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Background There has been no study systematically assessing the causal effects of putative modifiable risk factors on lung cancer. In this study, we aimed to construct a modifiable risk factors atlas of lung cancer by using the two‐sample Mendelian randomization framework. Methods We included 46 modifiable risk factors identified in previous studies. Traits with p‐value smaller than 0.05 were considered as suggestive risk factors. While the Bonferroni corrected p‐value for significant risk factors was set to be 8.33 × 10−4. Results In this two‐sample Mendelian randomization analysis, we found that higher socioeconomic status was significantly correlated with lower risk of lung cancer, including years of schooling, college or university degree, and household income. While cigarettes smoked per day, time spent watching TV, polyunsaturated fatty acids, docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid in blood were significantly associated with higher risk of lung cancer. Suggestive risk factors for lung cancer were found to be serum vitamin A1, copper in blood, docosahexaenoic acid in blood, and body fat percentage. Conclusions This study provided the first Mendelian randomization assessment of the causality between previously reported risk factors and lung cancer risk. Several modifiable targets, concerning socioeconomic status, lifestyle, dietary, and obesity, should be taken into consideration for the development of primary prevention strategies for lung cancer., With the utilization of Mendelian randomization analysis, we provided the evidence for the relationship between previously reported risk factors and lung cancer from the aspect of causation. We identified several modifiable targets for primary prevention of lung cancer, concerning socioeconomic status, lifestyle, dietary and obesity. ​

Previous researches have indicated physical activity (PA) may be associated with lower risk of lung cancer. However, causal relationship between PA and risk of lung cancer is not clear. We aimed to inspect the causal effect of PA on lung cancer. We analyzed summary data of accelerator-measured PA and lung cancer from the genome-wide association study (GWAS) using two‐sample Mendelian randomization (MR) method. We obtained summary data of accelerator-measured PA from UK Biobank, data of lung cancer patients from Consortium and International Lung Cancer Consortium (ILCCO) to investigate possible causal effect of PA on lung cancer. According to result of MR using inverse variance weighted method (IVW), we found that genetically predicted higher PA level did not causally decrease risk of lung cancer (OR 0.95, 95% CI 0.88–1.03, p = 0.238). Results of MR-Egger and weighted median method were consistent with IVW method. Our mendelian randomization study showed that genetically higher PA is not causally associated with risk of lung cancer. More researches are needed to investigate relationship between PA and lung cancer.

Patient-reported outcomes (PROs) have been widely accepted in western countries. However, limited attention has been given to PROs in China due to a lack of research on the agreement between doctors’ and patients’ reports of adverse events. This study aims to reveal the perception gap of chemotherapy-induced adverse events between doctors and cancer patients in China. An observational study was administered at Sun Yat-Sen University Cancer Center (SYSUCC). Totally, 200 adult cancer patients undergoing chemotherapy participated. Patient reports were collected by nurses via telephone. Doctor reports were collected by nurses based on their medical records. The agreement between doctors and patients was analyzed by Cohen’s κ. Agreement between doctors and patients varied among different symptoms: 0.26 for nausea/vomiting, 0.49 for constipation, 0.63 for diarrhea, 0.65 for general pain, and 0.76 for rash. Doctors’ underreporting rates were 70% for nausea/vomiting, 50% for diarrhea, 38% for rash, 33% for constipation, and 29% for general pain. The perception gap of chemotherapy-induced adverse events between doctors and patients exists in China, especially regarding subjective symptoms. Introduction of PROs in both clinical trials and routine clinical practice should be considered in China.

Polybromo-1 (PBRM1) gene is a promising biomarker for immunotherapy in clear cell renal cell carcinoma. But to our knowledge, the frequency and clinical relevance of PBRM1 mutation in lung cancer remain unknown. We conducted a retrospective study to evaluate the prevalence of PBRM1 mutation and its correlation with preliminary response to immunotherapy in non-small cell lung cancer (NSCLC). Our results indicated that PBRM1 mutation was more likely to be a negative predictive biomarker for immunotherapy in NSCLC.

Background We aimed to investigate whether more years spent in education are causally associated with a lower risk of lung cancer, through a two-sample Mendelian randomization study. Methods The main analysis used publicly available genetic summary data from two large consortia [International Lung Cancer Consortium (ILCCO) and Social Science Genetic Association Consortium (SSGAC)]. Genetic variants used as instrumental variables for years of education were derived from SSGAC. Finally, genetic data from three additional consortia (TAG, GLGC, GIANT) were analysed to investigate whether education could causally alter common lung cancer risk factors. The exposure was the genetic predisposition to higher levels of education, measured by 73 single nucleotide polymorphisms from SSGAC. The primary outcome was the risk of lung cancer (11 348 events in ILCCO). Secondary outcomes based on different histological subtypes were also examined. Analyses were performed using the package TwoSampleMR in R. Results Genetic predisposition towards 3.6 years of additional education was associated with a 52% lower risk of lung cancer (odds ratio 0.48, 95% confidence interval 0.34 to 0.66; P = 1.02 × 10 − 5). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely. The Mendelian randomization assumptions did not seem to be violated. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index and a favourable blood lipid profile. Conclusions Our study indicated that low education is a causal risk factor in the development of lung cancer. Further work is needed to elucidate the potential mechanisms.

