[Analysis of the effect of spread through air spaces on postoperative recurrence-free survival in patients with stage pT1N0M0 lung adenocarcinoma of different tumor size].

Objective: To investigate the effect of spread through air spaces (STAS) on the postoperative prognosis of patients with stage pT1N0M0 lung adenocarcinoma according to different tumor sizes. Methods: The clinicopathological and follow-up data of 511 patients with pT1N0M0 lung adenocarcinoma treated surgically in the Department of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Sciences from January 2014 to June 2018 were retrospectively analyzed. There were 285 males and 226 females, aged 60 (53, 66) years. Those patients were divided into two groups according to STAS status, including STAS (-) group (342 cases) and STAS (+) group (169 cases). And the stratified analysis was performed according to the American Cancer Consortium (AJCC) 8th edition postoperative pathological tumor size T-stage (pT) of lung cancer, which was divided into pT1a (pT≤1 cm, 93 cases), pT1b (1 cm0.05]. Before and after IPTW adjustment, statistically significant differences were found in RFS between STAS (+) group and STAS (-) group [(72.50±2.23) vs (85.12±0.72) months, (77.74±1.12) vs (84.59±0.64) months, all P<0.001]. In addition, the risks of both local and distant recurrence were higher in STAS (+) group compared to STAS (-) group (6.7% vs 1.2% and 8.2% vs 3.6%, respectively; both P<0.05). Conclusion: For lung adenocarcinoma patients with pT1bN0M0 and pT1cN0M0, those patients with STAS (+) had a higher incidence of both local and distant recurrence and with poor RFS.

[Analysis of low-dose computed tomography compliance and related factors among high-risk population of lung cancer in three provinces participating in the cancer screening program in urban China].

Objective: To analyze the compliance and related factors of low-dose computed tomography (LDCT) screening among the high-risk population of lung cancer in three provinces participating in the cancer early diagnosis and early treatment program in urban areas of China. Methods: From October 2017 to October 2018, 17 983 people aged between 40 and 74 years old at high risk of lung cancer were recruited from Zhejiang, Anhui and Liaoning provinces. The basic demographic characteristics, living habits, history of the disease and family history of cancer were collected by using a cancer risk assessment questionnaire, and the data of participants examined by LDCT were obtained from the hospitals participating in the program. The screening compliance was quantified by the screening participation rate, and it was calculated as the proportion of participants completing LDCT scan among high-risk population. The related factors of LDCT screening compliance were analyzed by using a multivariate logistic regression model. Results: The age of 17 983 participants was (56.52±8.22) years old. Males accounted for 51.9% (N=9 332), and 69.5% (N=12 495) had ever smoked, including former smokers and current smokers. A total of 6 269 participants were screened by LDCT, and the screening participation rate was 34.86%. The results of multivariate logistic regression analysis showed that the age group of 50 to 69 years old, female, passive smokers, alcohol consumption, family history of lung cancer and history of chronic respiratory diseases were more likely to be screened by LDCT, while the compliance of LDCT screening in current smokers was low. Conclusions: The LDCT screening compliance of the high-risk population of lung cancer in urban areas of China still needs to be improved. Age, sex, smoking, drinking, family history of lung cancer and history of chronic respiratory disease are associated with screening compliance.

Identification of peroxiredoxin 6 as a potential lung-adenocarcinoma biomarker for predicting chemotherapy response by proteomic analysis.

The prognosis of lung cancer remains poor due to the limited biomarker selection for treating patients with optimal chemotherapy. The aim of this study is to discover and identify new biomarkers with the value of predicting chemotherapy responses in a lung adenocarcinoma (AD) specimen. In this study, six pairs of pre-treatment fresh primary lung AD-cancer tumors with varied chemotherapy responses were used to discover new biomarkers by two-dimensional difference gel electrophoresis (2D DIGE). Among the matched protein spots, 19 were up-regulated and 18 were down-regulated in chemo-sensitive tumors versus chemo-resistant tissues. These differentially expressed proteins could be divided into five classes: redox regulation protein, the cytoskeletal protein, cell metabolism enzymes or proteins, apoptosis, signal transduction mediated molecules, and other functional proteins. Proteins of interest, including PRDX2, PRDX6, and Gelsolin, were differentially expressed in chemo-sensitive tumors versus chemo-resistant tissues and these observations were validated by immunohistochemistry in 92 formalin-fixed and paraffin-embedded (FFPE) specimens. Our results demonstrated that PRDX6 protein expression was closely related to tumor response (cc2 = 5.57, P < 0.05), whereas no relationship of PRDX2 and Gelsolin were obtained with tumor response (cc2 = 0.51 P > 0.05, cc2 = 0.41 P > 0.05). This tissue proteomics study provides evidence that PRDX6 may be regarded as a predictive biomarker for poor chemotherapy response, which can be helpful in guiding pretreatment protocols.

