lncRNA) that is reported to be upregulated and promotes cell proliferation in multiple human cancers; however, its function in lung cancer is unknown. We investigated the regulatory function and underlying mechanisms of OIP5-AS1 in lung cancer. Methods OIP5-AS1 and microRNA (miR)-378a-3p expression were assayed by quantitative real-time PCR, and proliferation-related protein expression was measured by Western blotting. Cell viability was detected using methyl thiazolyl tetrazolium assay. Luciferase reporter assay and RNA immunoprecipitation were used to detect the direct regulation of miR-378a-3p by OIP5-AS1. Nude mice were used to test the function of OIP5-AS1 in vivo. Results OIP5-AS1 was highly expressed in lung cancer tissues and was correlated with tumor size and tumor growth speed. OIP5-AS1 overexpression increased lung cancer cell proliferation in vitro. Further investigation revealed that OIP5-AS1 functions as a competing endogenous RNA of miR-378a-3p. MiR-378a-3p overexpression inhibited cell proliferation and caused proliferation-associated proteins CDK4 and CDK6 to decrease in A549 cells. Overexpression of wild type OIP5-AS1 led to strong CDK4 and CDK6 expression; however, these two proteins did not change when mutated OIP5-AS1 was upregulated. Finally, in vivo assay showed that the speed of tumor growth was increased and decreased when OIP5-AS1 was upregulated and downregulated, respectively. Conclusion Our results revealed that OIP5-AS1 acts as a growth-promoting lncRNA in lung cancer by suppressing miR-378a-3p function. OIP5-AS1 and miR-378a-3p interaction may provide a potential target for lung cancer treatment.

Role of long non‐coding RNA in drug resistance in non‐small cell lung cancer

Abstract: Lung cancer is the leading cause of cancer-associated death, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Many drugs have been used to treat NSCLC in order to improve patient prognosis. Platinum-based chemotherapy is the first-line treatment for locally advanced or metastatic patients. For patients with activating EGFR mutations, tyrosine kinase inhibitors are the best treatment choice. NSCLC initially exhibits an excellent response to treatment; however, acquired resistance has been observed in many patients, leading to ineffective treatment. Clinical resistance is an impediment in the treatment of patients with advanced NSCLC. Many sequencing technologies have shown that long non-coding RNA (lncRNA) is expressed differently between drug-resistant and drug-sensitive lung cancer cells. We review the literature on lncRNA in drug resistance of NSCLC. The aim of this review is to gain insight into the molecular mechanisms of drug resistance, mainly focusing on the role of lncRNA in NSCLC.

Tumor suppressive roles of eugenol in human lung cancer cells.

Abstract: Background Eugenol, a natural compound available in Syzigium aromaticum (cloves), is exploited for various medicinal applications. Eugenol induces apoptosis and functions as an anti-cancer drug in several types of tumors. We investigated the tumor suppressive role and potential mechanisms of eugenol in human lung cancer cells. Methods Human embryonic lung fibroblast MRC-5 and lung cancer adenocarcinoma A549 cells were incubated with or without various concentrations of eugenol for 24 hours. Cell counting kit 8 and crystal violet staining assays were performed to detect cell viability. The cell migration and invasion abilities were also determined by wound healing and transwell assays. Finally, Western blotting assay was performed to examine the changes in lung cancer cell viability and invasion of downstream targets after treatment with eugenol. Results Eugenol could inhibit cell viability in lung cancer cells. Furthermore, eugenol obviously impaired cell migration and invasion. Finally, the expression levels of phosphate-Akt and MMP-2 in lung cancer cells were reduced after treatment with eugenol. Conclusion Our results demonstrated the tumor suppressive roles of eugenol on lung cancer cell proliferation, migration, and invasion partially through the PI3K/Akt pathway and MMP activity in vitro. These results suggest eugenol as a potential chemotherapeutic agent against human lung cancer.

Correlation between progression-free survival, tumor burden, and circulating tumor DNA in the initial diagnosis of advanced-stage EGFR-mutated non-small cell lung cancer.

