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Sang Gon Lee,1,* Chang Hyun Kim,1,* Si Woo Sung,1 Eun Seok Lee,1 Min Su Goh,1 Ho Yub Yoon,1 Myung Joo Kang,2 Sangkil Lee,3 Young Wook Choi1 1College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 2College of Pharmacy, Dankook University, Chungnam, Republic of Korea; 3College of Pharmacy, Keimyung University, Daegu, Republic of Korea *These authors contributed equally to this work Background: To facilitate selective and enhanced drug delivery to hepsin (Hpn)-expressing cancer cells, RIPL peptide (IPLVVPLRRRRRRRRC, 16-mer)-conjugated nanostructured lipid carriers (RIPL-NLCs) were developed. Methods: NLCs were prepared using a solvent emulsification-evaporation method and the RIPL peptide was conjugated to the maleimide-derivatized NLCs via the thiol-maleimide reaction. Employing a fluorescent probe (DiI), in vitro target-selective intracellular uptake behaviors were observed using fluorescence microscopy and flow cytometry. Separately, docetaxel (DTX) was encapsulated by pre-loading technique, then cytotoxicity and drug release were evaluated. In vivo antitumor efficacy was investigated in BALB/c nude mice with SKOV3 cell tumors after intratumoral injections of different DTX formulations at a dose equivalent to 10 mg/kg DTX. Results: RIPL-NLCs showed positively charged nanodispersion, whereas NLCs were negatively charged. DTX was successfully encapsulated with an encapsulation efficiency and drug loading capacity of 95–98% and 44-46 µg/mg, respectively. DTX release was diffusion-controlled, revealing the best fit to the Higuchi equation. Cellular uptake of DiI-loaded RIPL-NLCs was 8.3- and 6.2-fold higher than that of DiI-loaded NLCs, in Hpn(+) SKOV3 and LNCaP cells, respectively. The translocation of RIPL-NLCs into SKOV3 cells was time-dependent with internalization within 1 h and distribution throughout the cytoplasm after 2 h. DTX-loaded RIPL-NLCs (DTX-RIPL-NLCs) revealed dose-dependent in vitro cytotoxicity, while drug-free formulations were non-cytotoxic. In SKOV3-bearing xenograft mouse model, DTX-RIPL-NLCs significantly inhibited tumor growth: the inhibition ratios of the DTX solution-treated and DTX-RIPL-NLC-treated groups were 61.4% and 91.2%, respectively, compared to those of the saline-treated group (control). Conclusion: RIPL-NLCs are good candidates for Hpn-selective drug targeting with a high loading capacity of hydrophobic drug molecules. Keywords: nanostructured lipid carriers, RIPL peptide, intracellular delivery, docetaxel, antitumor efficacy, targeting

Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection is essential to achieving a better outcome and prognosis. Volatile organic compounds (VOCs) reflect alterations in the pathophysiology and body metabolism processes, as shown in various types of cancers. The biosensor platform (BSP) urine test uses animals' unique, proficient, and accurate ability to scent lung cancer VOCs. The BSP is a testing platform for the binary (negative/positive) recognition of the signature VOCs of lung cancer by trained and qualified Long-Evans rats as biosensors (BSs). The results of the current double-blind study show high accuracy in lung cancer VOC recognition, with 93% sensitivity and 91% specificity. The BSP test is safe, rapid, objective and can be performed repetitively, enabling periodic cancer monitoring as well as an aid to existing diagnostic methods. The future implementation of such urine tests as routine screening and monitoring tools has the potential to significantly increase detection rate as well as curability rates with lower healthcare expenditure. This paper offers a first instructive clinical platform utilizing VOC's in urine for detection of lung cancer using the innovative BSP to deal with the pressing need for an early lung cancer detection test tool.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Assessments of air leaks are usually performed subjectively, precluding the use of air leaks as an evaluation factor. We aimed to identify objective parameters as predictive factors for prolonged air leak (PAL) and air leak cessation (ALC) from air flow data produced by a digital drainage system., Methods: Flow data records of 352 patients who underwent lung lobectomy were reviewed, and flow data at designated intervals (1, 2, and 3 hours postoperatively [POH] and 3 times a day thereafter [06:00, 13:00, 19:00]) were extracted. ALC was defined by flow less than 20 mL/min over 12 hours, and PAL was defined as ALC after 5 days. Cumulative incidence curves were obtained using Kaplan-Meier estimates of time to ALC. Cox regression analysis was performed to determine the effects of variables on the rate of ALC., Results: The incidence of PAL was 18.2% (64/352). Receiver operating characteristic curve analysis showed cut-off values of 180 mL/min for the flow at 3 POH and 73.3 mL/min for the flow on postoperative day 1; the sensitivity and specificity of these values were 88.9% and 82.5%, respectively. The rates of ALC by Kaplan-Meier analysis were 56.8% at 48 POH and 65.6% at 72 POH. Multivariate Cox regression analysis revealed that the flow at 3 POH (≤80 mL/min), operation time (≤220 minutes), and right middle lobectomy independently predicted ALC., Conclusion: Air flow measured by a digital drainage system is a useful predictor of PAL and ALC and may help optimize the hospital course.