High-level tissue tumor mutational burden (tTMB) or blood TMB (bTMB) are associated with better response of immunotherapy in non-small cell lung cancer (NSCLC) patients. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified. We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and evaluated single-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. TMB of > 9 mutations/Mb was classified as high. Besides, we used tTMB fold-change to evaluate the influence of the enrolled region number on tTMB. We found both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r = 0.94, P = 2E-84; Pearson r = 0.47, P = 0.0067). It showed extremely high specificity (100%) but low sensitivity (43%) when using bTMB to define TMB-high patients, while most false-negative predictions were in early-stage patients. Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions’ number more than three. Moreover, ITH-high patients had significantly higher tTMB fold-change compared with ITH-low patients (2.32 vs. 1.02, P = 8.879e-05). The conversion rate of tTMB level (tTMB-low to tTMB-high) was numerically higher in ITH-high group than that in ITH-low group (16.67% vs. 3.84%). In summary, single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB. ITH has an impact on tTMB, especially in high-level ITH patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0581-5) contains supplementary material, which is available to authorized users.

Introduction: Male breast cancer (MBC) is a rare tumor with few cases for research. Using the Surveillance, Epidemiology, and End Results program database, we carried out a competing risk analysis in patients with primary nonmetastatic MBC and built a predictive nomogram. Materials and Methods: We extracted primary nonmetastatic MBC patients according to the inclusion and exclusion criteria. Cumulative incidence function (CIF) and proportional subdistribution hazard model were adopted to explore risk factors for breast cancer-specific death (BCSD) and other cause-specific death (OCSD). Then we built a nomogram to predict the 3-year, 5-year and 8-year probabilities of BCSD and OCSD. C-indexes, Brier scores and calibration curves were chosen for validation. Results: We identified 1,978 nonmetastatic MBC patients finally. CIF analysis showed that the 3-year, 5-year and 8-year mortalities were 5.2%, 10.6% and 16.5% for BCSD, and 6.1%, 9.6% and 14.4% for OCSD. After adjustment of Fine and Gray models, black race, PR (-), advanced T/N/grade and no surgery were independently associated with BCSD. Meanwhile, elderly, unmarried status, advanced AJCC stage and no chemotherapy resulted in OCSD more possibly. A graphic nomogram was developed according to the coefficients from the Fine and Gray models. The calibration curves displayed exceptionally, with C-indexes nearly larger than 0.700 and Brier scores nearly smaller than 0.100. Conclusion: The competing risk nomogram showed good accuracy for predictive prognosis in nonmetastatic MBC patients. It was a useful implement to evaluate crude mortalities of BCSD and OCSD, and help clinicians to choose appropriate therapeutic plans.

Lacking quantitative evaluations of competing risk data of nasopharyngeal carcinoma (NPC), we aimed to evaluate the probability of NPC- and other cause-specific mortality (NPC-SM; OCSM) and develop competing risk nomograms to quantify survival differences.Using the institutional big-data intelligence platform, 7251 NPC patients undergoing intensity-modulated radiotherapy between 2009-2014 were identified to establish nomograms based on Fine and Gray's competing risk analysis.The 5-year NPC-SM and OCSM of the cohort were 13.1% and 1.2%, respectively, and elevated 5-year OCSMs were observed in patients aged ≥65 years (5.5%) or with severe comorbidities (4.3%). Age was most predictive of OCSM: patients aged 55-64 and ≥65 years exhibited subdistribution hazard ratios (SHRs) of 2.70 (95% confidence interval [CI], 1.64-4.4; P .001) and 5.78 (95% CI, 3.32-10.08; P .001), respectively. Comorbidity measured using the Charlson Comorbidity Index (CCI) was also strongly predictive of OCSM: patients with CCI scores of 1 and ≥2 exhibited SHRs of 2.33 (95% CI, 1.46-3.71; P .001) and 2.58 (95% CI, 1.16-5.73; P = .020), respectively. All validated factors were integrated into the competing nomograms: age, sex, histology type, tumor and node stages, plasma Epstein-Barr virus-DNA level, lactate dehydrogenase level, and C-reactive protein (CRP) level into the NPC-SM model (concordance [c]-index = 0.743); and age, CCI, Albumin level, and CRP level into the OCSM model (c-index = 0.793).OCSM represents a significant competing event for NPC-SM in elderly patients and patients with comorbidities. We present the first prognostic nomograms to quantify competing risks, which may help to tailor individualized treatment.