[Anatomical partial lobectomy for the treatment of 3 336 cases of patients with lung nodule].

Objective: To explore the feasibility, safety and effectiveness of anatomical partial lobectomy. Methods: The clinical data of 3 336 patients with lung nodules underwent anatomical partial lobectomy in our center from November 2013 to November 2019 were retrospectively analyzed. We set the safety margin distance according to the imaging feature of the lesion. The surgeons then anatomically detached the major vessels and bronchus in this region, resected the targeted lung tissue along the plane, and completed the resection of anatomical pulmonary lobe and clean and sampling of systemic lymph nodules. Results: A total of 668 cases were multiple nodules and 2 668 cases were solitary pulmonary nodules. According to the postoperative pathological results, 283 cases were benign, 1 197 cases were preinvasive lesions (including 38 cases of atypical adenomatous hyperplasia, 445 cases of adenocarcinoma in situ and 714 cases of minimally invasive adenocarcinoma), 1 713 cases were invasive adenocarcinoma, 73 cases were non-adenocarcinoma and 70 cases were metastatic carcinoma. Among 1 786 invasive primary lung cancers, 11 cases received preoperative neoadjuvant chemotherapy, and their postoperative pathologic diagnoses were stage ypIA. Other 1 775 cases who did not receive postoperative neoadjuvant treatment included 1 587 cases in stage ⅠA, 112 cases in stage ⅠB, 3 cases in stage ⅡA, 18 cases in stage ⅡB, 37 cases in stage ⅢA, 9 cases in stage ⅢB, 9 cases in stage Ⅳ. The average operation time was (127.3±55.3) minutes, and the mean postoperative hospital stay was (4.8±2.4) days. The incidence rate of complications (grade>2) was 1.1%(38/3 336), and no death occurred during 30 days after operation. Conclusion: Anatomic partial lobectomy has good clinical applicability, safety and effectiveness, which is worthy of clinical application and recommendation.

[Quality assessment of guidelines and consensus in lung cancer chemotherapy].

Objective: To understand the current status of clinical guidelines and consensus for lung cancer chemotherapy, evaluate and analyze the quality of lung cancer chemotherapy treatment guidelines, and provide references for the revision and improvement of lung cancer chemotherapy clinical decision-making and guidelines. Methods: Search Pubmed, EMbase, Cochrane Library (Cochrane Library), China Knowledge Network, Wanfang Database, China Biomedical Literature Database and other related databases and clinical practice guidelines related to lung cancer chemotherapy, and screen the literatures according to the established inclusion exclusion criteria. Use the appraisal of guidelines for research and evaluation Ⅱ (AGREE Ⅱ) and reporting items for practice guidelines in healthcare (RIGHT) tools to compare and evaluate the quality of the included guides and the level of reporting specifications. Results: A total of 14 guidelines were included. The assessment results of AGREE Ⅱ showed that the average score of scope and purpose was 94 points, the average score of stakeholder involvement was 60 points, the average score of rigour of development was 43 points, the average score of clarity of presentation was 88 points, the average score of applicability was 50 points, the average score of editorial independence was 61 points. Seven guidelines were evaluated as A level, 6 guidelines were evaluated as B level, 1 guideline was evaluated as C level. The assessment results of RIGHT showed that, in addition to the basic information, the included guidelines have many deficiencies in 6 areas including background, evidence, recommendation, review and quality assurance, funding, declaration and management of interests and other information, and the normative gap between domestic and foreign guides was large. Conclusions: The overall quality of clinical guidelines for lung cancer chemotherapy is high, but the standardization needs to be strengthened. There is a big gap between the quality and standardization of domestic and foreign guides. Further developments of high-quality clinical practice guidelines and guidelines consistent with our country's actual situation are needed.

[Exploratory research on developing lung cancer risk prediction model in female non-smokers].

