Quiescin Sulfhydryl Oxidase 1 (QSOX1) Secreted by Lung Cancer Cells Promotes Cancer Metastasis.

As lung cancer shows the highest mortality in cancer-related death, serum biomarkers are demanded for lung cancer diagnosis and its treatment. To discover lung cancer protein biomarkers, secreted proteins from primary cultured lung cancer and adjacent normal tissues from patients were subjected to LC/MS⁻MS proteomic analysis. Quiescin sulfhydryl oxidase (QSOX1) was selected as a biomarker candidate from the enriched proteins in the secretion of lung cancer cells. QSOX1 levels were higher in 82% (51 of 62 tissues) of lung cancer tissues compared to adjacent normal tissues. Importantly, QSOX1 serum levels were significantly higher in cancer patients (p < 0.05, Area Under curve (AUC) = 0.89) when measured by multiple reaction monitoring (MRM). Higher levels of QSOX1 were also uniquely detected in lung cancer tissues, among several other solid cancers, by immunohistochemistry. QSOX1-knock-downed Lewis lung cancer (LLC) cells were less viable from oxidative stress and reduced migration and invasion. In addition, LLC mouse models with QSOX1 knock-down also proved that QSOX1 functions in promoting cancer metastasis. In conclusion, QSOX1 might be a lung cancer tissue-derived biomarker and be involved in the promotion of lung cancers, and thus can be a therapeutic target for lung cancers.

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 mitotic checkpoint-related genes can influence survival outcomes of early-stage non-small cell lung cancer.

This study was conducted to investigate the association between variants in mitotic checkpoint-related genes and clinical outcomes of non-small cell lung cancer (NSCLC). A total of 766 patients with NSCLC who underwent curative surgery were enrolled. Among the 73 variants evaluated, 4 variants were related with survival outcomes. BUB3 rs7897156C>T was associated with worse overall survival under a recessive model (adjusted hazard ratio = 1.58, 95% confidence interval = 1.07-2.33, P = 0.02). AURKB rs1059476G>A was associated with better overall survival under a recessive model (adjusted hazard ratio = 0.64, 95% confidence interval = 0.41-0.99, P = 0.05). PTTG1 rs1895320T>C and RAD21 rs1374297C>G were associated with worse disease-free survival. In the functional study, relative luciferase activity was higher at the BUB3 rs7897156T allele compared to that at the C allele. Western blot showed that the phosphorylation of AKT and mTOR in the AURKB variant-type (M298) was significantly lower than in the AURKB wild-type (T298). We found that 4 variants of mitotic checkpoint-related genes were associated with survival outcomes in patients with surgically resected NSCLC. Particularly, our results suggest that BUB3 rs7897156C>T and AURKB rs1059476G>A are functional variants.

Association between polymorphisms in microRNA target sites and survival in early-stage non-small cell lung cancer.

A high-throughput mapping method of RNA-RNA interactions by crosslinking, ligation, and sequencing of hybrids (CLASH) can not only provide information about canonical but also non-canonical interactions. We evaluated the associations between variants in microRNA target sites using CLASH data and survival outcomes of 782 early-stage non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection. Among the 100 variants studied, two variants showed significant association with survival outcomes. The POLR2A rs2071504 C > T variant was associated with poor overall and disease-free survival under a dominant model (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08-1.88; P = 0.01 and HR 1.34, 95% CI 1.08-1.67; P = 0.01, respectively). Patients carrying the NR2F6 rs2288539 TT genotype showed significantly better overall survival than those with the NR2F6 rs2288539 CC or CT genotypes (HR 0.13, 95% CI 0.02-0.90; P = 0.04). These findings suggest that POLR2A rs2071504 C > T and NR2F6 rs2288539 C > T can influence prognosis in early-stage NSCLC patients.

Effects of polymorphisms identified in genome-wide association studies of never-smoking females on the prognosis of non-small cell lung cancer.

A number of genome-wide association studies have reported several variants that influence the risk of lung cancer in never-smoking females. We evaluated the impact of these variants on survival outcome in never-smoking females with non-small cell lung cancer (NSCLC). In total, 510 never-smoking females with NSCLC who underwent curative surgery were enrolled. Eleven variants associated with lung cancer susceptibility in never-smoking females were genotyped and their associations with survival outcome were analyzed. Among these 11 variants, TP63 rs7631358 and CSF1R rs10079250 affected survival outcomes. TP63 rs7631358 G > A was associated with a relatively worse overall survival (under a dominant model; hazard ratio = 2.31, 95% confidence interval = 1.18-4.52, P = 0.01). CSF1R rs10079250 A > G was associated with a relatively better disease-free survival (under a codominant model; hazard ratio = 0.70, 95% confidence interval = 0.53-0.93, P = 0.01). These results suggest that TP63 rs7631358 G > A and CSF1R rs10079250 A > G may affect the prognosis of NSCLC in never-smoking females, as well as the risk of lung cancer.

