Never-smoker Patients Research Articles

A Case of Paraneoplastic Encephalitis Arising from Concurrent Thymoma and Stage I Adenocarcinoma of the Lung

Paraneoplastic Encephalitis (PE) is a rare syndrome that arises as a tumor-induced autoimmune response which can cause focal or diffuse nervous system dysfunction. Patients commonly present with a variety of neurologic symptoms, depending on the inflammatory distribution, and possibly with other symptoms stemming from the primary cancer. We herein present a never-smoker patient who presented with dysarthria, dysphagia and cognitive decline, and required numerous diagnostic examinations, sometimes invasive ones, for correct staging and diagnosing of the primary malignancy. Of note, despite the lack of clear evidence suggesting metastatic disease based on neuroimaging, a brain biopsy was nonetheless performed for diagnostic purposes. The patient was diagnosed with paraneoplastic encephalitis stemming from two independent primary cancers: an early stage lung adenocarcinoma and a concomitant type B3 thymoma. In addition to displaying a unique case of a paraneoplastic disorder associated with two simultaneous cancers, this report highlights the diagnostic challenge of paraneoplastic encephalitis and discusses important imaging findings with the goal of preventing invasive and evitable brain biopsies in similar future cases.

Type 2 diabetes mellitus does not increase the risk of lung cancer among never-smokers: a nationwide cohort study.

Previous studies have reported higher incidences of lung cancer among smokers diagnosed with diabetes than those without. Accordingly, this study investigated whether type 2 diabetes mellitus (T2DM) diagnosis alone can be associated with increased lung cancer incidences among never-smokers in the Korean population. Newly diagnosed never-smoking T2DM patients were identified from the nationwide longitudinal cohort of health examination data of South Korea (2002-2013). Cox proportional hazards regression model was employed to estimate the hazard ratios (HRs) and 95% confidence interval (CI) of lung cancer in the T2DM patient and abnormal fasting blood sugar (FBS) groups. T2DM (HR =0.91, 95% CI: 0.71 to 1.17) and abnormal FBS level are no significant association with lung cancer incidence based on the given HR. T2DM does not increase the risk of lung cancer among never-smokers. A large cohort study affirms minimal impact of T2DM on lung cancer development in the never-smoking Korean population.

P151 NEVER SMOKER WITH ESOPHAGEAL SQUAMOUS-CELL CARCINOMA: DIFFERENT DEMOGRAPHICS BUT COMPARABLE SUVIVAL

Abstract Aim To assess clinical characteristics, tumor behavior and long-term of esophageal squamous-cell carcinoma in never-smoker (NS) and smoker (or former smoker) (S) patients. Background & Methods Despite a progressive decrease in the incidence of esophageal squamous-cell carcinoma (ESCC) in Europe since decades, related to the decrease in smoking, new cases of ESCC are observed in patients who have never smoked. Similar cases are described for head and neck cancers and non-small cell lung carcinomas, for which increased radiosensitivity and favorable prognosis is described. We conducted a retrospective analysis on single-center prospectively maintained database, including all patients undergoing esophagectomy for ESCC between 2010 and 2017. The primary endpoint was overall survival(OS). Secondary endpoints included disease-free survival(DFS), pathological response to preoperative treatment according to Mandard's classification (Tumor Regression Grade; TRG) and clinical characteristics of patients. Results Three hundred and two patients underwent esophagectomy for ESCC during study period, 57 in NS group and 245 in S group. Esophageal cancers in NS patients were more frequently observed in women (68.4% vs 20%;p<0.001) and older (65.42 vs 60.69; p<0.001) than patients in S group. Tumor location (ie. cervical, upper third, middle third, lower third/EGJ) was similar between the 2 groups. Neoadjuvant radiochemotherapy was more frequently performed in S group (64.2% vs 49.1%;p=0.035) and malnutrition was less frequent in NS group (6.3% vs 20.9%;p=0.05). Tumoral characteristics (usT and usN) were comparable between the 2 groups. Pathological response to preoperative radichemotherapy was similar between NS and S group: (TRG1-2: 53.8% vs 53.7%). Postoperative complications were more frequent in S group (77.4% vs 63.2%;p=0.024), with more postoperative deaths (5.8% vs 0; p=0.080). NS patients had better OS than S patients, without reaching significance (mean survival: 46.1±4.7 months vs 35.9±2.0 months;p=0.080), and better DFS (40.0±5.3 months vs 30.0±2.1;p=0.077) Conclusion Esophageal squamous cell carcinoma in never-smoker is characterized by low male-female sex-ratio, reduced post-operative morbidity and mortality. However, pathological response to preoperative radiochemotherapy and long-term outcomes seem to remain unaffected by tobacco use.

