The TLR7/8 agonist R848 optimizes host and tumor immunity to improve therapeutic efficacy in murine lung cancer.

Treatment with the Toll­like receptor 7 (TLR7) agonist, resiquimod (R848), is effective in various types of cancer, such as breast, pancreatic and colorectal cancer. The reported antitumor effect of R848 in lung cancer is considered to be achieved by targeting macrophages. In the present study, it was demonstrated that TLR7 expression on various immune cell types initially rises, then declines in the late stage of lung cancer. Intraperitoneal injection of R848 resulted in a reduction in tumor burden and prolonged survival in both subcutaneous and metastatic lung cancer models in C57BL/6 mice. Initial treatment with R848 at an early stage was found to be the optimal choice. Systemic injection of R848 promoted the activation of innate and adaptive immune responses. Systemic administration of R848 upregulated TLR7 expression in dendritic cells (DCs) and enhanced the activation of DCs and natural killer (NK) cells. Moreover, this treatment also resulted in increased production of T helper cell­associated cytokines in serum, including IFN­Î³, TNF­α and IL­2. In addition, continuous treatment with R848 increased the proportion of DCs, NK and CD8+ T cells, and reduced that of Foxp3+ regulatory T cells in the tumor microenvironment. These findings supported the use of R848 treatment for lung cancer via TLR7 targeting and provided insight into the underlying therapeutic mechanism.

Sublobar resection versus lobectomy for patients with stage T1-2N0M0 pulmonary typical carcinoid tumours: a population-based propensity score matching analysis.

OBJECTIVES: It is widely accepted that surgical resection of localized pulmonary typical carcinoid (TC) tumours remains the primary curative modality. However, the optimal extent of resection remains controversial. This study aimed to investigate the survival rates of patients with stage T1-2N0M0 TC tumours who underwent sublobar resection or lobectomy. METHODS: We queried the Surveillance, Epidemiology, and End Results database for patients who underwent surgery after being diagnosed with stage T1-2N0M0 TCs from 2004 to 2016. Propensity score matching (PSM) analysis was used to equalize the baseline characteristics between the sublobar resection group and the lobectomy group. Kaplan-Meier analysis and the Cox proportional hazard model were performed for survival analysis. RESULTS: Of the 2469 patients included, 658 (26.65%) underwent sublobar resection and 1811 (73.35%) underwent lobectomy. All 2469 patients were analysed with PSM and, following PSM, 812 patients were included in the final analysis and divided into 2 groups of 406 patients. In the matched cohort, Kaplan-Meier analysis demonstrated no significant difference in survival curves between the sublobar resection and lobectomy groups in patients with stage T1-2N0M0 TC tumours [5-year overall survival (OS) = 90.78% vs 93.30%; hazard ratio 1.18, 95% confidence interval: 0.77-1.80; P = 0.505]. Subgroup analysis by tumour size showed that the sublobar resection group was identical to the lobectomy group in OS for tumours ≤3.0 cm. In addition, no difference in OS between surgical groups was observed in any subgroups. In the multivariable Cox analysis, age ≤65 years, female sex, married status and adequate lymph node assessment (≥5) were associated with improved OS, whereas the extent of resection was not. CONCLUSIONS: Sublobar resection seems to be associated with similar survival to lobectomy for stage T1-2N0M0 TC tumours if lymph node assessment is performed adequately. This analysis suggests that sublobar resection should be considered an appropriate alternative for stage T1-2N0M0 TC tumours. However, further validations are needed in large, multicentre prospective studies.

Prognostic significance of visceral pleural invasion in patients with surgically resected small-cell lung cancer: a population-based study.

