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Metabolic alterations that are critical for cancer cell growth and metastasis are one of the key hallmarks of cancer. Here, we show that thymidine kinase 1 (TK1) is significantly overexpressed in tumor samples from lung adenocarcinoma (LUAD) patients relative to normal controls, and this TK1 overexpression is associated with significantly reduced overall survival and cancer recurrence. Genetic knockdown of TK1 with short hairpin RNAs (shRNAs) inhibits both the growth and metastatic attributes of LUAD cells in culture and in mice. We further show that transcriptional overexpression of TK1 in LUAD cells is driven, in part, by MAP kinase pathway in a transcription factor MAZ dependent manner. Using targeted and gene expression profiling-based approaches, we then show that loss of TK1 in LUAD cells results in reduced Rho GTPase activity and reduced expression of growth and differentiation factor 15 (GDF15). Furthermore, ectopic expression of GDF15 can partially rescue TK1 knockdown-induced LUAD growth and metastasis inhibition, confirming its important role as a downstream mediator of TK1 function in LUAD. Collectively, our findings demonstrate that TK1 facilitates LUAD tumor and metastatic growth and represents a target for LUAD therapy. [ABSTRACT FROM AUTHOR]

Drug-induced interstitial lung disease (DIILD) is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. In this study, to identify genetic variants with greater risk of DIILD, we carried out whole genome sequencing (WGS) of germline DNA samples from 26 patients who developed DIILD, and conducted a case-control association study between these 26 cases and general Japanese population controls registered in the integrative Japanese Genome Variation Database (iJGVD) as a screening study. The associations of 42 single nucleotide variants (SNVs) showing P < 0.0001 were further validated using an independent cohort of 18 DIILD cases as a replication study. A further combined analysis of the screening and replication studies showed a possible association of two SNVs, rs35198919 in intron 1 of the chromosome 22 open reading frame 34 (C22orf34) and rs12625311 in intron 1 of the teashirt zinc finger homeobox 2 (TSHZ2), with DIILD (Pcombined = 1.87 × 10−5 and 5.16 × 10−5, respectively). Furthermore, in a subgroup analysis of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI)-induced interstitial lung disease (ILD), we observed seven candidate SNVs that were possibly associated with ILD (P < 0.00001). This is the first study to identify genetic markers for the risk of DIILD using WGS. Collectively, our novel findings indicate that these SNVs may be applicable for predicting the risk of DIILD in patients receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Little is known about prognostic factors for lung squamous cell carcinoma (SCC). We aimed to explore radiologic and clinical factors affecting prognosis and to compare the prognosis of both central and peripheral lung SCCs. Materials and methods: Radiologic, clinical, and pathologic profiles of surgically confirmed SCCs from 382 patients were retrospectively reviewed. Tumor location, enhancement, necrosis, the presence of obstructive pneumonitis/atelectasis and underlying lung disease were evaluated on chest CT examination. Age, pulmonary function, tumor marker, and cancer stage were also assessed. Univariate and multivariate Cox regression analyses were performed to identify any correlation to overall survival (OS) and disease-free survival (DFS). Hazard rate estimation and competing risk analysis were done to evaluate recurrence pattern. Results: The median follow-up period was 56.2 months. Tumors were located centrally in 230 patients (60.2%) and peripherally in 152 patients (39.8%). Age (p = 0.002, hazard ratio [HR] 1.03, 95% confidence interval [CI] = [1.01, 1.06]) and interstitial lung abnormalities (ILAs) (p<0.001, HR 5.41, 95% CI = [3.08, 9.52]) were associated with poor OS on multivariate analysis. ILAs also had a strong association to DFS (p<0.001, HR 4.25, 95% CI = [3.08, 9.52]). Central cancers had two peaks of local recurrence development at 15 and 60 months after surgery, and peripheral tumors showed rising curves for metastasis development at 60 months. Conclusions: CT-determined ILAs are a strong biomarker predicting poor outcome. Prognosis may not vary according to tumor location, but the two groups exhibited different recurrence patterns. [ABSTRACT FROM AUTHOR]

Background: It remains unknown which is the optimal first-line treatment regimen for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). We performed a network meta-analysis to address this important issue. Methods: PubMed, Embase, Cochrane Library, Web of Science and major international scientific meetings were searched for relevant randomized controlled trials (RCTs). Progression-free survival (PFS) data was the primary outcome of interest, and overall survival (OS) and serious adverse events (SAEs) were the secondary outcomes of interests, reported as hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (CIs). Results: 25 RCTs with a total of 5005 patients randomized to receive seven treatments were included in the meta-analysis. Third-generation tyrosine kinase inhibitor (TKI) (osimertinib) and first-generation TKIs (F-TKIs) in combination with chemotherapy (F-TKIs+CT) were more effective than F-TKIs alone in terms of PFS (HR = 0.46, 95% CI: 0.22–0.93; P = 0.031 and HR = 0.62, 95% CI: 0.39–0.98; P = 0.041) and OS (HR = 0.63, 95% CI: 0.43–0.91; P = 0.014 and HR = 0.73, 95% CI: 0.57–0.92; P = 0.008). Second-generation TKIs (S-TKIs) showed significant OS advantage over F-TKIs (HR = 0.83, 95% CI: 0.70–0.99; P = 0.04). Based on treatment ranking in terms of PFS and OS, osimertinib had the highest probability of being the most effective treatment (89% and 86%) and with the best tolerability. F-TKIs+CT was ranked the second-most effective regimen, but with relatively high risk of SAEs. Conclusions: Osimertinib seemed to be the most preferable first-line treatment in advanced EGFR-mutated NSCLC. However, limitations of the study including a single RCT investigating osimertinib and immature OS data need to be considered. [ABSTRACT FROM AUTHOR]

Background: Pulmonary embolism (PE) is correlated with increased mortality among patients with lung cancer (LC). The characteristics of patients with LC presenting with PE have not been fully established, and our meta-analysis aims to comprehensively investigate the clinical characteristics associated with PE in patients with LC to help physicians identify PE earlier in these patients. Methods: Multiple databases were searched, including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure and Wanfang. Odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were used as effect measures for dichotomous and continuous variables, respectively. Moreover, Egger’s test, Begg’s test and a sensitivity analysis were performed to assess the publication bias and reliability of the articles. Results: In total, 16 studies were included in our meta-analysis. The results indicated that history of chronic obstructive pulmonary disease (OR = 2.59, 95% CI: 1.09, 6.15; P = 0.03), adenocarcinoma (OR = 2.28, 95% CI: 1.88, 2.77; P < 0.01), advanced tumour stage (TNM III-IV vs. I-II, OR = 2.38, 95% CI: 1.99, 2.86; P < 0.01), history of central venous catheter (OR = 1.95, 95% CI: 1.36, 2.78; P < 0.01), history of chemotherapy (OR = 2.32, 95% CI: 1.80, 2.99, P < 0.01), high levels of D-dimer (WMD = 4.31, 95% CI: 2.53, 6.10; P < 0.01) and carcinoembryonic antigen (WMD = 10.30, 95% CI: 9.95, 10.64; P < 0.01) and a low level of partial pressure of oxygen (WMD = -25.97, 95% CI: -31.31, -20.62; P < 0.01) were clinical features of LC patients with PE compared to those without PE. Conclusions: These results reveal that LC patients with PE have specific clinical features, including but not limited to several cancer- and treatment-related factors, that may help their early identification. [ABSTRACT FROM AUTHOR]

Background: Large cell neuroendocrine carcinoma (LCNEC) is a rare and typically aggressive malignancy with poor prognosis. This study developed a nomogram model to predict the overall survival (OS) of patients with LCNEC. Methods: LCNEC patients were identified from the Surveillance, Epidemiology, and End Results database between 2004–2014. Univariate and multivariate Cox regression models were used to determine demographic and clinicopathological features associated with OS. A nomogram model was generated to predict OS and its performance was assessed by Harrell’s concordance index (C-index), calibration plots, and subgroup analysis by risk scores. Results: Of 3048 eligible patients with LCNEC, 2138 were randomly grouped into the training set and 910 into the validation set. Age at diagnosis, gender, tumor stage, N stage, tumor size, and surgery of primary site were independent prognostic factors of OS. C-index values of the nomogram were 0.75 (95% CI, 0.74–0.76) and 0.76 (95% CI, 0.74–0.77) in the training and validation sets, respectively. In both cohorts, the calibration plots showed good concordance between the predicted and observed OS at 3 and 5 years. Kaplan-Meier curves revealed significant differences in OS in patients stratified by nomogram-based risk score, and patients with a higher-than-median risk score had poorer OS. Conclusion: This is the first nomogram developed and validated in a large population-based cohort for predicting OS in patients with LCNEC, and it shows favorable discrimination and calibration abilities. Use of this proposed nomogram has the potential to improve prediction of survival risk, and lead to individualized clinical decisions for LCNEC. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the change of CT texture features of esophageal squamous cell carcinoma (ESC) during RT delivery and to correlate these changes with the RT responses and survival. Methods: A total of 61 ESC patients received radical RT were screened. Weekly CTs (4–6 sets for each patient) were acquired during RT. The tumors, normal esophageal mucosa tissue (NEC) of 5 cm and the spinal cord in the relevant area were delineated. CT texture features were extracted with a home-made tool. The changes of these features were analyzed by t-test. The correlations of the changes of features with RT responses and with patient survival were investigated by Pearson analysis. Results: The average changes were increased by 0.00072 ±0.00197 for coarseness, by 0.14 ±0.40 for entropy, and by 2.34 ±3.56 for strength. In addition, the average changes were reduced by 8.88 ±15.71cc for volume and by 0.07 ±0.11 for busyness. The changes of the coarseness, strength, STD and entropy in ESC were different for the good and poor response groups. The survival rate of the patients was significantly correlated with the change of coarseness and strength (P = 0.0027 and P = 0.0001). Conclusions: During RT, changes of CT texture features of ESC, e.g., coarseness, strength, STD, entropy and volume are correlated with radiation response and survival rate. With more clinical data and robust research, CT features, e.g., coarseness and strength, can be selected as outstanding imaging biomarkers for prediction of RT prognosis of ESC. [ABSTRACT FROM AUTHOR]