P2.03-03 Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions

Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (∼10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers). Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line. Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown. In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.

P2.10-01 Analysis of Human Papilloma Viruses (HPV) and Human Polyoma Viruses (HPyV) in Lung Cancer from Swedish Never-Smokers

A possible role for oncogenic infections in the etiology of lung cancer has been investigated in a large number of studies, with contradictory results. High-risk mucosal human papillomaviruses (HPV), recognized as being associated with cervical cancer and oropharyngeal cancer, has been suggested as a causative factor also in lung cancer [1,2], whereas other studies found no, or at most very limited, involvement of HPV in lung cancer [3,4]. To investigate human papillomaviruses (HPV) and human polyomaviruses (HPyV) as possible causative factors behind lung cancer in never-smokers, we analyzed the presence of these viruses in a subset of tumors within a larger Swedish cohort of never-smoking lung cancer patients [Swedish Molecular Initiative against Lung cancer, SMIL; Salomonsson et al. Abstract WCLC 2019]. Eighty-seven surgically resected lung cancer samples from never-smokers, diagnosed 2005-2014 in Stockholm, Sweden, were analyzed by Luminex assays for the presence of 27 HPV types (including all HPV types currently regarded as high-risk types) and for 10 HPyV species (BKPyV, JCPyV, KIPyV, WUPyV, TSPyV, MWPyV, HPyV6, 7, 9, and 10). All samples were positive for the β-globin gene, confirming the presence, amplification and detection of cellular DNA. All samples were negative for the HPV types included in the assay. The only viral DNA detected in the tumors were low amounts of Merkel cell polyomavirus (MCPyV) DNA, of unknown significance, in 15 samples. Our study shows no evidence for neither HPV nor HPyV in the etiology of lung cancer in Swedish never-smokers.

Association of Untargeted Urinary Metabolomics and Lung Cancer Risk Among Never-Smoking Women in China

Chinese women have the highest rate of lung cancer among female never-smokers in the world, and the etiology is poorly understood. To assess the association between metabolomics and lung cancer risk among never-smoking women. This nested case-control study included 275 never-smoking female patients with lung cancer and 289 never-smoking cancer-free control participants from the prospective Shanghai Women's Health Study recruited from December 28, 1996, to May 23, 2000. Validated food frequency questionnaires were used for the collection of dietary information. Metabolomic analysis was conducted from November 13, 2015, to January 6, 2016. Data analysis was conducted from January 6, 2016, to November 29, 2018. Untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance metabolomic profiles were characterized using prediagnosis urine samples. A total of 39 416 metabolites were measured. Incident lung cancer. Among the 564 women, those who developed lung cancer (275 participants; median [interquartile range] age, 61.0 [52-65] years) and those who did not develop lung cancer (289 participants; median [interquartile range] age, 62.0 [53-66] years) at follow-up (median [interquartile range] follow-up, 10.9 [9.0-11.7] years) were similar in terms of their secondhand smoke exposure, history of respiratory diseases, and body mass index. A peak metabolite, identified as 5-methyl-2-furoic acid, was significantly associated with lower lung cancer risk (odds ratio, 0.57 [95% CI, 0.46-0.72]; P < .001; false discovery rate = 0.039). Furthermore, this peak was weakly correlated with self-reported dietary soy intake (ρ = 0.21; P < .001). Increasing tertiles of this metabolite were associated with lower lung cancer risk (in comparison with first tertile, odds ratio for second tertile, 0.52 [95% CI, 0.34-0.80]; and odds ratio for third tertile, 0.46 [95% CI, 0.30-0.70]), and the association was consistent across different histological subtypes and follow-up times. Additionally, metabolic pathway analysis found several systemic biological alterations that were associated with lung cancer risk, including 1-carbon metabolism, nucleotide metabolism, oxidative stress, and inflammation. This prospective study of the untargeted urinary metabolome and lung cancer among never-smoking women in China provides support for the hypothesis that soy-based metabolites are associated with lower lung cancer risk in never-smoking women and suggests that biological processes linked to air pollution may be associated with higher lung cancer risk in this population.

