Incidence of Lung Adenocarcinoma by Age, Sex, and Smoking Status in Taiwan.

Importance: Knowing whether the effects of smoking and other risk factors with lung adenocarcinoma (ADC) incidence varies by sex would provide information on lung cancer prevention strategies. Objective: To evaluate whether women in Taiwan have higher age- and tumor stage-specific lung ADC incidence rates than men irrespective of smoking status (ie, ever smoker or never smoker). Design, Setting, and Participants: This population-based cohort study used data sets synthesized from the Taiwan Cancer Registry (TCR) from 1979 to 2019; the TCR Long Form (TCRLF) from 2011 to 2019, which provides individual-level smoking and tumor stage information; the Taiwan Cause of Death Database (TCOD) from 1985 to 2019; the National Health Insurance Research Database (NHIRD) from 2000 to 2020; the Monthly Bulletin of Interior Statistics (MBIS) from 2011 to 2019; the National Health Interview Survey from 2001, 2005, 2009, 2013, and 2017; and Taiwan Biobank data from 2008 to 2021. Included patients were aged 40 to 84 years and had any invasive lung cancer from January 1, 2011, to December 31, 2019. Exposure: Smoking status. Main Outcomes and Measures: The main outcomes were age-specific female-to-male incidence rate ratios (IRRs) of lung ADC by smoking status and tumor stage. Linked data from the TCR, TCOD, NHIRD, Taiwan National Health Interview Survey, and MBIS were used to estimate the age- and sex-specific numbers of cancer-free individuals at midyears from 2011 to 2019 by smoking status. Using the TCR and TCRLF, age-, sex-, tumor stage-, and diagnosis year-specific numbers of patients with lung ADC from 2011 to 2019 by smoking status were estimated. Results: A total of 61 285 patients (32 599 women [53.2%]) aged 40 to 84 years (mean [SD] age, 64.66 [10.79] years) in the Taiwanese population of approximately 23 million were diagnosed with invasive lung ADC as their first lifetime cancer between 2011 and 2019. Among smokers, men had higher tobacco use by almost all examined metrics, including nearly twice the mean (SD) number of pack-years smoked (eg, 7.87 [8.30] for men aged 30-34 years vs 4.38 [5.27] for women aged 30-34 years). For 5-year age bands between 40 and 84 years, incidence of lung ADC was significantly higher among females than males for nearly all age groups irrespective of tumor stage and smoking status (eg, for the age group 70-74 years, the female-to-male IRR for late-stage lung ADC among never smokers was 1.38 [95% CI, 1.30-1.50]). Conclusions and Relevance: In this cohort study, women had higher age- and stage-specific lung ADC incidence rates than men in Taiwan for both never and ever smokers, suggesting the possibility of differential exposures between sexes to risk factors other than smoking and the potential modification of ADC risk factors by sex. Further work is needed to determine whether this pattern replicates in other populations, discover the causes of lung ADC, and put preventive measures in place.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Molecular characterization of MET fusions from a large real-world Chinese population: A multicenter study.

PURPOSE: MET is a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under-reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizing MET fusions in a large, real-world Chinese cancer population. METHODS: We retrospectively included patients with solid tumors who had DNA-based genome profiles acquired through targeted sequencing from August 2015 to May 2021. MET fusion-positive (MET+) patients were subsequently selected for clinical and molecular characterization. RESULTS: We screened 79,803 patients across 27 tumor types and detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%-0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. High heterogeneity was observed for partners, with ST7, HLA-DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence of TP53 in MET+ alterations, EGFR L858R, EGFR L861Q, and MET amplification. CONCLUSION: To our knowledge, this is currently the largest study in characterizing MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.

Incidence trends and spatial distributions of lung adenocarcinoma and squamous cell carcinoma in Taiwan.

