Stuck fragment of totally implantable central venous access ports during removal: risk factor analysis in children.

BACKGROUND: Totally implantable central venous access ports (TICVAPs) have increasingly been used in pediatric patients because they provide reliable venous access. However, many complications associated with TICVAPs have been reported. Here, we aimed to analyze the risk factors of stuck fragment of TICVAPs during removal in children and recommend the appropriate periods of use or exchange. METHODS: We retrospectively reviewed the medical records of 121 patients, including 147 cases of TICVAP insertion, between January 2010 and July 2020. RESULTS: Among these, 98 cases in 72 patients involved of TICVAP removal, with 8 patients having had incomplete TICVAP removal resulting in a stuck fragment of the catheter in the central venous system (Group S). All Group S patients were male and had acute leukemia, and their TICVAPs were used for chemotherapy. Compared with the complete removal group (Group N), stuck fragment in Group S were significantly found in patients diagnosed with acute leukemia than those with other diagnoses (p < 0.001). Indwelling duration and body weight change during TICVAP indwelling were significantly longer and larger in Group S, respectively (p < 0.001). In multivariate logistic regression analysis, indwell duration (odds ratio [OR], 1.13; 95% confidence interval [Cl] 1.02-1.37, p = 0.10), body weight change during indwell (OR, 1.00; 95% Cl 0.83-1.18, p = 0.97), and platelet count at TICVAP insertion (OR, 0.98; 95% Cl 0.95-0.99; p = 0.48) showed an increased trend of risk for a stuck catheter. CONCLUSIONS: We suggest prophylactic catheter exchange before indwell duration of 46 months (area under the curve [AUC], 0.949; 95% Cl 0.905-0.993) and body weight change up to 9.9 kg (AUC, 0.903; 95% Cl 0.840-0.966) to prevent a catheter from becoming stuck, especially in children with rapidly growing acute leukemia. Management of a stuck fragment remains controversial in asymptomatic patients, and we suggest careful, close observation rather than aggressive and invasive treatment.

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.

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.

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.

Visceral Pleural Invasion Is a Significant Prognostic Factor in Patients with Partly Solid Lung Adenocarcinoma Sized 30 mm or Smaller.

BACKGROUND: This study analyzed the impact of visceral pleural invasion (VPI) on the disease-free survival (DFS) of patients with partly solid pulmonary adenocarcinoma sized 30 mm or smaller. METHOD: This is a retrospective study of 147 patients with surgically resected pathologic N0 pulmonary adenocarcinoma that had a partly solid appearance on preoperative computed tomography. All patients presented with tumors of size 30 mm or smaller. The DFS rate was estimated using Kaplan-Meier method. A multivariate analysis for prognostic factors was performed using the Cox proportional hazards regression model. RESULTS: VPI was found in 36 patients. The 5-year DFS in 111 patients without VPI (97.6%) was significantly higher than that in 36 patients with VPI (63%) (p < 0.0001). Univariate analysis revealed three significant poor prognostic predictors: the presence of VPI, the presence of lymphovascular invasion, and the size of the solid component on computed tomography (>20, ≤30 mm). According to the multivariate analysis, VPI was found to be a significant poor prognostic predictor (hazard ratio for DFS = 7.31, 95% confidence interval = 1.444-37.014, p = 0.016). CONCLUSION: VPI is a significant predictor of poor prognosis for small-sized (≤30 mm) partly solid lung adenocarcinoma. Therefore, upstaging of the T factor from T1 to T2 on the basis of VPI as described by the TNM staging system is mandatory regardless of ground-glass opacity in small lung adenocarcinoma.

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.

Polymorphisms in cancer-related pathway genes and lung cancer.