Abstract: Background This study was conducted to identify whether the presence of circulating tumor DNA (ctDNA) in plasma before treatment with EGFR-tyrosine kinase inhibitors (TKIs) is associated with clinical outcomes. Methods Fifty-seven pairs of tissues and plasma samples were obtained from patients with NSCLC adenocarcinoma harboring activating EGFR mutations before the administration of EGFR-TKI treatment. ctDNA mutation was identified using the PANAMutyper EGFR mutation kit. Both qualitative and quantitative analyzes of the data were performed. Results Concordance rates with tissue biopsy were 40.4% and 59.6% for the qualitative and quantitative methods, respectively. Bone metastasis showed a statistically significant correlation with ctDNA detection (odds ratio 3.985, 95% confidence interval [CI] 1.027-15.457; P = 0.046). Progression-free survival (PFS) was significantly shorter in the group detected with ctDNA than in the undetected ctDNA group (median PFS 9.8 vs. 20.7 months; hazard ratio [HR] 2.30, 95% CI 1.202-4.385; P = 0.012). Detection of ctDNA before treatment with EGFR-TKIs (HR 2.388, 95% CI 1.138-5.014; P = 0.021) and extra-thoracic lymph node metastasis (HR 13.533, 95% CI 2.474-68.747; P = 0.002) were independently associated with PFS. Six of 11 patients (45.5%) monitored by serial sampling showed a dynamic change in ctDNA prior to disease progression. Conclusion Quantitative testing can increase the sensitivity of the ctDNA detection test. Patients with detectable ctDNA had significantly shorter PFS after receiving EGFR-TKIs than those with undetectable ctDNA. Tumor burden may be associated with plasma ctDNA detection. A shorter PFS was associated with detection of ctDNA and extra-thoracic lymph node metastasis. Dynamic changes in the ctDNA level may help predict clinical outcomes.

High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma.

Abstract: BACKGROUND Tumor-associated immune factors are heterogeneous and play an important role in determining outcome in cancer patients. In this study, the expression levels of immune factors in tumor tissue-conditioned media from lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were analyzed. METHODS LUAD and LUSC tissue specimens were collected immediately after surgery for antibody array analysis and real-time quantitative PCR. RESULTS Higher levels of chemokines MCP1/CCL2 (21.11-fold increase) and MIP-1β/CCL4 (19.33-fold increase) were identified in LUAD than in LUSC. Western blot and quantitative real-time PCR analyses showed higher co-expression of CCL2 and CCL4 in LUAD tissues compared to LUSC (P < 0.0001). Immunofluorescent co-staining showed a high percentage of CCL2+ /CD68+ and CCL4+ /CD68+ tumor-associated macrophages in LUAD compared to LUSC tissues, which might be responsible for the higher expression of CCL2 and CCL4 in LUAD samples. Kaplan-Meier curves showed that CCL2 overexpression in patients with LUSC was associated with beneficial overall survival (OS; P = 0.048) and progression-free survival (PFS; P = 0.012); however, LUAD patients with higher CCL2 expression had unfavorable OS (P = 6.7e-08) and PFS (P = 0.00098). Similarly, CCL4 overexpression predicted favorable PFS (P = 0.021) in patients with LUSC, but patients with high CCL4 levels in LUAD had shorter OS (P = 0.013). CONCLUSION Our study revealed that CCL2 and CCL4 expression levels could serve as potential prognostic biomarkers and therapeutic targets for NSCLC patients.

New method of lung cancer detection by saliva test using surface-enhanced Raman spectroscopy.

Abstract: Surface-enhanced Raman spectroscopy (SERS) is a surface-sensitive technique that enhances Raman scattering by molecules adsorbed on nanostructures. The advantages of using SERS include high detection sensibility and fast analysis, thus it is a potentially promising tool for sensing metabolic cancer molecules in trace amounts. To explore this new method of lung cancer detection, we analyzed saliva samples from 61 lung cancer patients and 66 healthy controls. An SERS system and a nano-modified chip were used in this study. Statistics were analyzed using support vector machine (SVM) and random forest algorithms. The leave-one-out algorithm was used based on SVM results to analyze differences in saliva between lung cancer patients and controls. There was a significant difference between the saliva of patients with lung cancer and healthy controls using the Raman spectrum; the intensity of the spectral line in lung cancer patients was weaker than in controls and 12 characteristic peaks were detected. Saliva SERS peaks have been characterized to refer to tissues, body fluids, and biological standard Raman peaks, but it is difficult to identify molecules with current information. The sensitivity and specificity of Raman spectroscopy data and SVM classification results of lung cancer patients and normal saliva samples were both 100%. Using the leave-one-out algorithm, the sensitivity was 95.08% and the specificity was 100%. The sensitivity of the random forest method was 96.72% and specificity was 100%. Our results show that SERS has the potential to detect lung cancer.

hsa_circ_0000729, a potential prognostic biomarker in lung adenocarcinoma.