Extent of visceral pleural invasion and the prognosis of surgically resected node-negative non-small cell lung cancer.

BACKGROUND: Visceral pleural invasion (VPI) is generally considered a poor prognostic factor in non-small cell lung cancer (NSCLC). VPI is defined as penetration beyond the elastic layer of visceral pleura (PL1), including the visceral pleural surface without the involvement of adjacent structures (PL2) by cancer cells. The aim of this study was to evaluate the influence of the extent of VPI on NSCLC prognosis. METHODS: This was a retrospective study of 90 patients with resected node-negative NSCLC with VPI. The overall survival (OS) and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. Multivariate analysis for prognostic factors was performed using a Cox proportional hazards regression model. The pattern of recurrence was also compared between PL1 and PL2 groups. RESULTS: Seventy-three patients had PL1. The three-year OS rates for the PL1 and PL2 groups were 97.4% and 82.4%, respectively ( P = 0.004). The two-year DFS rates for PL1 and PL2 groups were 81.0% and 76.5%, respectively ( P = 0.419). According to the multivariate analysis, PL2 was not a significant prognostic factor for survival outcome in node-negative NSCLC with VPI compared to PL1 (hazard ratio for DFS 1.753, 95% confidence interval 0.582-5.284; P = 0.319). In this study, six patients in the PL1 and one in PL2 group developed ipsilateral pleural recurrence ( P = 1.000). CONCLUSION: VPI extent may not influence survival outcomes in patients with surgically resected node-negative NSCLC with VPI.

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.

Inadvertently transected left superior pulmonary vein during thoracoscopic left lower lobectomy.

BACKGROUND: There are several anatomical variations of the pulmonary vein which can cause serious complications in pulmonary lobectomy. CASE PRESENTATION: We inadvertently divided the left superior pulmonary vein during thoracoscopic left lower lobectomy in a lung cancer patient. Retrospective review of the preoperative computed tomography showed extra-pericardial common trunk of the left pulmonary venous system. Left superior pulmonary vein was reimplanted into stump of divided common trunk via thoracotomy. CONCLUSIONS: Awareness of vascular anomalies will help thoracic surgeons to prevent potential morbidity and mortality from complications.

Putative functional variants of XRCC1 identified by RegulomeDB were not associated with lung cancer risk in a Korean population.

The Encyclopedia of DNA elements (ENCODE) project revealed that nearby or distantly located non-coding DNA regulates the expression of coding genes. RegulomeDB (http://regulome.stanford.edu) is a new database that can be used to predict whether a variant affects transcription factor binding and gene expression. We investigated the association between lung cancer risk and potentially functional polymorphisms of XRCC1 that were selected using RegulomeDB in a Korean population. A total of 185 polymorphisms of XRCC1 were evaluated using RegulomeDB. Strong evidence suggested that 10 polymorphisms, from among the 185, affected XRCC1 expression with scores of 1a-1f that were based on the RegulomeDB scoring system. The rs2854510 polymorphism was rare in Asians (minor allele frequency < 0.05). Eight polymorphisms were in strong linkage disequilibrium (LD). The rs2854509 polymorphism, which was one of the 8 polymorphisms in LD, and rs7248167, which was not in the LD block, were genotyped in 610 lung cancer patients and 607 age- and sex-matched controls. Additionally, four polymorphisms of XRCC1 (rs25487, rs25489, rs1799782, and rs3213245), which were investigated with regard to their association with lung cancer risk in previous studies, were also genotyped. Two polymorphisms (rs2854509 and rs7248167) that were predicted to affect XRCC1 expression based on their RegulomeDB scores were not associated with lung cancer risk (P = 0.31 and 0.93, respectively). When stratified according to age, gender, smoking status, and tumor histology, the two polymorphisms of XRCC1 were not associated with lung cancer risk. Among the four polymorphisms that were previously studied, only rs25489 of XRCC1 was significantly associated with lung cancer risk (dominant model, adjusted odds ratio = 0.61, 95% confidence interval = 0.46-0.83, P = 0.002). Although RegulomeDB is an attractive tool for predicting the regulatory potential of variants, the two polymorphisms that were selected using RegulomeDB were not associated with lung cancer risk.

Replication of results of a genome-wide association study on lung cancer survival in a Korean population.