Transcutaneous carbon dioxide (PtcCO 2 ) monitoring is known to be effective at estimating the arterial partial pressure of carbon dioxide (PaCO 2 ) in patients with sedation-induced respiratory depression. We aimed to investigate the accuracy of PtcCO 2 monitoring to measure PaCO 2 and its sensitivity to detect hypercapnia (PaCO 2 > 60 mmHg) compared to nasal end-tidal carbon dioxide (PetCO 2 ) monitoring during non-intubated video-assisted thoracoscopic surgery (VATS). This retrospective study included patients undergoing non-intubated VATS from December 2019 to May 2021. Datasets of PetCO 2 , PtcCO 2 , and PaCO 2 measured simultaneously were extracted from patient records. Overall, 111 datasets of CO 2 monitoring during one-lung ventilation (OLV) were collected from 43 patients. PtcCO 2 had higher sensitivity and predictive power for hypercapnia during OLV than PetCO 2 (84.6% vs. 15.4%, p < 0.001; area under the receiver operating characteristic curve; 0.912 vs. 0.776, p = 0.002). Moreover, PtcCO 2 was more in agreement with PaCO 2 than PetCO 2 , indicated by a lower bias (bias ± standard deviation; -1.6 ± 6.5 mmHg vs. 14.3 ± 8.4 mmHg, p < 0.001) and narrower limit of agreement (-14.3-11.2 mmHg vs. -2.2-30.7 mmHg). These results suggest that concurrent PtcCO 2 monitoring allows anesthesiologists to provide safer respiratory management for patients undergoing non-intubated VATS.

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-663). Wenhua L serves as an unpaid Associate Editor-in-Chief of Translational Lung Cancer Research. The other authors have no conflicts of interest to declare.

A cascade control system comprising the primary and secondary controllers suffers from a cascade-type integral windup problem in which the output saturation of the secondary control loop can considerably increase the integral part of the primary control loop. In this paper, we present a new predictive antiwindup technique that can completely eliminate the possibility of secondary controller output saturation, resulting in no cascade-type integral windup phenomenon. The proposed method does not require any type of process models; thus, its implementation is simple and straightforward, which is a very favorable advantage compared to the model-based antiwindup techniques from the practical viewpoint. Our simulation confirms that the proposed method can completely remove the primary controller's cascade-type integral windup resulting from the saturation of the secondary controller output. Further, the proposed method exhibited good control performance without needing any type of process model for the various types of processes and controllers. Our experimental study successfully demonstrated that there are no problems in applying the proposed method to real plants., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)

A hydrogen (H 2 )-rich gas mixture is used as the fuel of the proton exchange membrane fuel cell (PEMFC). A small amount of the carbon monoxide (CO) gas in the gas mixture can significantly deactivate the catalyst of the PEMFC, resulting in a reduction in the efficiency of power generation. Preferential oxidation is used to reduce the CO concentration less than 10 ppm in the gas mixture. It has an optimal reaction temperature at which the reaction shows the minimum exit CO concentration with minimum consumption of H 2 . This optimal temperature continuously changes under the varying conditions of operation and catalyst deactivation. In this study, two modified extremum seeking control (ESC) methods were proposed to continuously seek and maintain this optimal reaction temperature, guaranteeing CO concentration under 10 ppm even under time-varying conditions. The proposed methods have a smaller number of design parameters than the conventional extremum seeking approaches so that tuning the ESC method is much easier, more intuitive, and efficient. In addition, the proposed method can additionally use the secondary measurement to improve the performance of the ESC method by removing the possibility that the modeling error of the linear dynamic block can deteriorate the accuracy of calculating the gradient of the nonlinear static block. The experimental results confirmed that the proposed methods can track the optimal temperature within a short time compared to the conventional approach while successfully maintaining the CO concentration below 10 ppm., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women., (Copyright © 2019. Published by Elsevier Inc.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Aim: To investigate predictive and prognostic role of metabolic parameters using [ 18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography ( 18 F-FDG PET) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with docetaxel-platinum induction chemotherapy (IC)., Methods: Medical records of 31 patients with pre- and post-IC 18 F-FDG PET were reviewed. Using 18 F-FDG PET, metabolic parameters, including metabolic tumor response, adjusted peak standardized uptake values using lean body mass at baseline (pre-SUL peak ) and after IC (post-SUL peak ), and percentage change of pre- and post-SUL peak (ΔSUL peak ), were assessed., Results: Response rate (RR) was 71%, with a metabolic RR of 83.9%. Nineteen (61.3%) patients underwent surgery, R0 resection was achieved for 17 (89.5%) patients. Median relapse-free survival (RFS) and overall survival (OS) were 8.9 months (95% CI: 4.5-12.1) and 24.1 months (95% CI: 17.1-34.1), respectively. Post-SUL peak  < 2 was identified as a favorable prognostic factor for RFS (hazard ratio [HR]: 0.12; P = .004), while ΔSUL peak ≥60% and R0 resection were found as positive prognostic factors for OS (HR: 0.09 and 0.13; P = .011 and P = .042, respectively). Using a receiver operating characteristics curve, post-SUL peak  > 1.4 could predict recurrence with a sensitivity of 84% and a specificity of 100%., Conclusion: In patients with locally advanced NSCLC receiving IC, post-SUL peak and ΔSUL peak showed clinical significance for survival outcome., (© 2019 John Wiley & Sons Australia, Ltd.)

