Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). METHODS: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. RESULTS: Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D' = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10-5). CONCLUSION: These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.

Pectoralis Muscle Area as a Predictor of Mortality in Patients Hospitalized with Bronchiectasis Exacerbation.

INTRODUCTION: Data on factors related to mortality in patients with bronchiectasis exacerbation are insufficient. Computed tomography (CT) can measure the pectoralis muscle area (PMA) and is a useful tool to diagnose sarcopenia. This study aimed to evaluate whether PMA can predict mortality in patients with bronchiectasis exacerbation. METHODS: Patients hospitalized due to bronchiectasis exacerbation at a single center were retrospectively divided into survivors and non-survivors based on 1-year mortality. Thereafter, a comparison of the clinical and radiologic characteristics was conducted between the two groups. RESULTS: A total of 66 (14%) patients died at 1 year. In the multivariate analysis, age, BMI <18.4 kg/m2, sex-specific PMA quartile, ≥3 exacerbations in the previous year, serum albumin <3.5 g/dL, cystic bronchiectasis, tuberculosis-destroyed lung, and diabetes mellitus were independent predictors for the 1-year mortality in patients hospitalized with bronchiectasis exacerbation. A lower PMA was associated with a lower overall survival rate in the survival analysis according to sex-specific quartiles of PMA. PMA had the highest area under the curve during assessment of prognostic performance in predicting the 1-year mortality. The lowest sex-specific PMA quartile group exhibited higher disease severity than the highest quartile group. CONCLUSIONS: CT-derived PMA was an independent predictor of 1-year mortality in patients hospitalized with bronchiectasis exacerbation. Patients with lower PMA exhibited higher disease severity. These findings suggest that PMA might be a useful marker for providing additional information regarding prognosis of patients with bronchiectasis exacerbation.

Genetic Variants in Histone Modification Regions Predict Clinical Outcomes of Pemetrexed Chemotherapy in Lung Adenocarcinoma.

OBJECTIVE: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. METHODS: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. RESULTS: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36-0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09-1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. CONCLUSION: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.

Complication Analysis in Korean Patients With Hemophilia A From 2007 to 2019: A Nationwide Study by the Health Insurance Review and Assessment Service Database.

BACKGROUND: There has been remarkable progress in hemophilia A (HA) treatment in Korea. Viral inactivation products were developed in 1989, use of recombinant factor VIII (FVIII) concentrates started in 2002, and prophylaxis expanded thereafter. This study was conducted to identify the changes in complications in HA before and after 1989 or 2002. METHODS: The study was performed using the 2007-2019 Healthcare Big Data Hub of the Health Insurance Review and Assessment Service. RESULTS: Among 2,557 patients, 1,084 had ≥ 1 complication; 829 had joint problems, 328 had viral infections, 146 had neurologic sequelae, and 87 underwent 113 surgeries or procedures due to complications. Patients born after 1989 had a significantly lower risk of viral infections than those born before 1989; 27.1% vs. 1.4% (P < 0.001, odds ratio [OR], 0.037). Patients born after 2002 had a significantly lower risk of joint problems than those born before 2002; 36.8% vs. 24.7% (P < 0.001, OR, 0.538). Patients born after 2002 had a higher incidence of neurologic sequelae than those born before 2002; 3.7% vs. 11.1% (P < 0.001, OR, 3.210). Medical expenses for complication-associated surgeries or procedures were ₩2,957,557,005. CONCLUSION: Viral infections have significantly decreased in Korean patients with HA. The degree of reduction of joint problems was lower than we expected, because it took > 10 years to expand prophylaxis widely. Neurologic sequelae have not decreased; thus, additional efforts to decrease intracranial hemorrhage are needed. We suggest personalized dosing of FVIII and more meticulous care during childbirth to further reduce the complications.

Promoter-Specific Variants in NeuroD1 and H3K4me3 Coincident Regions and Clinical Outcomes of Small Cell Lung Cancer.