Abstract: BACKGROUND Increasing evidence has demonstrated that circular RNAs (circRNAs) may play an important role in oncogenesis and tumor development; however, their role in lung adenocarcinoma (LUAD) remains unclear. We identified the differentially expressed circRNAs in LUAD and investigated the potential mechanisms for cancer progression. METHODS We examined differentially expressed circRNAs in LUAD and paired normal tissues using downloaded circRNA microarrays from the Gene Expression Omnibus. We constructed gene co-expression networks based on the degree of Pearson correlation to predict the critical circRNA in LUAD. Gene Ontology analysis was performed on the genes in the network. We observed one novel circRNA upregulated in LUAD, hsa_circ_0000792, as well as its potential sponged microRNA, miR-375. Subsequent real-time quantitative PCR was used to verify the bioinformatics analysis. RESULTS Several circRNAs showed significantly different expression levels in LUAD tissues. Real-time quantitative PCR and further co-expression network analysis of 42 matched tissue samples showed a significant difference in expression between LUAD and normal tissues in hsa_circ_0000792 (P < 0.001). We built a network of hsa_circ_0000792-targeted miRNA gene interactions, including miR-375 and the corresponding messenger RNAs. Gene Ontology analysis revealed that hsa_circ_0000792 could participate in signal transduction and cell communication during LUAD development. Larger area under the curve by receiver operating characteristic curve analysis of hsa_circ_0000792 and miR-375 (0.815 and 0.772, respectively) in LUAD indicated greater potential as biomarkers. CONCLUSIONS We identified hsa_circ_0000792 as a potential LUAD biomarker; however, further studies are required to determine the mechanism of this circRNA in LUAD development.

Diagnostic value of microRNAs derived from exosomes in bronchoalveolar lavage fluid of early-stage lung adenocarcinoma: A pilot study.

Abstract: BACKGROUND Low-dose computed tomography can identify smaller nodules more often than chest radiography in lung screening. However, complications from invasive diagnostic procedures performed to detect nodules are common. Exosomes contain a diverse array of biomolecules that reflect the biological state of the cell from which they are released. The aim of this study was to investigate the diagnostic value of bronchoalveolar lavage (BAL) fluid exosomal microRNAs (miRNAs) for early-stage lung adenocarcinoma. METHODS We evaluated miRNAs (miR-7, miR-21, miR-126, Let-7a, miR-17, and miR-19) known to have diagnostic value for lung adenocarcinoma. Exosomes were isolated from the BAL fluid of control subjects (n = 15) and patients with lung adenocarcinoma (n = 13). Exosomal miRNA was analyzed using a commercial kit containing probes targeting six selected miRNAs. Results were validated via quantitative PCR. RESULTS The presence of miRNAs was confirmed in exosomes from BAL fluid of both lung adenocarcinoma patients and control subjects. miR-126 (P < 0.001) and Let-7a (P = 0.015) levels were significantly higher in the BAL fluid of lung adenocarcinoma patients than in control subjects. The BAL fluid miRNA signature was confirmed using an independent set of paired adenocarcinoma and normal tissue samples (n = 4). Lung adenocarcinoma tissues showed increased expression of miR-126 (P = 0.039) compared to normal tissue samples. CONCLUSION We identified a close correlation between BAL fluid exosomal miRNAs and tumor miRNAs. BAL fluid exosomal miRNAs obtained through noninvasive methods could serve as diagnostic biomarkers in early-stage lung adenocarcinoma.

Neutrophil-to-lymphocyte ratio after four weeks of nivolumab administration as a predictive marker in patients with pretreated non-small-cell lung cancer.

Abstract: BACKGROUND Although phase III trials have shown improved overall and progression-free survival (PFS) using nivolumab compared to docetaxel in patients with non-small-cell lung cancer, the progressive disease ratio of nivolumab is higher than docetaxel. Furthermore, nonconventional response patterns of nivolumab make it difficult to determine the time point for nivolumab discontinuation. Therefore, a method to detect non-responders to nivolumab at an early time point is crucial. This retrospective study was conducted to identify immunological and nutritional markers, including neutrophil-to-lymphocyte ratios (NLR), which would predict the efficacy of nivolumab treatment. Because the expression of these markers fluctuates dramatically during treatment, repeat evaluation was performed. METHODS We retrospectively investigated 30 patients with non-small-cell lung cancer who were treated with nivolumab. The stratified data of each marker obtained during four weeks after nivolumab treatment were evaluated by Cox proportional hazards regression to verify the differences in PFS. RESULTS One and four patients experienced progressive disease within two and four weeks, respectively. Therefore, 29 and 26 patients were analyzed two and four weeks after nivolumab administration, respectively. The results showed that the NLR after four weeks could predict PFS. The median PFS in 21 patients with NLR < 5 after four weeks of nivolumab administration was 95 days (95% confidence interval [CI] 50-NA), while the mPFS in five patients with NLR ≥ 5 was 10 days (95% CI 6-NA). NLR ≥ 5 showed a hazard ratio of 5.995 (95% CI 1.225-29.35). CONCLUSION Clarifying NLR four weeks after nivolumab administration may be useful to predict outcomes in nivolumab-treated patients.