We apply the Google matrix algorithms for analysis of interactions and influence of 37 cancer types, 203 cancer drugs and 195 world countries using the network of 5 416 537 English Wikipedia articles with all their directed hyperlinks. The PageRank algorithm provides a ranking of cancers which has 60% and 70% overlaps with the top 10 deadliest cancers extracted from World Health Organization GLOBOCAN 2018 and Global Burden of Diseases Study 2017, respectively. The recently developed reduced Google matrix algorithm gives networks of interactions between cancers, drugs and countries taking into account all direct and indirect links between these selected 435 entities. These reduced networks allow to obtain sensitivity of countries to specific cancers and drugs. The strongest links between cancers and drugs are in good agreement with the approved medical prescriptions of specific drugs to specific cancers. We argue that this analysis of knowledge accumulated in Wikipedia provides useful complementary global information about interdependencies between cancers, drugs and world countries. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors targeted to anaplastic lymphoma kinase (ALK) have been demonstrated to be effective for lung cancer patients with an ALK fusion gene. Application of liquid biopsy, i.e., detection and quantitation of the fusion product in plasma cell-free DNA (cfDNA), could improve clinical practice. To detect ALK fusions, because fusion breakpoints occur somewhere in intron 19 of the ALK gene, sequencing of the entire intron is required to locate breakpoints. Results: We constructed a target sequencing system using an adapter and a set of primers that cover the entire ALK intron 19. This system can amplify fragments, including breakpoints, regardless of fusion partners. The data analysis pipeline firstly detected fusions by alignment to selected target sequences, and then quantitated the fusion alleles aligning to the identified breakpoint sequences. Performance was validated using 20 cfDNA samples from ALK-positive non-small cell lung cancer patients and samples from 10 healthy volunteers. Sensitivity and specificity were 50 and 100%, respectively. Conclusions: We demonstrated that PCR-based target sequencing using a tiling primer set and two-step mapping/alignment quantitatively detected ALK fusions in cfDNA from lung cancer patients. The system offers an alternative to existing approaches based on hybridization capture. [ABSTRACT FROM AUTHOR]

Objectives: To determine the factors associated with lung cancer diagnosis and mortality after detecting a solitary pulmonary nodule (SPN) in routine clinical practice, in men and in women for both chest radiograph and CT. Materials and methods: A 5-year follow-up of a retrospective cohort of of 25,422 (12,594 men, 12,827 women) patients aged ≥35 years referred for chest radiograph or CT in two hospitals in Spain (2010–2011). SPN were detected in 893 (546 men, 347 women) patients. We estimated the cumulative incidence of lung cancer at 5-years, the association of patient and nodule characteristics with SPN malignancy using Poisson logistic regression, stratifying by sex and type of imaging test. We calculated lung cancer specific mortality rate by sex and SPN detection and hazard rates by cox regression. Results: 133 (14.9%) out of 893 patients with an SPN and 505 (2.06%) of the 24,529 patients without SPN were diagnosed with lung cancer. Median diameter of SPN in women who developed cancer was larger than in men. Men who had a chest radiograph were more likely to develop a lung cancer if the nodule was in the upper-lobes, which was not the case for women. In patients with an SPN, smoking increased the risk of lung cancer among men (chest radiograph: RR = 11.3, 95%CI 1.5–83.3; CT: RR = 7.5, 95%CI 2.2, 26.0) but smoking was not significantly associated with lung cancer diagnosis or mortality among women with an SPN. The relative risk of lung cancer diagnosis in women with SPN versus those without was much higher compared to men (13.7; 95%CI 9.2, 20.4 versus 6.2; 95%CI 4.9,7.9). Conclusion: The factors associated with SPN malignancy and 5-year lung cancer mortality were different among men and women, especially regarding smoking history and SPN characteristics, where we observed a relatively high rate of lung cancer diagnosis among female non-smokers. [ABSTRACT FROM AUTHOR]

SWItch/Sucrose NonFermentable (SWI/SNF) is a set of multi-subunits chromatin remodeling complexes, playing important roles in a variety of biological processes. Loss-of-function mutations in the genes encoding SWI/SNF subunits have been reported in more than 20% of human cancers. Thus, it was widely considered as a tumor suppressor in the past decade. However, recent studies reported that some genes encoding subunits of SWI/SNF complexes were amplified and play oncogenic roles in human cancers. In present study, we summarized the genetic alteration spectrum of SWI/SNF complexes, and firstly systematically estimated both the copy number variations and point mutations of all 30 genes encoding the subunits in this complex. Additionally, the bioinformatics analyses were performed for two significantly amplified genes, ACTL6A and BRD9, to investigate their oncogenic roles in human cancers. Our findings may lay a foundation for the discovery of potential treatment targets in SWI/SNF complexes of cancers. [ABSTRACT FROM AUTHOR]

The importance of the role of fibroblasts in cancer microenvironment is well-recognized. However, the relationship between fibroblasts and asbestos-induced lung cancer remains underexplored. To investigate the effect of the asbestos-related microenvironment on lung cancer progression, lung cancer cells (NCI-H358, Calu-3, and A549) were cultured in media derived from IMR-90 lung fibroblasts exposed to 50 mg/L asbestos (chrysotile, amosite, and crocidolite) for 24 h. The kinetics and migration of lung cancer cells in the presence of asbestos-exposed lung fibroblast media were monitored using a real-time cell analysis system. Proliferation and migration of A549 cells increased in the presence of media derived from asbestos-exposed lung fibroblasts than in the presence of media derived from normal lung fibroblasts. We observed no increase in proliferation and migration in lung cancer cells cultured in asbestos-exposed lung cancer cell medium. In contrast, increased proliferation and migration in lung cancer cells exposed to media from asbestos-exposed lung fibroblasts was observed for all types of asbestos. Media derived from lung fibroblasts exposed to other stressors, such as hydrogen peroxide and UV radiation didn’t show as similar effect as asbestos exposure. An enzyme-linked immunosorbent assay (ELISA)-based cytokine array identified interleukin (IL)-6 and IL-8, which show pleiotropic regulatory effects on lung cancer cells, to be specifically produced in higher amounts by the three types of asbestos-exposed lung fibroblasts than normal lung fibroblasts. Thus, the present study demonstrated that interaction of lung fibroblasts with asbestos may support the growth and metastasis of lung cancer cells and that chrysotile exposure can lead to lung cancer similar to that caused by amphibole asbestos (amosite and crocidolite). [ABSTRACT FROM AUTHOR]

Adenosine deaminase RNA-specific B1 (ADARB1), an adenosine-to-inosine (A-to-I) RNA-editing enzyme, has been found to play an essential role in the development of cancer. However, the specific function of ADARB1 in lung cancer, especially in lung adenocarcinoma (LUAD), is still not fully understood and requires further study. In our study, integrative bioinformatics were used to analyze the detailed function of ADARB1 in LUAD. By conducting bioinformatics analyses of several public databases, such as Gene Expression Profiling Interactive Analysis (GEPIA), GE-mini, and Oncomine, we found significantly decreased ADARB1 expression in LUAD cells and tissues. Moreover, RT-PCR and Western blot showed lower ADARB1 expression in H358 and A549 LUAD cells compared to human bronchial epithelial Beas-2B cells. Wound Healing Assay indicated that knockdown ADARB1 could promote LUAD cell metastasis. By using the Kaplan-Meier Plotter tool, we found that downregulation of ADARB1 was related to shorter first progression (FP), overall survival time (OS) and post-progression survival time (PPS). The relevant clinical data acquired from the Wanderer database indicated that the expression and methylation values of ADARB1 were significantly associated with the clinical characteristics of LUAD. Using DNA methylation inhibitor, we found DNMT inhibitor 5-aza-2-deoxycytidine (5-azaD) could promote the expression of ADARB1 and reverse the inhibition effect of ADARB1 in migration. In addition, functional enrichment analysis of ADARB1-associated coexpression genes was further conducted. Our investigation demonstrated that low levels of ADARB1 were specifically found in LUAD, and this gene might be a potential target in the diagnostic and prognostic evaluation of LUAD patients. [ABSTRACT FROM AUTHOR]