BACKGROUND: Neurogenic differentiation 1 (NeuroD1) is a representative small cell lung cancer (SCLC) transcription regulator involved in the carcinogenesis and behavior of SCLC. Histone modifications play an important role in transcription, and H3 lysine 4 trimethylation (H3K4me3) is primarily associated with promoter regions. METHODS: We investigated the association between single nucleotide polymorphisms (SNPs) in NeuroD1 and H3K4me3 coincident regions, selected using ChIP sequencing (ChIP-seq), and the clinical outcomes of 261 patients with SCLC. RESULTS: Among 230 SNPs, two were significantly associated with both the chemotherapy response and overall survival (OS) of patients with SCLC. RNF145 rs2043268A>G was associated with worse chemotherapy response and OS (under a recessive model, adjusted odds ratio [aOR], 0.50, 95% confidence interval [CI], 0.26-0.94, P = 0.031, and adjusted hazard ratio [aHR], 1.88, 95% CI, 1.38-2.57, P < 0.001). CINP rs762105A>G was also associated with worse chemotherapy response and OS (under a dominant model, aOR, 0.47, 95% CI, 0.23-0.99, P = 0.046, and aHR, 2.03, 95% CI, 1.47-2.82, P < 0.001). ChIP-quantitative polymerase chain reaction and luciferase assay confirmed that the two SNPs were located in the active promoter regions and influenced the promoter activity of each gene. CONCLUSION: To summarize, among SNPs selected using ChIP-seq in promoter regions with high peaks in both NeuroD1 and H3K4me3, RNF145 rs2043268A>G and CINP rs762105A>G were associated with clinical outcomes in patients with SCLC and also affected the promoter activity of each gene.

Prehospital factors associated with out-of-hospital cardiac arrest outcomes in a metropolitan city: a 4-year multicenter study.

BACKGROUND: Prehospital factors play a vital role in out-of-hospital cardiac arrest (OHCA) survivability, and they vary between countries and regions. We investigated the prehospital factors associated with OHCA outcomes in a single metropolitan city in the Republic of Korea. METHODS: This study included adult medical OHCA patients enrolled prospectively, using data from the citywide OHCA registry for patients registered between 2018 and 2021. The primary outcome was survival to hospital discharge. Multivariable logistic regression analysis was conducted to determine the factors associated with the study population's clinical outcomes, adjusting for covariates. We performed a sensitivity analysis for clinical outcomes only for patients without prehospital return of spontaneous circulation prior to emergency medical service departure from the scene. RESULTS: In multivariable logistic regression analysis, older age (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.95-0.97), endotracheal intubation (adjusted odds ratio [aOR] 0.29; 95% [CIs] 0.17-0.51), supraglottic airway (aOR 0.29; 95% CI 0.17-0.51), prehospital mechanical chest compression device use (OR 0.13; 95% CI 0.08-0.18), and longer scene time interval (OR 0.96; 95% CI 0.93-1.00) were negatively associated with survival. Shockable rhythm (OR 24.54; 95% CI 12.99-42.00), pulseless electrical activity (OR 3.11; 95% CI 1.74-5.67), and witnessed cardiac arrest (OR 1.59; 95% CI 1.07-2.38) were positively associated with survival. In the sensitivity analysis, endotracheal intubation, supraglottic airway, prehospital mechanical chest compression device use, and longer scene time intervals were associated with significantly lower survival to hospital discharge. CONCLUSIONS: Regional resuscitation protocol should be revised based on the results of this study, and modifiable prehospital factors associated with lower survival of OHCA should be improved.

Sex-specific effect of body mass index and fasting glucose on gastric cancer risk and all causes mortality; a cohort study of 5.17 million.

BACKGROUND: Simultaneous evaluation of sex-specific effect of body mass index (BMI) and hyperglycemia on the risk of gastric cancer has been rarely reported. Here, we investigated the sex-specific effect of BMI and hyperglycemia on gastric cancer. METHODS: Persons who underwent National gastric cancer screening from 2006 to 2007 and had no gastric cancer at baseline, were enrolled and followed up to 2015. The risk of gastric cancer by BMI and glucose was measured using risk ratios (RRs) and 95% confidence intervals (CI). Adjusted Cox analysis was performed to evaluate the risk of death. RESULTS: Gastric cancers developed in 29,775 of 5.17 million. In the adjusted analysis, low BMI (<18.5 kg/m2; RR, 1.44; 95% CI, 1.36-1.53) and high fasting glucose (≥126 mg/dL; RR, 1.09; 95% CI, 1.05-1.13) increased the risk of gastric cancer. In sex-specific analysis, its risk by BMI was modified L-shape with cut-off value of 23 kg/m2 in men and 18.5 kg/m2 in women. Low BMI increased gastric cancer risk in men (RR, 1.39; 95% CI, 1.30-1.50) and women (RR, 1.48; 95% CI, 1.33-1.64). High fasting glucose increased the risk of gastric cancer in women (RR, 1.19; 95% CI, 1.11-1.28), but not in men. Low BMI increased all-cause mortality with cut-off value of 23 kg/m2 in men and 18.5 kg/m2 in women. CONCLUSIONS: Gastric cancer risk and all-cause mortality by BMI was L-shape with sex-specific cut-off value. The effect of fasting glucose on gastric cancer risk was different by sex.