We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.A total of 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes involved in carcinogenesis were evaluated using an Affymetrix custom-made GeneChip in 610 nonsmall cell lung cancer patients and 610 healthy controls. A replication study was conducted in an independent set of 490 cases and 486 controls. 68 SNPs were significantly associated with lung cancer in the discovery set and tested for replication.Among the 68 SNPs, three SNPs (corepressor interacting with RBPJ 1 (CIR1) rs13009079T>C, ribonucleotide reductase M1 (RRM1) rs1465952T>C and solute carrier family 38, member 4 (SLC38A4) rs2429467C>T) consistantly showed significant associations with lung cancer in the replication study. In combined analysis, adjusted odds ratio for CIR1 rs13009079T>C, RRM1 rs1465952T>C and SLC38A4 rs2429467C>T were 0.69, 0.71 and 0.73, respectively (p=4×10-5, 0.01 and 0.001, respectively) under the dominant model. The relative mRNA expression level of CIR1 was significantly associated with rs13009079T>C genotypes in normal lung tissues (ptrend=0.03).These results suggest that the three SNPs, particularly CIR1 rs13009079T>C, may play a role in the pathogenesis of lung cancer.

The Different Effect of VEGF Polymorphisms on the Prognosis of Non-Small Cell Lung Cancer according to Tumor Histology.

Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56-1.03 in SCC; aHR = 1.33, 95% CI = 0.98-1.82 in AC; P for heterogeneity = 0.01) and DFS (aHR = 0.75, 95% CI = 0.58-0.97 in SCC; aHR = 1.26, 95% CI = 1.00-1.60 in AC; P for heterogeneity = 0.004) according to the rs833061T>C genotypes. Our results suggest that the prognostic role of VEGF rs833061T>C may differ depending on tumor histology.

Morcellation in semi-exteriorized pouch in thoracoscopic surgery.

Extraction of small specimens such as excised blebs through trocar site is a simple procedure. However, working thoracotomy is mandatory for removal of large solid intrathoracic tumors. We have used an instrument to morcellate a specimen in semi-exteriorized pouch during video-assisted thoracoscopic surgery. Morcellation has provided the solution for removing large solid benign tumors without a working thoracotomy.

Serial changes in pulmonary function after video-assisted thoracic surgery lobectomy in lung cancer patients.

BACKGROUND: The aim of this study is to evaluate the serial changes in pulmonary function and the recovery time for the observed postoperative values to reach the predicted postoperative values after video-assisted thoracic surgery (VATS) lobectomy for lung cancer. PATIENTS AND METHODS: Patients undergoing VATS lobectomy for lung cancer were prospectively evaluated using complete preoperative and repeated postoperative pulmonary function tests (PFTs). The parameters of PFT at each time were compared according to the resected lobe as well as the presence of chronic obstructive pulmonary disease (COPD). The differences between the observed and predicted postoperative values of PFT and the recovery time for the observed values to reach the predicted values were calculated. RESULTS: Seventy-two patients (33 men, 39 women; mean age: 63.9 years) received complete pre- and postoperative regular PFT after undergoing VATS lobectomy. Of these patients, 24 (33.3%) patients satisfied the criteria for COPD. During the immediate postoperative period, forced vital capacity (FVC) percentage of the patients who received right lower lobectomy patients was decreased most significantly compared with the preoperative values. Compared with the upper lobectomy (UL) group, the lower lobectomy (LL) group showed a significant decrease of FVC% up to 6 months. However, there was no significant difference at 12 months after surgery. Patients with COPD showed little reduction of FEV1% that persisted significantly until 1 month after the surgery in both UL and LL groups. The recovery time was shortest in the left lower lobectomy patients, and it was shorter in the LL group than in the UL group. CONCLUSIONS: Postoperative pulmonary function and recovery time were different depending on the lobe resected and presence of COPD in VATS lobectomy patients. The information obtained from postoperative serial PFT would help accurately predict postoperative pulmonary function changes and recovery time after VATS lobectomy for lung cancer.

Left-sided catamenial pneumothorax associated with diaphragmatic fenestrations.

Catamenial pneumothorax is a rare disorder with an unknown etiology. It is characterized by recurrent spontaneous pneumothorax during or preceding menstruation. One proposed mechanisms is diaphragmatic fenestration. The majority of catamenial pneumothorax is right sided. We report a left-sided catamenial pneumothorax associated with multiple diaphragmatic fenestrations.

Exonuclease 1 genetic variant is associated with clinical outcomes of pemetrexed chemotherapy in lung adenocarcinoma.