IL-37 inhibits invasion and metastasis in non-small cell lung cancer by suppressing the IL-6/STAT3 signaling pathway

Abstract: Background IL-37 has been identified as a fundamental inhibitor of inflammatory and immunity responses. It plays a crucial protective role in several cancers, but its anti-tumor activity and the potential regulatory mechanism of IL-37 in non-small cell lung cancer (NSCLC) is largely unclear. Methods Enzyme-linked immunosorbent assay was used to detect plasma IL-37 expression in NSCLC patients and healthy controls. The NSCLC cell line A549 was cultured with recombinant human IL-37 or recombinant human IL-6 protein. A549 invasion and metastasis were detected using Transwell invasion and scratch wound healing assays, respectively. Protein expression of STAT3, pSTAT3, E-cadherin, vimentin, and N-cadherin were detected using Western blotting, and messenger RNA expression of STAT3, E-cadherin, vimentin, and N-cadherin was assessed in each group using real time PCR. Results IL-37 plasma expression was decreased in NSCLC patients, and the downregulation of IL-37 was correlated with tumor stage. In vitro, IL-37 inhibited invasion and migration in A549 cells, while IL-6 promoted invasion and migration in A549 cells. pSTAT3, vimentin, and N-cadherin expression was increased. E-cadherin expression was lower in the IL-6 group than in the control group; however, the opposite pattern was observed in the IL-37 + IL-6 group. Conclusion Our results showed that IL-37 plays an inhibitory role in NSCLC progression, possibly by suppressing STAT3 activation and decreasing epithelial-to-mesenchymal transition by inhibiting IL-6 expression. IL-37 could serve as a potential novel tumor suppressor in NSCLC.

MiR‐577 suppresses epithelial‐mesenchymal transition and metastasis of breast cancer by targeting Rab25

Abstract: BACKGROUND MicroRNAs can act as both tumor suppressor genes and oncogenes and participate in cell proliferation, metastasis, and apoptosis. Low levels of miR-577 are found in several cancers, for example, thyroid carcinoma, glioblastoma, and hepatocellular carcinoma. The aim of this study was to investigate the effect of miR-577 on breast cancer (BC). METHODS The relative level of miR-577 in 120 BC tissues and cells was detected by real-time PCR. MDA-MB-231 cells with upregulated miR-577 and MCF-7 cells with downregulated miR-577 were established. Transwell invasion assays were used to examine the invasiveness of cells. Epithelial-mesenchymal transition (EMT) markers were evaluated by immunofluorescence and Western blot. Targeted combinations of miR-577 and Rab25 were analyzed by luciferase assays. Xenograft models were used to examine the effect of miR-577 on BC metastasis. RESULTS MiR-577 expression was significantly suppressed in BC tissues. Tumor size, tumor stage, and lymphatic metastasis were attributed to miR-577 expression. Moreover, miR-577 overexpression strongly inhibited the invasiveness and EMT of BC cells in vitro. MiR-577 directly regulated Rab25 in BC. Rab25 upregulation by miR-577 decreased the levels of E-cadherin and increased the levels of Vimentin. Notably, Rab25 knockdown inhibited BC invasion; however, an increase in Rab25 counteracted the invasive effect of miR-577 in BC. CONCLUSION Results indicated that miR-577 suppressed EMT by inhibiting Rab25 expression in BC. MiR-577 and Rab25 are considered potential targets of BC treatment.

Comparison and discussion of the treatment guidelines for small cell lung cancer.

Abstract: Small cell lung cancer (SCLC), which accounts for 15% to 17% of all lung cancers, is one of the leading causes of cancer-related death worldwide. More than 130 000 new diagnoses of SCLC and 100 000 deaths from the disease were estimated to have occurred in China in 2013. The existing guidelines of SCLC therapeutic principles differ by region. In recent years, new immunotherapy and targeted therapy treatments have been lacking. In order to understand the current status of SCLC treatment in more detail, we identified the similarities and differences among the latest National Comprehensive Cancer Network Clinical Practice Guidelines for SCLC, the Chinese Society of Clinical Oncology Lung Cancer Guidelines, and the European Society for Medical Oncology Clinical Practice Guidelines for Metastatic SCLC, and present a reference of treatment strategies that should prove beneficial for the treatment of patients with SCLC.

Location of stage I-III non-small cell lung cancer and survival rate: Systematic review and meta-analysis.

Abstract: Background The association between the location of non-small cell lung cancer (NSCLC) and prognosis is a debated issue. Some studies have provided evidence of better prognosis of upper lobe tumors than lower to middle lobe tumors, while other studies have reported contrasting conclusions. The aim of this study was to further assess this association through a systematic review and meta-analysis. Methods Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched up to 27 January 2017. Patients pathologically diagnosed with stage I-III NSCLC with three or five-year survival data were included. The main meta-analysis compared differences in survival rates according to the primary tumor location using the Mantel-Haenszel method with a random effect model. Sensitivity analysis was conducted according to lymph node metastasis, tumor node metastasis stage, staging method, and treatment modality. Results Ten clinical studies and 35 570 patients were recruited. Patients with tumors in the upper lobes had a higher rate of five-year survival compared to those with tumors in non-upper lobes (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.15-1.49). Similarly, the three-year survival rate was high in patients with tumors in the upper lobes (OR 1.99, 95% CI 1.02-3.86) and low in those with lower lobe tumors (OR 0.31, 95% CI 0.12-0.77). Conclusions Stage I-III NSCLC located in the upper lobes showed higher five-year survival rates compared to other tumor locations.