Prognostic factors in patients hospitalized with community-acquired aspiration pneumonia.

INTRODUCTION: Patients with aspiration pneumonia (AP) exhibit higher mortality than those with non-AP. However, data regarding predictors of short-term prognosis in patients with community-acquired AP are limited. METHODS: Patients hospitalized with community-acquired pneumonia (CAP) were retrospectively classified into aspiration pneumonia (AP) and non-AP groups. The AP patients were further divided into nonsurvivors and survivors by 30-day mortality, and various clinical variables were compared between the groups. RESULTS: Of 1249 CAP patients, 254 (20.3%) were classified into the AP group, of whom 76 patients (29.9%) died within 30 days. CURB-65, pneumonia severity index (PSI), and Infectious Diseases Society of America/American Thoracic Society criteria for severe CAP (SCAP) showed only modest prognostic performance for the prediction of 30-day mortality (c-statistics, 0.635, 0.647, and 0.681, respectively). Along with the PSI and SCAP, Eastern Cooperative Oncology Group performance status (ECOG-PS) and blood biomarkers, including, N-terminal of prohormone brain natriuretic peptide (NT-proBNP) and albumin, were independent predictors of 30-day mortality. In models based on clinical prediction rules, including CURB-65, PSI, and SCAP, the addition of ECOG-PS further improved their c-statistics compared to the clinical prediction rules alone. In the four combinations based on SCAP, ECOG-PS, and two blood biomarkers (NT-proBNP and albumin), the c-statistics further increased to reach approximately 0.8. CONCLUSIONS: CURB-65, PSI, and SCAP exhibited only modest discriminatory power in predicting the 30-day mortality of patients with community-acquired AP. The addition of performance status and blood biomarkers, including NT-proBNP and albumin, further increased prognostic performance, showing good predictive accuracy in the SCAP-based model.

Beta-Lactam Plus Macrolide for Patients Hospitalized With Community-Acquired Pneumonia: Difference Between Autumn and Spring.

BACKGROUND: The 2017 Korean guideline on community-acquired pneumonia (CAP) recommended beta-lactam plus macrolide combination therapy for patients hospitalized with severe pneumonia, and beta-lactam monotherapy for mild-to-moderate pneumonia. However, antibiotic treatment regimen for mild-to-moderate CAP has never been evaluated for Korean patients. METHODS: In this retrospective cohort study, study patients were selected from three evaluation periods (October 1 to December 31, 2014; April 1 to June 30, 2016; October 1 to December 31, 2017) of the National Quality Assessment Program for CAP management and the National Health Insurance data on the selected patients was extracted from 1 year before the first patient enrollment and 1 year after the last patient enrollment at each evaluation period for the analysis of risk adjustment and outcomes. The survival rates between beta-lactam plus macrolide (BM) groups and beta-lactam monotherapy (B) were compared using a Kaplan-Meier survival analysis after propensity score matching by age, gender, confusion, urea, respiratory rate, blood pressure at age of 65 years or older (CURB-65), and Charlson comorbidity index for risk adjustment. The differences between autumn and spring season were also evaluated. RESULTS: A total of 30,053 patients were enrolled. Mean age and the male-to-female ratio were 64.7 ± 18.4 and 14,197:15,856, respectively. After matching, 2,397 patients in each group were analyzed. The 30-day survival rates did not differ between the BM and B groups (97.3% vs. 96.5%, P = 0.081). In patients with CURB-65 ≥ 2, the 30-day survival rate was higher in the BM than in the B group (93.7% vs. 91.0%, P = 0.044). Among patients with CURB-65 ≥ 2, the 30-day survival rate was higher in the BM than in the B group (93.3% vs. 88.5%, P = 0.009) during autumn season, which was not observed during spring (94.2% vs. 94.1%, P = 0.986). CONCLUSION: Beta-lactam plus macrolide combination therapy shows potential as an empirical therapy for CAP with CURB-65 ≥ 2, especially in autumn.