Background: Neuropathic pain is one of the common complications after spinal cord injury (SCI), affecting individuals’ quality of life. The molecular mechanism for neuropathic pain after SCI is still unclear. We aimed to discover potential genes and microRNAs (miRNAs) related to neuropathic pain by the bioinformatics method. Methods: Microarray data of GSE69901 were obtained from Gene Expression Omnibus (GEO) database. Peripheral blood samples from individuals with or without neuropathic pain after SCI were collected. Twelve samples from individuals with neuropathic pain and 13 samples from individuals without pain as controls were included in the downloaded microarray. Differentially expressed genes (DEGs) between the neuropathic pain group and the control group were detected using the GEO2R online tool. Functional enrichment analysis of DEGs was performed using the DAVID database. Protein-protein interaction network was constructed from the STRING database. MiRNAs targeting these DEGs were obtained from the miRNet database. A merged miRNA-DEG network was constructed and analyzed with Cytoscape software. Results: In total, 1134 DEGs were identified between individuals with or without neuropathic pain (case and control), and 454 biological processes were enriched. We identified 4 targeted miRNAs, including mir-204-5p, mir-519d-3p, mir-20b-5p, mir-6838-5p, which may be potential biomarkers for SCI patients. Conclusion: Protein modification and regulation of the biological process of the central nervous system may be a risk factor in SCI. Certain genes and miRNAs may be potential biomarkers for the prediction of and potential targets for the prevention and treatment of neuropathic pain after SCI.

Lung cancer patients have an increased risk for committing suicide. But no comprehensive study about the suicide issues among non‐small‐cell lung cancer (NSCLC) patients has been published. We aimed to estimate the trend of suicide rate and identify the high‐risk group of NSCLC patients. Patients diagnosed with primary NSCLC were identified from Surveillance, Epidemiology, and End Results (SEER) database (1973‐2013). Suicide mortality rate (SMR) were calculated. Multivariable logistic regression was employed to find out independent risk factors for suicide. Among 495 889 NSCLC patients, 694 (0.14%) of them died from suicide. The suicide mortality rates have significantly decreased (before 1993: 0.21%, 1994‐2003: 0.16%, after 2004: 0.09%, P 75 vs, There is significant decrease in suicide mortality among NSCLC patients in US over past decades. Older age, male sex, unmarried status, surgery were risk factors of committing suicide.

Background: Prognosis prediction is indispensable in clinical practice and machine learning has been proved to be helpful. We expected to predict survival of pancreatic neuroendocrine tumors (PNETs) with machine learning, and compared it with the American Joint Committee on Cancer (AJCC) staging system. Methods: Data of PNETs cases were extracted from The Surveillance, Epidemiology, and End Result (SEER) database. Statistic description, multivariate survival analysis and preprocessing were done before machine learning. Four different algorithms (logistic regression (LR), support vector machines (SVM), random forest (RF) and deep learning (DL)) were used to train the model. We used proper imputations to manage missing data in the database and sensitive analysis was performed to evaluate the imputation. The model with the best predictive accuracy was compared with the AJCC staging system using the SEER cases. Results: The four models had similar predictive accuracy with no significant difference existed (p = 0.664). The DL model showed a slightly better predictive accuracy than others (81.6% (± 1.9%)), thus it was used for further comparison with the AJCC staging system and revealed a better performance for PNETs cases in SEER database (Area under receiver operating characteristic curve: 0.87 vs 0.76). The validity of missing data imputation was supported by sensitivity analysis. Conclusions: The models developed with machine learning performed well in survival prediction of PNETs, and the DL model have a better accuracy and specificity than the AJCC staging system in SEER data. The DL model has potential for clinical application but external validation is needed.

Pancreatic neuroendocrine tumor (pancreatic NETs), is an important cause of cancer‐related death worldwide. No study has rigorously explored the impact of ethnicity on pancreatic NETs. We aimed to demonstrate the relationship between ethnicity and the survival of patients with pancreatic NETs. We used the SEER database to identify patients with pancreatic NETs from 2004 to 2013. Kaplan–Meier methods and Cox proportional hazard models were used to evaluate the impact of race on survival in pancreatic NETs patients. A total of 3850 patients were included: 3357 Non‐Blacks, 493 Blacks. We stratified races as “Black” and “White/Other.” Blacks were more likely to be diagnosed with later stages of tumors (P = 0.021). As for the treatment, the access to surgery seemed to be more limited in Blacks than non‐Black patients (P = 0.012). Compared with non‐Black patients, Black patients have worse overall survival (OS) (HR = 1.17, 95% CI: 1.00–1.37, P = 0.046) and pancreatic neuroendocrine tumors specific survival (PNSS) (HR = 1.22, 95% CI: 1.01–1.48, P = 0.044). Multivariate Cox analysis identified that disease extension at the time of diagnosis and surgical status contributed to the ethnical survival disparity. Black patients whose stages at diagnosis were localized had significantly worse OS (HR = 2.09, 95% CI: 1.18–3.71, P = 0.011) and PNSS (HR = 3.79, 95% CI: 1.62–8.82, P = 0.002). As for the patients who did not receive surgery, Blacks also have a worse OS (HR = 1.18, 95% CI: 1.00–1.41, P = 0.045). The Black patients had both worse OS and PNSS compared to non‐Black patients. The restricted utilization of surgery, and the advanced disease extension at the time of diagnosis are the possible contributors to poorer survival of Blacks with pancreatic NETs.