OBJECTIVE: Visceral pleural invasion is an adverse prognostic factor in non-small-cell lung cancer, but its value in small-cell lung cancer remains unclear. Thus, we investigated the prognostic impact of visceral pleural invasion in patients with surgically resected small-cell lung cancer. METHODS: We queried the Surveillance, Epidemiology and End Results Program database for patients diagnosed with stages I-III (excluding N3 and nodal metastasis cannot be evaluated (NX)) small-cell lung cancer from 2004 to 2016, who underwent surgery. To minimize unbalanced baseline characteristics between the visceral pleural invasion and non-visceral pleural invasion groups, one-to-one propensity score matching was employed. A Kaplan-Meier curve was used to compare the overall survival of the two cohorts. A Cox proportional hazards model was adopted to determine the impact of visceral pleural invasion on survival. RESULTS: Of the 1416 patients included, 372 (26.27%) presented with visceral pleural invasion. Patients with visceral pleural invasion showed significantly worse overall survival (P < 0.001) both before and after propensity score matching. Multivariable analysis indicated that visceral pleural invasion was an independent adverse factor affecting survival. Patients with visceral pleural invasion showed poorer overall survival (hazard ratio: 1.44; 95% confidence interval: 1.17-1.76; P < 0.001). Subgroup analyses revealed that the non-visceral pleural invasion group was associated with favourable overall survival in N0 patients (P = 0.003) but not in N1 or N2 patients (P = 0.774 and 0.248, respectively). Patients diagnosed at younger ages, females, lower N stage, resection with a lobectomy and adjuvant chemotherapy were associated with improved overall survival in the visceral pleural invasion group. CONCLUSIONS: Visceral pleural invasion was an indicator of a poor prognosis for small-cell lung cancer, especially in those with N0 disease. Adjuvant chemotherapy significantly improves patient outcomes for patients with visceral pleural invasion.

Long-term survival analysis of sublobar resection versus lobectomy for older patients with early-stage pulmonary carcinoid tumour: a database-based propensity score-matched study.

BACKGROUND: The optimal extent of surgery for older patients with early-stage pulmonary carcinoid tumour (PC) remains controversial. AIMS: To compare prognostic differences between sublobar resection versus lobectomy in older patients with early-stage PC. METHODS: The SEER database was searched for stage T1N0M0 PC patients aged ≥ 65 years who underwent lobectomy or sublobar resection from 2000 to 2017. Propensity score matching (PSM) was used to determine intergroup covariate differences. Kaplan-Meier curves and the log-rank test were used for intergroup comparison of overall survival (OS). A Cox proportional hazard model was used to evaluate independent risk factors. RESULTS: Among 1023 participants, 650 and 373 underwent lobectomy and sublobar resection, respectively. Before PSM, the 5- and 10-year OS in the sublobar resection group were lower than that of the lobectomy group (5-year OS 84.12% vs. 91.16%; 10-year OS 57.43% vs. 64.77%; p = 0.014); after PSM, no significant prognostic difference existed between lobectomy and sublobar resection (5-year OS 88.17% vs. 89.23%; 10-year OS 58.32% vs. 62.75%; p = 0.811). Subgroup analysis included tumour size, age, number of lymph nodes examined and histological type, and showed no statistically significant survival differences between the lobectomy and sublobar resection groups. Multivariable Cox analysis indicated that age ≥ 77 years, male sex, inadequate lymph node assessment (< 7), and atypical carcinoid were associated with reduced OS. CONCLUSION: Sublobar resection showed a similar long-term survival rate for early-stage PC patients aged ≥ 65 years as with lobectomy, thereby providing a basis for the selection of surgical methods for PC.

Survival benefit of thermal ablation combined with chemotherapy for the treatment of stage IV nonsmall cell lung cancer: a propensity-matched analysis.

OBJECTIVE: To investigate the survival benefit of thermal ablation (TA) plus chemotherapy for Stage-IV nonsmall cell lung cancer (NSCLC). METHODS: From the Surveillance, Epidemiology and End Results (SEER) database, data of Stage-IV NSCLC patients receiving different treatment modalities (TA plus chemotherapy vs. chemotherapy) from 2004 to 2016 were retrospectively analyzed using propensity-score matching (PSM) for covariates. Kaplan-Meier curves and the log-rank test for intergroup comparison of overall survival (OS) and lung cancer-specific survival (LCSS) and subgroup analyses in the PSM cohort evaluated possible survival benefits. Cox proportional risk models evaluated independent prognostic factors. RESULTS: Among 52,574 patients, 152 received TA plus chemotherapy. After PSM, the TA plus chemotherapy and chemotherapy groups included 150 and 445 patients, respectively. Compared to the chemotherapy group, the TA plus chemotherapy group had better OS (p = 0.042) and LCSS (p = 0.031), especially in patients aged 70 and older in age-stratified subgroup analysis; no statistically significant beneficial trend was noted for patients younger than 70 years. Subgroup analysis by tumor size showed superior OS and LCSS with TA plus chemotherapy than chemotherapy for tumors ≤3.0 cm; however, no significant difference was found in subgroups with larger tumors. Multivariate analysis showed that TA plus chemotherapy was an independent prognostic factor for OS and LCSS (hazard ratio 0.70 [95% confidence interval 0.59-0.84] and 0.70 [0.58-0.84], respectively; p < 0.001). CONCLUSION: TA plus chemotherapy is a potential treatment option for Stage-IV NSCLC, especially for patients aged 70 or older with tumor size ≤3 cm.