Introduction: Tobacco use disorder (TUD), previously known as nicotine dependence, was associated with increased risk of lung cancer. However, little is known about the prevalence of TUD and symptom manifestation in smokers with lung cancer. Objectives: The aim of the present study was to investigate the prevalence of TUD using DSM-5 diagnostic criteria in patients diagnosed with lung cancer and analyze their tobacco use characteristics. Methods: A total of 200 histologically confirmed lung cancer patients who used tobacco within the prior 12-month period at the time of diagnosis were recruited for this study. Participants were assessed using interviewer-administered questionnaires to determine TUD symptoms and smoking-related behaviors, and self-administered Fagerstrom Test for Nicotine Dependence (FTND) was also administered. Results: The prevalence of DSM-5 TUD was 92.0% (n = 184). Of a total of 200 subjects, 23 (11.5%), 35 (17.5%), and 126 (63.0%) were classified into mild, moderate, and severe TUD categories, respectively. A total of 19 (81.3%) moderate TUD and 98 (77.8%) severe TUD patients had attempted smoking cessation. Of these subjects, 21 (21.4%) severe TUD and 12 (63.2%) moderate TUD patients tried more than three times. The number of satisfied criteria under DSM-5 TUD was positively correlated with FTND score, cumulative lifetime smoking amount, and daily smoking levels. Conclusions: Smokers diagnosed with lung cancer showed a high prevalence of DSM-5 TUD. Their heavy and consistent tobacco use suggests reduced motivation to abstain from smoking. [ABSTRACT FROM AUTHOR]

Radiomics studies require large patient cohorts, which often include patients imaged using different imaging protocols. We aimed to determine the impact of variability in imaging protocol parameters and interscanner variability using a phantom that produced feature values similar to those of patients. Positron emission tomography (PET) scans of a Hoffman brain phantom were acquired on GE Discovery 710, Siemens mCT, and Philips Vereos scanners. A standard-protocol scan was acquired on each machine, and then each parameter that could be changed was altered individually. The phantom was contoured with 10 regions of interest (ROIs). Values for 45 features with 2 different preprocessing techniques were extracted for each image. To determine the impact of each parameter on the reliability of each radiomics feature, the intraclass correlation coefficient (ICC) was calculated with the ROIs as the subjects and the parameter values as the raters. For interscanner comparisons, we compared the standard deviation of each radiomics feature value from the standard-protocol images to the standard deviation of the same radiomics feature from PET scans of 224 patients with non-small cell lung cancer. When the pixel size was resampled prior to feature extraction, all features had good reliability (ICC > 0.75) for the field of view and matrix size. The time per bed position had excellent reliability (ICC > 0.9) on all features. When the filter cutoff was restricted to values below 6 mm, all features had good reliability. Similarly, when subsets and iterations were restricted to reasonable values used in clinics, almost all features had good reliability. The average ratio of the standard deviation of features on the phantom scans to that of the NSCLC patient scans was 0.73 using fixed-bin-width preprocessing and 0.92 using 64-level preprocessing. Most radiomics feature values had at least good reliability when imaging protocol parameters were within clinically used ranges. However, interscanner variability was about equal to interpatient variability; therefore, caution must be used when combining patients scanned on equipment from different vendors in radiomics data sets. [ABSTRACT FROM AUTHOR]

Distinguishing certain and uncertain information is of crucial importance both in the scientific field in the strict sense and in the popular scientific domain. In this paper, by adopting an epistemic stance perspective on certainty and uncertainty, and a mixed procedure of analysis, which combines a bottom-up and a top-down approach, we perform a comparative study (both qualitative and quantitative) of the uncertainty linguistic markers (verbs, non-verbs, modal verbs, conditional clauses, uncertain questions, epistemic future) and their scope in three different corpora: a historical corpus of 80 biomedical articles from the British Medical Journal (BMJ) 1840–2007; a corpus of 12 biomedical articles from BMJ 2013, and a contemporary corpus of 12 scientific popular articles from Discover 2013. The variables under observation are time, structure (IMRaD vs no-IMRaD) and genre (scientific vs popular articles). We apply the Generalized Linear Models analysis in order to test whether there are statistically significant differences (1) in the amount of uncertainty among the different corpora, and (2) in the categories of uncertainty markers used by writers. The results of our analysis reveal that (1) in all corpora, the percentages of uncertainty are always much lower than that of certainty; (2) uncertainty progressively diminishes over time in biomedical articles (in conjunction with their structural changes–IMRaD–and to the increase of the BMJ Impact Factor); and (3) uncertainty is slightly higher in scientific popular articles (Discover 2013) as compared to the contemporary corpus of scientific articles (BMJ 2013). Nevertheless, in all corpora, modal verbs are the most used uncertainty markers. These results suggest that not only do scientific writers prefer to communicate their uncertainty with markers of possibility rather than those of subjectivity but also that science journalists prefer using a third-person subject followed by modal verbs rather than a first-person subject followed by mental verbs such as think or believe. [ABSTRACT FROM AUTHOR]

Understanding intrinsic and acquired resistance is crucial to overcoming cancer chemotherapy failure. While it is well-established that intratumor, subclonal genetic and phenotypic heterogeneity significantly contribute to resistance, it is not fully understood how tumor sub-clones interact with each other to withstand therapy pressure. Here, we report a previously unrecognized behavior in heterogeneous tumors: cooperative adaptation to therapy (CAT), in which cancer cells induce co-resistant phenotypes in neighboring cancer cells when exposed to cancer therapy. Using a CRISPR/Cas9 toolkit we engineered phenotypically diverse non-small cell lung cancer (NSCLC) cells by conferring mutations in Dicer1, a type III cytoplasmic endoribonuclease involved in small non-coding RNA genesis. We monitored three-dimensional growth dynamics of fluorescently-labeled mutant and/or wild-type cells individually or in co-culture using a substrate-free NanoCulture system under unstimulated or drug pressure conditions. By integrating mathematical modeling with flow cytometry, we characterized the growth patterns of mono- and co-cultures using a mathematical model of intra- and interspecies competition. Leveraging the flow cytometry data, we estimated the model’s parameters to reveal that the combination of WT and mutants in co-cultures allowed for beneficial growth in previously drug sensitive cells despite drug pressure via induction of cell state transitions described by a cooperative game theoretic change in the fitness values. Finally, we used an ex vivo human tumor model that predicts clinical response through drug sensitivity analyses and determined that cellular and morphologic heterogeneity correlates to prognostic failure of multiple clinically-approved and off-label drugs in individual NSCLC patient samples. Together, these findings present a new paradox in drug resistance implicating non-genetic cooperation among tumor cells to thwart drug pressure, suggesting that profiling for druggable targets (i.e. mutations) alone may be insufficient to assign effective therapy. [ABSTRACT FROM AUTHOR]

Osimertinib showed encouraging efficacy in patients with advanced EGFR T790M-positive NSCLC in previous randomized controlled trials. This real-world study aimed to evaluate the effectiveness and safety of osimertinib in a real-world setting. This observational study (NCT03133234) included 74 patients with metastatic EGFR T790M-positive NSCLC who progressed on prior EGFR TKI therapy and received osimertinib between May 2016 and April 2018 at the Kiang Wu Hospital in Macau. Response rate (RR) and other endpoints (progression-free survival [PFS], overall survival [OS], disease control rate [DCR], stable disease rate, and adverse events) were assessed. Survival data were estimated using the Kaplan-Meier method. All patients had stage IV lung adenocarcinoma and 25.6% had brain metastases; median age was 58 years (range 28–84 years) and 83.8% of patients had received at least three prior lines of treatment. The median duration of osimertinib treatment was 8 months (range, 1–25 months). RR and DCR were 67.5% (95% CI 56.9–78.1) and 79.8% (95% CI 70.7–88.9), respectively, while 12.1% had stable disease. The median PFS was 9.0 months (95% CI 6.7–11.2 months), and the median OS was 12.0 months (95% CI 8.8–15.1 months). Nausea (25.8%) and decreased appetite (20.2%) were the most common adverse events associated with osimertinib treatment. Even though most patients had at least three lines of prior treatment, real-world RR and PFS with osimertinib in this study were consistent with those from randomized controlled trials; no new safety signals were observed. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer frequently co-exists with idiopathic interstitial pneumonia (IIP), which can be subdivided into idiopathic pulmonary fibrosis (IPF) and IIP other than IPF (other IIP). Although chemotherapy in small cell lung cancer (SCLC) patients with IIP may result in the exacerbation of IIP, these patients commonly receive chemotherapy. This study aimed to assess the risks and benefits of chemotherapy in SCLC patients with IIP. Methods: We retrospectively analyzed the medical records of 122 patients with SCLC who received chemotherapy. Patients with secondary interstitial lung disease (ILD) of known etiology were excluded. Eligible patients were divided into two groups: SCLC with and without IIP. The former group was subdivided into those with IPF and other IIP. Results: Of the 47 (39.2%) SCLC patients with IIP, 20 had IPF and 27 had other IIP. The frequency of chemotherapy-induced ILD development or IIP exacerbation was higher in patients with IPF (40.0%) than in those with other IIP (3.7%) and non-IIP (1.4%). Logistic regression analysis demonstrated that ILD development or IIP exacerbation was independently associated with IPF (P = 0.007). Time to treatment failure (P < 0.001) and overall survival (P = 0.001) were different among the groups. Cox proportional hazard model revealed that IPF was independently associated with time to treatment failure (P = 0,017) and overall survival (P = 0.006). Other IIP had no impact on time to treatment failure or overall survival. Development of ILD or exacerbation of IIP independently reduced time to treatment failure and overall survival. Conclusions: Comorbid IPF can be an independent, negative prognostic indicator and at high risk of ILD development or IIP exacerbation in SCLC patients. Early diagnosis and intervention for chemotherapy-induced IIP exacerbation will be beneficial for SCLC patients with IPF, who need close monitoring for its onset. [ABSTRACT FROM AUTHOR]