PD-1/PD-L1 inhibitors have demonstrated unparalleled therapeutic efficacy in multiple tumor types. Additionally, metformin has been linked to favorable outcomes in tumors. Many researchers have reported immune-mediated adverse events induced by immune checkpoint inhibitors (ICI) single agent. However, little is documented on the adverse events of the combined use of ICI and metformin. To address this question, we used the Food and Drug Administration Adverse Event Reporting System (FAERS) to display the landscape of adverse events associated with the combined use of ICI and metformin. We identified 38 adverse event cases about the combination treatment between January 1, 2015 and June 30, 2018. There are 36 cases in patients receiving nivolumab plus metformin (NM) therapy, and the other 2 cases were pembrolizumab plus metformin (PM). Among the 36 patients receiving NM therapy, the most common indication was for treatment of malignant lung cancer (20, 55.56%), Notably, 9 cases of inflammatory bowel disease (IBD) and diarrhea were reported. Our findings revealed that higher risk of IBD might occur in lung cancer patients during the combined therapy of nivolumab plus metformin. Further studies are needed to verify our findings.

BACKGROUND: Significance of plasma Epstein-Barr virus deoxyribonucleic acid (EBV DNA)—a proven robust indicator for nasopharyngeal carcinoma (NPC)—is not yet clarified in risk stratification of metastatic NPC (mNPC). We aim to establish effective M1 stage subdivisions in mNPC by integrating radiological features and EBV DNA at diagnosis of metastasis (mEBV DNA). METHODS: The study comprised 1,007 mNPC patients, including 817 metachronous mNPC (mmNPC) patients randomized into training (n=613) and internal validation (n=204) cohorts, and 190 synchronous mNPC (smNPC) patients defined as smNPC validation cohort. Primary clinical end-point was overall survival (OS). Covariate inclusion to recursive partitioning analysis (RPA)-generated risk stratification was qualified by a multivariable two-sided P

Immune checkpoint inhibitors (ICIs), including cytotoxic T cell–associated protein-4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors, have greatly improved the clinical outcomes of cancer patients (1). However, immune-related adverse effects involving various organs, including endocrine organs, can occur during ICI therapy (2). Cases of diabetes associated with ICI therapy have also been reported, which can be life-threatening (3–5). However, the incidence and characteristics of ICI-associated diabetes mellitus (ICI-DM) remain unclear. Therefore, we conducted a retrospective study with data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), a pharmacovigilance database, to investigate this issue (6). We used the FAERS to identify all reported cases of new-onset diabetes that were associated with ICIs approved by the FDA (i.e., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemiplimab) between 1 January 2015 and 31 December 2019. Patients with new-onset type 1 diabetes, fulminant type 1 diabetes, diabetic ketoacidosis (DKA), or diabetic ketosis secondary to ICI therapy were considered to have ICI-DM. Those with DKA or diabetic ketosis secondary to type 2 diabetes or diabetes without detailed subtypes were excluded. We then used the χ …

Background: Identifying the nerve block region is important for the less experienced operators who are not skilled in ultrasound technology. Therefore, we constructed and shared a dataset of ultrasonic images to explore a method to identify the femoral nerve block region. Methods: Ultrasound images of femoral nerve block were retrospectively collected and marked to establish the dataset. The U-net framework was used for training data and output segmentation of region of interest. The performance of the model was evaluated by Intersection over Union and accuracy. Then the predicted masks were highlighted on the original image to give an intuitive evaluation. Finally, cross validation was used for the whole data to test the robust of the results. Results: We selected 562 ultrasound images as the whole dataset. The training set intersection over union (IoU) was 0.713, the development set IoU is 0.633 and the test set IoU is 0.638. For the single image, the median and upper/lower quartiles of IoU were 0.722 (0.647–0.789), 0.653 (0.586–0.703), 0.644 (0.555–0.735) for the training set, development set and test set respectively. The segmentation accuracy of the test set was 83.9%. For 10-fold cross validation, the median and quartiles of the 10-iteration sum IoUs was 0.656 (0.628–0.672); for accuracy, they were 88.4% (82.1–90.7%). Conclusions: We provided a dataset and trained a model for femoral-nerve region segmentation with U-net, obtaining a satisfactory performance. This technique may have potential clinical application.