Pemetrexed is an anti-folate agent which is one of the most frequently used chemotherapy agents for non-squamous non-small cell lung cancer (NSCLC) patients. However, clinical response to pemetrexed chemotherapy and survival outcome of patients varies significantly. We evaluated whether the genetic variants in miRNA target sites may affect the treatment outcome of pemetrexed chemotherapy in lung adenocarcinoma patients. One hundred SNPs in miRNA binding regions in cancer-related genes were obtained from the crosslinking, ligation, and sequencing of hybrids (CLASH) and CancerGenes database, and the associations with the response to pemetrexed chemotherapy and survival outcomes were investigated in 314 lung adenocarcinoma patients. Two polymorphisms, EXO1 rs1047840G>A and CAMKK2 rs1653586G>T, were significantly associated with worse chemotherapy response (adjusted odds ratio [aOR] = 0.41, 95% CI = 0.24-0.68, P = 0.001, under dominant model; and aOR = 0.33, 95% CI = 0.16-0.67, P = 0.002, under dominant model, respectively) and worse OS (adjusted hazard ratio [aHR] = 1.34, 95% CI = 1.01-1.77, P = 0.04, under dominant model; and aHR = 1.50, 95% CI = 1.06-2.13, P = 0.02, under dominant model, respectively) in multivariate analyses. Significantly increased luciferase activity was noted in EXO1 rs1047840 A allele compared to G allele. In conclusion, two SNPs in miRNA binding sites, especially EXO1 rs1047840G>A, were associated with the chemotherapy response and survival outcome in lung adenocarcinoma patients treated with pemetrexed.

Synchrotron Radiation-Based Refraction-Contrast Tomographic Images Using X-ray Dark-Field Imaging Optics in Human Lung Adenocarcinoma and Histologic Correlations.

The aim of this study was to evaluate the clinical implication of synchrotron radiation imaging techniques for human lung adenocarcinoma in comparison with pathologic examination. A refraction-based tomographic imaging technique called the X-ray dark-field imaging (XDFI) method was used to obtain computed tomographic images of human lung adenocarcinoma at the beam line at Photon Factory BL 14B at the High Energy Accelerator Research Organization (KEK) in Tsukuba, Japan. Images of normal lung tissue were also obtained using the same methods and reconstructed as 3D images. Both reconstructed images were compared with pathologic examinations from histologic slides which were made with identical samples. Pulmonary alveolar structure including terminal bronchioles, alveolar sacs, and vasculatures could be identified in synchrotron radiation images of normal lung. Hyperplasia of interstitial tissue and dysplasia of alveolar structures were noticed in images of lung adenocarcinoma. Both synchrotron radiation images were considerably correlated with images from histologic slides. Lepidic patterns of cancer tissue were distinguished from the invasive area in synchrotron radiation images of lung adenocarcinoma. Refraction-contrast tomographic techniques using synchrotron radiation could provide high-resolution images of lung adenocarcinoma which are compatible with those from pathologic examinations.

Clinical implication of minimal presence of solid or micropapillary subtype in early-stage lung adenocarcinoma.

BACKGROUND: We investigated the clinical features and surgical outcomes of lung adenocarcinoma with minimal solid or micropapillary (S/MP) components, with a focus on stage IA. METHODS: We enrolled 506 patients with lung adenocarcinoma who underwent curative resection in this study. Clinical features and surgical outcomes were compared between the groups with and without the S/MP subtype (S/MP+ and S/MP-, respectively), and between the group with an S/MP proportion of ≤5% (S/MP5) and the S/MP-. RESULTS: The S/MP subtype was present in 247 patients (48.8%); 129 (25.5%) were grouped as the S/MP5 group. The S/MP+ and S/MP5 groups had larger tumors, higher frequency of lymph node metastasis, and more advanced stages of disease than the S/MP- group (P < 0.001, all comparisons). Pleural, lymphatic, and vascular invasions occurred more frequently in the S/MP+ and S/MP5 groups (P < 0.001, all comparisons for S/MP+ vs. S/MP-; P ≤ 0.01, all comparisons for S/MP5 vs. S/MP-). The S/MP+ and S/MP5 groups showed a shorter time to recurrence and cancer-related death than the S/MP- group(P < 0.001, both comparisons). For stage I, the presence or absence of the S/MP subtype defined prognostic subgroups better than the stage IA/IB classification. Notably, in the multivariate analysis, the minimal S/MP component was a significant predictor of recurrence, even in stage IA. CONCLUSIONS: The presence of the minimal S/MP component was a significant predictor of poor prognosis after surgery, even in stage IA patients. Clinical trials to evaluate the advantages of adjuvant chemotherapy for this subset of patients and further investigations to understand underlying biological mechanisms of poor prognosis are needed. KEY POINTS: Significant findings of the study: We demonstrated that only minimal presence of solid or micropapillary component was profoundly associated with aggressive clinicopathological features and poor prognosis after complete resection even in stage IA lung adenocarcinoma. WHAT THIS STUDY ADDS: Our results suggest that minimal presence of these subtypes is a strong prognostic factor which should be taken into account in the risk assessment for adjuvant chemotherapy in lung adenocarcinoma.