The relay (on-off) controller can stabilize wide ranges of processes including open-loop stable, integrating, and unstable processes, producing sustained oscillations. For improved proportional-integral-derivative controller tunings, methods to find process models with mixed closed-loop tests of relay feedback and proportional-derivative (PD) controllers are proposed. For unknown processes with arbitrary initial states, relay feedback tests are first applied and, after cyclic steady states are obtained, PD controllers or other relay feedback tests with set point changes are followed. This full closed-loop operation is desirable for integrating and unstable processes and will be useful even for stable processes when processes are far from their desirable operating points. Refined methods to find exact frequency responses of processes from initial and final cyclic steady states are derived. Whole relay feedback responses need not be saved. Several integrals at the relay switching times are used without iterative tests or computations., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Competing Interests: Conflicts of Interests: The authors have no conflicts of interest to declare.

Background: Uniportal video-assisted thoracoscopic surgery (VATS) has proven safe and effective for pulmonary wedge resection and lobectomy. The objective of this study was to evaluate the safety and feasibility of uniportal VATS segmentectomy by comparing its outcomes with those of the multiportal approach at a single center., Methods: The records of 84 patients who underwent VATS segmentectomy from August 2010 to August 2018, including 33 in the uniportal group and 51 in the multiportal group, were retrospectively reviewed and analyzed., Results: Anesthesia and operative times were similar in the uniportal and multiportal groups (215 minutes vs. 220 minutes, respectively; p=0.276 and 180 minutes vs. 198 minutes, respectively; p=0.396). Blood loss was significantly lower in the uniportal group (50 mL vs. 100 mL, p=0.013) and chest tube duration and hospital stay were significantly shorter in the uniportal group (2 days vs. 3 days, p=0.003 and 4 days [range, 1-14 days] vs. 4 days [range, 1-62 days], p=0.011). The number of dissected lymph nodes tended to be lower in the uniportal group (5 vs. 8, p=0.056)., Conclusion: Our preliminary experience indicates that uniportal VATS segmentectomy is safe and feasible in well-selected patients. A randomized, prospective study with a large group of patients and long-term follow-up is necessary to confirm these results., Competing Interests: Conflict of interest No potential conflict of interest relevant to this article was reported.

Purpose: To evaluate the prognostic value of FDG PET/CT metabolic parameter compared to clinico-pathological risk factors in surgical margin-negative stage IA non-small cell lung cancer (NSCLC) patients., Methods: 167 patients with consecutive FDG PET/CT scans from 2009 to 2015 performed for staging of NSCLC stage IA with plans for curative surgery were retrospectively reviewed. Maximum standardized uptake value (SUVmax) of primary tumor and mean SUV of liver were acquired from PET/CT. Tumor-to-liver SUV ratio (TLR) was calculated. Charts were reviewed to obtain basic patient characteristics (age, sex, smoking history, LDH, histologic subtype) and high-risk factors for adjuvant chemotherapy (tumor size, poorly differentiation, vascular invasion, and sub-lobar resection). Patients were dichotomized into two groups using optimal cut-off from receiver operating characteristic curve analysis of TLR to predict recurrence. Statistical analysis was done using Cox regression analysis and Kaplan-Meier method. Factors with P < 0.2 in univariate analysis were included in multivariate analysis., Results: Recurrence rate was 12.6% (21/167). Median disease-free survival (DFS) was 47.2 months while 2-year and 5-year DFS rates were 93% and 86%, respectively. The optimal cut-off for TLR was 2.3. In univariate analysis, P value of sex, vascular invasion, and TLR were less than 0.2. In multivariable analysis, high TLR was the only factor that showed significant association with tumor recurrence (hazard ratio 3.795, P = 0.0048)., Conclusions: TLR was an independent prognostic factor for recurrence and TLR could be an important risk factor to be considered in decision-making for adjuvant chemotherapy, even for those with stage IA NSCLC.