Lung cancer is the second most common cancer in Taiwan. After Taiwan implemented the Tobacco Hazards Prevention Act in 1997, smoking rates declined. However, the incidence rates of lung cancer for both sexes are still increasing, possibly due to risk factors other than smoking. We used age-period-cohort analysis to examine the secular trends of lung cancer incidence rates by histological type in Taiwan. A stabilized kriging method was employed to map these lung cancer incidence rates. Lung adenocarcinoma incidence rates increased, but lung squamous cell carcinoma incidence rates decreased, for both the sexes in recent birth cohorts, particularly in women. In Taiwan, the hotspots of lung adenocarcinoma incidence rates were in the northern, northeastern, and western coastal areas; the incidence rates increased rapidly in the western and southern coastal regions and southern mountainous regions. The high incidence rates of lung squamous cell carcinoma in men were in the southwestern and northeastern coastal areas. The incidence rates rapidly increased in the central and southern coastal and mountainous regions. For both sexes in Taiwan, lung squamous cell carcinoma incidence rates declined from 1997 to 2017, but lung adenocarcinoma increased. The increased incidence rates of lung adenocarcinoma may be related to indoor and outdoor air pollution. Some areas in Taiwan have increasing lung cancer incidence rates, including the northwestern and southern coasts and mountains, and warrant particular attention.

Isoflavone and soy food intake and risk of lung cancer in never smokers: report from prospective studies in Japan and China.

PURPOSE: Evidence from several cohorts has suggested that a higher intake of isoflavone is associated with lower risk of lung cancer in never smokers, but the association has not been investigated by histologic type of lung cancer. Adenocarcinoma is a common histologic type found in never smokers. We hypothesized that a higher intake of isoflavone is associated with a lower risk of lung adenocarcinoma among never smokers. Here, we examined the associations of isoflavone and soy food intake with lung cancer and its histologic types in never smokers. METHODS: We performed a pooled analysis using data from the Japan Public Health Center-based Prospective Study, Shanghai Women's Health Study and Shanghai Men's Study with 147,296 never smokers aged 40-74 years with no history of cancer. During 1,990,040 person-years of follow-up, 1247 lung cancer cases were documented. Dietary isoflavone and soy food intake were assessed using a food-frequency questionnaire. Multivariable Cox proportional hazards models assessed the associations between isoflavone and soy intake with incidence of lung cancer by histologic type. RESULTS: A higher intake of dietary isoflavone and soy food were associated with reduced risk of lung adenocarcinoma. The multivariable hazard ratios (HRs) (95% CI) of risk of lung adenocarcinoma for the highest versus lowest intakes of isoflavone and soy food were 0.74 (0.60-0.92) and 0.78 (0.63-0.96), respectively. The multivariable HRs of risk of lung adenocarcinoma associated with each 10 mg/day increase in isoflavone and each 50 g/day increase in soy food intake were 0.81 (0.70-0.94) and 0.84 (0.73-0.96), respectively. CONCLUSION: Higher intake of isoflavone and soy food was associated with lower risk of lung adenocarcinoma in never smokers.

Cambios en la tendencia histológica del cáncer pulmonar / Changes in lung cancer's histological trend

El cáncer pulmonar se establece como la segunda causa de muerte en países desarrollados y en algunos en vías de desarrollo. Su diagnóstico es tardío, sus opciones de resección y su curación aun con terapias adyuvantes son limitadas, lo que incide en la pobre sobrevida a 5 años, es por ello que se necesitan mayores esfuerzos para combatir el hábito del tabaco, principal agente etiológico. Material y Métodos: Se trata de un estudio descriptivo transversal en pacientes adultos atendidos de 01 de enero del 2011 al 31 de diciembre del 2021, ingresados al servicio de cirugía del Hospital San Vicente de Guatemala, con diagnósticos de cáncer pulmonar, masa pulmonar, derrame pleural o nódulo pulmonar solitario. Resultados: Se atendieron 202 pacientes con diagnósticos presuntivos de cáncer pulmonar, no encontrando diferencias significativas en relación al sexo. La edad mayormente afectada se estableció entre los 50 y 70 años. Prevalecieron los estadíos IIIA, IIIB y IV basados en los hallazgos clínicos, tomográficos y transoperatorios y solo al 10% se le sometió a una cirugía de resección pulmonar mayor. Los cánceres de células no pequeñas NSCLC fueron reportados en el 68.7% y el adenocarcinoma fue la variedad más frecuente con el 54.95% sobre el 7.29% del epidermoide. La mortalidad a los treinta días se estableció en 2.97%. Conclusión: El adenocarcinoma pulmonar ocupa el primer lugar en la incidencia de los cánceres pulmonares, desplazando así al carcinoma epidermoide popularizado desde la mitad del siglo pasado. Esta tendencia en el cambio histológico está firmemente asociado a las modificaciones en los hábitos del fumar (AU)