Platelet-to-lymphocyte ratio predicts the prognosis of patients with non-small cell lung cancer treated with surgery and postoperative adjuvant chemotherapy.

Abstract: Background Markers of preoperative tumor immunity, such as platelet-to-lymphocyte ratio (PLR), have been reported to be prognostic factors for patients with various cancers. However, the relationship between PLR and the prognosis of non-small cell lung cancer (NSCLC) patients treated with surgery and adjuvant chemotherapy as a multidisciplinary treatment is unknown. Methods We enrolled 327 NSCLC patients treated surgically with or without adjuvant chemotherapy (78 and 249 patients, respectively) at our hospital from 2008 to 2012. Patients had no preoperative hematological disease or infection. Preoperative PLR and clinicopathologic characteristics were recorded and their potential associations and prognostic values were assessed by Kaplan–Meier and multivariate Cox regression. The optimal cut-off value for high and low PLR was calculated from receiver operating characteristic curves. Results The five-year overall survival rates for patients with low and high PLR were 78% and 57% (P < 0.01) for all patients, and 69% and 37% (P < 0.01) for patients who received adjuvant chemotherapy, respectively. Similarly, the five-year disease-free survival rates for patients with low and high PLR were 66% and 62% (P = 0.03) for all patients, and 47% and 14% (P < 0.01) for patients who received adjuvant chemotherapy, respectively. Cox proportional hazard regression indicated that high PLR was an independent prognostic factor for both overall and disease-free survival in the adjuvant chemotherapy group. Conclusion Elevated PLR predicts poor prognosis in surgically treated NSCLC patients, especially those who receive adjuvant chemotherapy.

Modified method for distinguishing the intersegmental border for lung segmentectomy

Abstract: This paper analyzed the results of a modified and simpler technique for distinguishing the intersegmental border during lung segmentectomy surgery. From January 2013 to December 2015, 539 patients with screening-detected lung nodules <2 cm in maximum diameter underwent anatomic segmentectomy. With the guidance of preoperative three-dimensional computed tomography bronchography and angiography, the bronchus, artery, and intrasegmental vein of the targeted segment could be precisely dissected under unilateral differential ventilation, and then intersegmental demarcation was confirmed by the modified inflation-deflation method. The demarcation presented by this method was highly coincident with the real intersegmental border. Dissection along the border between the collapsed and inflated segments using either electrocautery or staples was safe, with almost no air leak or bleeding. This technique is a simple and effective alternative to previously described intersegmental border marking methods.

Single-institution study of correlations between skeletal muscle mass, its density, and clinical outcomes in non-small cell lung cancer patients treated with first-line chemotherapy.

Abstract: Background Sarcopenia and muscle tissue degradation are hallmarks of the majority of chronic diseases, including non-small cell lung cancer (NSCLC). A computed tomography scan could be an easy modality to estimate the skeletal muscle mass through cross-sectional image analysis at the level of the third lumbar vertebra. Methods Baseline skeletal muscle mass (SMM) was evaluated through the skeletal muscle index (SMI), together with skeletal muscle radiodensity (SMD), in NSCLC patients undergoing first-line chemotherapy to evaluate correlations with safety and clinical outcomes. When SMIs at different time points were available, further comparison was made between patients with worse and improved SMIs. Results Among 81 stage IV NSCLC patients, 28 had low SMM and 23 had low SMD. There were no significant differences in univariate analysis of progression-free survival (PFS) between patients with baseline low and non-low SMM (P = 0.06388) or between patients with low and non-low SMD (P = 0.9126). Baseline low SMM, however, proved a significant predictor of shorter PFS in multivariate analysis (hazard ratio 0.54, 95% confidence interval 0.31-0.93; P = 0.0278), but not low SMD. There were no differences in overall survival (OS) between patients with baseline low and non-low SMM or low and non-low SMD. No differences in PFS and OS between evaluable patients with worse or improved SMI were found. A significant difference in hematological toxicities between patients with baseline low and non-low SMM (P = 0.0358) was observed. Conclusions Low SMM is predictive of shorter PFS, while consecutive changes in muscular mass do not seem to be a predictor of PFS or OS. The role of muscle radiodensity remains a matter of debate.

EGFR mutations in early-stage and advanced-stage lung adenocarcinoma: Analysis based on large-scale data from China.