Introduction: Several non-comparative phase II studies have evaluated metronomic oral vinorelbine (MOV) in metastatic non-small cell lung cancer (NSCLC) but the small size of each study limits their conclusions. Purpose: To perform an individual patient-data metaanalysis of studies evaluating MOV in metastatic NSCLC in order to measure survival and safety of treatment with this regimen. Methods: Studies were selected if (1) administration of oral vinorelbine thrice a week; (2) fixed daily dose comprised between 30 and 50 mg, and; (3) being published before October 4th 2018. Database encompassed 8 variables characterizing disease and demography, 3 informing therapy, and 12 describing survival and toxicity. Results: Nine studies encompassing 418 patients fulfilled the selection criteria, 80% of them having frailty characteristics. Median overall survival (OS) was 8.7 months (95%CI: 7.6–9.5). OSrates at 6 months, one year and at two years after starting vinorelbine were 64%, 30.3% and 8.9%, respectively. In the Cox model, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 2, and anemia of any grade were significant determinants of shorter OS. Median progression-free survival(PFS) was 4.2 months (95%CI: 3.9–5). At 6 months and at one-year, PFS rates were 35% and 11.9% respectively. In the Cox model stratified for the variable "study", PS = 2and stage IV were significant determinants of shorter PFS. No toxicity was reported for 40% of patients, and 66 (15.8%) patients experienced a grade 3–4 toxicity. The most frequent toxicity was anemia of any grade (35.8%) that was higher with the 50 mg dosage. Conclusion: MOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients. [ABSTRACT FROM AUTHOR]

The thermoanalytical technique differential scanning calorimetry (DSC) has been applied to characterize protein denaturation patterns (thermograms) in blood plasma samples and relate these to a subject's health status. The analysis and classification of thermograms is challenging because of the high-dimensionality of the dataset. There are various methods for group classification using high-dimensional data sets; however, the impact of using high-dimensional data sets for cancer classification has been poorly understood. In the present article, we proposed a statistical approach for data reduction and a parametric method (PM) for modeling of high-dimensional data sets for two- and three- group classification using DSC and demographic data. We compared the PM to the non-parametric classification method K-nearest neighbors (KNN) and the semi-parametric classification method KNN with dynamic time warping (DTW). We evaluated the performance of these methods for multiple two-group classifications: (i) normal versus cervical cancer, (ii) normal versus lung cancer, (iii) normal versus cancer (cervical + lung), (iv) lung cancer versus cervical cancer as well as for three-group classification: normal versus cervical cancer versus lung cancer. In general, performance for two-group classification was high whereas three-group classification was more challenging, with all three methods predicting normal samples more accurately than cancer samples. Moreover, specificity of the PM method was mostly higher or the same as KNN and DTW-KNN with lower sensitivity. The performance of KNN and DTW-KNN decreased with the inclusion of demographic data, whereas similar performance was observed for the PM which could be explained by the fact that the PM uses fewer parameters as compared to KNN and DTW-KNN methods and is thus less susceptible to the risk of overfitting. More importantly the accuracy of the PM can be increased by using a greater number of quantile data points and by the inclusion of additional demographic and clinical data, providing a substantial advantage over KNN and DTW-KNN methods. [ABSTRACT FROM AUTHOR]

Introduction: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. Objective: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. Patients and methods: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. Results: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 μg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30μg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30μg/l or ≥55 years with pre-ablation sTg <30 μg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30μg/l) representing 3% of the cohort. Conclusion: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 μg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 μg/l have the worst survival rate. [ABSTRACT FROM AUTHOR]

Introduction: The sponging of microRNAs by a long non-coding RNA (lncRNA) away from their coding gene targets is a conceptually-simple, yet biologically-complex method of lncRNA-mediated gene regulation. Currently, predictions of genes that participate in sponge-based regulation are largely based on sequence homology alone, which may not adequately reflect the cellular environment in which lncRNA:miRNA pairs interact. The vast number of potential interactions generated by these predictions impedes the identification of functional gene regulatory relationships, which necessitates an approach that considers biological context. XIST, the female-specific lncRNA canonically involved in silencing the X chromosome, has been suggested by many studies to act as a miRNA sponge. The sex-specificity of XIST provides the opportunity to study the biological feasibility of proposed XIST-miRNA interactions. Here we take a comprehensive approach by considering factors that affect possible regulation through XIST-miRNA sponging. Results: To identify the most feasible candidates in a particular tissue (lung adenocarcinomas), we considered protein-coding genes that (1) were positively correlated with XIST expression within sexes, (2) were targeted by miRNAs shared with XIST, and (3) expressed in lung adenocarcinoma. This revealed a robust set of 124 genes potentially positively regulated by XIST through the sequestration of 804 shared miRNAs. We then used the basic sex-specific nature of XIST to compare the changes in miRNA-target gene relationships in endogenously high-XIST and low-XIST systems to discover a high-confidence set of only 13 miRNA-gene pairs. As XIST is expressed exclusively in the nucleus, we validated the nuclear presence of several of these high-confidence miRNAs using RT-qPCR, confirming the co-localization required for XIST to interact with these species. Conclusions: We use a biology-driven approach to identify genes defended from miRNA-based inhibition by the lncRNA XIST. Importantly, we identify that only a small subset of miRNAs predicted by sequence homology alone have the capacity to mediate the XIST-target gene axis, as they are enriched in the nucleus and able to co-localize with XIST for sponging. Our results reinforce the necessary consideration of biological features in future studies of lncRNA:miRNA interactions. [ABSTRACT FROM AUTHOR]

Spatial scan statistics are widely used for cluster detection analysis in geographical disease surveillance. While this method has been developed for various types of data such as binary, count, and continuous data, spatial scan statistics for matched case-control data, which often arise in spatial epidemiology, have not been considered. We propose spatial scan statistics for matched case-control data. The proposed test statistics consider the correlations between matched pairs. We evaluate the statistical power and cluster detection accuracy of the proposed methods through simulations compared to the Bernoulli-based method. We illustrate the proposed methods using a real data example. The simulation study clearly revealed that the proposed methods had higher power and higher accuracy for detecting spatial clusters for matched case-control data than the Bernoulli-based spatial scan statistic. The cluster detection result of the real data example also appeared to reflect a higher power of the proposed methods. The proposed methods are very useful for spatial cluster detection for matched case-control data. [ABSTRACT FROM AUTHOR]

Background: It is cost-effective to perform an HIV test in people with specific indicator conditions (IC) with an undiagnosed HIV prevalence of at least 0.1%. Our aim was to determine the HIV prevalence for 14 different conditions across 20 European countries. Methods: Individuals aged 18–65 years presenting for care with one of 14 ICs between January 2012 and June 2014 were included and routinely offered an HIV test. Logistic regression assessed factors associated with testing HIV positive. Patients presenting with infectious mononucleosis-like syndrome (IMS) were recruited up until September 2015. Results: Of 10,877 patients presenting with an IC and included in the analysis, 303 tested positive (2.8%; 95% CI 2.5–3.1%). People presenting with an IC in Southern and Eastern Europe were more likely to test HIV positive as were people presenting with IMS, lymphadenopathy and leukocytopenia/ thrombocytopenia. One third of people diagnosed with HIV after presenting with IMS reported a negative HIV test in the preceding 12 months. Of patients newly diagnosed with HIV where data was available, 92.6% were promptly linked to care; of these 10.4% were reported lost to follow up or dead 12 months after diagnosis. Conclusion: The study showed that 10 conditions had HIV prevalences > 0.1%. These 10 ICs should be adopted into HIV testing and IC specialty guidelines. As IMS presentation can mimic acute HIV sero-conversion and has the highest positivity rate, this IC in particular affords opportunities for earlier diagnosis and public health benefit. [ABSTRACT FROM AUTHOR]