Collateral Effect of the Coronavirus Disease 2019 Pandemic on Emergency Department Visits in Korea.

Background and Objectives: The ongoing coronavirus disease 2019 (COVID-19) pandemic represents a global public health crisis that has had a serious impact on emergency department (ED) utilization trends. The aim of this study was to investigate the collateral effects of the COVID-19 pandemic on ED utilization trends by patients with mild and severe conditions as well as on 7-day fatality rates. Materials and Methods: We analyzed entries in the Korean National Health Insurance claims database between 1 January 2018 and 31 December 2020. Six target patient groups were identified using the main diagnosis codes in the 10th revision of the International Classification of Diseases. Numbers of patients visiting the ED, their age, regional differences, 7-day fatality rate, and rate of emergency procedures were compared between 2018 and 2019 as the control period and 2020, when the COVID-19 pandemic was in full force. Results: During the 2020 COVID-19 pandemic, the number of patients who visited the ED with low-acuity diseases and severe acute respiratory infection diseases sharply decreased to −46.22% and −56.05%, respectively. However, the 7-day fatality rate after ED visits for low-acuity diseases and severe acute respiratory infection diseases increased to 0.04% (p < 0.01), and 1.65% (p < 0.01), respectively, in 2020 compared to that in the control period. Conclusions: During the 2020 COVID-19 pandemic, ED utilization impacted and 7-day fatality rate after ED visit increased. Health authorities and health care providers must strive to ensure prompt delivery of optimal care in EDs for patients with severe or serious symptoms and time-dependent diseases, even during the ongoing COVID-19 or potential future pandemics.

Short-term serial assessment of electronic patient-reported outcome for depression and anxiety in breast Cancer.

PURPOSE: The incidence of depression and anxiety is higher in patients with breast cancer than in the general population. We evaluated the degree of depression and anxiety and investigated the changes in patients with breast cancer during the treatment period and short-term follow-up period. METHODS: Overall, 137 patients with breast cancer were evaluated using the Patient Health Questionnaire 9-item depression scale (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7). The scales were developed as a web-based electronic patient-reported outcome measure, and serial results were assessed before the operation, after the operation, in the post-treatment period, and in the 6-month follow-up period after surgery. RESULTS: The degree of depression and anxiety increased during treatment and decreased at 6-month follow-up, even if there were no statistical differences among the four periods (PHQ-9: p = 0.128; GAD-7: p = 0.786). However, daily fatigue (PHQ-9 Q4) and insomnia (PHQ-9 Q3) were the most serious problems encountered during treatment and at 6-month follow-up, respectively. In the GAD-7, worrying too much (Q3) consistently showed the highest scores during the treatment and follow-up periods. Of the patients, 7 (5.11%) and 11 (8.03%) patients had a worsened state of depression and anxiety, respectively, after treatment compared with before treatment. CONCLUSION: Most factors associated with depression and anxiety improved after treatment. However, factors such as insomnia and worrying too much still disturbed patients with breast cancer, even at 6-month follow-up. Therefore, serial assessment of depression and anxiety is necessary for such patients.

Polymorphisms in Glycolysis-Related Genes Are Associated with Clinical Outcomes of Paclitaxel-Cisplatin Chemotherapy in Non-Small Cell Lung Cancer.