Abstract 632: Associations of coffee and tea consumption with lung cancer risk: A pooled analysis of 17 cohort studies involving over 1.2 million participants

Abstract Background Epidemiological studies investigating the associations of coffee and tea intake with lung cancer risk have yielded inconsistent results. These previous studies included mostly lung cancer patients diagnosed among smokers. Because coffee and tea consumption are closely related to smoking behavior, these previous studies could suffer from biases due to residual confounding of smoking. To better characterize the relationship, a large study with a large number of lung cancer cases diagnosed among never smokers and detailed information on tea and coffee consumption, is needed. Using data from a large-scale pooled analysis that consists of over 1.2 million participants in the U.S. and Asia, we carried out a comprehensive evaluation on the association of coffee and tea intake with lung cancer risk. Methods Individual-level data from seven prospective cohort studies conducted in the U.S., and ten studies conducted in Asia, were included. Demographic, lifestyle, coffee and tea intake data were collected at the baseline survey for each study. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The first 2 years of follow-up time was excluded to minimize potential influence of reverse causality on study results. Subgroup analyses by smoking status, sex, race, histologic subtype and coffee type (caffeinated or decaffeinated) were also conducted to assess potential effect modification, as well as heterogeneity of the association. Results After a median follow-up of 8.6 years, 20,519 incident lung cancer cases were identified. Both coffee and tea consumption were associated with an increased risk of lung cancer. Comparing non-coffee and non-tea consumption, HRs for lung cancer associated with exclusive coffee drinkers (≥2 cups/day) among current, former and never smokers were 1.30 (95% CI, 1.15-1.47), 1.49 (1.27-1.74) and 1.41 (95% CI, 1.21-1.63), respectively. Similar positive associations were observed for caffeinated and decaffeinated coffee. The HRs associated with exclusive tea drinkers (&amp;gt;2 cups/day) were 1.16 (95% CI, 1.02-1.32), 1.10 (0.92, 1.32) and 1.37 (95% CI, 1.17-1.60) for current, former and never smokers, respectively. These associations did not differ significantly by sex, race or histologic subtypes. Conclusion A high consumption of coffee or tea was both associated with an increased risk of lung cancer regardless of race or smoking status. Our study included a large number of never-smoker lung cancer patients, which minimized potential confounding effects due to smoking. The positive association observed for both caffeinated and decaffeinated coffee suggests that compounds other than caffeine may play a role in the etiology of lung cancer. Citation Format: Jingjing Zhu, Wei Zheng, Rashimi Sinha, Stephanie A. Smith-Warner, Yong-Bing Xiang, Yikyung Park, Shoichiro Tsugane, Emily White, Woon-Puay Koh, Sue K. Park, Norie Sawada, Seiki Kanemura, Yumi Sugawara, Ichiro Tsuji, Kim Robien, Yasutake Tomata, Keun-Young Yoo, Jeongseon Kim, Jian-Min Yuan, Yu-Tang Gao, Yumie Takata, Eiko Saito, William Blot, Xiao-Ou Shu. Associations of coffee and tea consumption with lung cancer risk: A pooled analysis of 17 cohort studies involving over 1.2 million participants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 632.

Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma

ObjectivesRadon, a natural radiation, is the leading environmental cause of lung cancer in never-smokers. However, the radon exposure impact on the mutational landscape and tumor mutation burden (TMB) of lung cancer in never-smokers has not been explored. The aim of this study was to investigate the mutational landscape of lung adenocarcinoma in never-smokers who were exposed to various degrees of residential radon. Materials and methodsTo investigate the effect of indoor radon exposure, we estimated the cumulative exposure to indoor radon in each house of patients with lung cancer with a never-smoking history. Patients with at least 2 year-duration of residence before the diagnosis of lung adenocarcinoma were included. Patients were subgrouped based on the median radon exposure level (48 Bq/m3): radon-high vs. radon-low and targeted sequencing of tumor and matched blood were performed in all patients. ResultsAmong 41 patients with lung adenocarcinoma, the TMB was significantly higher in the radon-high group than it was in the radon-low group (mean 4.94 vs. 2.6 mutations/Mb, P = 0.01). The recurrence rates between radon-high and radon-low group did not differ significantly. Mutational signatures of radon-high tumors showed features associated with inactivity of the base excision repair and DNA replication machineries. The analysis of tumor evolutionary trajectories also suggested a series of mutagenesis induced by radon exposure. In addition, radon-high tumors revealed a significant protein-protein interaction of genes involved in DNA damage and repair (P < 0.001). ConclusionsIndoor radon exposure increased the TMB in never-smoker patients with lung adenocarcinoma and their mutational signature was associated with defective DNA mismatch repair.