Background: Increasingly Burden of Disease (BOD) measures are being used to influence policy decisions because they summarise the complete effects of morbidity and mortality in an equitable manner. An important element of producing non-fatal BOD estimates are severity distributions. The Global Burden of Disease (GBD) study use the same severity distributions across countries due to a lack of available country-specific data. In the Scottish BOD (SBOD) study we developed national severity distributions for cancer types. The main aim of this study was to consider the extent to which the use of worldwide severity distributions in BOD studies are influencing cross-country comparisons, by comparing weighted-average disability weights (DW) based on GBD severity distributions with nationally derived severity distributions in Scotland for cancer types. Methods: We obtained individual records from the Scottish Cancer Registry for 21 cancer types and linked these to registered deaths. We estimated prevalent cancer cases for 2016 and assigned each case to sequelae using GBD 2016 study definitions. We compared the impact of using severity distributions based on GBD 2016, a Scotland-wide distribution, and distributions specific to deprivation strata in Scotland, on the weighted-average DW for each cancer type. Results: The relative difference in point estimates of weighted-average DW based on GBD 2016 worldwide severity distributions compared with Scottish national severity distributions resulted in overestimates in the majority of cancers (17 out of 21 cancer types). The largest overestimates were for gallbladder and biliary tract cancer (70.8%), oesophageal cancer (31.6%) and pancreatic cancer (31.2%). Furthermore, the use of weighted-average DW based on Scottish national severity distributions rather than sub-national Scottish severity distributions stratified by deprivation quintile overestimated weighted-average DW in the least deprived areas (16 out of 18 cancer types), and underestimated in the most deprived areas (16 out of 18 cancer types). Conclusion: Our findings illustrate a bias in point estimates of weighted-average DW created using worldwide severity distributions. This bias would have led to the misrepresentation of non-fatal estimates of the burden of individual cancers, and underestimated the scale of socioeconomic inequality in this non-fatal burden. This highlights the importance of not interpreting non-fatal estimates of burden of disease too precisely, especially for sub-national estimates and those comparing populations when relying on data inputs from other countries. It is essential to ensure that any estimates are based upon country-specific data as far as possible. [ABSTRACT FROM AUTHOR]

The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression. [ABSTRACT FROM AUTHOR]

Purpose: Lung cancer in never smokers is recognized as a distinct molecular, clinicopathologic and epidemiologic entity. The aim of the study was to investigate the molecular profile in Swiss never smokers with lung adenocarcinoma and to correlate the mutation status with clinicopathologic and demographic patient characteristics and outcome. Methods: One hundred thirty-eight never smokers diagnosed with lung adenocarcinoma at the University Hospital Zurich between 2011–2018 were included in the study. Data from the electronic medical records were reviewed to characterize clinicopathologic and demographic features, molecular profile, treatment and outcome. Results: The majority of patients were female (58.7%) with a median age at diagnosis of 64.5 years (range, 27.1–94.2 years). The most common mutations were EGFR (58.7%) followed by ALK (12.3%), TP53 (5.8%), MET (5.8%), KRAS (4.3%), ERBB2 (4.3%), PIK3CA (2.9%), BRAF (2.2%), ROS1 (1.4%), RET (1.4%), CTNNB1 (0.7%), PARP1 (0.7%), TET1 (0.7%) and PIK3CG (0.7%). Median overall survival (mOS) was 51.0 months (mo). Early clinical stage (p = 0.002) and treatment with targeted therapy (HR 2.53, 95% CI 1.35–4.74, p = 0.004) were independently associated with longer mOS. Patients with oncogenic driver mutations had significantly longer mOS (52.2 mo) compared to patients without mutations (16.9 mo) (HR 3.38, 95% CI 1.52–7.55, p = 0.003). Besides, patients with EGFR mutated (57.8 mo) or ALK rearranged (59.9 mo) tumors had significantly longer mOS compared to the EGFR wildtype (35.0 mo), ALK wildtype (46.5 mo) and pan-negative (16.9 mo) cohorts (HR 2.35, 95% CI 1.37–4.04, p = 0.002; HR 7.80, 95% CI 3.28–18.55, p < 0.001; HR 3.96, 95% CI 1.21–12.95, p = 0.023 and HR 34.78, 95% CI 3.48–34.65, p = 0.003). Conclusion: Never smokers with lung adenocarcinoma display distinct clinicopathologic and molecular features and are characterized by a high incidence of targetable mutations. Never smokers with targetable mutations have significantly longer survival compared to patients without mutations. [ABSTRACT FROM AUTHOR]

Somatic mutations of MET gene are emerging as important driver mutations for lung cancers. To identify the common clinicopathological features of MET exon 14 skipping mutations and amplification and clarify whether the two MET gene alterations cause protein overexpression were investigated using 196 lung cancer samples of Taiwan through real time-qPCR/sequencing, fluorescence in situ hybridization, and immunohistochemistry. The two MET gene alterations are both present in low frequency, ~1%, in the studied lung cancer population of Taiwan. MET exon 14 skipping mutations were identified from two early-stage patients, who were both relatively advanced in age, and did not carry other driver mutations. One was an adenocarcinoma and the other was a rare carcinosarcoma. Three gene amplifications cases were identified. Neither of the two MET gene alterations would lead to protein overexpression; hence, direct detection in nucleic acid level would be a preferred and straightforward solution for the identification of skipping mutations. The presence of MET exon 14 mutations in minor histological types of lung cancers urge to extend screening scope of this mutation in lung cancer and treatment response evaluation in clinical trials. These would be important next steps for the success of MET target therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Our purpose was to assess the differences in growth rates of multiple pulmonary metastatic nodules using three-dimensional (3D) computed tomography (CT) volumetry and propose a concept of CT spatial tumor heterogeneity. Materials and methods: We manually measured the largest diameter of metastatic pulmonary nodules on chest CT scans, and calculated the 3D maximum diameter and the volume using a semi-automated 3D CT volumetry of each nodule. The tumor response was assessed according to the revised RECIST 1.1. We defined a nodule as an outlier based on 1.5 times growth during follow-up. The CT spatial tumor heterogeneity was statistically analyzed by the “minimum combination t-test method” devised in our study. Results: On manual measurement, the tumor response category was stable disease (SD) in all 10 patients. Of them, total 155 metastatic nodules (4–52 nodules per patient) were segmented using the 3D CT volumetry. In the 3D maximum diameter, 9 patients had SD except for one patient with partial response in the two selected nodules; for the volume, all 10 patients were SD. For the 3D maximum diameter, six patients had at least one outlier; whereas five patients had the outlier on the volume measurement. Six patients were proven to have overall CT spatial tumor heterogeneity. Conclusions: The spatial tumor heterogeneity determined in a CT parametric approach could be statistically assessed. In patients with CT spatial heterogeneity, tumors with different growth rates may be neglected when the nodules are assessed according to the current guideline. [ABSTRACT FROM AUTHOR]