Liver ischemia and reperfusion (I/R) injury is of primary concern in cases of liver disease worldwide and is associated with hemorrhagic shock, resection and transplantation. Numerous studies have previously been conducted to investigate the underlying mechanisms of liver I/R injury, however these have not yet been fully elucidated. To determine the difference between ischemia and reperfusion in signaling pathways and the relative pathological mechanisms, the present study downloaded microarray data {"type":"entrez-geo","attrs":{"text":"GSE10657","term_id":"10657"}}GSE10657 from the Gene Expression Omnibus database. A total of two data groups from 1-year-old mice were selected for further analysis: i) A total of 90 min ischemia; ii) 90 min ischemia followed by 1 h of reperfusion, n=3 for each group. The Limma package was first used to identify the differentially expressed genes (DEGs). DEGs were subsequently uploaded to the Database for Annotation Visualization and Integrated Discovery online tool for Functional enrichment analysis. A protein-protein interaction (PPI) network was then constructed via STRING version 10.0 and analyzed using Cytoscape software. A total of 114 DEGs were identified, including 21 down and 93 upregulated genes. These DEGs were primarily enriched in malaria and influenza A, in addition to the tumor necrosis factor and mitogen activated protein kinase signaling pathways. Hub genes identified in the PPI network were C-X-C motif chemokine ligand (CXCL) 1, C-C motif chemokine ligand (CCL) 2, interleukin 6, Jun proto-oncogene, activator protein (AP)-1 transcription factor subunit, FOS proto-oncogene, AP-1 transcription factor subunit and dual specificity phosphatase 1. CXCL1 and CCL2 may exhibit important roles in liver I/R injury, with involvement in the immune and inflammatory responses and the chemokine-mediated signaling pathway, particularly at the reperfusion stage. However, further experiments to elucidate the specific roles of these mediators are required in the future.

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood. Experimental Design: We performed genomic profiling of 78 patients with non–small cell lung cancer (NSCLC) who underwent anti–PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response. Results: We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32–4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09–4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types. Conclusions: We identified novel genomic biomarkers that were predictive of response to anti–PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.

BackgroundPrior cancer is a common exclusion criterion in nasopharyngeal carcinoma (NPC) trials. However, whether a prior cancer diagnosis affects trial outcomes is still unknown. We aimed to determine the impact of prior cancer on survival in NPC.MethodsWe identified patients diagnosed with NPC between 2004 and 2009 in the Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by chi-squared test and t-test as appropriate. Propensity score-adjusted Kaplan-Meier methods and Cox proportional hazard models were used to evaluate the impact of prior cancer on overall survival (OS).ResultsAmong 3,131 eligible NPC patients, 349 (11.15%) patients had a history of prior cancer. The Kaplan-Meier curves did not show a statistically significantly different OS (p=0.19). Subgroup analyses stratified by timing of prior cancer and AJCC TNM stage of index cancer displayed the same tendency, prior cancer didn’t adversely affect OS compared with patients without prior cancer (p>0.05). Furthermore, in propensity score–adjusted COX models analysis, patients with prior cancer had the same/non-inferior OS (hazard ratio [HR] = 1.12, 95% confidence interval= 0.88 to 1.42).ConclusionsAmong patients with nasopharyngeal carcinoma, prior cancer does not convey an adverse effect on clinical outcomes, regardless of the timing of prior cancer and AJCC TNM stage of index cancer. Broader inclusion trial criteria could be adopted in nasopharyngeal carcinoma patients with a history of prior cancer. However, further studies are still needed to confirm.

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH. Electronic supplementary material The online version of this article (10.1186/s12943-019-0939-9) contains supplementary material, which is available to authorized users.

Recent randomized phase III trials (KEYNOTE-407 and IMpower131) reported that adding anti-programmed death (ligand) 1 (anti-PD-(L)1) antibodies in combination with taxane-platinum improve the therapeutic efficacy for advanced squamous non-small-cell lung cancer (NSCLC). However, there is no head-to-head comparison of pembrolizumab (anti-PD-1) plus chemotherapy vs. atezolizumab (anti-PD-L1) plus chemotherapy. Therefore, we performed an indirect comparison to explore the optimal choice of anti-PD-(L)1 treatment for advanced squamous NSCLC in combination with chemotherapy. The clinical outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse event (AE). For overall patients, pembrolizumab had significantly superior OS (hazard ratio (HR) with 95% confidence interval, 0.67, 0.47–0.94; P = 0.02) and numerically better PFS (HR, 0.79, 0.60–1.04; P = 0.10) than atezolizumab, while they had similar ORR, all cause AE and grade 3–5 AE. For PD-L1 high patients, pembrolizumab and atezolizumab showed similar OS and PFS. However, for PD-L1 low/negative patients, pembrolizumab had superior OS (HR, 0.43, 0.24–0.76; P

Background Observational studies have shown that excessive dietary fat may be associated with lung carcinogenesis. However, findings from previous studies are inconsistent and it remains unclear whether docosapentaenoic acid (DPA), a kind of polyunsaturated fatty acid, is linked to the risk of lung cancer. The aim of this study is to investigate the causal effect of DPA on lung cancer with Mendelian randomization (MR) method. Methods With a two‐sample MR approach, we analyzed the summary data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, 8866 individuals of European ancestry) Consortium and International Lung Cancer Consortium (ILCCO, 11 348 lung cancer cases and 15 861 controls; European ancestry) to assess the possible causal relationship of DPA on the risk of lung cancer. Results Our results indicated that genetically predicted higher DPA level has a positive association with lung cancer, where 1% higher DPA was associated with a 2.01‐fold risk of lung cancer (odds ratio [OR]: 2.01, 95% CI = 1.34‐3.01; P = 7.40 × 10−4). Additionally, lung cancer was not a causal factor for DPA. The results of MR‐Egger regression analysis showed that there was no evidence for the presence of directional horizontal pleiotropy. Conclusions Genetically elevated DPA is positively associated with risk of lung cancer, and more work is needed to investigate the potential mechanisms.