OBJECTIVE: This study was conducted to investigate whether polymorphisms in glycolysis-related genes are associated with clinical outcomes of patients with advanced-stage non-small cell lung cancer (NSCLC) undergoing chemotherapy. METHODS: A total of 377 patients with NSCLC were enrolled. Sixty-five single-nucleotide polymorphisms in 26 genes involved in the glycolytic pathway were evaluated. The associations of the variants with the chemotherapy response and overall survival (OS) were analyzed. RESULTS: Among the 65 variants investigated, PFKL rs2073436C>G and GPI rs7248411C>G significantly correlated with clinical outcomes after chemotherapy in multivariate analyses. PFKL rs2073436C>G was significantly associated with both a worse response to chemotherapy (adjusted odds ratio [aOR] = 0.64, 95% CI = 0.45-0.90, p = 0.01) and a worse OS (adjusted hazard ratio [aHR] = 1.35, 95% CI = 1.14-1.61, p = 0.001). GPI rs7248411C>G was significantly associated with both a better chemotherapy response (aOR = 1.58, 95% CI = 1.07-2.23, p = 0.02) and a better OS (aHR = 0.80, 95% CI = 0.66-0.98, p = 0.03). When stratified by tumor histology, PFKL rs2073436C>G was significantly associated with OS only in squamous cell carcinoma, whereas GPI rs7248411C>G exhibited a significant association with the chemotherapy response and OS only in adenocarcinoma. CONCLUSION: This result suggests that the PFKL rs2073436C>G and GPI rs7248411C>G are useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.

Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). METHODS: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. RESULTS: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54-0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13-4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08-1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10-3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41-1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11-6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17-2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12-6.88, p = 0.03, respectively). CONCLUSIONS: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

Reliability of digital measurement methods on the marginal fit of fixed prostheses: A systematic review and meta-analysis of in vitro studies.

STATEMENT OF PROBLEM: Digital methods have been increasingly used to evaluate the fit of prostheses, but the accuracy of digital methodology has not been fully clarified. PURPOSE: The purpose of this systematic review and meta-analysis was to assess the reliability of digital measurement methods for evaluating the marginal fit of fixed dental prostheses (FDPs) and to identify the potential factors that can influence the accuracy of the measurement methods. MATERIAL AND METHODS: The differences between digital and conventional measurement methods were analyzed by searching PubMed, Scopus, Web of Science, and Google Scholar databases for studies reporting the marginal fit of FDPs. The agreement of data collection among the reviewers was confirmed by the Cohen kappa coefficient, and the MINORS scale was used to rate the quality of the included studies. The heterogeneity among the studies was evaluated, and meta-analyses with global and subgroup analyses were performed. RESULTS: Ten in vitro studies were selected according to the eligibility criteria with substantial interreader concordance (κ=0.88). The standard mean difference of the meta-analysis for marginal discrepancy was 0.12 µm (95% confidence interval: -0.12 to 0.35), indicating that no statistically significant differences were found in the marginal discrepancies observed with digital and conventional methods (P=.343). The subgroup analysis for alloy-based prostheses was not significantly different, nor between the material and measurement methods (P=.060). CONCLUSIONS: Digital methods appear to be reliable as an alternative to conventional methods for evaluating the marginal fit of FDPs. To confirm the results of this study and to identify the influencing factors on the accuracy of digital measurement methods, further controlled laboratory and clinical studies are needed.

Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery.

BACKGROUND: We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC. METHODS: Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated. RESULTS: Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64-0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71-0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (Ptrend = 0.02) in tumor tissues. CONCLUSIONS: These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.

Functional intronic variant of SLC5A10 affects DRG2 expression and survival outcomes of early-stage non-small-cell lung cancer.

RegulomeDB is a new tool that can predict the regulatory function of genetic variants. We applied RegulomeDB in selecting putative functional variants and evaluated the relationship between these variants and survival outcomes of surgically resected non-small-cell lung cancer. Among the 244 variants studied, 14 were associated with overall survival (P < 0.05) in the discovery cohort and one variant (rs2257609 C>T) was replicated in the validation cohort. In the combined analysis, rs2257609 C>T was significantly associated with worse overall and disease-free survival under a dominant model (P = 2 × 10-5 and P = 0.001, respectively). rs2257609 is located in the SLC5A10 intron, but RegulomeDB predicted that this variant affected DRG2, not SLC5A10 expression. The expression level of SLC5A10 was not different with the rs2257609 genotype. However, DRG2 expression was different according to the rs2257609 genotype (Ptrend   = 0.03) and was significantly higher in tumor than in non-malignant lung tissues (P = 1 × 10-5 ). Luciferase assay also showed higher promoter activity of DRG2 in samples with the rs2257609 T allele (P < 0.0001). rs2257609 C>T affected DRG2 expression and, thus, influenced the prognosis of early-stage non-small-cell lung cancer. This study was approved by the Institutional Review Broad of Kyungpook National University of Hospital (Approval No. KNUMC 2014-04-210-003).