Lung cancer is established as the second cause of death in developed countries and in some developing ones. Its diagnosis is late, its resection options and its cure even with adjuvant therapies are limited, which affects the poor survival at 5 years, which is why greater efforts are needed to combat the tobacco habit, the main etiological agent. Material and Methods: This is a cross-sectional descriptive study in adult patients treated from January 1, 2011 to December 31, 2021, admitted to the surgery service of the Hospital San Vicente de Guatemala, with diagnoses of lung cancer, lung mass, effusion pleural or solitary pulmonary nodule. Results: 202 patients with presumptive diagnoses of lung cancer were treated, finding no significant differences in relation to sex and the most affected age was established between 50 and 70 years. Stages IIIA, IIIB, and IV prevailed based on clinical, tomographic, and intraoperative findings, and only 10% underwent major lung resection surgery. NSCLC non-small cell cancers were reported in 68.7% and adenocarcinoma was the most frequent variety with 54.95% over 7.29% of epidermoid. Thirty-day mortality was established at 2.97%. Conclusion: Pulmonary adenocarcinoma occupies the first place in the incidence of lung cancers, thus displacing squamous cell carcinoma popularized since the middle of the last century. This trend in histological change is strongly associated with changes in smoking habits.

Development and Validation of a Prognostic Model to Predict Overall Survival for Lung Adenocarcinoma: A Population-Based Study From the SEER Database and the Chinese Multicenter Lung Cancer Database.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer (NSCLC). The aim of our study was to determine prognostic risk factors and establish a novel nomogram for lung adenocarcinoma patients. Methods: This retrospective cohort study is based on the Surveillance, Epidemiology, and End Results (SEER) database and the Chinese multicenter lung cancer database. We selected 22,368 eligible LUAD patients diagnosed between 2010 and 2015 from the SEER database and screened them based on the inclusion and exclusion criteria. Subsequently, the patients were randomly divided into the training cohort (n = 15,657) and the testing cohort (n = 6711), with a ratio of 7:3. Meanwhile, 736 eligible LUAD patients from the Chinese multicenter lung cancer database diagnosed between 2011 and 2021 were considered as the validation cohort. Results: We established a nomogram based on each independent prognostic factor analysis for 1-, 3-, and 5-year overall survival (OS) . For the training cohort, the area under the curves (AUCs) for predicting the 1-, 3-, and 5-year OS were 0.806, 0.856, and 0.886. For the testing cohort, AUCs for predicting the 1-, 3-, and 5-year OS were 0.804, 0.849, and 0.873. For the validation cohort, AUCs for predicting the 1-, 3-, and 5-year OS were 0.86, 0.874, and 0.861. The calibration curves were observed to be closer to the ideal 45° dotted line with regard to 1-, 3-, and 5-year OS in the training cohort, the testing cohort, and the validation cohort. The decision curve analysis (DCA) plots indicated that the established nomogram had greater net benefits in comparison with the Tumor-Node-Metastasis (TNM) staging system for predicting 1-, 3-, and 5-year OS of lung adenocarcinoma patients. The Kaplan-Meier curves indicated that patients' survival in the low-risk group was better than that in the high-risk group (P < .001). Conclusion: The nomogram performed very well with excellent predictive ability in both the US population and the Chinese population.

Impact of sleep status on lung adenocarcinoma risk: a prospective cohort study.