TGFBI Promoter Methylation is Associated with Poor Prognosis in Lung Adenocarcinoma Patients.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide and has high rates of metastasis. Transforming growth factor beta-inducible protein (TGFBI) is an extracellular matrix component involved in tumour growth and metastasis. However, the exact role of TGFBI in NSCLC remains controversial. Gene silencing via DNA methylation of the promoter region is common in lung tumorigenesis and could thus be used for the development of molecular biomarkers. We analysed the methylation status of the TGFBI promoter in 138 NSCLC specimens via methylation-specific PCR and evaluated the correlation between TGFBI methylation and patient survival. TGFBI promoter methylation was detected in 25 (18.1%) of the tumours and was demonstrated to be associated with gene silencing. We observed no statistical correlation between TGFBI methylation and clinicopathological characteristics. Univariate and multivariate analyses showed that TGFBI methylation is significantly associated with poor survival outcomes in adenocarcinoma cases (adjusted hazard ratio = 2.88, 95% confidence interval = 1.19-6.99, P = 0.019), but not in squamous cell cases. Our findings suggest that methylation in the TGFBI promoter may be associated with pathogenesis of NSCLC and can be used as a predictive marker for lung adenocarcinoma prognosis. Further large-scale studies are needed to confirm these findings.

Traumatic Right Pulmonary Artery Rupture after Accidentally Being Stepped on the Chest.

Traumatic pulmonary artery rupture is a rare, life-threatening injury. Currently, no strict guidelines for its management exist. Herein, we report a successful surgical repair of a right pulmonary artery rupture caused by being stepped on.

TSC2 genetic variant and prognosis in non-small cell lung cancer after curative surgery.

This study was conducted to investigate the associations between polymorphisms of genes involved in the LKB1 pathway and the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Twenty-three single nucleotide polymorphisms (SNPs) in the LKB1 pathway were investigated in 782 patients with NSCLC who underwent curative surgery. The association of SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. Among the 23 SNPs investigated, TSC2 rs30259G > A was associated with significantly worse OS and DFS (adjusted hazard ratio for OS 1.88, 95% confidence interval 1.21-2.91, P = 0.005; adjusted hazard ratio for DFS 1.65, 95% confidence interval 1.15-2.38, P = 0.01, under codominant models, respectively). Subgroup analysis showed that SNPs were significantly associated with survival outcomes in squamous cell carcinoma, ever-smokers, and stage I, but not in adenocarcinoma, never-smokers, and stage II-IIIA. The results suggest that TSC2 rs30259G > A may be useful to predict prognosis in patients with NSCLC, especially squamous cell carcinoma, after curative surgery.

Glucose transporter 3 gene variant is associated with survival outcome of patients with non-small cell lung cancer after surgical resection.