More than 50% of the world’s lung cancer cases occur in Asia and more than 20% of cancer deaths in Asia are attributable to lung cancer. The U.S. National Lung Screening Trial has shown that lung cancer screening with computed tomography (CT) can reduce lung cancer deaths. Using the Lung Cancer Policy Model–Asia (LCPM-Asia), we estimated the potential mortality reduction achievable through the implementation of CT-based lung cancer screening in China, Japan, Singapore, and South Korea. The LCPM-Asia was calibrated to the smoking prevalence of each of the aforementioned countries based on published national surveys and to lung cancer mortality rates from the World Health Organization. The calibrated LCPM-Asia was then used to simulate lung cancer deaths under screening and no-screening scenarios for the four countries. Using screening eligibility criteria recommended by the U.S. Centers for Medicare & Medicaid Services (CMS), which are based on age and smoking history, we estimated the lung cancer mortality reduction from screening through year 2040. By 2040, lung cancer screening would result in 91,362 life-years gained and 4.74% mortality reduction in South Korea; 290,325 life-years gained and 4.33% mortality reduction in Japan; 3,014,215 life-years gained and 4.22% mortality reduction in China; and 8,118 life-years gained and 3.76% mortality reduction in Singapore. As for mortality reduction by smoker type, current smokers would have the greatest mortality reduction in each country, ranging from 5.56% in Japan to 6.86% in Singapore. Among the four countries, lung cancer screening under CMS eligibility criteria was most effective in South Korea and least effective in Singapore. Singapore’s low smoking prevalence and South Korea’s aging population and higher smoking prevalence may partially explain the discrepancy in effectiveness. CT screening was shown to be promising as a means of reducing lung cancer mortality in the four countries. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of death caused by malignant tumors. PD-L1(programmed cell death protein-1) has shown tremendous achievement in treating NSCLC. We sought to find the relationship between CTCs in the pulmonary vein and postoperative PFS, besides we detected PD-L1 in CTCs. Method: We enrolled 112 NSCLC patients. CTC tests were performed at four time points (preoperative, pulmonary vein, intraoperative and postoperative) on every NSCLC patient who received surgery. The RNA of PD-L1 was tested by FISH. The levels of the PD-L1 mRNA and protein in tissue samples were detected. Results: The CTCs in the PV were the highest (P< 0.001), and CTCs in the PPA were the lowest (P< 0.001). The PFS in the group with PV CTCs≥ 16/5 ml was shorter than that in the group with PV CTCs< 16/5 ml (11.1 months vs 21.2 months, respectively; P< 0.001). The PFS in the group with PPA CTCs≥ 3/5 ml was shorter than that in the group with CTCs< 3/5 ml (14.8 months vs 20.7 months, respectively; P< 0.001). The CTCs in stage I were lower than those in stage II-IV (P = 0.025). No linear relationship was found between the CTCs and tumor size (P> 0.05) or LN metastasis (P> 0.05). In total, fifty-two (50.5%) patients had positive PD-L1 expression in CTC. In PD-L1-positive CTC patients, the value of PD-L1 tissue expression was higher than that in PD-L1-negative CTC patients (P = 0.0153). Conclusion: CTCs in the pulmonary vein can be an effective prognosis indicator of NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: To assess the relationship between lung cancer and emphysema subtypes. Objective: Airflow obstruction and emphysema predispose to lung cancer. Little is known, however, about the lung cancer risk associated with different emphysema phenotypes. We assessed the risk of lung cancer based on the presence, type and severity of emphysema, using visual assessment. Methods: Seventy-two consecutive lung cancer cases were selected from a prospective cohort of 3,477 participants enrolled in the Clínica Universidad de Navarra’s lung cancer screening program. Each case was matched to three control subjects using age, sex, smoking history and body mass index as key variables. Visual assessment of emphysema and spirometry were performed. Logistic regression and interaction model analysis were used in order to investigate associations between lung cancer and emphysema subtypes. Results: Airflow obstruction and visual emphysema were significantly associated with lung cancer (OR = 2.8, 95%CI: 1.6 to 5.2; OR = 5.9, 95%CI: 2.9 to 12.2; respectively). Emphysema severity and centrilobular subtype were associated with greater risk when adjusted for confounders (OR = 12.6, 95%CI: 1.6 to 99.9; OR = 34.3, 95%CI: 25.5 to 99.3, respectively). The risk of lung cancer decreases with the added presence of paraseptal emphysema (OR = 4.0, 95%CI: 3.6 to 34.9), losing this increased risk of lung cancer when it occurs alone (OR = 0.7, 95%CI: 0.5 to 2.6). Conclusions: Visual scoring of emphysema predicts lung cancer risk. The centrilobular phenotype is associated with the greatest risk. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) plays a key role in tumor progression, drug resistance and metastasis. Recently, numerous microRNA (miRNA) have been described to regulate EMT in tumor progression. In this study, we found that conditioned medium from the LC212 non-small-cell lung cancer (NSCLC) cell line (LC212-CM) induces morphological changes and overexpression of Vimentin, CD90, SMAD 2/3, SLUG and TWIST in A549 NSCLC cells, consistent with a mesenchymal phenotype. To identify the soluble mediators in LC212-CM involved in this phenomenon, we performed miRNA profiling and TGF-β1 quantification. We found that LC212-CM contains high levels of TGF-β1 as well as different secreted miRNAs. We focused our attention on Homo sapiens-microRNA21 (hsa-miR21), one of most relevant miRNA associated with lung cancer progression, metastasis and EMT. An hsa-miR21 antagomiR was able to prevent the LC212-CM-induced EMT phenotype in A549 cells. Furthermore, we found that TGF-β1 and hsa-miR21 cooperate in the induction of EMT in A549 cells. Intriguingly, TGF-β1 was found to induce hsa-miR21 expression in A549 cell, thus suggesting that the hsa-miR21 mediates at least in part the pro-EMT effects of TGF-β1. In conclusion, hsa-miR21 and TGF-β1 are involved in autocrine and paracrine circuits that regulate the EMT status of lung cancer cells. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) are an independent prognostic marker in non-small cell lung cancer (NSCLC). CTC numbers are closely related to early diagnosis, clinical stage, therapy surveillance, and prognosis of NSCLC. We used a more efficient nano-enrichment method to detect CTCs in NSCLC patients and explored the clinical value of CTCs. The results showed that CTC numbers in stage IV cases were significantly higher than those in stage I, II or III cases. The number of CTCs in poorly-differentiated cases was significantly higher than that in well-differentiated cases. During six chemotherapy cycles, the average CTC number decreased from 5.8/7.5 ml in cycle #1 to 2.4/7.5 ml in cycle #4 and remained at almost the same level from 4 to 6 cycles. CTC numbers in patients with EGFR mutations was significantly higher than those in patients with no mutations. The average progression free survival (PFS) in the favorable group (CTC ≤ 5/7.5 ml) was 11.3 months, which was longer than that in the unfavorable group (CTC > 5/7.5 ml, 7.2 months). In conclusion, the assessment of NSCLC cannot be performed using a single CTC analysis. The clinical value is more significant in the continuous analysis of CTC data, as well as the cross-validation of other indexes and imaging results. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disorder associated with lung microbiome dysbiosis. Although the upper airway microbiome is the source of the lung microbiome, the relationships between the oral, nasal, and sputum microbiota are incompletely understood. Our objective was to determine features that differentiate the oral, nasal, and sputum microbiome among subjects with stable COPD. Methods: We recruited 15 current or former smokers to provide oral and sputum samples on day 1. On day 2, another oral sample and a nasal sample were obtained. Each sample and control underwent DNA extraction, 16S V4 rRNA amplification, 16S V4 sequencing, and qPCR of 16S rRNA. Data were analyzed using dada2 and R. Results: Most (14 of 15) subjects were male with a mean age of 65.2. One subject had no pulmonary obstruction, while 5 had mild COPD, 7 had moderate COPD, and 2 had severe COPD. Three subjects (20%) were current tobacco users and 2 subjects (13%) used inhaled corticosteroids (ICS). Subjects had a mean of 49.1 pack-years of tobacco exposure. Bacterial biomass was associated with anatomic site, but no differences in biomass were observed with age, FEV1 percent predicted (FEV1pp), ICS use, smoking status, or edentulous state. Shannon index was associated with site (lower nasal diversity than oral and sputum diversity, p<0.001), but not age, ICS use, FEV1pp, tobacco use, or edentulous state. β-diversity was illustrated by principal coordinate analysis using Bray-Curtis dissimilarity and PERMANOVA analyses, showing sample clustering by anatomic site (p = 0.001) with nasal samples forming a cluster separate from the combined oral wash samples and sputum samples. Clustering was also observed with ICS use (p = 0.029) and edentulous state (p = 0.019), while FEV1pp and current tobacco use were not significant. In an amplicon sequencing variant (ASV)-level analysis of oral samples using a linear regression model with Benjamini-Hochberg correction at an FDR<0.10, 10 ASVs were associated with age while no ASVs were associated with FEV1pp or smoking status. Sputum sample analysis demonstrated that 51 ASVs (25 unique genera) were associated with age, 61 ASVs (32 genera) were associated with FEV1pp, and no ASVs were associated with smoking status. In a combined dataset, the frequent exacerbator phenotype, rather than ICS use, was associated with decreased sputum Shannon diversity. Conclusions: Among the upper airway microbiota of COPD subjects, anatomic site was associated with bacterial biomass, Shannon diversity, and β-diversity. ICS use and edentulous state were both associated with β-diversity. Age was associated with taxa relative abundance in oral and sputum samples, while FEV1pp was associated with taxa relative abundance in sputum samples only. [ABSTRACT FROM AUTHOR]

Background: To investigate the detrimental effects of prolonged overall radiotherapy duration (ORTD) on survival outcomes of stage IIIB/C NSCLC patients treated with concurrent chemoradiotherapy (C-CRT) Methods: The study cohort consisted of 956 patients who underwent C-CRT for stage IIIB/C NSCLC. Primary endpoint was the association between the ORTD and overall survival (OS) with locoregional progression-free survival (LRPFS) and PFS comprising the secondary endpoints. Receiver operating characteristic (ROC) curve analysis was utilized for accessibility of the cut-off that interacts with survival outcomes. Multivariate Cox model was utilized to identify the independent associates of survival outcomes. Results: The ROC curve analysis exhibited significance at 49 days of ORTD cut-off that dichotomized patients into ORTD<50 versus ORTD≥50 days groups for OS [area under the curve (AUC): 82.8%; sensitivity: 81.1%; specificity: 74.8%], LRPFS (AUC: 91.9%; sensitivity: 90.6%; specificity: 76.3%), and PFS (AUC: 76.1%; sensitivity: 72.4%; specificity: 68.2%), respectively. Accordingly, ORTD≥50 days group had significantly shorter median OS (P<0.001), LRPFS (P<0.001), and PFS (P<0.001); and 10-year actuarial locoregional control (P<0.001) and distant metastases-free (P<0.011) rates than the ORTD<50 days group. The ORTD retained its significant association with survival outcomes at multivariate analyses independent of the other favorable covariates (p<0.001, for OS, LRPFS, and PFS): Stage IIIB disease (versus IIIC), lymph node bulk <2 cm (versus ≥2 cm), and 2–3 chemotherapy cycles (versus 1). The higher sensitivity for LRPFS (90.6%) than PFS (72.4%) on ROC curve analysis suggested the prolonged ORTD-induced decrements in locoregional control rates as the major cause of the poor survival outcomes. Conclusions: Longer ORTD beyond ≥50 days was associated with significantly poorer OS, LRPFS and PFS outcomes, where reduced locoregional control rates appeared to be the main causative. [ABSTRACT FROM AUTHOR]