OBJECTIVE: The association between sleep status and lung adenocarcinoma risk was analyzed using long-term follow-up data from 60,443 patients over the period 2016-2022 to provide a reference for exploring the association between sleep status and lung adenocarcinoma development. PATIENTS AND METHODS: Based on long-term follow-up data, a total of 60,443 people were included. Sleep data collected for the study included insomnia symptoms, lunch break habits, and sleep duration. A sleep score (0-3) was constructed based on difficulty falling asleep, premature awakening and sleep duration. Proportional risk regression models were used to analyze the association between each sleep factor, sleep score and lung cancer risk. RESULTS: The study population was followed up for 9.9 ± 4.8 years and a total of 307 cases of lung adenocarcinoma were first recorded during the follow-up period. After controlling for potential confounders, the risk ratios (HR) for lung adenocarcinoma in those with difficulties going asleep or waking up too early were 1.12 (95% CI: 1.02-1.14) and 1.07 (95% CI: 1.01-1.11), respectively, compared to those without symptoms of insomnia. The HR for lung adenocarcinoma in those with less than 7 h of sleep [HR = 1.17 (95% CI: 1.05-1.21)] was compared to those with ≥ 7 h of sleep per day. Compared to those with a sleep score of 3 (highest quality sleep), those with a sleep score of 2, 1 and 0 corresponded to HR of 1.06 (95% CI: 1.01-1.12), 1.11 (95% CI: 1.09-1.18) and 1.15 (95% CI: 1.01-1.32) respectively. CONCLUSIONS: Patients who suffer from insomnia or have a short sleep schedule are at increased risk of developing lung cell cancer. Sleep has an important impact on health and improving sleep conditions can reduce the incidence of lung cancer.

Characteristics of Women with Lung Adenocarcinoma in the World Trade Center Environmental Health Center.

The destruction of the World Trade Center towers on 11 September 2001 exposed local residents, workers, and individuals in the area (Survivors) to dust and fumes that included known and suspected carcinogens. Given the potential for inhalation of toxic substances and the long latency after exposure, the incidence of lung cancer is expected to increase in WTC-exposed individuals. We describe the characteristics of women WTC Survivors with lung adenocarcinoma who were enrolled in the WTC Environmental Health Center (WTC EHC) between May 2002 and July 2021. A total of 173 women in WTC EHC had a diagnosis of any type of lung cancer, representing 10% of all cancers in women. Most of the lung cancers (87%) were non-small cell carcinomas, with adenocarcinoma (77%) being the most common subtype. Nearly half (46%) of these patients were exposed to dust clouds on 11 September 2001. Race and ethnicity varied by smoking status, as follows: 44% of Asian women compared with 29% of non-Hispanic White women were never-smokers (p < 0.001). There was no significant difference between the pathologic characteristics of adenocarcinomas between never and ever smokers. We also summarize EGFR, ALK, KRAS, ROS-1 and BRAF mutation status stratified by smoking, race and ethnicity. The identification of a relatively high proportion of women never-smokers with lung cancer warrants further investigation into the role of WTC dust exposure.

PM2.5 exposure and risk of lung adenocarcinoma in women of Taiwan: A case-control study with density sampling.

BACKGROUND AND OBJECTIVE: The prevalence of smoking among women in Taiwan is <5%, but the incidence of lung cancer remains high. This study determined the association between PM2.5 (fine particulate matter with an aerodynamic diameter of ≤2.5 µm) exposure and lung cancer among women in Taiwan. METHODS: In total, 21,301 female lung cancer cases nationwide were newly diagnosed between 2012 and 2017. Each case was age-, sex- and calendar year-matched with four controls randomly selected from the general population. Allowing a latent period of 5 years, we estimated the PM2.5 and nitrogen dioxide (NO2 ) exposures for each individual according to the residential changes from 2000. We adopted self-reported smoking statuses for the cases, while those of controls were estimated using annual surveys in each residential county. We performed multiple logistic regression analyses to examine the associations between PM2.5 and NO2 exposures and incident lung cancer cases. RESULTS: The ORs of lung adenocarcinoma for the third (30.5-35.1 µg/m3 ), fourth (35.1-39.3 µg/m3 ) and fifth PM2.5 exposure quintiles (39.3-48.1 µg/m3 ) relative to the first quintile were 1.10 (95% CI: 1.04-1.16), 1.12 (95% CI: 1.06-1.19) and 1.10 (95% CI: 1.04-1.16), respectively, after adjusting for smoking, residence and comorbidities. A dose-response relationship (p = 0.004) was found. The associations persisted with a 10-year latency and were not detected for small-cell and squamous cell carcinoma after control for smoking. We did not observe a similar effect for NO2 exposure. CONCLUSION: Residential PM2.5 exposure higher than 30 µg/m3 was associated with an increased risk of lung adenocarcinoma in women of Taiwan.