There is no conclusive evidence for the effects of prolonged infusion of dexmedetomidine in critically ill patients. We aimed to investigate the safety of long-term dexmedetomidine infusion in a large critically ill patients cohort from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database.We retrospectively extracted records from MIMIC-III database. Dexmedetomidine administration time was the basis for group. Variables were compared by chi-square tests, and Mann-Whitney U test as appropriate. We used logistic regression model for multivariate analysis. Contour maps were drawn to measure rebound of heart rate (HR) and blood pressure (BP).We finally got 1,946 records including 1,368 distinct individuals. Age, body mass index (BMI), length of stay in hospital, accumulated doses of dexmedetomidine and Sequential Organ Failure Assessment (SOFA) score were independent risk factors of in-hospital mortality (P0.05). But prolonged dexmedetomidine infusion (≥24 h) and abrupt cessation did not increase in-hospital mortality. Furthermore, the rebound of HR and BP was more likely to occur in patients with prolonged infusion of dexmedetomidine.Prolonged dexmedetomidine infusion is not related to an increased in-hospital mortality, but it is associated with the rebound effect of HR and BP. Further prospective studies are needed.

The population of cancer survivors with prior cancer is rapidly growing. Whether a prior cancer diagnosis interferes with outcome is unknown. We conducted a pan-cancer analysis to determine the impact of prior cancer history for patients newly diagnosed with cancer. We identified 20 types of primary solid tumors between 2004 and 2008 in the Surveillance, Epidemiology, and End Results database. Demographic and clinicopathologic variables were compared by χ2 test and t-test as appropriate. The propensity score-adjusted Kaplan-Meier method and Cox proportional hazards models were used to evaluate the impact of prior cancer on overall survival (OS). Among 1,557,663 eligible patients, 261,474 (16.79%) had a history of prior cancer. More than 65% of prior cancers were diagnosed within 5 years. We classified 20 cancer sites into two groups (PCI and PCS) according to the different impacts of prior cancer on OS. PCI patients with a prior cancer history, which involved the colon and rectum, bone and soft tissues, melanoma, breast, cervix uteri, corpus and uterus, prostate, urinary bladder, kidney and renal pelvis, eye and orbits, thyroid, had inferior OS. The PCS patients (nasopharynx, esophagus, stomach, liver, gallbladder, pancreas, lung, ovary and brain) with a prior cancer history showed similar OS to that of patients without prior cancer. Our pan-cancer study presents the landscape for the survival impact of prior cancer across 20 cancer types. Compared to the patients without prior cancer, the PCI group had inferior OS, while the PCS group had similar OS. Further studies are still needed.

Objectives We aimed to evaluate the global scientific output of gene research of myocardial infarction and explore their hotspots and frontiers from 2001 to 2015, using bibliometric methods. Methods Articles about the gene research of myocardial infarction between 2001 and 2015 were retrieved from the Web of Science Core Collection (WoSCC). We used the bibliometric method and Citespace V to analyze publication years, journals, countries, institutions, research areas, authors, research hotspots, and trends. We plotted the reference co-citation network, and we used key words to analyze the research hotspots and trends. Results We identified 1,853 publications on gene research of myocardial research from 2001 to 2015, and the annual publication number increased with time. Circulation published the highest number of articles. United States ranked highest in the countries with most publications, and the leading institute was Harvard University. Relevant publications were mainly in the field of Cardiovascular system cardiology. Keywords and references analysis indicated that gene expression, microRNA and young women were the research hotspots, whereas stem cell, chemokine, inflammation and cardiac repair were the frontiers. Conclusions We depicted gene research of myocardial infarction overall by bibliometric analysis. Mesenchymal stem cells Therapy, MSCs-derived microRNA and genetic modified MSCs are the latest research frontiers. Related studies may pioneer the future direction of this filed in next few years. Further studies are needed.