This study was conducted to explore whether polymorphisms of glucose transporter 3 (GLUT3) gene affect the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Four single nucleotide polymorphisms (SNPs) in GLUT3 were investigated in a total of 782 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. Among the four SNPs investigated, GLUT3 rs7309332C>T was significantly associated with OS and DFS in multivariate analyses. The SNP was associated with significantly worse OS (adjusted hazard ratio [aHR] = 1.62, 95% confidence interval [CI] = 1.04-2.53, P = 0.03, under recessive model), and worse DFS (aHR = 1.64, 95% CI = 1.18-2.29, P = 0.003, under recessive model). When stratified by tumor histology, the association between the GLUT3 rs7309332C>T and OS/DFS was not limited to either squamous cell carcinoma (SCC) or adenocarcinoma (AC), although the significant association remained only in AC for OS (P = 0.40 for SCC and P = 0.04 for OS) and only in SCC for DFS (P = 0.03 for SCC and P = 0.08 for OS). When AC patients were stratified according to EGFR mutation status, the SNP was significantly associated with DFS in patients with EGFR mutant tumors (aHR = 2.47, 95% CI = 1.15-5.30, P = 0.02, under recessive model), but not in those with EGFR wild-type tumors. This study suggests that genetic variation in GLUT3 may be useful in predicting survival of patients with early stage NSCLC.

Intronic variant of EGFR is associated with GBAS expression and survival outcome of early-stage non-small cell lung cancer.

BACKGROUND: Genome-wide association studies have indicated that most of the currently identified disease and trait-associated single nucleotide polymorphisms (SNPs) are intronic or intergenic. RegulomeDB is a recently developed database that provides functional annotations for regulatory features of SNPs located in non-coding regions. We evaluated the potential regulatory SNPs in the EGFR gene region using RegulomeDB and their associations with prognosis after surgery in non-small cell lung cancer (NSCLC) patients. METHODS: A total of 698 patients with surgically resected NSCLC were enrolled and seven SNPs were selected based on the RegulomeDB database. All SNPs were genotyped using SEQUENOM MassARRAY iPLEX assay. RESULTS: Among the seven SNPs evaluated, rs9642391 (EGFR ivs19+2851C>G) was significantly associated with survival outcome (adjusted hazard ratio [HR] for overall survival = 0.70, 95% confidence interval [CI] 0.56-0.87, P = 0.001; adjusted HR for disease-free survival = 0.82, 95% CI 0.70-0.97, P = 0.02; under a codominant model). According to RegulomeDB, rs9642391C>G, which is located in intron 19 of EGFR, was predicted to influence the expression of GBAS but not EGFR. As predicted, rs9642391C>G was associated with GBAS (P = 0.024) but not EGFR messenger RNA expression in tumor tissues. CONCLUSION: In conclusion, our study provides evidence that rs9642391C>G in the intron of EGFR is associated with GBAS expression and survival outcomes of patients with surgically resected early-stage NSCLC.

Regulatory variants in cancer-related pathway genes predict survival of patients with surgically resected non-small cell lung cancer.

BACKGROUND: We conducted this study to identify genetic variants in cancer-related pathway genes which can predict prognosis of NSCLC patients after surgery, using a comprehensive list of regulatory single nucleotide polymorphisms (SNPs) prioritized by RegulomeDB. METHOD: A total of 509 potentially functional SNPs in cancer-related pathway genes selected from RegulomeDB were evaluated. These SNPs were analyzed in a discovery set (n=354), and a replication study was performed in an independent set (n=772). The association of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: In the discovery set, 76 SNPs were significantly associated with OS or DFS. Among the 76 SNPs, the association was consistently observed for 5 SNPs (ERCC1 rs2298881C>A, BRCA2 rs3092989G>A, NELFE rs440454C>T, PPP2R4 rs2541164G>A, and LTBP4 rs3786527G>A) in the validation set. In combined analysis, ERCC1 rs2298881C>A, BRCA2 rs3092989, NELFE rs440454C>T, and PPP2R4 rs2541164G>A were significantly associated with OS and DFS (adjusted HR ·aHR· for OS=1.46, 0.62, 078, and 0.76, respectively; P=0.003, 0.002, 0.007, and 0.003 respectively; and aHR for DFS=1.27, 0.69, 0.86, and 0.82, respectively; P=0.02, 0.002, 0.03, and 0.008, respectively). The LTBP4 rs3786527G>A was significantly associated with better OS (aHR=0.75; P=0.003). CONCLUSION: Our results suggest that five SNPs in the cancer-related pathway genes may be useful for the prediction of the prognosis in patients with surgically resected NSCLC.