Abstract: BACKGROUND EGFR-tyrosine kinase inhibitors play an important role in the treatment of advanced non-small cell lung cancer (NSCLC). EGFR mutations in advanced NSCLC occur in approximately 35% of Asian patients and 60% of patients with adenocarcinoma. However, the frequency and type of EGFR mutations in early-stage lung adenocarcinoma remain unclear. METHODS We retrospectively collected data on patients diagnosed with lung adenocarcinoma tested for EGFR mutation. Early stage was defined as pathological stage IA-IIIA after radical lung cancer surgery, and advanced stage was defined as clinical stage IIIB without the opportunity for curative treatment or stage IV according to the American Joint Committee on Cancer Staging Manual, 7th edition. RESULTS A total of 1699 patients were enrolled in this study from May 2014 to May 2016; 750 were assigned to the early-stage and 949 to the advanced-stage group. Baseline characteristics of the two groups were balanced, except that there were more smokers in the advanced-stage group (P < 0.001). The total EGFR mutation rate in the early-stage group was similar to that in the advanced-stage group (53.6% vs. 51.4%, respectively; P = 0.379). There was no significant difference in EGFR mutation type between the two groups. In subgroup analysis of smoking history, there was no difference in EGFR mutation frequency or type between the early-stage and advanced-stage groups. CONCLUSION Early-stage and advanced-stage groups exhibited the same EGFR mutation frequencies and types.

Generalization and representativeness of phase III immune checkpoint blockade trials in non‐small cell lung cancer

Abstract: Background Strict eligibility criteria for patient enrollment in phase III trials raise questions regarding generalization to ineligible patients. We evaluated whether pivotal phase III trials of immune checkpoint blockades (ICBs) represent the overall population of non-small cell lung cancer (NSCLC) patients. Methods We reviewed the inclusion and exclusion criteria of three phase III trials (CheckMate057, CheckMate017, and KEYNOTE-010). Stage IIIB or IV NSCLC patients diagnosed from 2011 to 2013 at Seoul National University Hospital (cohort 1) were reviewed. We also analyzed the criteria in 53 patients with NSCLC who were treated with nivolumab or pembrolizumab as routine practice (cohort 2). Results Among the 715 patients in cohort 1, 499 (69.9%) were ineligible for the three trials. Reasons for ineligibility included: no prior platinum doublet treatment (23.6%), lack of tissue availability (22.7%), Eastern Cooperative Oncology Group performance status > 1 (14.1%), steroid use (18.2%), active cerebral nervous system metastasis (8.3%), hepatitis B/hepatitis C/human immunodeficiency virus (8.0%), and no measurable lesion (7.3%). EGFR mutations were more common in the ineligible group. In cohort 2, 67.9% of patients were classified as ineligible. Treatment outcomes of ICB in cohort 2 appeared inferior to those in the three pivotal trials, with a response rate of 11.3% and median progression-free survival of 1.67 months. Conclusion Only 30% of NSCLC patients were eligible for ICB phase III trials. The actual efficacy in the 70% of ineligible patients is unknown. These findings suggest a huge gap between practice-changing phase III trials and the overall population of NSCLC patients.

Exopolysaccharides from a Codonopsis pilosula endophyte activate macrophages and inhibit cancer cell proliferation and migration

Abstract: Background Exopolysaccharides with structural diversity have shown wide applications in biomaterial, food, and pharmaceutical industries. Herein, we isolated an endophytic strain, 14-DS-1, from the traditional medicinal plant Codonopsis pilosula to elucidate the characteristics and anti-cancer activities of purified exopolysaccharides. Methods HPLC and GC-MS were conducted to purify and characterize the exopolysaccharides isolated from 14-DS-1. Quantitative RT-PCR, cell migration assays, immunofluorescence staining, and flow cytometry analysis were conducted to investighate the biological activity of DSPS. Results We demonstrated that exopolysaccharides isolated from 14-DS-1 (DSPS), which were predominately composed of six monosaccharides, showed anti-cancer activities. Biological activity analysis revealed that exposure to DSPS induced macrophage activation and polarization by promoting the production of TNF-α and nitric oxide. Further analysis revealed that DSPS treatment promoted macrophage infiltration, whereas cancer cell migration was suppressed. In addition, DSPS exposure led to S-phase arrest and apoptosis in cancer cells. Immunofluorescence staining revealed that treatment with DSPS resulted in defects in spindle orientation and positioning. Conclusion These findings thus suggest that DSPS may have promising potential in cancer therapy.

Pretreatment hematological markers predict clinical outcome in cancer patients receiving immune checkpoint inhibitors: A meta-analysis.

Abstract: Background Immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment of multiple cancers. Recent studies revealed the potential prognostic value of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients receiving ICIs; however, the results were inconsistent. We conducted a meta-analysis to identify the prognostic significance of baseline NLR and PLR in cancer patients treated with ICIs. Methods We conducted a thorough literature search of PubMed, Embase, and Cochrane databases for studies dealing with the prognostic impact of pretreatment NLR and/or PLR levels in cancer patients treated with ICIs. The clinical outcomes were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and sensitivity and subgroup analyses were performed to investigate heterogeneity. Results Seventeen articles involving 2092 patients were included in the final analysis. The pooled HRs of PFS and OS for NLR were 1.81(95% CI 1.36-2.41) and 2.26 (95% CI 1.68-3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between PLR and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88-1.48 for PFS; HR = 1.35, 95% CI 0.86-2.12 for OS). Conclusion These results indicate that high pretreatment NLR but not PLR level, as a routinely obtained hematological parameter, is a potential prognostic predictor for poor PFS and OS in cancer patients receiving ICIs.