The prognostic value of lymph node ratio in patients with surgically resected stage I-III small-cell lung cancer: a propensity score matching analysis of the SEER database.

OBJECTIVES: Due to the lack of prospective studies, the role of the lymph node ratio (LNR) in small-cell lung cancer (SCLC) remains unknown. This study aimed to assess the prognostic effect of LNR in surgically resected stage I-III SCLC patients. METHODS: Clinical data of stage I-III (excluding N3 and NX) SCLC patients diagnosed between 1998 and 2016 were extracted from the Surveillance, Epidemiology and End Results database. Patients were divided into low-risk and high-risk subsets based on the LNR cut-off value of 0.15 using X-tile software. Propensity score matching analysis was employed to reduce bias in baseline characteristics. Kaplan-Meier analysis was performed to determine the overall survival (OS) and lung cancer-specific survival (LCSS). Cox regression analysis was performed to evaluate the effects of multiple variables. RESULTS: A total of 978 patients were identified, of whom 669 (68.40%) had LNR ≤0.15. Patients with LNR ≤0.15 showed better OS (P < 0.001) and LCSS (P < 0.001) both before and after propensity score matching. Multivariable analyses of the matched population confirmed LNR as an independent prognostic factor. Patients with LNR >0.15 showed poorer OS [hazard ratio (HR) 1.55, 95% confidence interval (CI) 1.09-2.19; P = 0.015] and LCSS (HR 1.65, 95% CI 1.13-2.43; P = 0.010). Subgroup analyses revealed that LNR ≤0.15 was associated with favourable OS (P = 0.009 and 0.197, respectively) and LCSS (P = 0.010 and 0.169, respectively) in N1 and N2 patients. CONCLUSIONS: LNR was determined as an independent predictor for surgically resected stage I-III SCLC, indicating that higher LNR is associated with reduced survival. The predictive value of LNR should to be further validated in prospective studies.

Immune thrombocytopenia induces autophagy and suppresses apoptosis in megakaryocytes.

Immune thrombocytopenia (ITP) is the main pathogenesis of excessive platelet destruction and abnormal megakaryocyte apoptosis, however, the mechanism underlying this abnormality in megakaryocytes remains to be elucidated. Since autophagy and apoptosis are closely interrelated, it can be speculated that the abnormal apoptosis of ITP megakaryocytes is associated with autophagy. To test this hypothesis, a total of 14 patients with ITP and 23 healthy controls were recruited. MEG­01 cell line was cultured in vitro, and morphological changes were observed by light microscopy, apoptosis was evaluated by flow cytometric analysis of Annexin V­FITC/propidium iodide staining and western blot analysis of B­cell lymphoma (Bcl)­2, Bcl­associated X protein (Bax), Beclin­1 and cleaved caspase 3. Apoptotic abnormalities and autophagy were observed in the ITP plasma group. Furthermore, Bax expression was downregulated, while Beclin­1 was upregulated. Chloroquine can block autophagy induced by ITP and remove the ITP plasma inhibition of apoptosis. Therefore, it may be concluded that ITP may induce autophagy, the inhibition of which may be a novel treatment for ITP.

Analyzing epidermal growth factor receptor mutation status changes in advanced non-small-cell lung cancer at different sampling time-points of blood within one day.