Background Oral tongue squamous cell carcinoma (OTSCC) is the most common subtype of oral cancer. A predictive gene signature is necessary for prognosis of OTSCC. Methods Five microarray data sets of OTSCC from the Gene Expression Omnibus (GEO) and one data set from The Cancer Genome Atlas (TCGA) were obtained. Differentially expressed genes (DEGs) of GEO data sets were identified by integrated analysis. The DEGs associated with prognosis were screened in the TCGA data set by univariate survival analysis to obtain a gene signature. A risk score was calculated as the summation of weighted expression levels with coefficients by Cox analysis. The signature was used to distinguish carcinoma, estimated by receiver operator characteristic curves and the area under the curve (AUC). All were validated in the GEO and TCGA data sets. Results Integrated analysis of GEO data sets revealed 300 DEGs. A 16-gene signature and a risk score were developed after survival analysis. The risk score was effective to stratify patients into high-risk and low-risk groups in the TCGA data set (P P Discussion We identified a useful 16-gene signature for prognosis of OTSCC patients, which could be applied to clinical practice. Further studies were needed to prove the findings.

Background The objective of this study was to evaluate the probability of cause-specific death and other causes of death in patients with stage I non–small-cell lung cancer (NSCLC) who underwent surgery. We also built competing risk nomograms to predict the prognosis of patients with NSCLC. Patients and Methods Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients who underwent surgery with stage I NSCLC between 2004 and 2013. We estimated the cumulative incidence function (CIF) for cause-specific death and other causes of death, and tested the differences using Gray’s test. The Fine and Gray proportional subdistribution hazard approach was applied to model CIF. We also built competing risk nomograms on the basis of Fine and Gray’s model. Results We identified 20,850 stage I NSCLC patients from 2004 to 2013 in the SEER database. The 5-year cumulative incidence of cause-specific death for stage I NSCLC was 21.9% and 14.2% for other causes of death. Variables associated with cause-specific mortality included age, sex, marital status, histological grade, TNM stage, and surgery. The nomograms were well calibrated, and had good discriminative ability, with a c-index of 0.64 for the cancer-specific mortality model and 0.66 for the competing mortality model. Conclusion We evaluated the CIF of cause-specific death and competing risk death in patients with surgically resected stage I NSCLC using the SEER database. We also built proportional subdistribution models and the first competing risk nomogram to predict prognosis. Our nomograms show a relatively good performance and can be a convenient individualized predictive tool for prognosis.

Background: Many researchers have studied suicide risk factors of patients with one specific cancer. But there is no comprehensive study to compare suicide issues between adolescents and young adult (AYA) group and all-age groups in a pan-cancer view. Methods: Patients diagnosed with 20 solid malignancies were identified from SEER database. Multivariable logistic regression was operated to find out risk factors of suicide. Results: Male sex has less impact on AYA than all-age patients (OR 2.72, 95% CI: 2.23–3.31, P vs . OR 4.64, 95% CI: 4.37–4.94, P vs . OR 3.40, 95% CI: 3.02–3.84, P vs . OR 1.39, 95% CI: 1.33–1.46, P vs . OR 1.76, 95% CI: 1.61–1.92; P vs . 1.24, P Conclusions: Male sex, white race and unmarried status, earlier cancer stage and longer survival time within 5 years are similar prevalent risk factors for both AYA group patients and all-age patients. It is not necessary to pick AYA cancer patients out when considering suicide risk of cancer patients.

BACKGROUND: With the improvement of survival for non-small cell lung cancer (NSCLC), research focused on second primary malignancy (SPM) in NSCLC survivors is becoming urgent. This study aimed to estimate the risk of SPM in NSCLC patients. METHODS: We retrospectively analysed NSCLC patients diagnosed between 2004 and 2010 in SEER database. We firstly evaluated the crude and cumulative incidence of SPM. SPM incidence in NSCLC survivors compared to that in the reference population was calculated as standardized incidence ratio (SIR). A competing risk nomogram was also built, to predict the incidence of SPM. RESULTS: The crude and 10-year cumulative incidences of SPM were 4.04% and 5.05%, respectively, while the SIR was 1.62. The nomogram was well calibrated and had good discriminative ability, with c-index of 0.80. It showed a significantly wide interval of SPM cumulative incidence between the first and tenth-decile according to the risk model (1.04% vs. 16.70%, P