Background: The aim of this study was to evaluate the outcomes of patients with pathological N1 non-small cell lung cancer who did not receive adjuvant chemotherapy. We attempted to identify those patients for whom adjuvant chemotherapy would be indispensable., Methods: Among 132 patients who were diagnosed with pathological N1 lung cancer at a single institution from January 2010 to December 2016 were 32 patients who did not receive adjuvant treatment after curative surgical resection. The surgical and oncological outcomes of these patients were analyzed. Candidate factors for predicting recurrence were analyzed to identify patients at high risk of recurrence., Results: The median follow-up time for all 32 patients was 1044 days. The 5-year recurrence-free survival (RFS) and disease-specific survival rates of the patients without adjuvant therapy were 50.3% and 77.6%, respectively. By multivariate analysis, tumors with a lepidic growth pattern [hazard ratio (HR) 0.119, p = 0.024] and extralobar lymph node metastasis (HR 6.848, p = 0.015) were significant factors predicting recurrence. The difference between the 5-year RFS rates of patients with tumors with or without a lepidic growth pattern was statistically significant (63.5% vs 40.0%, respectively; p = 0.050). The 5-year RFS rates of patients with intralobar lymph node metastasis versus those with extralobar lymph node metastasis were 63.3% and 18.8%, respectively (p = 0.002)., Conclusions: Patients with tumors without a lepidic growth pattern or with extralobar lymph node metastasis who do not receive adjuvant chemotherapy have a high recurrence rate after surgery. Therefore, these patients should be encouraged to undergo adjuvant chemotherapy if their overall condition is not a contraindication for chemotherapy.

Background/aims: The outcome of local treatment for advanced non-small cell lung cancer (NSCLC) remains poor, with therapies such as induction chemotherapy (IC) yielding conflicting results. This study aimed to assess the clinicopathologic and prognostic significance of the excision repair cross-complementation group 1 (ERCC1), beclin-1, and glucose-regulated protein of molecular mass 78 (GRP78) in patients with locally advanced NSCLC receiving docetaxel-platinum IC, along with efficacy and safety., Methods: This is a retrospective observational cohort study. We reviewed medical records of 31 NSCLC patients receiving docetaxel-platinum IC, and conducted immunohistochemical staining of ERCC1, beclin-1, and GRP78., Results: Response rate was 67.8% with 10.7 months of median relapse-free survival (RFS) and 23.1 months of median overall survival (OS), and no treatment-related death was reported. High expression of ERCC1, beclin-1, and GRP78 was identified in 67.7%, 87.1%, and 67.7%, respectively. Expression of ERCC1 and GRP78 did not reveal statistical significance in survival, whereas high beclin-1 expression revealed longer OS (7.6 months vs. 23.2 months; log-rank p = 0.024). In multivariate analysis, histologic differentiation (hazard ratio [HR], 3.48; p < 0.001), stage (HR, 8.5; p = 0.024), and adjuvant treatment (HR, 16.1; p = 0.001) were related to RFS, and in OS, stage (HR, 5.4; p = 0.037), adjuvant treatment (HR, 8.6; p = 0.004), and beclin-1 expression (HR, 8.2; p = 0.011) were identified as significant prognostic factors., Conclusion: Our findings suggest that high beclin-1 expression predicts longer survival in locally advanced NSCLC and docetaxel-platinum IC is a treatment option that deserves consideration.

As a platform for hepsin-specific drug delivery, we previously prepared IPLVVPLRRRRRRRRC peptide (RIPL)-conjugated nanostructured lipid carriers (RIPL-NLCs) composed of Labrafil ® M 1944 CS (liquid oil) and Precirol ® ATO 5 (solid lipid). In this study, to prevent the recognition by the mononuclear phagocyte system, polyethylene glycol (PEG)-modified RIPL-NLCs (PEG-RIPL-NLCs) were prepared using PEG3000 at different grafting ratios (1, 5, and 10 mole %). All prepared NLCs showed a homogeneous dispersion (130⁻280 nm), with zeta potentials varying from -18 to 10 mV. Docetaxel (DTX) was successfully encapsulated in NLCs: encapsulation efficiency (93⁻95%); drug-loading capacity (102⁻109 µg/mg). PEG-RIPL-NLCs with a grafting ratio of 5% PEG or higher showed significantly reduced protein adsorption and macrophage phagocytosis. The uptake of PEG(5%)-RIPL-NLCs by cancer cell lines was somewhat lower than that of RIPL-NLCs because of the PEG-induced steric hindrance; however, the uptake level of PEG-RIPL-NLCs was still greater than that of plain NLCs. In vivo biodistribution was evaluated after tail vein injection of NLCs to normal mice. Compared to RIPL-NLCs, PEG(5%)-RIPL-NLCs showed lower accumulation in the liver, spleen, and lung. In conclusion, we found that PEG(5%)-RIPL-NLCs could be a promising nanocarrier for selective drug targeting with a high payload of poorly water-soluble drugs.