BACKGROUND: We investigated whether different sampling time-points within one day would influence epidermal growth factor receptor mutation (EGFRm) status in plasma and evaluated the clinical outcomes according to the quantity analysis of EGFRm in circulating tumor DNA (ctDNA) in non-small-cell lung cancer (NSCLC). METHODS: EGFR-tyrosine kinase inhibitor naïve advanced NSCLC patients who carried EGFRm in both tissues and ctDNA were enrolled in this study. Plasma samples were collected at three time-points within one day (at 8 am, 11 am and 2 pm) for EGFRm analysis by droplet digital PCR. RESULTS: Twenty-two advanced NSCLC patients were enrolled in the study. In a total of 66 blood specimens, the median EGFRm frequency was 7.13% (range 0-35.09%), and among them six specimens had less than 1.0% EGFRm frequency. Moreover, one time-point blood specimen did not display any EGFRm, even by droplet digital PCR. The frequency of EGFRm changed dynamically across different time-points within one day, but the differences were not significant (P = 0.557). We observed that patients with a relatively high frequency of EGFRm (>6.76%) had a better response to gefitinib (P = 0.024). CONCLUSION: The release of ctDNA maybe a temporal heterogenous process. The different sampling time-points within one day did not seem to influence EGFRm status in ctDNA. The relative EGFRm frequency in ctDNA could predict a benefit of EGFR-tyrosine kinase inhibitor treatment for advanced NSCLC patients.

[Intercalated Combination of Chemotherapy and EGFR-TKIs versus Chemotherapy Alone in the First-line Treatment of Advanced Non-small Cell Lung Cancer: A Meta-analysis].

BACKGROUND: The combination therapy of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has attracted the attention of more and more investigators. The aim of this meta-analysis is to evaluate the clinical efficacy and safety of intercalated combination of chemotherapy and EGFR- TKIs versus chemotherapy alone in the first-line therapy of advanced non-small cell lung cancer (NSCLC). METHODS: We retrieved the Cochrane Library, PubMed, EMBASE, CBM, CNKI and Wanfang databases for randomized controlled trials which involved the intercalated combination of chemotherapy and EGFR-TKIs, and chemotherapy alone in the first-line treatment of advanced NSCLC. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were analyzed. The quality evaluation and cross-checked data were independently performed by two investigators according to the Cochrane Systematic Reviews Handbook. The Stata 12.0 software was used to conduct the meta-analysis. RESULTS: This study included 933 NSCLC patients from 6 RCTs. The meta-analysis demonstrated that the intercalated combination of chemotherapy and EGFR-TKIs significantly prolonged the PFS (HR=0.72, 95%CI: 0.53-0.98, P=0.037) of advanced NSCLC patients compared with mono-chemotherapy. However, there was no statistical difference in OS (HR=0.85, 95%CI: 0.72-1.01, P=0.060), ORR (OR=1.59, 95%CI: 0.86-2.95, P=0.142) and DCR (OR=1.09, 95%CI: 0.95-1.25, P=0.226) between the two groups. Further, the subgroup analysis showed that the intercalated combination markedly improved the PFS in female, adenocarcinoma, never smoking, EGFR mutant patients. In the aspect of safety, the main side effects of the intercalated combination therapy were rash (OR=7.81, 95%CI: 3.74-16.34, P<0.001) and diarrhea (OR=2.73, 95%CI: 1.92-3.89, P<0.001). CONCLUSIONS: The intercalated combination of chemotherapy and EGFR-TKIs significantly prolonged the PFS in the first-line therapy of advanced NSCLC patients compared with mono-chemotherapy, and the main adverse events were tolerable rash and diarrhea. Together, the intercalated combination shows promising results, and more large-scale and high-quality RCTs are still needed.

[The influence shuxuetong on the membrane viscoelasticity of erythrocyte taken from patients with chronic pulmonary heart disease].

The present paper was aimed to explore the effect of Shuxuetong on the membrane viscoelasticity of erythrocyte taken from the acute phase patients suffering from chronic pulmonary heart disease. The membrane viscoelasticity of erythrocyte was taken from the acute phase patients suffering from chronic pulmonary heart disease. The changes of membrane viscoelasticity of erythrocyte after treated with shuxuetong were detected by micropipette aspiration technique. The results showed that the Shuxuetong of certain concentration could cause the decrease of membrane elastic modulus and viscous coefficients in acute phase patients suffering from chronic pulmonary heart disease. The study offers experimental evidences that the comprehensive treatment of pulmonary heart disease should involve the drug or measure to improve the erythrocyte deformability.