Visualization and Quantification of Radiochemical Purity by Cerenkov Luminescence Imaging.

Determination of radiochemical purity is essential for characterization of all radioactive compounds, including clinical radiopharmaceuticals. Radio-thin layer chromatography (radio-TLC) has been used as the gold standard for measurement of radiochemical purity; however, this method has several limitations in terms of sensitivity, spatial resolution, two-dimensional scanning, and quantification accuracy. Here, we report a new analytical technique for determination of radiochemical purity based on Cerenkov luminescence imaging (CLI), whereby entire TLC plates are visualized by detection of Cerenkov radiation. Sixteen routinely used TLC plates were tested in combination with three different radioisotopes (131I, 124I, and 32P). All TLC plates doped with a fluorescent indicator showed excellent detection sensitivity with scanning times of less than 1 min. The new CLI method was superior to the traditional radio-TLC scanning method in terms of sensitivity, scanning time, spatial resolution, and two-dimensional scanning. The CLI method also showed better quantification features across a wider range of radioactivity values compared with radio-TLC and classical zonal analysis, especially for ß--emitters such as 131I and 32P.

Glucose Transporter 1 Gene Variants Predict the Prognosis of Patients with Early-Stage Non-small Cell Lung Cancer.

BACKGROUND: This study was conducted to investigate whether polymorphisms of glucose transporter 1 (GLUT1) gene are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. METHODS: Five single nucleotide polymorphisms (SNPs) in GLUT1 were investigated in a total of 354 patients with NSCLC who underwent curative surgery. The association of the SNPs with patients' survival was analyzed. RESULTS: Among the five SNPs investigated, two SNPs (GLUT1 rs3820589T > A and rs4658G > C) were significantly associated with OS in multivariate analyses. GLUT1 rs3820589T > A was associated with significantly better OS (adjusted hazard ratio [aHR] = 0.57, 95% confidence interval [CI] = 0.34-0.94, P = 0.03, under dominant model), and rs4658G > C was associated with significantly worse OS (aHR = 1.91, 95% CI = 1.09-3.33, P = 0.02, under recessive model). In the stratified analysis by tumor histology, the effect of these SNPs on OS was only significant in squamous cell carcinoma but not in adenocarcinoma. When the two SNPs were combined, OS decreased as the number of bad genotypes increased (Ptrend = 4 × 10-3). CONCLUSIONS: This study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.

Polymorphisms in Epithelial-Mesenchymal Transition-Related Genes and the Prognosis of Surgically Treated Non-small Cell Lung Cancer.

BACKGROUND: This study was conducted to determine whether single-nucleotide polymorphisms (SNPs) in EMT-related genes may influence the prognosis of NSCLC after surgery. METHODS: There were 88 SNPs in EMT-related genes evaluated in a discovery set of 376 patients who underwent curative surgery for NSCLC. Significantly, 14 SNPs were evaluated in a validation set of 428 patients. Luciferase assay and RT-PCR were conducted to examine functional relevance of polymorphisms. RESULTS: Fourteen SNPs that were associated with survival outcomes in a discovery set were selected for validation. Among those, two SNPs (FOXF2 rs1711972A>C and HEYL rs784621G>A) were replicated in a validation study. In combined analysis, FOXF2 rs1711972 AC+CC genotype was associated with significantly better overall survival (OS) and disease-free survival (DFS) compared with AA genotype (adjusted hazard ratio [aHR] for OS = 0.67, 95% confidence interval [CI] 0.51-0.88, P = 0.004; and aHR for DFS = 0.77, 95% CI 0.62-0.95, P = 0.01). HEYL rs784621 AA genotype exhibited a significantly worse OS compared with GG+GA genotype (aHR for OS = 2.65, 95% CI 1.63-4.31, P = 8 × 10-5). FOXF2 rs1711972C allele had a significantly increased promoter activity than rs1711972A allele (P = 0.01), and HEYL rs784621A allele had a significantly lower promoter activity than rs784621G allele (P = 0.004). FOXF2 rs1711972A>C was significantly associated with increased FOXF2 mRNA expression. CONCLUSIONS: FOXF2 rs1711972A>C and HEYL rs784621G>A were associated with survival outcomes of surgically treated NSCLC. These SNPs may help to identify patients at high risk of poor disease outcomes.