Background: We report our surgical technique for nonintubated uniportal video-assisted thoracoscopic surgery (VATS) pulmonary resection and early postoperative outcomes at a single center., Methods: Between January and July 2017, 40 consecutive patients underwent nonintubated uniportal VATS pulmonary resection. Multilevel intercostal nerve block was performed using local anesthesia in all patients, and an intrathoracic vagal blockade was performed in 35 patients (87.5%)., Results: Twenty-nine procedures (72.5%) were performed in patients with lung cancer (21 lobectomies, 6 segmentectomies, and 2 wedge resections), and 11 (27.5%) in patients with pulmonary metastases, benign lung disease, or pleural disease. The mean anesthesia time was 166.8 minutes, and the mean operative duration was 125.9 minutes. The mean postoperative chest tube duration was 3.2 days, and the mean hospital stay was 5.8 days. There were 3 conversions (7.5%) to intubation due to intraoperative hypoxemia and 1 conversion (2.5%) to multiportal VATS due to injury of the segmental artery. There were 7 complications (17.5%), including 3 cases of prolonged air leak, 2 cases of chylothorax, 1 case of pleural effusion, and 1 case of pneumonia. There was no in-hospital mortality., Conclusion: Nonintubated uniportal VATS appears to be a feasible and valid surgical option, depending on the surgeon's experience, for appropriately selected patients., Competing Interests: Conflict of interest No potential conflict of interest relevant to this article was reported.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure to evaluate suspicious lymph node involvement of lung cancer because computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography-CT (PET-CT) have limitations in their sensitivity and specificity. There are a number of benign causes of false positive lymph node such as anthracosis or anthracofibrosis, pneumoconiosis, old or active tuberculosis, interstitial lung disease, and other infectious conditions including pneumonia. The purpose of this study was to evaluate possible causes of false positive lymph node detected in chest CT or PET-CT., Methods: Two hundred forty-seven patients who were initially diagnosed with lung cancer between May 2009 and December 2012, and underwent EBUS-TBNA to confirm suspicious lymph node involvement by chest CT or PET-CT were analyzed for the study., Results: Of 247 cases, EBUS-TBNA confirmed malignancy in at least one lymph node in 189. The remaining 58 patients whose EBUS-TBNA results were negative were analyzed. Age ≥65, squamous cell carcinoma as the histologic type, and pneumoconiosis were related with false-positive lymph node involvement on imaging studies such as chest CT and PET-CT., Conclusion: These findings suggest that lung cancer staging should be done more carefully when a patient has clinically benign lymph node characteristics including older age, squamous cell carcinoma, and benign lung conditions., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright©2018. The Korean Academy of Tuberculosis and Respiratory Diseases.)