Expression and clinical significance of matrix metalloproteinase (MMP)-26 protein in non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: Matrix metalloproteinase (MMP)-26 has been implicated in genesis, progression, invasion and metastasis of several types of human cancers. This study was to investigate the expression of MMP-26 protein in invasive non-small cell lung cancer (NSCLC), pre-invasive lung cancer and normal lung tissues, thus to explore the role of MMP-26 in the progression and prognosis of NSCLC. METHODS: SP immunohistochemistry was used to measure the expression of MMP-26 protein in 72 specimens of NSCLC, 14 specimens of atypical hyperplasia and 10 specimens of normal lung tissues. RESULTS: The high expression rate of MMP-26 was 0 (0/10) in normal lung tissues, 14.3% (2/14) in atypical hyperplasia and 59.7% (43/72) in NSCLC. The expression rate of MMP-26 protein was significantly higher in NSCLC than in atypical hyperplasia and normal lung tissues (p < 0.01); the expression was higher in atypical hyperplasia than in normal lung tissues, but the difference was not significant (p > 0.05). The high expression rate of MMP-26 protein was significantly correlated to stage (p < 0.05) and lymph node metastasis (p < 0.05), but not to age, gender, tumor size and differentiation (p > 0.05). Multivariate analysis showed that MMP-26 and stage were independent prognostic factors of NSCLC (p < 0.05). The disease-free survival and overall survival were shorter in NSCLC patients with high expression of MMP-26 than in those with low expression of MMP-26 (log-rank = 19.34 and 23.2, both p < 0.001). CONCLUSIONS: High expression of MMP-26 protein is correlated to carcinogenesis, lymph node metastasis, clinical stage and prognosis of NSCLC. Therefore, MMP-26 may be served as a tumor marker in monitoring progression and predicting prognosis of NSCLC.

[The expression of vascular endothelial growth factor, CD44v6 in non-small cell lung carcinoma].

OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF), CD44v6 in non-small cell lung carcinoma. METHODS: The expression of VEGF and CD44v6 in 35 cases I approximately II stages, 27 cases III approximately IV stages and 50 cases with the metastasis of lymph nodes, 12 cases without metastasis of non-small cell lung carcinoma (NSCLC) tissues were studied by SP immunohistochemistry staining, and the 3 years survival rates were calculated in 42 cases patients. RESULTS: The positive rates of VEGF and CD44v6 in NSCLC were 73% and 69%, respectively. They were both higher than those of matched normal lung tissues, P < 0.01. The expression of VEGF and CD44v6 were related to clinical stages and metastasis of lymph nodes significantly. The expression rates of the two markers in NSCLC with the metastasis of lymph nodes were higher than those without metastasis, chi(2) = 7.146 and 5.376 respectively, and those of III approximately IV stages were higher than those of I approximately II Stages, chi(2) = 6.392 and 12.152 respectively. Survival rates of three years were lower to those patients with positive expression of the two makers than those with negative expression. In a multivariate analysis, besides TNM stages and metastasis of lymph nodes, the positive expression of CD44v6 and the positive expression of VEGF were also the independent prognostic factors to affect the Survival time. CONCLUSION: The VEGF and CD44v6 protein may act as one of important indexes to indicate the process of infiltration and metastasis in NSCLC.

Significance and expression of vascular endothelial growth factor and E-cadherin in non-small cell lung Carcinomas.

OBJECTIVES: To study the expression of vascular endothelial growth factor (VEGF) and E-cadherin (E-cd) in non-small cell lung carcinomas (NSCLC) and explore the mechanism of invasion and metastasis of tumor cell. METHOD: The expression of VEGF and E-cd was analyzed in surgical specimens (43 cases of NSCLC) by SP immunohistochemical method. RESULTS: The positive rates of VEGF in the case of good-differentiation and poor-middle-differentiation were 60.0% and 86.9% respectively, and those of E-cd were 65.0% and 34.9%. The expression of VEGF and E-cd in the case of metastasis was significantly different from that in the case without metastasis. CONCLUSION: The expression of VEGF and E-cd is correlated well with invasion and metastasis of NSCLC.