Association between H3K4 methylation and cancer prognosis: A meta-analysis.

Abstract: Background Histone H3 lysine 4 methylation (H3K4 methylation), including mono-methylation (H3K4me1), di-methylation (H3K4me2), or tri-methylation (H3K4me3), is one of the epigenetic modifications to histone proteins, which are related to the transcriptional activation of genes. H3K4 methylation has both tumor inhibiting and promoting effects, and the prognostic value of H3K4 methylation in cancer remains controversial. Therefore, we performed a systematic review and meta-analysis to examine the association between H3K4 methylation and cancer prognosis. Methods A comprehensive search of PubMed, Web of Science, ScienceDirect, Embase, and Ovid databases was conducted to identify studies investigating the association between H3K4 methylation and prognosis of patients with malignant tumors. The data and characteristics of each study were extracted, and the hazard ratio (HR) at a 95% confidence interval (CI) was calculated to estimate the effect. Results A total of 1474 patients in 10 studies were enrolled in this meta-analysis. The pooled HR of 1.52 (95% CI 1.02-2.26) indicated that patients with a lower level of H3K4me2 expression were expected to have shorter overall survival, while the pooled HR of 0.45 (95% CI 0.27-0.74) indicated that patients with a lower level of H3K4me3 expression were expected to have longer overall survival. Conclusion This meta-analysis indicates that increased H3K4me3 expression and decreased H3K4me2 expression might be predictive factors of poor prognosis in cancer. Further large cohort studies are needed to confirm these findings.

Melatonin inhibits the proliferation of breast cancer cells induced by bisphenol A via targeting estrogen receptor-related pathways.

Abstract: Background Background: Bisphenol A (BPA) is an estrogen-like chemical widely contained in daily supplies. There is evidence that environmental exposure to BPA could contribute to the development of hormone-related cancers. As is reported in numerous studies, melatonin, an endogenous hormone secreted by the pineal gland, could markedly inhibit estrogen-induced proliferation of breast cancer (BC) cells. In this study, we intended to reveal the effects of melatonin on BPA-induced proliferation of estrogen receptor-positive BC cells. Methods Methods: We used methyl thiazolyl tetrazolium, luciferase reporter gene and western blotting assays to testify the effect of melatonin on BPA-mediated proliferation of MCF-7 and T47D cells. Results Methyl thiazolyl tetrazolium and colony formation assays showed that melatonin could significantly abolish BPA-elevated cell proliferation. Meanwhile, BPA-upregulated phosphorylation of ERK and AKT was decreased by melatonin treatment. Mechanistically, we found that BPA was capable of upregulating the protein levels of steroid receptor coactivators (SRC-1, SRC-3), as well as promoting the estrogen response element activity. However, the addition of melatonin could remarkably block the elevation of steroid receptor coactivators expression and estrogen response element activity triggered by BPA. Conclusion Conclusions: Therefore, these results demonstrated that melatonin could abrogate BPA-induced proliferation of BC cells. Therapeutically, melatonin could be regarded as a potential medication for BPA-associated BC.

Therapeutic targeting of cellular stress responses in cancer.

Abstract: Similar to bacteria, yeast, and other organisms that have evolved pathways to respond to environmental stresses, cancer cells develop mechanisms that increase genetic diversity to facilitate adaptation to a variety of stressful conditions, including hypoxia, nutrient deprivation, exposure to DNA-damaging agents, and immune responses. To survive, cancer cells trigger mechanisms that drive genomic instability and mutation, alter gene expression programs, and reprogram the metabolic pathways to evade growth inhibition signaling and immune surveillance. A deeper understanding of the molecular mechanisms that underlie the pathways used by cancer cells to overcome stresses will allow us to develop more efficacious strategies for cancer therapy. Herein, we overview several key stresses imposed on cancer cells, including oxidative, metabolic, mechanical, and genotoxic, and discuss the mechanisms that drive cancer cell responses. The therapeutic implications of these responses are also considered, as these factors pave the way for the targeting of stress adaption pathways in order to slow cancer progression and block resistance to therapy.