Lung cancer survival among never smokers

Lung cancer incidence among never smokers has increased in recent decades with 10–30% of all lung cancers occurring in never smokers, where exposure to residential radon is the leading cause of this disease. Lung cancer survival is low, ranging from 12% to 16% at 5 years of diagnosis. There is scant evidence to date on survival from this disease in never smokers. We aim to evaluate lung cancer survival in never smokers and ascertain whether there might be differences regarding smokers, through a systematic review applying predefined inclusion and exclusion criteria. 17 Studies were included. Never-smoker lung cancer patients seem to experience longer survival times than do smokers or ex-smokers. Lung cancer in never smokers displays distinctive clinical characteristics, is more frequent among women, is diagnosed at more advanced stages, and the predominant histologic type is adenocarcinoma. Further studies are necessary to ascertain lung cancer survival among never smokers.

Clinical and Microbiological Effects of the Use of Erbium: Yttrium-Aluminum-Garnet Laser on Chronic Periodontitis in Addition to Nonsurgical Periodontal Treatment: A Randomized Clinical Trial-6 Months Follow-Up.

Background and objective: The purpose of this randomized controlled clinical trial is to evaluate the efficiency of erbium-doped:yttrium-aluminum-garnet (Er:YAG) laser adjunct to nonsurgical periodontal debridement on clinical periodontal parameters and red complex periodontopathogens. Materials and methods: Thirty-eight systematically healthy, never-smoker patients with chronic periodontitis were randomly assigned to one of two groups in a parallel design: 1-scaling and root planing (SRP) and 2-SRP + Laser (SRP + L). SRP and SRP + L administration were completed within 24 h. Clinical attachment level (CAL), probing depth (PD), plaque index (PI), and bleeding on probing (BOP) were recorded at baseline and 3 and 6 months after treatment. Subgingival plaque samples were also measured 1 month after treatment. Microbiological evaluation was performed using real-time polymerase chain reaction. Results: All clinical parameters significantly improved 3 and 6 months after treatment in both groups. In the deep and moderately deep pockets, PD reduction and CAL gain between baseline and 6 months were significantly different between the groups (p < 0.05). There were no statistically significant differences regarding BOP and PI between the groups. There were no statistically significant differences in Pg, Tf, and Td levels between the SRP and SRP + L groups at any time point (p > 0.05). Conclusions: Within the limits of this randomized clinical trial, the adjunctive use of Er:YAG laser with SRP may be beneficial in moderately deep and deep pockets to improve CAL and PD. However, Er:YAG laser failed to demonstrate additional microbiological benefits in nonsurgical periodontal treatment. Clinicaltrials.gov #NCT03387371.

The genomic imprint of cancer therapies helps timing the formation of metastases.

A retrospective determination of the time of metastasis formation is essential for a better understanding of the evolution of oligometastatic cancer. This study was based on the hypothesis that genomic alterations induced by cancer therapies could be used to determine the temporal order of the treatment and the formation of metastases. We analysed the whole genome sequence of a primary tumour sample and three metastatic sites derived from autopsy samples from a young never-smoker lung adenocarcinoma patient with an activating EGFR mutation. Mutation detection methods were refined to accurately detect and distinguish clonal and subclonal mutations. In comparison to a panel of samples from untreated smoker or never-smoker patients, we showed that the mutagenic effect of cisplatin treatment could be specifically detected from the base substitution mutations. Metastases that arose before or after chemotherapeutic treatment could be distinguished based on the allele frequency of cisplatin-induced dinucleotide mutations. In addition, genomic rearrangements and late amplification of the EGFR gene likely induced by afatinib treatment following the acquisition of a T790M gefitinib resistance mutation provided further evidence to tie the time of metastasis formation to treatment history. The established analysis pipeline for the detection of treatment-derived mutations allows the drawing of tumour evolutionary paths based on genomic data, showing that metastases may be seeded well before they become detectable by clinical imaging.