Background: Non-intubated, or awake, video-assisted thoracoscopic surgery has been implemented for non-anatomical lung resection and the results obtained were encouraging to consider the approach for anatomical pulmonary resection. This study was conducted to evaluate the perioperative outcomes of the non-intubated and intubated video-assisted thoracoscopic lobectomy in lung cancer in regards to feasibility and safety., Methods: A retrospective analysis of 62 consecutive video-assisted thoracoscopic lobectomies (31 lobectomies as non-intubated, 31 lobectomies as intubated) performed in Seoul St. Mary's Hospital, The Catholic University of Korea between January and December 2016., Results: Both groups share comparable clinical characteristics including the age, sex, BMI, FEV1, DLCO, smoking history, lung lobes procedure, histological type and pathological staging. There was no difference in the mean of postoperative hospitalization period (6.9 versus 7.6 days, P=0.578) and the total chest tube duration (5.6 versus 5.4 days, P=0.943) between non-intubated and intubated lobectomy respectively. Both groups had a comparable surgical outcome for the anesthesia duration, operative time, blood loss and postoperative complications. The operative time required for lobe-specific surgery was shorter in the non-intubated group except for the LLL (mean 121.7 minutes for non-intubated group versus 118.3 minutes for the intubated group). The only statistically significant surgical outcome was for the number of dissected lymph nodes between both groups (the mean number of nodes for the non-intubated group was 12.6 versus 18.0 nodes for the intubated group, P=0.003). One patient in the non-intubated group required conversion to single lung intubation and mini-thoracotomy because of bleeding with no conversion in the intubated group. No mortality encountered in either group., Conclusions: The perioperative surgical outcomes for the non-intubated video-assisted thoracoscopic lobectomy are comparable to the intubated technique. Non-intubated video-assisted thoracoscopic lobectomy is safe and is technically feasible. However, further prospective randomized studies are needed for a better comparison between non-intubated and intubated VATS lobectomy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Non-intubated thoracoscopic surgery is an evolving form of minimally-invasive thoracic surgery. We commenced performing non-intubated thoracoscopic surgery at our center in August 2016. We would like to report our initial experience, over a period of 1 year, with this procedure., Methods: From August 2016 to August 2017, non-intubated thoracoscopic surgery was performed in a series of consecutive patients who underwent thoracoscopic surgery in those who did not meet any of the following exclusion criteria: body mass index (BMI) >30, expected difficult airway, expected extensive pleural adhesion, severe cardiopulmonary dysfunction, persistent cough or excessive airway secretion, high risk of gastric reflux, and underlying neurological disorder., Results: A total of 115 consecutive patients underwent non-intubated thoracoscopic surgery. Of these, 83 (72.2%) of patients had lung cancers that had undergone pulmonary resection and the other 32 (27.8%) patients were diagnosed with pulmonary metastasis, benign lung diseases, thymic tumor or other conditions. The mean time of anesthesia was 172.4 min and time of operation was 130 min. The mean postoperative chest tube duration was 3.9 days and time of hospital stay was 6.0 days. There were 9 conversions (7.8%) to intubation, due to increased respiratory movement with intraoperative hypoxemia or severe pleural adhesion. There were 16 complications (13.9%) following surgery, but all of these were successfully managed during the period of hospital stay. There was no postoperative mortality. In multivariate analysis, old age and high BMI were significant risk factors for conversion to intubation (hazard ratio =1.122, P=0.038; hazard ratio =1.408, P=0.042, respectively)., Conclusions: Non-intubated thoracoscopic surgery can safely be performed in selected patients., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: We screened resected tumor tissues from patients with lung cancer for EGFR mutations, ALK rearrangements, and rearranged during transfection (RET) gene variants (including RET rearrangements and the Kinesin Family Member 5B (KIF5B)-RET fusion gene) using various methods including reverse transcription polymerase chain reaction (RT-PCR), transcript assays, fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). We also examined the protein expression of associated downstream signaling molecules to assess the effect of these variants on patient outcome., Method: We constructed a tissue microarray (TMA) comprising 581 resected tumor tissues from patients with lung adenocarcinoma and analyzed the microarray by both FISH (using RET break-apart and KIF5B-RET SY translocation probes) and a commercial RET transcript assay. We evaluated the expression of RET and RET-related signaling molecules, including p-AKT and p-ERK, by TMA -based IHC staining., Results: Among the 581 specimens, 51 (8.8%) specimens harbored RET rearrangements, including 12 cases (2.1%) carrying a KIF5B-RET fusion gene. Surprisingly, RET expression was lower in KIF5B-RET fusion gene-positive than in RET wild-type specimens. We detected activating EGFR mutations in 11 (21.6%) of the 51 RET variant-positive specimens. Among the KIF5B-RET fusion gene-positive specimens, p-ERK expression was significantly lower in the EGFR mutation subgroup showing RET expression than in the EGFR mutation subgroup that did not express RET. Similarly, the RET rearrangement group showed significant variation in the expression level of p-AKT (P = 0.028) and p-ERK, whose expression remarkably increased in specimens not expressing RET. The expression of p-ERK markedly increased in the RET rearrangement group regardless of RET expression., Conclusion: This result suggests that a combination of RET and ERK inhibitors may be an effective treatment strategy for lung adenocarcinoma patients harboring RET variants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: We aimed to evaluate the incidence and clinical features of vascular stump thrombus after oncologic lung surgery., Methods: A retrospective analysis of records from our institutional database dated between 2009 and 2016 was performed. Data regarding demographics, clinical presentation, medication use, operative findings, pathology, and radiologic findings were retrieved., Results: The study cohort consisted of 648 oncologic surgeries for primary lung cancer. The incidence of thrombus in the entire population was 5.7% (37/648). Most thrombi were incidentally found on follow-up chest computed tomography scans. Univariate Cox proportional hazard analysis showed that age (p = 0.02), adjuvant therapy (p <0.001), neoadjuvant therapy (p = 0.04), left-sided surgery (p = 0.02), complex surgery greater than simple lobectomy or segmentectomy (p <0.001), advanced stages (p <0.001), non-adenocarcinoma (p = 0.003), and thoracotomy approach (p = 0.009) were associated with an increased risk of vascular stump thrombus. There were no embolic events in our cohort, except for a case of pulmonary thromboembolism. During follow-up, 43.2% (16/37) of thrombi had completely resolved, 48.6% (18/37) showed partial regression and stabilization, and 8.1% (3/37) had progressed., Conclusions: The incidence of vascular stump thrombus in our study was not negligible. The clinical course of stump thrombus appears to be benign in most cases. Anticoagulation may be used with caution based on an individual basis depending on each patient's risk factors.