Objective: To develop a lung cancer risk prediction model for female non-smokers. Methods: Based on the Kailuan prospective dynamic cohort (2006.05-2015.12), a nested case-control study was conducted. Participants diagnosed with primary pathologically confirmed lung cancer during follow-up were identified as the case group, and others were identified as the control group. A total of 24 701 subjects were included in the study, including 86 lung cancer cases and 24 615 control population, respectively. Questionnaires, physical examinations, and laboratory tests were conducted to collect relevant information. Multivariable-adjusted logistic regressions were conducted to develop a lung cancer risk prediction model. Area Under the Curve (AUC) and Hosmer-Lemeshow tests were used to evaluate discrimination and calibration, respectively. Ten-fold cross-validation was used for internal validation. Results: Two sets of models were developed: the simple model (including age and monthly income) and the metabolic index model [including age, monthly income, fasting blood glucose (FBG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C)].The AUC (95%CI) [0.745 (0.719-0.771)] of the metabolic index model was higher than that of the simple prediction model [0.688 (0.660-0.716)] (P=0.004). Both the simple model (PHL=0.287) and the metabolic index model (PHL=0.134) were well-calibrated. The results of ten-fold cross-validation indicated sufficient stability, with an average AUC of 0.699 and a standard error (SD) of 0.010. Conclusion: By incorporating metabolic markers, accurate and reliable lung cancer risk prediction model for female non smokers could be developed.

[The development and validation of risk prediction model for lung cancer: a systematic review].

Objective: To systematically understand the global research progress in the construction and validation of lung cancer risk prediction models. Methods: "lung neoplasms" , "lung cancer" , "lung carcinoma" , "lung tumor" , "risk" , "malignancy" , "carcinogenesis" , "prediction" , "assessment" , "model" , "tool" , "score" , "paradigm" , and "algorithm" were used as search keywords. Original articles were systematically searched from Chinese databases (CNKI, and Wanfang) and English databases (PubMed, Embase, Cochrane, and Web of Science) published prior to December 2018. The language of studies was restricted to Chinese and English. The inclusion criteria were human oriented studies with complete information for model development, validation and evaluation. The exclusion criteria were informal publications such as conference abstracts, Chinese dissertation papers, and research materials such as reviews, letters, and news reports. A total of 33 papers involving 27 models were included. The population characteristics of all included studies, study design, predicting factors and the performance of models were analyzed and compared. Results: Among 27 models, the number of American-based, European-based and Asian-based model studies was 12, 6 and 9, respectively. In addition, there were 6 Chinese-based model studies. According to the factors fitted into the models, these studies could be divided into traditional epidemiological models (11 studies), clinical index models (6 studies), and genetic index models (10 studies). 15 models were not validated after construction or were cross-validated only in the internal population, and the extrapolation effect of models was not effectively evaluated; 8 models were validated in single external population; only 4 models were verified in multiple external populations (3-7); the area under the curve (AUC) of models ranged from 0.57 to 0.90. Conclusion: Research on risk prediction models for lung cancer is in development stage. In addition to the lack of external validation of existing models, the exploration of potential clinical indicators was also limited.

[The relationship between inflammatory markers and the risk of lung cancer: a prospective cohort study].

Objective: To investigate whether elevated levels of C-reactive protein (CRP) and neutrophil (NE) in the blood is associated with an increased risk of lung cancer incidence. Methods: From 2006 to 2007, all employees and retirees from Kailuan (Group) Limited liability Corporation were included in this Kailuan Cohort study. The last follow-up date was December 2015. Data on new cases of lung cancer were collected, and multivariable Cox proportional hazards regression models were used to the relationship between baseline CRP and NE at baseline and risk of lung cancer. Results: A total of 92 735 participants were enrolled in this study. During the follow-up, 850 new cases of lung cancer were identified. All subjects were divided into four groups according to the combination level of CRP and NE at baseline: CRP≤3 mg/L and NE≤4×10(9)/L(Group A), CRP≤3 mg/L and NE>4×10(9)/L(Group B), CRP>3 mg/L and NE≤4×10(9)/L(Group C), CRP>3 mg/L and NE>4×10(9)/L(Group D). The cumulative incidence of lung cancer were 950/100 000, 1 030/100 000, 1 081/100 000 and 1 596/100 000 in these four groups, respectively (P<0.001). Multivariate Cox proportional risk model showed that participants from Group D had an significantly increased 72% risks of lung cancer when compared to Group A (95% CI: 1.40~2.12, P<0.001). Stratified analyses gender showed that males in Group D had higher risk of lung cancer when compared with participants in Group A (HR=1.73, 95% CI: 1.40~2.15, P<0.001). Conclusion: Elevated levels of CRP and NE might increase the risk of lung cancer.