Non-Smoking-Associated Lung Cancer: A distinct Entity in Terms of Tumor Biology, Patient Characteristics and Impact of Hereditary Cancer Predisposition.

Non-small cell lung cancer (NSCLC) in non-, and especially in never-smoking patients is considered a biologically unique type of lung cancer, since risk factors and tumorigenic conditions, other than tobacco smoke, come into play. In this review article, we comprehensively searched and summarized the current literature with the aim to outline what exactly triggers lung cancer in non-smokers. Changes in the tumor microenvironment, distinct driver genes and genetic pathway alterations that are specific for non-smoking patients, as well as lifestyle-related risk factors apart from tobacco smoke are critically discussed. The data we have reviewed highlights once again the importance of personalized cancer therapy, i.e., careful molecular and genetic assessment of the tumor to provide tailored treatment options with optimum chances of good response—especially for the subgroups of never-smokers.

Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status.

Smoking has historically been recognized as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). This study aimed to assess the mutational differences between heavy smokers (>20 pack years) and never smokers among the HNSCC patients within The Cancer Genome Atlas (TCGA). Single nucleotide variation and copy number aberration differences between heavy smokers and never smokers were compared within human papillomavirus-positive (HPV-positive) (n = 67) and HPV-negative (n = 431) TCGA cohorts with HNSCC, and the impact of these mutations on survival were assessed. No genes were differentially mutated between smoking and never-smoking patients with HPV-positive tumors. By contrast, in HPV-negative tumors, NSD1 and COL1A11 were found to be more frequently mutated in heavy smokers, while CASP8 was more frequently altered in never smokers. HPV-negative patients with NSD1 mutations experienced significantly improved overall survival compared with NSD1 WT patients. This improved prognosis was validated in an independent cohort of 77 oral cavity cancer patients and a meta-analysis that included 2 additional data sets (688 total patients, hazard ratio for death 0.44, 95% CI, 0.30-0.65). NSD1 mutations are more common in HPV-negative heavy smokers, define a cohort with favorable prognosis, and may represent a clinically useful biomarker to guide treatment deintensification for HPV-negative patients.

A Strong Graded Relationship between Level of Obesity and COPD: Findings from a National Population-Based Study of Lifelong Nonsmokers.

Factors associated with chronic obstructive pulmonary disease (COPD) among never-smokers have received little research attention. One potential risk factor for COPD is obesity, which is of particular importance in light of the global obesity epidemic. The objective of this study was to investigate the association between COPD and levels of obesity in a nationally representative sample of non-Hispanic white never-smokers. Data were drawn from the 2012 Center for Disease Control's Behavioral Risk Factor Surveillance System (BRFSS). Pearson's chi-square tests and logistic regression analyses were conducted in a large nationally representative sample of non-Hispanic white respondents aged 50 and over (76,004 women; 37,618 men) who reported that they had never smoked. A dose-response relationship was observed for both men and women: the prevalence of COPD increased from 2.5% in men and 3.5% in women who were of a healthy weight (BMI < 25) to 7.6% in men and 13.4% in women who had a BMI of 40 or higher. Even after adjusting for 7 potential confounds (e.g., age, education, and income), the odds of COPD were 3.21 higher for men (95% CI = 2.46, 4.20) and 4.00 higher for women with class III obesity (95% CI = 3.52, 4.55) in comparison with those of healthy weight. Regular screening for COPD is warranted in never-smoking obese patients who are aged 50 and over. Future research is needed to investigate plausible mechanisms for this association, including (1) the role of chronic inflammation associated with obesity and (2) the impact of central obesity on respiratory system mechanics.

Nivolumab in never-smokers with advanced squamous non-small cell lung cancer: Results from the Italian cohort of an expanded access program.

Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.

Association between the Ratio of FEV₁ to FVC and the Exposure Level to Air Pollution in Neversmoking Adult Refractory Asthmatics Using Data Clustered by Patient in the Soonchunhyang Asthma Cohort Database.