Recently, a genome-wide association study (GWAS) identified single nucleotide polymorphisms (SNPs) that may influence the prognosis of early-stage non-small cell lung cancer (NSCLC) in Caucasians. We attempted to replicate the impact of genetic variants identified in the GWAS on lung cancer survival in a Korean population. A total of 363 patients with surgically resected NSCLCs were enrolled, and 12 SNPs were genotyped using the SEQUENOM MassARRAY iPLEX assay, TaqMan assay, or a polymerase chain reaction-restriction fragment length polymorphism analysis. The association between genotypes and overall survival (OS) was analyzed. Among the 12 SNPs, the rs6034368T>C was associated with OS. Patients with the rs6034368C allele showed a better OS than the patients with the rs6034368T allele (adjusted hazard ratio = 0.72, confidence interval = 0.56-0.93, P = 0.01). The rs12446308A>G had an effect on OS, but it was marginally significant (under a codominant model, adjusted hazard ratio = 1.85, confidence interval = 0.98-3.47, P = 0.06). We identified that the rs6034368T>C was associated with survival in early-stage NSCLC in a Korean population.

Simple stapled division of aberrant artery during thoracoscopic resection of pulmonary sequestration.

Pulmonary sequestration is a rare developmental abnormality where pulmonary tissue lacks normal connections to the tracheobronchial tree, in addition to its having an anomalous systemic blood supply. Lobectomy via open thoracotomy has long been the procedure of choice for the resection of pulmonary sequestration. We present three cases of thoracoscopic lobectomies performed using video-assisted thoracic surgery (VATS). Transection of the associated aberrant artery was performed using only a single staple.

Bronchial stump coverage with fibrin glue-coated collagen fleece in lung cancer patients who underwent pneumonectomy.

PURPOSE: Bronchopleural fistula (BPF) is a serious complication following pneumonectomy in lung cancer patients. The aim of this retrospective study is to investigate the efficacy of bronchial stump reinforcement with a collagen fleece coated with fibrin glue(TachoComb®). METHODS: The bronchial stumps of 43 lung cancer patients who underwent pneumonectomy between January 1998 and January 2003 were covered with pericardial fat pad.From February 2003 to the March 2011, we used TachoComb to cover the bronchial stumps of all lung cancer patients undergoing pneumonectomy (20 cases). Several preoperative, intraoperative, and postoperative variables were recorded retrospectively. RESULTS: Univariate analysis of comorbidities and risk factors did not show any significant differences between the two groups except for neoadjuvant chemotherapy. Postpneumonectomy BPF occurred in three of the 43 (7%) patients who had pericardial fat pad coverage and in none of the patients treated by TachoComb. CONCLUSION: Reinforcement of the bronchial stump with TachoComb is a simple procedure, comparable to coverage with viable tissue, and should be considered in the prevention of postpneumonectomy BPF.

Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer.

Telomere shortening leads to genomic instability that drives oncogenesis through the activation of telomerase and the generation of other mutations necessary for tumor progression. This study was conducted to determine the impact of telomere shortening on the survival of patients with early stage non-small cell lung cancer (NSCLC). Relative telomere length in tumor tissues was measured by quantitative polymerase chain reaction in 164 patients with surgically resected NSCLC. The association between telomere length and overall survival (OS) and disease-free survival (DFS) was analyzed. When the patients were categorized into quartiles based on telomere length, those patients with the 1st quartile (shortest) of telomere length had a significantly worse OS and DFS compared to patients with the 2nd to the 4th quartiles of telomere length (adjusted hazard ratio for OS = 2.67, 95% confidence interval = 1.50-4.75, P = 0.001; and adjusted hazard ratio for DFS = 1.92, 95% confidence interval = 1.17-3.14, P = 0.01). An association between telomere length and survival outcome was more pronounced in squamous cell carcinomas than adenocarcinomas (P-value of test for homogeneity for OS and DFS = 0.05 and 0.02, respectively). Telomere length of tumor tissues is an independent prognostic factor in patients with surgically resected early stage NSCLC.

Impact of smoking history on postoperative pulmonary complications: a review of recent lung cancer patients.

PURPOSE: Smoking is a well-known risk factor for postoperative pulmonary complications. As a consequence of pre and postoperative procedures continuing to be developed, postoperative complications continue to decrease. In this study, smoking as a risk factor for postoperative pulmonary complications is studied. METHODS: From January 2005 to June 2009, postoperative pulmonary complications and smoking factors were analyzed from among 232 lung cancer patients with a smoking history. Smoking factors included cessation duration and pack-years. Also, relationships between pulmonary complications and patient factors, including gender, age, histological features, surgery methods, pulmonary function test, and body mass index were analyzed. RESULTS: Univariate and multivariate analysis revealed that smoking factors were not significant risk factors for the development of postoperative pulmonary complications. CONCLUSION: Recently, the effect of smoking on the development of postoperative pulmonary complications has been reduced due to the increase in quality of pre and postoperative management and surgery procedures. Accordingly, there seems to be no need to delay operative procedures to secure a significant duration of smoking cessation duration in lung cancer patients.

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.

Association between genetic variants in pre-microRNAs and survival of early-stage NSCLC.