Apatinib monotherapy for advanced non‐small cell lung cancer after the failure of chemotherapy or other targeted therapy

Abstract: Background Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), has proven to be effective and safe for treating patients with advanced gastric cancer after second-line chemotherapy failure. As VEGFR-2 targeted therapy has made encouraging progress for the treatment of a broad range of malignancies, we explored the efficacy and safety of apatinib for the treatment of advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy. Methods We retrospectively analyzed the data of 34 patients (11 with squamous carcinoma and 23 with adenocarcinoma) who were treated with apatinib alone in a daily oral dose of 250 mg in the second-line or third-line setting from January 2016 to July 2017. The primary endpoint was progression-free survival (PFS). Results EGFR mutation or amplification was detected in 15 patients. The median PFS of the whole group was four months (95% confidence interval 0.3-7.7). A partial response was observed in 2 patients (5.88%) and stable disease in 19 (55.88%). The disease control rate was 61.76%. Common side effects of apatinib were hypertension (n = 12), hand-foot syndrome (n = 8), and proteinuria (n = 5), which accounted for 35.30%, 23.53%, and 14.71%, respectively, and no grade 3/4 adverse reactions occurred. Apatinib toxicity was controllable and tolerable. Conclusions Apatinib appears to be effective and safe for advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy.

Remarkable response of nivolumab-refractory lung cancer to salvage chemotherapy.

Abstract: Promising outcomes of salvage chemotherapy after nivolumab therapy have been reported; however, little is known about the detailed clinical and immunologic features in lung cancer patients in whom nivolumab is unsuccessful. We report two cases of nivolumab-refractory lung cancer, in which chemotherapy resulted in rapid regression of the lung cancer. Upon initial diagnosis, the biopsy specimens showed PD-ligand 1 (PD-L1)-expressing cancer cells, accompanied by tumor-infiltrating lymphocytes with a favorable CD8/CD4 ratio. Immunosuppressive regulatory T cells and cells positive for TIM-3 were also observed. Physicians should take caution in treating lung cancer patients after progression on nivolumab. Further studies with a large cohort are warranted to identify the patients that may benefit from salvage chemotherapy.

Nrf2 and Keap1 abnormalities in esophageal squamous cell carcinoma and association with the effect of chemoradiotherapy.

Abstract: Background The Keap1-Nrf2 pathway is a key antioxidant and redox signaling cascade. Pathway abnormalities enhance the reactive oxygen species scavenging ability of cancer cells; thus the pathway is involved in carcinogenesis and resistance to chemoradiotherapy (CRT). This retrospective study was conducted to examine the status of the Keap1-Nrf2 pathway in locally advanced esophageal squamous cell carcinoma (ESCC) and to analyze its prognostic value in patients receiving CRT. Methods Nrf2 and Keap1 expression were immunohistochemically examined in 152 ESCC and 31 normal esophageal mucosae. All ESCC specimens were obtained from patients with locally advanced ESCC who underwent CRT. Results Strong staining of nuclear and cytoplasmic Nrf2 and limited or absent Keap1 expression was uncommon in normal tissues, but frequently observed in ESCC. Interaction between Nrf2 and Keap1 in normal mucosae is negatively correlated, while in tumors there is no negative correlation, indicating that there is little to no interaction between Nrf2 and Keap1 in ESCC. Positive Nrf2 expression in the nucleus was of diagnostic value for predicting ESCC from normal esophageal mucosae, and was significantly associated with poorer clinical response and poor progression-free survival after CRT. The value of Keap1 expression for diagnosis and predicting CRT outcomes was marginal. These different influences of Keap1 and Nrf2 on ESCC indicated that the signaling of this pathway was disturbed and displayed a Keap1-independent pattern. Conclusion Aberrant signaling via the Keap1-Nrf2 pathway was common in ESCC and was associated with response and survival after CRT.

Comparison of hook wire versus coil localization for video-assisted thoracoscopic surgery

Abstract: BACKGROUND A hook wire has been most widely used for computed tomography (CT)-guided localization before video-assisted thoracoscopic surgery (VATS). However, microcoils have been suggested to replace wires. The purpose of this study was to compare the efficacy, VATS procedure time, and excised volume of specimens of CT-guided localization using a hook wire and microcoil. METHODS The medical records of 106 patients with 110 pulmonary nodules who underwent CT-guided localization using a hook wire (group A) or microcoil (group B) before VATS performed between March 2013 and January 2017 were retrospectively reviewed. RESULTS The procedure success rate was 100% in both groups. Dislodgement occurred in four patients in group A and not in group B. Patient pain score was significantly lower for group B than group A (4.0 vs. 6.3; P < 0.001). The VATS success rate was higher in group B than in group A (98.1% vs. 91.1%; P = 0.174). The VATS procedure time was significantly shorter for group B than group A (18.8 vs. 23.6 minutes; P = 0.004). The excised volume of surgical specimens was significantly smaller for group B than group A (8.5 vs. 11.7 cm3 ; P = 0.043). No major complications related to the localization procedure were noted in either group. CONCLUSIONS This study showed similar effectiveness of VATS localization between groups. However, microcoil is superior to hook wire for localization of pulmonary nodules in terms of VATS procedure time and excised volume of surgical specimens, with the advantages of no dislodgement and less patient pain.