Prevalence of targeted therapy-related genetic variations in NSCLC and their relationship with clinicopathological characteristics.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cancer type in China. Targeted therapies have been used to treat NSCLC for two decades, which is only suitable for a subgroup of patients with specific genetic variations. The aim of this study was to investigate the prevalence of genetic variations leading to sensitivity or resistance to targeted therapies in NSCLC, and their relationship with clinicopathological characteristics of the patients. METHODS: Tumor samples were collected from 404 patients who were diagnosed to have NSCLC and underwent surgery, transthoracic biopsy, bronchoscopy biopsy, or pleural aspiration in Sichuan Provincial People's Hospital from January 2019 to March 2020. Commercial amplification-refractory mutation system kits were used to detect targeted therapy-related genetic variations in those tumor samples. The prevalence of genetic variations and their relationship with patient clinicopathological characteristics were analyzed using statistical software, followed by subgroup analysis. RESULTS: In all, 50.7% of the NSCLC patients had sensitive genetic variations to anti-EGFR therapies, and 4.9% of those patients had co-existing resistant genetic variations. Fusions in ALK, ROS1, or RET were found in 7.7% of the patients, including 2 patients with co-existing EGFR exon 19 deletion or L858R. EGFR exon 19 deletion and L858R were more common in female patients and adenocarcinoma. Further subgroup analysis confirmed the observation in female patients in adenocarcinoma subgroup, and in adenocarcinoma in male patients. In addition, smokers were more likely to have squamous cell carcinoma and KRAS mutation and less likely to have EGFR L858R, which were also confirmed after standardization of gender except KRAS mutations. CONCLUSION: Nearly half of the NSCLC patients were eligible for anti-EGFR treatments. In NSCLC, female gender and adenocarcinoma may indicate higher chance of EGFR exon 19 deletion or L858R, and smoking history may indicate squamous cell carcinoma and EGFR L858R.

Consideration of the Optimal Surgical Procedure Based on the Risk of Recurrence in Clinical Stage 0 or IA Lung Adenocarcinoma.

BACKGROUND/AIM: Sublobar resection is widely performed for early-stage non-small cell lung cancer in the clinical setting. This study evaluated the optimal surgical procedures of clinical stage 0 or IA adenocarcinoma from the perspective of recurrence. PATIENTS AND METHODS: A total of 508 lung adenocarcinoma patients diagnosed as c-stage 0 or IA were retrospectively investigated. RESULTS: The types of surgical procedures were lobectomy (n=328), segmentectomy (n=73), and wedge resection (n=107). Clinical T descriptors were cTis in 74, cT1mi in 68, cT1a in 94, cT1b in 181 and cT1c in 91 patients. Recurrence was observed in 46 cases (9%), including 3 (3.1%) with cT1a, 23 (12.7%) with cT1b and 20 (22.0%) with cT1c. The patients who received sublobar resection developed recurrence more often than the patients who received lobectomy among cT1b cases (10.1% vs. 21.4%) and cT1c cases (18.0% vs. 46.2%) (p=0.053 and p=0.023). CONCLUSION: The cT1b and cT1c cases should be considered for lobectomy to prevent recurrence.

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; Pnonadjusted  = .003, Padjusted  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.

High KIF11 expression is associated with poor outcome of NSCLC.