Background and Objective: Visceral pleural invasion is an upstaging factor that increases cancer staging from stage IA to IB for tumours of 3 cm or less. However, lymphatic invasion has not been associated with the tumour-node-metastasis (TNM) staging system. The purpose of this study was to compare visceral pleural invasion and lymphatic invasion as prognostic factors., Methods: We retrospectively reviewed 353 consecutive patients who underwent curative resection for stage I non-small cell lung cancer (NSCLC) tumours of 3 cm or less. Patients were divided into three groups and compared. Group A contained no invasions; group B contained visceral pleural invasion only and group C had lymphatic invasion only., Results: Group A patients had stage IA, but group B patients had stage IB tumours. However, group C patients had stage IA tumours. The 5-year recurrence-free survival for the three groups was 86.2%, 71.5% and 48.0%, respectively. There was a significant difference in survival between groups A and C (P = 0.001).Survival was not different between groups A and B (P = 0.547). In a multivariate analysis conducted to determine risk factors for recurrence, lymphatic invasion was a significant independent risk factor for recurrence (hazard ratio = 2.570, P = 0.006). Pleural invasion was not a significant risk factor for recurrence., Conclusion: Lymphatic invasion is a more significant prognostic factor than visceral pleural invasion in NSCLC of 3 cm or less., (© 2017 Asian Pacific Society of Respirology.)

We previously synthesized the RIPL peptide (IPLVVPLRRRRRRRRC) to facilitate selective delivery into hepsin-expressing cancer cells and showed that RIPL peptide-conjugated liposomes (RIPL-L) enhanced the intracellular delivery of fluorescent probes in vitro. In this study, docetaxel-loaded RIPL-L (DTX-RIPL-L) were prepared and evaluated for in vitro drug release, cytotoxicity, and in vivo antitumor efficacy. DTX was successfully encapsulated by pre-loading, with an average encapsulation efficiency and drug loading capacity of 32.4% and 21.39±2.05 (μg/mg), respectively. A DTX release study using dialysis showed a biphasic release pattern, i.e., rapid release for 6h, followed by sustained release up to 72h. The first-order equation provided the best fit for drug release (r 2 =0.9349). In vitro cytotoxicity was dose-dependent, resulting in IC 50 values of 36.10 (SK-OV-3) and 48.62ng/mL (MCF-7) for hepsin-positive, and 61.12 (DU145) and 53.04ng/mL (PC-3) for hepsin-negative cell lines. Live/dead cell imaging was carried out to visualize the proportion of viable and nonviable SK-OV-3 cells. Compared to DTX solution, DTX-RIPL-L significantly inhibited tumor growth and prolonged survival time in BALB/c nude mice with SK-OV-3 cell tumors. We suggest that DTX-RIPL-L is a good candidate for efficient drug targeting to hepsin-expressing cancer cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: We retrospectively assessed the role of C-MET expression and epidermal growth factor receptor (EGFR) mutation on survival following platinum-based adjuvant chemotherapy. The impact of C-MET on survival was also investigated in relation to EGFR mutation status., Methods: We enrolled 311 patients with resected lung adenocarcinoma (high-risk stage 1B-3A), and performed immunohistochemistry (IHC) using C-MET- and mutant EGFR (EGFRmut)-specific antibodies in tissue microarrays., Results: Adjuvant chemotherapy was administered to 151 patients, 96 of whom relapsed and 85 died by the end of the study. On IHC, C-MET and EGFRmut were positive in 141 (45.3 %) and 88 (28.3 %) cases, respectively. On univariate analysis, adjuvant chemotherapy prolonged relapse-free survival (RFS) and overall survival (OS) in C-MET(+) patients (RFS p = 0.035; OS p = 0.013) but not in C-MET(-) patients. On multivariate analysis, adjuvant chemotherapy was a positive independent prognostic factor in C-MET(+) (RFS p = 0.013; OS p = 0.006) but not in C-MET(-) patients. In addition, univariate analysis showed no effect of EGFRmut status on RFS and OS after chemotherapy, whereas multivariate analysis revealed that adjuvant chemotherapy increased RFS in both EGFRmut(+) and EGFRmut(-) patients [EGFRmut(+) p = 0.033; EGFRmut(-) p = 0.030]. C-MET was a negative prognostic factor for RFS (p = 0.045) and OS (p = 0.007) in the EGFRmut(-) group but not in the EGFRmut(+) group, on multivariate analysis., Conclusions: Our data indicate that patients with C-MET overexpression should be considered for adjuvant chemotherapy, and that C-MET negatively correlates with survival in patients with wild-type, but not mutant, EGFR.

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.)