Using real-world cases, asthma-related clinical data were clustered by patient; 5% of all asthmatics were found to have refractory asthma (RA) with a relatively low lung function (forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) less than 80%). Using a multilevel study design for clustered spirometry data observed between 2005 and 2014, we evaluated the association between changes in the ratio of FEV1 to FVC and variations in acute exposure to air pollution. We analyzed 2310 episodes of RA from 214 neversmoking patients. In spring, a 1 µg/m³ increase in concentration of particles ≤10 μm (PM10) on Lag 1 significantly reduced the ratio by 0.4% (95% confidence interval (CI): 0.1–0.7%) after adjusting for sex, age, body mass index (BMI), and total Immunoglobulin E (IgE) level. Unit (ppb) increase in SO2 concentration on Lag 3 and 4 in fall and on Lag 6 in winter significantly reduced the ratio by 2 to 3% (p < 0.05). We found that acute exposure to PM10 in spring or SO2 in fall or winter were positively associated with lung function drop indicating necessity of control strategies of target air pollutant source by season to protect susceptible population.

MA27.01 Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids

Patient-derived xenograft (PDX) models allow for cancer tissue expansion, providing an effective method to evaluate tumor biology and mechanisms of response or resistance. Our study aims to establish models in patients enriched for lung adenocarcinoma (LUAD) with EGFR mutations or ALK fusion genes which respond initially to oral targeted therapy, but typically develop resistance and disease relapse within 2 years. The PDXs will be evaluated for their potential to model therapy outcomes, to determine resistance mechanisms and to evaluate novel therapy strategies to overcome resistance. From August 2015 to January 2018, we collected 109 samples from patients with EGFR- or ALK-driven LUAD and from never-smoker LUAD patients with unknown mutation status. Five samples with low tissue viability (i.e. necrotic) or very low tumor content (<100 malignant cells) were excluded. Adequate samples were implanted into the subcutaneous tissue of NOD-SCID mice. At this time, 16 samples have reached the study endpoint (tumor growth ≥1.5cm3) and 60 showed no tumor-growth following implantation (median follow-up: 8m). Results are currently pending for 18 models. Samples were collected from surgical resections (31, 36%), CT-guided biopsies (12, 14%), EBUS (19, 22%) and pleural fluid effusions (24, 28%). Most patients were female (51/86, 59%), never smokers (62/85, 73%), and had stage III or IV cancer (55/79, 70%). Mutations in EGFR and ALK were found in 55/81 (68%) and 12/84 (14%) primary cancers, respectively. Early-passage xenograft engraftment (XG) was observed in only 16 (19%) PDXs, including 9/55 (16%) EGFR- and 1/12 (8%) ALK-mutant cancers. The phenotype and molecular changes (EGFR and ALK) were consistent within the PDX model and its corresponding patient sample. Samples collected from surgical-resection specimens showed a trend towards higher engraftment rates (p=0.084). Conversely, the presence of EGFR or ALK mutations showed a trend towards non-engraftment (noXG, p=0.075). Patient smoking status and tumor stage did not influence engraftment rate. To identify reasons for no tumor-growth, we conducted histological analysis in the subcutaneous fat-pads (nodes in the implant sites) of 28 noXG mice. Interestingly, we identified small non-palpable foci of carcinoma in 8 animals (4 EGFR+ and 2 ALK+). Environmental or molecular factors may impair engraftment rates of EGFR+ and ALK+ LUAD samples in PDX models. Nevertheless, these models recapitulate the primary disease and could be useful for population-based drug-screening studies.

Increased B-cell activating factor, interleukin-6, and interleukin-8 in induced sputum from primary Sjögren’s syndrome patients