PURPOSE: To clarify the correlation between KIF11 (kinesin family member 11) and clinicopathologic characteristics of non-small cell lung cancer (NSCLC) and identify the prognostic value of KIF11 in patients with NSCLC. METHODS: For investigating the expression of KIF11 in NSCLC, two tissue microarrays (TMAs: one contained 60 paired NSCLC tissues and paratumor tissues, the other contained 140 NSCLC tissues and 10 normal lung tissues) were constructed, stained, and scored. The Cancer Genome Atlas (TCGA) datasets were used to explore the differential expression level of KIF11 between NSCLC and paratumor. Kaplan-Meier survival curves were plotted and multivariate analysis were carried out. RESULTS: The staining of KIF11 mainly distributed throughout the cytoplasm of tumor cells. Its expression was higher in NSCLC than paratumor cells, and similar results were obtained from TCGA datasets. We found that high expression of KIF11 had a significant correlation with lymph node metastases (p = 0.024) and pathologic stage (p = 0.018); that significant difference was not found in any other clinicopathologic characteristic. As univariate and multivariate analysis showed, KIF11 expression was significantly correlated with overall survival time of NSCLC (p = 0.002, p = 0.025, respectively). High KIF11 expression was found to significantly associate with overall survival of stage II-III (p = 0.001) and lung adenocarcinoma (p = 0.036). CONCLUSION: High KIF11 expression predicts poor outcome in NSCLC. KIF11 is expected to be a viable prognostic biomarker for NSCLC.

Comprehensive analysis of PD-L1 expression, tumor-infiltrating lymphocytes, and tumor microenvironment in LUAD: differences between Asians and Caucasians.

BACKGROUNDS: The characteristics of programmed cell death protein-1 (PD-L1) expression, tumor-infiltrating lymphocytes (TILs), and tumor microenvironment (TME) in lung adenocarcinoma (LUAD) patients are closely related to immunotherapy, and there are differences between Asians and Caucasians. METHODS: Acquire the transcriptome data of the Cancer Genome Atlas and Chinese LUAD patients. R software was used to analyze the differential expression of genes, prognosis, and gene function. Use CIBERSORT for TIL-related analysis and ESTIMATE for TME-related analysis. RESULTS: The expression of PD-L1 in tumor tissues of Caucasian LUAD patients was lower than that in normal tissues, while there was no significant difference in Asians. There was no statistical difference between PD-L1 expression and prognosis. The composition of TILs between Caucasian and Asian LUAD patients was quite different. There was no correlation between TILs and prognosis in Caucasians. However, the higher content of resting mast cells indicated a better prognosis in Asians. The Caucasian patients with higher immune and estimate scores had a better prognosis (p = 0.021, p = 0.025). However, the Asian patients with a higher estimate score had a worse prognosis (p = 0.024). The high expression of COL5A2 (p = 0.046, p = 0.027) and NOX4 (p = 0.020, p = 0.019) were both associated with the poor prognosis in Caucasians and Asians. CONCLUSION: There are many differences in the characteristics of PD-L1 expression, TILs, and TME between Caucasian and Asian LUAD patients. This provides a certain hint for the selection of specific immunotherapy strategies separately for Caucasian and Asian LUAD patients.

Genomic Profiling of Lung Adenocarcinoma in Never-Smokers.

PURPOSE: Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. METHODS: We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. RESULTS: We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. CONCLUSION: In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.

Cross-Sectional Study to Establish the Utility of Serum Tumor Markers in the Diagnosis of Lung Cancer.

BACKGROUND: Reliable blood markers for aiding lung cancer (LC) diagnosis and differentiating LC from tuberculosis are lacking in India. METHODOLOGY: In this single-centre, cross-sectional, real-world study, serum levels of 5 TMs (CEA, CYFRA 21-1, SCC, ProGRP, NSE) were measured from consented patients with suspicious lung nodules who were candidates for biopsy, and also from healthy controls. TM level measurement was done through electrochemiluminescent immunoassay, followed by histological diagnosis on the biopsied specimen. Using package insert cut-offs, sensitivity and specificity of the 5 TMs were evaluated individually and in combination. Using receiver operating characteristic (ROC) curves of individual TMs, the ability of CEA, CYFRA 21-1, and ProGRP taken together was evaluated for its ability to differentiate LC from no-LC. RESULTS: Out of 178 subjects, 160 had LC (147 NSCLC; 13 SCLC). NSCLC patients had higher median values of CYFRA 21-1 and SCC; SCLC patients had higher median values of CEA, NSE, and ProGRP. Adenocarcinoma-NSCLC patients had higher median values of CEA, CYFRA 21-1, NSE, and ProGRP; squamous-NSCLC patients had higher median value of SCC. For differentiating LC from no-LC, the combination of all 5 TMs (sensitivity:97.5%, specificity:33.3%) and combination of CEA, CYFRA 21-1 and ProGRP (sensitivity:91.3%, specificity:88.9%) were found suitable. CONCLUSION: Combination of all 5 TMs, and combination of CEA, CYFRA 21-1, and ProGRP represents an easy and non-invasive method for aid in LC diagnosis that does not require technical expertise. TM evaluation can also supplement histological diagnosis of LC. 
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Dynamic nomograms combining N classification with ratio-based nodal classifications to predict long-term survival for patients with lung adenocarcinoma after surgery: a SEER population-based study.