Alternative transcript isoforms are common in tumors and act as potential drivers of cancer. Mechanisms determining altered isoform expression include somatic mutations in splice regulatory sites or altered splicing factors. However, since DNA methylation is known to regulate transcriptional isoform activity in normal cells, we predicted the highly dysregulated patterns of DNA methylation present in cancer also affect isoform activity. We analyzed DNA methylation and RNA-seq isoform data from 18 human cancer types and found frequent correlations specifically within 11 cancer types. Examining the top 25% of variable methylation sites revealed that the location of the methylated CpG site in a gene determined which isoform was used. In addition, the correlated methylation-isoform patterns classified tumors into known subtypes and predicted distinct protein functions between tumor subtypes. Finally, methylation-correlated isoforms were enriched for oncogenes, tumor suppressors, and cancer-related pathways. These findings provide new insights into the functional impact of dysregulated DNA methylation in cancer and highlight the relationship between the epigenome and transcriptome. [ABSTRACT FROM AUTHOR]

Our current study is to identify clinical significance of minichromosome maintenance (MCM) gene expression in Lung Adenocarcinoma (LUAD) using genome-wide RNA sequencing (RNA-seq) dataset and bioinformatics analysis tools. The biological function and potential process for function of the MCM1-10 were identified by multiple bioinformatics analysis tools. Clinical significance and molecular mechanism of the MCM1-10 were investigated by the RNA-seq dataset of LUAD from The Cancer Genome Atlas. Functional assessment substantiated involvement of MCM1-10 in cell cycle progression and DNA replication, and co-expressed with each other. We also observed that the MCM1-10 were dysregulation in LUAD tumor tissues, and may be have diagnostic implications in LUAD. Prognosis analysis in TCGA and KM plotter cohorts suggest that high abundance of MCM5, MCM8 and MCM4 notably correlated to poor LUAD overall survival. Mechanistic exploration of MCM4, MCM5, and MCM8 by gene set enrichment analysis suggests that these genes may influence the LUAD prognosis by regulating the cell cycle, DNA replication and other multiple biological processes and pathways. In comclusion, our study suggests that MCM1-10 can serve as diagnostic biomarkers for LUAD patients. Of them, MCM4, MCM5, and MCM8 may act as potential prognostic indicators for LUAD. [ABSTRACT FROM AUTHOR]

Objectives: SCLC makes up approximately 15% of all lung carcinomas and is characterized by relatively aggressive spread and poorer prognosis compared to other lung cancers. Treatment options are limited, and their efficacy in randomized trials is poor, whilst outcomes in clinical practice remain unclear. The aim of this study was to assess the real-world effectiveness and tolerability of SCLC treatments. Methods: An SLR was conducted across nine databases accessed through OVID, capturing observational, non-randomized studies published between 01/2006–11/2018. In total, 554 abstracts were retrieved and systematically screened for eligibility. The eligible publications included effectiveness and tolerability data from adult SCLC patients (at any line of therapy). Additional grey literature searches were conducted. Results: Forty-three publications were included in this review—data from first-line therapies were captured most often (n = 32), while data from second (n = 14) and third line (n = 7) and beyond (n = 7) were less frequent. The publications reported primarily on chemotherapy/radiotherapy. The majority of publications lacked robustness and only 14/43 conducted statistical analyses or controlled for bias. Median OS for the largest SCLC populations were 9.6 months at first line (n = 23,535) and 4.9 months at second line (n = 254) for treatment with chemotherapy, and 4.7 months at third line (n = 120) for predominantly platinum-based chemotherapy or cyclophosphamide/adriamycin/vincristine. Hematologic toxicities (such as neutropenia, thrombocytopenia and anemia) were the most frequently reported TRAEs (n = 9). Conclusions: Real-world treatment effectiveness and tolerability data were fragmented and inconsistently reported, and available publications were primarily of poor quality and lacked statistical analyses. This SLR showed limited treatment options and poor OS in SCLC, with no treatment option being clearly superior. TRAEs additionally increased the burden of this already challenging disease. Recent data suggest real-world outcomes are even poorer that those reported in clinical trials, and that novel therapies are needed to offer new treatment options for patients. [ABSTRACT FROM AUTHOR]

Introduction: Although second-line immunotherapy obtained better outcomes than chemotherapy for patients with advanced non-small–cell lung cancers (NSCLCs), it is expensive and only a minority of patients seem to benefit, based on early tumor progression post-immunotherapy. Notable host inflammation, characterized by biomarkers (e.g. neutrophil-to-lymphocyte ratio (NLR])), prolongs overall survival (OS) of surgery-, chemotherapy- and immunotherapy-treated patients. To our knowledge, no previous studies used biomarker evolution to analyze the immunotherapy impact on host inflammation. Immunotherapy mainly exerts its activity by lymphocyte reactivation. Methods: This retrospective study was conducted on patients, selected by their progression status just before their 4th nivolumab injection, and treated at Bordeaux and Limoges University Hospitals. A comparative group of at least 1-year responders was also selected. Clinical parameters and hematological data just before the 1st (baseline) and 4th nivolumab infusions were collected to calculate the NLR change (ΔNLR) between those two infusions. The combined impact of the different known prognostic factors was also analyzed with multivariable analyses. Results: Fifty-nine patients were included. The 29 early progressors had significantly more frequent ΔNLR > 1 (p = 0.0007), OR 18.08 [95% CI 2.96–246.24] with progressive disease as best response to prior treatment line (p = 0.0014). ΔNLR < 1 prolonged OS (HR 0.001 [0.0007–0.18], p = 0.001); as did a partial response to prior line of systemic treatment (HR 0.14 [0.03––0.56], p = 0.005). Conclusion: Based on selected early progressors given second-line immunotherapy for advanced NSCLC, progression as best response to prior treatment and ΔNLR > 1 characterized the early progressors and shortened OS after starting nivolumab. This phenomenon questions nivolumab utility in patients with a major host neutrophil inflammation. [ABSTRACT FROM AUTHOR]

Background: Detection of pulmonary nodules is an important aspect of an automatic detection system. Incomputer-aided diagnosis (CAD) systems, the ability to detect pulmonary nodules is highly important, which plays an important role in the diagnosis and early treatment of lung cancer. Currently, the detection of pulmonary nodules depends mainly on doctor experience, which varies. This paper aims to address the challenge of pulmonary nodule detection more effectively. Methods: A method for detecting pulmonary nodules based on an improved neural network is presented in this paper. Nodules are clusters of tissue with a diameter of 3 mm to 30 mm in the pulmonary parenchyma. Because pulmonary nodules are similar to other lung structures and have a low density, false positive nodules often occur. Thus, our team proposed an improved convolutional neural network (CNN) framework to detect nodules. First, a nonsharpening mask is used to enhance the nodules in computed tomography (CT) images; then, CT images of 512×512 pixels are segmented into smaller images of 96×96 pixels. Second, in the 96×96 pixel images which contain or exclude pulmonary nodules, the plaques corresponding to positive and negative samples are segmented. Third, CT images segmented into 96×96 pixels are down-sampled to 64×64 and 32×32 size respectively. Fourth, an improved fusion neural network structure is constructed that consists of three three-dimensional convolutional neural networks, designated as CNN-1, CNN-2, and CNN-3, to detect false positive pulmonary nodules. The networks’ input sizes are 32×32×32, 64×64×64, and 96×96×96 and include 5, 7, and 9 layers, respectively. Finally, we use the AdaBoost classifier to fuse the results of CNN-1, CNN-2, and CNN-3. We call this new neural network framework the Amalgamated-Convolutional Neural Network (A-CNN) and use it to detect pulmonary nodules. Findings: Our team trained A-CNN using the LUNA16 and Ali Tianchi datasets and evaluated its performance using the LUNA16 dataset. We discarded nodules less than 5mm in diameter. When the average number of false positives per scan was 0.125 and 0.25, the sensitivity of A-CNN reached as high as 81.7% and 85.1%, respectively. [ABSTRACT FROM AUTHOR]