[The value of the planned neoadjuvant radiotherapy or chemoradiotherapy for the non-radical resection of esophageal squamous cell carcinoma].

Objective: The role of planned neoadjuvant radiotherapy or chemoradiotherapy in the non-radical resection of esophageal squamous cell carcinoma was unclear. The study aimed to evaluate their therapeutic effect and analyze the prognostic factors. Methods: We retrospectively analyzed the clinical data of locally advanced esophageal squamous cell carcinoma who received neoadjuvant radio therapy (33 patients) and concurrent chemoradiotherapy (119 patients) from January 2004 to December 2016 in our single-institution database.The survival rates were calculated by Kaplan-Meier method. The prognostic factors were analyzed by using Log rank test and Cox proportional hazards model. Results: The median follow-up was 29.8 months. One hundred and one patients survived more than 3 years. The rates of overall survival (OS) and disease-free survival (DFS) at 3 years were 63.9% and 55.6%, respectively.The rates of complete, partial and minimal pathological response of the primary tumor were 50.3%, 38.4%, 11.3%, the corresponding 3-year OS were 75.5%, 57.4%, 27.3% (P<0.001) and 3-year DFS were 72.0%, 44.7%, 17.6% (P<0.001), respectively.The postoperative lymph node metastasis rate was 27.0%. The 3-year OS and DFS of the lymph node positive group was 45.6% and 32.8%, significantly lower than 70.8% and 63.7% of the negative group (both P<0.001). The 3-year OS and DFS of pathologic stage Ⅰ, Ⅱ, ⅢA, ⅢB and Ⅵ A were 76.2%, 57.4%, 64.7%, 35.0%, 33.3% (P<0.001) and 70.1%, 49.3%, 41.2%, 22.1%, 33.3% (P<0.001), respectively.The operation-related mortality was 3.3%. Multivariate analysis showed that chest pain, postoperative respiratory failure, pathological differentiation, more than 15 lymph node dissection and ypTNM stage were the independent prognostic factors of OS (P<0.05 for all). Conclusions: The planned neoadjuvant radiotherapy or chemoradiotherapy for the non-radical resection of advanced esophageal squamous cell carcinoma could result in favorable survival. The chest pain, postoperative respiratory failure, pathological differentiation, the number of lymph node resection and ypTNM stage are the independent prognostic factors of the prognosis of these patients.

[Alcohol consumption and the risk of lung cancer in males: a prospective cohort study].

Objective: To investigate the association between alcohol consumption and lung cancer risk in Chinese males. Methods: Information on alcohol consumption and outcomes were collected on a biennial basis among males in Kailuan Cohort (2006-2015). In addition, electronic databases of hospitals affiliated to Kailuan Community, Insurance Systems of Kailuan Community and Tangshan were also used for supplementary information retrieval. Cox proportional hazards regression models were used to evaluate the hazard ratio (HR) and 95%CI of baseline frequency and type of alcohol consumption associated with lung cancer risk in males. Non-drinkers were used as control group. Results: A total of 101 751 males were included and 913 new lung cancer cases were identified in the Kailuan male cohort study, with a total follow-up time of 808 146.56 person-years and a median follow-up time of 8.88 years by 31 December 2015. After adjusting for potential confounding factors, the HR of former drinkers, occasional drinkers (<1/day) and drinkers (≥1/day) were 1.30 (95%CI: 0.90-1.88), 0.80 (95%CI: 0.64-1.01) and 1.04 (95%CI: 0.85-1.27), respectively, compared with non-drinkers. In addition, drinking beer/red wine (HR=0.91, 95%CI: 0.69-1.20) and white wine (HR=0.99, 95%CI: 0.83-1.19) showed no significant association with lung cancer. The results were similar when stratified analysis were conducted. Conclusion: Our study results don't support the hypothesis that alcohol consumption is significantly associated with the risk of lung cancer in males.

[Association between total cholesterol and risk of lung cancer incidence in men: a prospective cohort study].