BACKGROUND: The prognostic roles of three lymph node classifications, number of positive lymph nodes (NPLN), log odds of positive lymph nodes (LODDS), and lymph node ratio (LNR) in lung adenocarcinoma are unclear. We aim to find the classification with the strongest predictive power and combine it with the American Joint Committee on Cancer (AJCC) 8th TNM stage to establish an optimal prognostic nomogram. METHODS: 25,005 patients with T1-4N0-2M0 lung adenocarcinoma after surgery between 2004 to 2016 from the Surveillance, Epidemiology, and End Results database were included. The study cohort was divided into training cohort (13,551 patients) and external validation cohort (11,454 patients) according to different geographic region. Univariate and multivariate Cox regression analyses were performed on the training cohort to evaluate the predictive performance of NPLN (Model 1), LODDS (Model 2), LNR (Model 3) or LODDS+LNR (Model 4) respectively for cancer-specific survival and overall survival. Likelihood-ratio χ2 test, Akaike Information Criterion, Harrell concordance index, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were used to evaluate the predictive performance of the models. Nomograms were established according to the optimal models. They're put into internal validation using bootstrapping technique and external validation using calibration curves. Nomograms were compared with AJCC 8th TNM stage using decision curve analysis. RESULTS: NPLN, LODDS and LNR were independent prognostic factors for cancer-specific survival and overall survival. LODDS+LNR (Model 4) demonstrated the highest Likelihood-ratio χ2 test, highest Harrell concordance index, and lowest Akaike Information Criterion, and IDI and NRI values suggested Model 4 had better prediction accuracy than other models. Internal and external validations showed that the nomograms combining TNM stage with LODDS+LNR were convincingly precise. Decision curve analysis suggested the nomograms performed better than AJCC 8th TNM stage in clinical practicability. CONCLUSIONS: We constructed online nomograms for cancer-specific survival and overall survival of lung adenocarcinoma patients after surgery, which may facilitate doctors to provide highly individualized therapy.

Association between Sleep Traits and Lung Cancer: A Mendelian Randomization Study.

Multidimensional sleep trait, which is related to circadian rhythms closely, affects some cancers predominantly, while the relationship between sleep and lung cancer is rarely illustrated. We aimed to investigate whether sleep is causally associated with risk of lung cancer, through a two-sample Mendelian randomization study. The main analysis used publicly available GWAS summary data from two large consortia (UK Biobank and International Lung Cancer Consortium). Two-sample Mendelian randomization (MR) analysis was used to examine whether chronotype, getting up in the morning, sleep duration, nap during the day, or sleeplessness was causally associated with the risk of lung cancer. Additionally, multivariate MR analysis was also conducted to estimate the direct effects between sleep traits and lung cancer risks independent of smoking status including pack years of smoking or current tobacco smoking. There was no evidence of causal association between chronotype, getting up in the morning, or nap during the day and lung cancer. Sleeplessness was associated with higher risk of lung adenocarcinoma (odds ratio 5.75, 95% confidence intervals 2.12-15.65), while sleep duration played a protective role in lung cancer (0.46, 0.26-0.83). In multivariate MR analysis, sleeplessness and sleep duration remained to have similar results. In conclusion, we found robust evidence for effect of sleeplessness on lung adenocarcinoma risk and inconsistent evidence for a protective effect of sleep duration on lung cancer risk.