Health disparities are commonplace and of broad interest to policy makers, but are also challenging to measure and communicate. The Health Disparity Calculator software (HD*Calc, v1.2.4) offers Monte Carlo simulation (MCS)-based confidence interval (CI) estimation of eleven disparity measures. The MCS approach provides accurate CI estimation, except when data are scarce (e.g., rare cancers). To address sparse data challenges to CI estimation, we propose two solutions: 1) employing the gamma distribution in the MCS and 2) utilizing a zero-inflated Poisson estimate for Poisson sampling in simulation experiments. We evaluate each solution through simulation studies using female breast, female brain, lung, and cervical cancer data from the Surveillance, Epidemiology, and End Results (SEER) program. We compare the coverage probabilities (CPs) of eleven health disparity measures based on simulated datasets. The truncated normal distribution implemented in the MCS with the standard Poisson samples (the default setting of HD*Calc) leads to less-than-optimal coverage probabilities (<95%). When both the gamma distribution and the estimated mean from the zero-inflated Poisson are used for the MCS, the coverage probabilities are close to the nominal level of 95%. Simulation studies also demonstrate that collapsing age categories for better CI estimation is not a pragmatic solution. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a high mortality rate due to limited treatment options. Hence, the response of HCC to different cancer immunotherapies is being intensively investigated in clinical trials. Immune checkpoint blockers (ICB) show promising results, albeit for a minority of HCC patients. Mouse models are commonly used to evaluate new therapeutic agents or regimens. However, to make clinical translation more successful, better characterized preclinical models are required. We therefore extensively investigated two immune-competent orthotopic HCC mouse models, namely transplanted Hep-55.1c and transgenic iAST, with respect to morphological, immunological and genetic traits and evaluated both models’ responsiveness to immunotherapies. Hep-55.1c tumors were characterized by rich fibrous stroma, high mutational load and pronounced immune cell infiltrates, all of which are features of immune-responsive tumors. These characteristics were less distinct in iAST tumors, though these were highly vascularized. Cell depletion revealed that CD8+ T cells from iAST mice do not affect tumor growth and are tumor tolerant. This corresponds to the failure of single and combined ICB targeting PD-1 and CTLA-4. In contrast, combining anti-PD-1 and anti-CTLA-4 showed significant antitumor efficacy in the Hep-55.1c mouse model. Collectively, our data comprehensively characterize two immune-competent HCC mouse models representing ICB responsive and refractory characteristics. Our characterization confirms these models to be suitable for preclinical investigation of novel cancer immunotherapy approaches that aim to either deepen preexisting immune responses or generate de novo immunity against the tumor. [ABSTRACT FROM AUTHOR]

Objective: The current paradigm in the treatment of patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a diagnostic lobectomy rather than complete thyroidectomy and postoperative radioiodine treatment. Consequently, preoperative diagnosis of NIFTP is considered to be important. Methods: We performed the comprehensive analysis for diagnosis of preoperative 20 NIFTPs in comparison with 41 invasive encapsulated follicular papillary thyroid carcinomas (I-EFVPTCs) using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and molecular analysis for BRAF and RAS mutations. Results: K-TIRADS 3 was identified as the most common sonographic diagnosis in both NIFTP and I-EFVPTC. Unlike I-EFVPTC, K-TIRADS 5 was not identified in NIFTP. AUS/FLUS was the most common cytopathological diagnosis and none of the cases were classified as malignant category in both groups, although the difference in distribution was not significant between the groups. BRAF mutation was not found in NIFTP but was present in 9.8% of cases in I-EFVPTC. The frequency of RAS mutation in I-EFVPTCs was twice as high as that of NIFTP. Wild-type BRAF and RAS in NIFTP was significantly higher than I-EFVPTC. Conclusion: The existence of overlapping features between the groups was evident, hence conclusive distinction between radiology, cytology and molecular analysis could not be achieved. Apparently, the diagnosis of NIFTP based on comprehensive analysis was not confirmable but could perceive or at least favor the diagnosis of NIFTP. [ABSTRACT FROM AUTHOR]

Introduction: Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC. Materials and methods: All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3–4 toxicity were registered. Results: Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31–236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3–4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation. Conclusion: Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR. [ABSTRACT FROM AUTHOR]

Background: Multigene-based PCR tests are time-consuming and limiting aspects of the protocol include increased risk of operator-based variation. In addition, such protocols are complex to transfer and reproduce between laboratories. Aims: Evaluate the clinical utility of a pre-spotted PCR plate (PSP) for a novel multigene (n = 51) blood-based gene expression diagnostic assay for neuroendocrine tumors (NETs). Methods: A pilot study (n = 44; 8 controls and 36 NETs) was undertaken to compare CQ, normalized gene expression and algorithm-based output (NETest score). Gene expression was then evaluated between matched blood:tumor tissue samples (n = 7). Thereafter, two prospective sets (diagnostic: n = 167; clinical validation: n = 48, respectively) were evaluated for diagnostic and clinical utility value. Two independent molecular diagnostics facilities were used to assess assay reproducibility and inter-laboratory metrics. Samples were collected (per CLIA protocol) processed to mRNA and cDNA and then either run per standard assay (liquid primers) or on PSPs. Separately, matching plasma samples were analyzed for chromogranin A (CgA). Statistics included non-parametric testing, Pearson-concordance, Predictive Modeling and AUROC analyses. Results: In the pilot study (n = 44), CQ values were highly concordant (r: 0.82, p<0.0001) and normalized gene expression data significantly related (p<0.0001) (Pearson-pairwise correlation). NETest values were not different (49.7±33 standard vs. 48.5±31.5 PSP) and the overall concordance in output 96%. Predictive modelling confirmed this concordance (F1 score = 0.95). Gene expression levels were highly correlated between blood and tumor tissue (R: 0.71–0.83). In the diagnostic cohort (n = 30 controls, n = 87 non-NET controls, n = 50 NET), NETest was significantly lower (p<0.0001) in controls (11±6.5) and non-NET controls (13±18) than NETs (61±31). The AUROCs were 0.93–0.97 and the diagnostic accuracy was 90–97.5%. As a diagnostic, the PSP-NETest was significantly better than CgA (accuracy: 56%, p<0.0001). For clinical samples, the PSP generated robust and accurate (>96%) scores and was significantly better (p<0.0001) than CgA. The assay protocol was consistent (r: 0.97) and reproducible (co-efficient of variation: 1.3–4.2%) across the two facilities. Conclusion: The PSP protocol for the NETest has been established and prospectively tested in clinical samples. It is highly reproducible, has similar metrics (CV, categorization by control or NET) to the standard PCR assay and generates clinically concordant (>96%) NETest results. Moreover, it functions significantly more accurately than CgA. [ABSTRACT FROM AUTHOR]

Aim: To in detail delineate sex differences in non-small cell lung cancer outcome and investigate possible underlying drivers. Methods: We performed a nationwide, population-based cohort study using data on all incident cases of lung squamous cell carcinoma (n = 10,325) and adenocarcinoma (n = 23,465) recorded in the Swedish Lung Cancer Register in 2002–2016. Flexible parametric models were applied to compute adjusted female-to-male hazard ratios (aHRs) and standardized survival proportions over follow-up including age, calendar year, education, marital status, birth country, health care region, performance status, smoking history, comorbidities, and tumor location in the final model. Results: Women presented with better performance status, were younger, and more often never-smokers. Women with adenocarcinoma also had lower comorbidity burden, less advanced stage, and were more often EGFR positive. Men with adenocarcinoma had a consistently poorer lung cancer-specific survival across stage; HR 0.69; 95% CI 0.63–0.76 (stage IA-IIB) to 0.94; 95% CI 0.88–0.99 (stage IIIB-IV), remaining largely unchanged after adjustments; aHR 0.74; 95% CI 0.66–0.82 to 0.84; 95% CI 0.81–0.87. The same pattern was observed in squamous cell carcinoma, except in stage IIIA disease, where we found no sex differences in survival. Conclusions: Men with non-small cell lung cancer have a consistently poorer prognosis, even after careful adjustments for a wide range of prognostic factors. While the pattern was similar in both squamous cell and adenocarcinoma, it was larger and more consistent in the latter. [ABSTRACT FROM AUTHOR]

Background: In some patients with metastatic differentiated thyroid cancer, even if they had substantial of radioactive iodine (RAI) uptake, the RAI therapy response was poor. We investigated the usefulness of FDG PET/CT for the early prediction of RAI therapy response in the patients with metastatic differentiated thyroid cancer (DTC). Methods: The 54 metastatic DTC patients who underwent both RAI therapy scan and FDG PET/CT at the same period were enrolled in the study. Clinical information and several parameters from RAI therapy scan and FDG PET/CT were investigated. Therapeutic response of RAI was assessed as two categories: response rate (RR) and disease control rate (DCR). Results: Twenty-two patients (41%) had therapeutic response to RAI therapy, whereas 32 (59%) patients did not. There were no significant differences in age, sex, stage, histology, metastasis site, stimulated Tg or Tg-Ab, therapeutic doses, and even RAI uptake pattern among two groups. However, there was a significant negative correlation between FDG avidity of metastatic lesions and RR (OR = 0.233; p = 0.016). Although the patient group with only RAI uptake showed a significant correlation with RR (OR = 5.833; p = 0.01), the patient group with both RAI and FDG uptake did not show any significant correlation with RR. In the subgroup analysis, uptake grades of RAI or FDG was well correlated with DCR. Conclusions: The patient group with FDG uptake in metastatic DTC showed poor response to RAI therapy regardless of the degree of RAI uptake. Therefore, FDG PET/CT may help us identify the patients with radioiodine refractory DTC and establish an appropriate treatment strategy in the early period. [ABSTRACT FROM AUTHOR]