e13007 Background: Germline mutations in BRCA1/2 (BReast CAncer genes 1 and 2), which are targets for PARP inhibitors in breast and ovarian cancer, have been previously identified in patients with non-small cell lung cancer (NSCLC). However, its prevalence and clinical outcomes to targeted therapy in NSCLC still remains unknown. Methods: We conducted a retrospective review of 9,324 Chinese NSCLC patients who underwent targeted next-generation sequencing (NGS) during 2015/11/01 and 2018/10/31. Patients with BRCA1/2 somatic and germline mutations were identified. We summarized their prevalence and explored their co-existing driver mutations. Then we initially reviewed the response to PARP-inhibitor targeted therapy in patient with BRCA2 germline mutation. Results: 459 (4.9%) patients are BRCA1/2 positive (germline/somatic mutation). Most patients are diagnosed with LUAD (372, 81.1%), with a median age of 63 years (range: 2-101). Slightly more male patients were carrying BRCA1/2 mutations (59.9%, 275 out of 459). The prevalence of BRCA1 and BRCA2 somatic mutations was similar (145, 1.56% vs. 169, 1.81%, p = 0.19). BRCA2 germline mutation was more common in lung cancer than BRCA1 germline mutation (148, 1.59% vs. 20, 0.21%, p < 0.0001). When specified to the common driver gene mutation subgroups, the prevalence of BRCA2 germline mutation is similar to the entire population (EGFR 1.79%; ALK 1.74%; KRAS 2.05%; BRAF 2.86%; ERBB2 0.93%; p > 0.05). K2729N is the most common BRCA2 germline mutation (41, 27.7%), followed by C315S (26, 17.6%), V2109I (12, 8.1%), R2108C (11, 7.4%), I2490T (10, 6.8%), T582P (5, 3.4%). About 20% patients with BRCA2 germline mutation carried at least one concomitant mutations of DNA repair genes, including MLH1, MLH3, MSH6, CHEK2, BARD1, BLM, BRCA1, MUTYH, RAD50, RECQL4 and XRCC1. One 56-year-old male LUAS patient, with germline BRCA2 rs80359490 frameshift deletion mutation (p.S1722Yfs*4), received the targeted therapy with PARP inhibitor Olaparib after multi lines therapies. This patient showed a great PR response to Olaparib, with a PFS of at least 6 months. Conclusions: BRCA1/2 germline mutations were rare in Chinese NSCLC patients. Patients with BRCA2 germline mutations might benefit from PARP-inhibitor treatment.

Pancreatic neuroendocrine tumors are relatively rare pancreatic neoplasms over the world. Investigations about molecular biology of PNETs are insufficient for nowadays. We aimed to explore the expression of messenger RNA and regulatory processes underlying pancreatic neuroendocrine tumors from different views. The expression profile of GSE73338 were downloaded, including samples with pancreatic neuroendocrine tumors. First, the Limma package was utilized to distinguish the differentially expressed messenger RNA. Gene Ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to explore the functions and pathways of target genes. In addition, we constructed a protein-protein interaction network. NEK2, UBE2C, TOP2A and PPP1R1A were revealed with continuous genomic alterations in higher tumor stage. 91 up-regulated and 36 down-regulated genes were identified to be differentially expressed in malignant PNETs. Locomotory behavior was significantly enriched for biological processes of metastasis PNETs. GCGR and GNAS were identified as the hub of proteins in the protein-protein interaction sub-network of malignant PNETs. We showed the gene expression differences in PNETs according to different clinicopathological aspects. NEK2, UBE2C, TOP2A are positively associated with high tumor grade, and PPP1R1A negatively. GCGR and GNAS are regarded as the hub of the PPI sub-network. CXCR4 may affect the progression of PNETs via the CXCR4-CXCL12-CXCR7 chemokine receptor axis. However, more studies are required.

Summary Background and objectives Marital status's prognostic impact on pancreatic neuroendocrine tumors (PNET) has not been rigorously studied. We aimed to explore the relationship between marital status and outcomes of PNET. Methods We retrospectively investigated 2060 PNET cases between 2004 and 2010 from Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by Chi 2 test, t -test as appropriate. Kaplan–Meier methods and COX proportional hazard models were used to ascertain independent prognostic factors. Results Married patients had better 5-year overall survival (OS) (53.37% vs. 42.27%, P P = 0.001) comparing with unmarried patients. Multivariate analysis revealed marital status is an independent prognostic factor, with married patients showing better OS (HR = 0.74; 95% CI: 0.65–0.84; P P = 0.004). Subgroup analysis suggested marital status plays a more important role in the PNET patients with distant stage rather than regional or localized disease. Conclusions Marital status is an independent prognostic factor for survival in PNET patients. Poor prognosis in unmarried patients may be associated with a delayed diagnosis with advanced tumor stage, psychosocial and socioeconomic factors. Further studies are needed.

Stroke is one of the most common causes of death, only second to heart disease. Molecular investigations about stroke are in acute shortage nowadays. This study is intended to explore a gene expression profile after brain ischemia reperfusion. Meta-analysis, differential expression analysis, and integrated analysis were employed on an eight microarray series. We explored the functions and pathways of target genes in gene ontology (GO) enrichment analysis and constructed a protein-protein interaction network. Meta-analysis identified 360 differentially expressed genes (DEGs) for Mus musculus and 255 for Rattus norvegicus. Differential expression analysis identified 44 DEGs for Mus musculus and 21 for Rattus norvegicus. Timp1 and Lcn2 were overexpressed in both species. The cytokine-cytokine receptor interaction and chemokine signaling pathway were highly enriched for the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. We have exhibited a global view of the potential molecular differences between middle cerebral artery occlusion (MCAO) animal model and sham for Mus musculus or Rattus norvegicus, including the biological process and enriched pathways in DEGs. This research helps contribute to a clearer understanding of the inflammation process and accurate identification of ischemic infarction stages, which might be transformed into a therapeutic approach.