Objective: Small airway disease and chronic obstructive pulmonary disease are common in primary Sjögren’s syndrome (pSS). However, the underlying inflammatory mechanisms behind pSS-associated airway disease have not been studied in detail. We therefore wanted to study cytokine and leucocyte levels in induced sputum in never-smoking patients with pSS.Method: Induced sputum cytokines and leucocytes were assessed in 20 never-smoking patients with pSS and 19 age- and gender-matched population-based controls. In addition, pulmonary function, disease activity, respiratory symptoms, and inflammatory and serological features of pSS were assessed.Results: B-cell activating factor (BAFF), interleukin-6 (IL-6) and IL-8 were significantly increased in induced sputum in pSS patients compared to population-based controls, while IL-1β, interferon-α, and tumour necrosis factor-α levels and leucocytes were not. The proportion of lymphocytes and BAFF levels in induced sputum correlated significantly in pSS patients. However, cytokine levels in induced sputum were not associated with pulmonary function tests, disease activity, respiratory symptoms, or serological features of pSS.Conclusion: The increase in BAFF, IL-6, and IL-8 in induced sputum suggests a specific ongoing inflammatory disease process in the airways in pSS patients. Its association with pSS-associated airway disease needs to be further examined in future larger studies.

Association of the daily ratio of FEV1 to FVC with the real-time exposure level to indoor PM2.5 and CO2 after controlling for other risk factors in adult non-smoking refractory asthmatics in urban areas of South Korea: Results from Environmental Health Study with Connectivity and Remote Sensing Technologies

BackgroundAs acute exacerbations of refractory asthma (RA) can be fatal, it is important to recognize the risk factors with consideration that the immune system may undergo continuing change by age among adults and adult asthmatics tend to stay indoor. We evaluated the associations between variation in daily exposure levels to indoor air quality, and daily changes in lung function (FEV1/FVC ratio) of RA sufferers, after controlling for total immunoglobulin E (IgE) levels, smoking status, and seasonality.MethodsWe analyzed sensing technology based spirometry data from refractory asthmatics whose mean FEV1/FVC ratio is lower than &amp;lt; 80%, lived in Seoul or Kyunggi Province, South Korea , and attended hospital between 2016 and 2017 with multiple exacerbations. We constructed mixed model using the data clustered within each patient.ResultsWe analysed 1100 episodes data relating to 25 never-smoking patients. After adjusting for sex, age, body mass index (BMI), and total IgE level, a unit increase in concentration of particles &amp;#8804;2.5 &amp;#956;m (PM2.5), or CO2 concentration on Lag 0, reduced the FEV1/FVC ratio by 0.1% (95% confidence interval [CI]: 0.0&amp;#8211;0.4%). Patients living in house with high damp scores (3 and 4) showed lower ratio than the others (1 and 2).ConclusionsThis study demonstrated that reduction in pulmonary function in adult asthma patients were potentially associated with acute exposure to increased indoor PM2.5, CO2 and damp levels with irrespective to total IgE level.

Integrative Bioinformatics Analysis Reveals Potential Long Non-Coding RNA Biomarkers and Analysis of Function in Non-Smoking Females with Lung Cancer

BackgroundLung cancer is the most lethal cancer worldwide. The aim of this study was to identify the tumor-related lncRNAs and explore their functions in female non-smokers with lung cancer.Material/MethodsThe gene expression microarray datasets GSE19804, GSE31210, and GSE31548 were downloaded from the Gene Expression Omnibus database. The differentially-expressed lncRNAs between non-smoking female lung cancer samples and non-tumor lung tissues were identified using GEO2R.ResultsIn total, 25, 40, and 15 differentially-expressed lncRNAs were obtained from GSE19804, GSE31210, and GSE31548 datasets (|logFC| >1, adj. P<0.05), respectively. Eight lncRNAs were screened out in all 3 datasets. Of these, 5 lncRNAs were up-regulated and 3 lncRNAs were down-regulated in lung cancer tissues compared to non-tumor lung tissues. Then, the target miRNAs of aberrantly expressed lncRNAs and target mRNAs corresponding to miRNAs were predicted. Subsequently, the ceRNA network with 8 key lncRNAs, 20 miRNAs, and 38 mRNAs were constructed. Functional and pathway enrichment analysis showed these target genes were mainly enriched in biological processes associated with protein binding, nucleus, metal ion binding, regulation of transcription from RNA polymerase II promoter, nucleic acid binding, cell differentiation, microRNAs in cancer, and the hippo signaling pathway. Survival analysis of these lncRNAs revealed that low LINC00968 (P=0.0067) and TBX5-AS1 (P=0.0028) expression were associated with unfavorable prognosis in never-smoking female lung cancer patients.ConclusionsThe present study promotes understanding of the molecular mechanism of the pathogenesis of non-smoking female lung cancer and provides potential biomarkers for diagnosis and treatment.