Objective: To assess the association and intensity of baseline TC level with the incidence of lung cancer in men in China. Methods: Since May 2006, all the male workers, including the employees and the retirees in Kailuan Group were recruited in the Kailuan male dynamic cohort study. Information about demographics, medical history, anthropometry and TC level were collected at the baseline interview, as well as the information of newly-diagnosed lung cancer cases during the follow-up period. According to guidelines for blood lipids in Chinese adults and the distribution in the population, TC level was classified into five groups as followed: <160, 160-, 180-, 200- and ≥240 mg/dl, with the second quintile group (160- mg/dl) serving as the referent category. Cox proportional hazards regression model and restricted cubic spline (RCS) model were used to evaluate the association and the nonlinear association between baseline TC level and the risk of lung cancer in the men. Results: By December 31, 2014, for the 109 884 men, a follow up of 763 819.25 person-years was made with a median follow-up period of 7.88 years. During the follow up, 808 lung cancer cases were identified. After adjustment for age, education level, income level, smoking status, alcohol consumption level, history of dust exposure, FPG level and BMI, HR (95%CI) of lung cancer for men with lower TC level (<160 mg/dl) and higher TC level (≥240 mg/dl) were 1.34 (1.04- 1.72) and 1.45 (1.09-1.92), respectively, compared with men with normal TC level (160- mg/dl). The results didn't change significantly after exclusion of newly diagnosed cancer cases within 2 years of follow up and subjects with the history of hyperlipidemia. Conclusion: Our results showed that TC might be associated with higher risk of lung cancer. Men with lower TC level or higher TC level had higher risk for lung cancer. Keep moderate TC level might be one of the effective precaution for the prevention of lung cancer.

[Comparison of lung cancer surgery in China, 2005 vs. 2015].

Objective: To study the impact of the advance of the times and technological progress on the surgical treatment of lung cancer. Methods: The data of patients with non-small cell lung cancer treated by thoracic surgery at Cancer Hospital of Chinese Academy of Medical Sciences from 2005 to 2015 were retrospectively analyzed. The population distribution, operation methods and treatment results were analyzed retrospectively. Results: 510 patients (in 2005) and 1 235 (in 2015) non-small cell lung cancer patients were included in this study. The proportions of male patients (79.0% vs. 55.8%), smoking (52.9% vs. 30.1%), squamous cell carcinoma (50.2% vs. 22.4%) and video-assisted thoracoscopic surgery (VATS) (0 vs. 61.1%), stage Ⅰ (15.2% vs. 36.8%), the number of lymph node dissection (21.8 vs. 16.6), intraoperative blood transfusion rate (9.6% vs. 1.9%), palliative resection rate (7.5% vs. 2.0%), the average length of stay (10.8 d vs. 7.6 d) were significantly changed. There was no significant difference in the average age of patients and operation time. Conclusion: There was a significant change in the distribution of population and surgical techniques in patients undergoing lung cancer surgery in last ten years.

[Tea consumption and the risk of lung cancer in Chinese males: a prospective cohort study].

Objective: To investigate the association between tea consumption and lung cancer risk in Chinese males. Methods: Tea consumption and incident lung cancer cases were collected on a biennial basis among males in Kailuan Cohort during 2006-2015. Up to 31st December 2015, a total of 103 010 male candidates from the Chinese Kailuan Male Cohort Study were enrolled in the present study. Cox proportional hazards regression model was used to evaluate the association between tea consumption and risk of lung cancer in males. Results: The age of male candidates was (51.3±13.4)years old. There were 828 810.74 person-years of follow-up and 8.91 years of median follow-up period. During the follow-up, 964 lung cancer cases were identified. In male, the rate of never cosumers, tea drinkers (<4/week) and tea drinkers (≥4/week) were 58.17%(n=59 926), 24.04%(n=24 765) and 17.78%(n=18 319), respectively. After adjustment for potential confounding factors, HR (95%CI) of lung cancer for subjects with tea drinkers (<4/week) and tea drinkers (≥4/week) were 0.80 (0.63-1.02) and 1.02 (0.80-1.30), respectively, as compared with never cosumers. The results showed no significant association with lung cancer. Stratification analysis and sensitivity analysis showed no significant changes. Conclusion: Our study has not found that tea consumption is significantly associated with the risk of male lung cancer.

Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen).

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of [3H]flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH2CH2- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).