INTRODUCTION: MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. Recent evidence indicates that altered miRNA expression plays an important role in the initiation and progression of lung cancer. Single nucleotide polymorphisms (SNPs) in pre-miRNAs could alter miRNAs processing, or expression, and hence, could influence the prognosis of lung cancer. To test this hypothesis, we evaluated the effects of four SNPs in pre-miRNAs (pre-miR-146a rs2910164, pre-miR-149 rs2292832, pre-miR-196a rs11614913, and pre-miR-499 rs3746444) on the survival outcomes of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Three hundred sixty-three patients with surgically resected NSCLC were enrolled. The four SNPs were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: Of the four SNPs examined, the pre-miR-149 rs2292832T>C and pre-miR-196a rs11614913C>T were found to be significantly associated with OS and DFS. The rs2292832 TC or CC genotype exhibited a significantly better OS and DFS compared with the rs2292832 TT genotype (adjusted hazard ratio [aHR] for OS, 0.66; 95% confidence interval [CI], 0.47-0.92; p = 0.01 and aHR for DFS, 0.64; 95% CI, 0.48-0.87; p = 0.004). For the pre-miR-196a rs11614913C>T, patients with the CT or TT genotype had a significantly better OS and DFS than those with the CC genotype (aHR for OS, 0.70; 95% CI, 0.49-0.99; p = 0.05 and aHR for DFS, 0.66; 95% CI, 0.48-0.90; p = 0.01). When the two SNPs were combined, OS and DFS improved in a dose-dependent manner as the number of good genotypes increased (p = 0.002 and 0.0001, respectively). CONCLUSIONS: These results suggest that miR-149 and miR-196a may be involved in the pathogenesis of NSCLC, and that rs2292832 and rs11614913 can be used as prognostic markers for patients with surgically resected early-stage NSCLC.

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.

Respiratory complications during mid- and long-term follow-up periods in patients who underwent pneumonectomy for non-small cell lung cancer.

BACKGROUND: Pneumonectomy is associated with higher early mortality and morbidity, and it is also known to predispose the patient to respiratory complications during mid- and long-term follow-up. Therefore, the purpose of this study was to identify risk factors associated with respiratory complications during the follow-up period after pneumonectomy. METHODS: We retrospectively reviewed 98 patients who underwent pneumonectomy for non-small cell lung cancer (NSCLC) between Jan 1995 and Dec 2005 Univariate and multivariate analyses were used to identify risk factors of late respiratory complications among preoperative and intraoperative data. RESULTS: The median follow up duration of 98 patients was 33.1 months(4.2-180.0 months). The late mortality rate was 68.4% (n = 67). Causes of late death were cancer specific in 37 patients (55.2%) and respiratory specific in 25 patients(37.3%). Compared with 59 patients who had no respiratory infection after pneumonectomy during mid- or long-term follow-up, being male, a lower BMI (<22 kg/m(2)), presence of chronic obstructive pulmonary disease (COPD) and preoperative pneumonia were significant risk factors by univariate analysis. Multivariate analysis revealed that presence of preoperative pneumonia was the only independent factor associated with late mortality from respiratory complications during the mid- and long-term follow-up periods (OR = 2.41, 95% CI = 1.10-5.32, p = 0.028). CONCLUSION: Respiratory infection was a comparable risk factor of mortality in the mid- and long-term after pneumonectomy with cancer recurrence. The presence of preoperative pneumonia was an independent factor related to respiratory infection.Careful follow-up for these patients may be required.

Delayed presentation of traumatic diaphragmatic rupture with complicated cholecystitis.

The right-sided diaphragmatic rupture is often clinically occulted due to buffering effects of the liver and thus, erroneous diagnosis of such rupture may result in life-threatening conditions. A 44-year-old female who had a history of car accident in 2006 was admitted to our hospital for pleuritic pain. On the chest computed tomography, she was diagnosed with diaphragmatic rupture accompanied by herniation of hypertrophic left liver with complicated cholecystitis and we carried out cholecystectomy, reduction of the liver, pleural drainage, and primary closure of the diaphragm via thoracic approaches. Our case is presented in three unique aspects: herniation of left hemiliver, hypertrophic liver herniated up to the 4(th) rib level, and combination of complicated cholecystitis. Although the diagnosis of right-sided diaphragmatic rupture can be challenging for the surgeon, an early diagnosis can prevent further complications on the clinical presentation.

Sleeve lobectomy of mucoepidermoid carcinoma in a 5-year-old girl.

A 5-year-old girl presented to our hospital with prolonged pneumonic symptoms over 3 months. After a complete work-up, she was diagnosed with endobronchial mucoepidermoid carcinoma and treated with a left upper sleeve lobectomy. The patient is cured and doing well, 8 months after the surgical resection.