Esophageal cancer is the malignant tumor arising from the esophagus and has a poor prognosis. Squamous cell carcinoma and adenocarcinoma are the main subtypes of esophageal cancer with different risk factors. In the early stage, surgical resection is the most curative treatment modality. However, the procedure is considered an advanced and technically demanding surgery because esophageal cancer surgery includes esophagectomy, lymph node dissection, and a creation of esophageal conduit. Stomach is the commonest organ for the esophageal substitute. In open procedures, pulmonary complications and anastomotic failure are the most severe problems. Minimally invasive esophagectomy (MIE) has been introduced to decrease the postoperative pulmonary complications, but anastomotic failure remains a serious issue because of the extra-anatomical anastomosis between the esophagus and the conduit in the thorax or the neck., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Several studies have suggested risk factors for poor survival in stage IB non-small-cell lung cancer (NSCLC) patients. However, these factors are not definite indicators of adjuvant chemotherapy for stage IB cancer, and most of them can be used to consider adjuvant chemotherapy. We aimed to determine the clinicopathologic factors and assess whether c-MET is a prognostic factor in stage IB NSCLC patients who have undergone surgery. Additionally, we determined the relevance of the factors and the recurrence pattern in these patients., Patients and Methods: This study included 115 patients who underwent resection of pathologic stage IB NSCLC between January 2005 and December 2013. We retrospectively reviewed the clinicopathologic data and performed immunohistochemical analysis for c-MET. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were evaluated according to clinicopathologic factors and c-MET expression., Results: Lymphovascular invasion (LVI) and c-MET overexpression were significantly associated with poor RFS. A large tumor with visceral pleural invasion (VPI) or LVI, moderate/poor differentiation with LVI, and VPI with LVI were negative prognostic factors for RFS and CSS. c-MET overexpression with a large tumor, VPI, or LVI was an independent prognostic factor for poor RFS and CSS, and LVI was a significant factor for distant recurrence., Conclusion: LVI and c-MET overexpression might be associated with poor prognosis in stage IB NSCLC patients. Additionally, survival might be poor in stage IB patients with multiple pathologic risk factors. Moreover, there is a high possibility of distant recurrence in patients with LVI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ground glass opacity (GGO) generally associated with the lepidic component of lung adenocarcinoma. However, in some cases, GGO nodules have been associated with invasive adenocarcinomas, where a lepidic component is minimal or absent. The purpose of this study is to evaluate the clinicopathological characteristics and prognosis of non-lepidic invasive adenocarcinoma presenting as GGO nodules., Methods: We reviewed computed tomography (CT) images from 168 patients diagnosed with non-lepidic invasive adenocarcinoma classified as stage T1N0M0 (≤3 cm) who underwent curative anatomical resection. Tumors were classified according to radiologic features: 31 were GGO predominant (Group A) and 137 were solid predominant (Group B). The clinicopathological findings and recurrence free survival were used as outcome measures., Results: The mean percentages of micropapillary and solid component in tumor was higher in Group B than Group A (P<0.001) Pleural invasion and lymphatic invasion were more frequently seen in Group B. The presence of tumors with a micropapillary component was higher in Group B (P=0.040). The 3-year recurrence-free survival was lower in Group B than Group A (80.4% vs . 100%, P=0.019). Risk factors for recurrence such as presence of a micropapillary component and lymphatic invasion were more frequently seen in Group B., Conclusions: Non-lepidic invasive adenocarcinoma presenting as GGO has fewer risk factors and better prognosis when compared with those presenting as solid tumors. Therefore, the presence of GGO on chest CT is a good prognostic indicator for lung cancer irrespective of histomorphologic classification., Competing Interests: The authors have no conflicts of interest to declare.

Background: The prognosis of non-small cell lung cancer (NSCLC) presenting as a ground glass opacity (GGO) nodule is better than other types of lung cancer. The purpose of this study was to evaluate the necessity of mediastinal lymph node evaluation (MLE) in clinical N0 GGO-predominant NSCLC., Methods: We conducted a retrospective chart review of 358 patients treated for clinical N0 NSCLC that was found by curative resection to be 3 cm or smaller in size. We analyzed clinicopathological findings and survival among three groups with either GGO-predominant or solid-predominant tumor: no mediastinal lymph node evaluation (NoMLE) group, mediastinal lymph node sampling (MLS) group, and mediastinal lymph node dissection (MLND) group., Results: Except for sex, there were no differences in clinicopathological characteristics among the three groups with GGO-predominant tumor or solid-predominant tumor. There was no difference in the 5-year recurrence-free survival (RFS) rate among three groups in the GGO-predominant patients (100%, 92.9%, 93.8%, respectively; P=0.889). However, in the solid-predominant tumor group, the 5-year recurrence free survival of the NoMLE group was lower than in the MLND group (48.6% vs . 73.1%, P=0.007). MLE was not a significant risk factor for recurrence in GGO-predominant tumor [hazard ratio (HR) =1.021; P=0.987]. GGO-predominant tumor [odds ratio (OR) =0.063; P=0.008] was identified as the sole parameter that significantly impacted nodal upstaging., Conclusions: MLE is not an essential procedure for clinical N0 NSCLC presenting as a 3 cm or smaller GGO-predominant nodule., Competing Interests: The authors have no conflicts of interest to declare.

Background: Sublobar resection is considered controversial for non-small cell lung cancer (NSCLC) presenting as a solid-predominant nodule. The aim of this study was to identify risk factors related to recurrence in small-sized NSCLC presenting as a solid-predominant nodule., Methods: We conducted a retrospective chart review of 118 patients who were treated for clinical N0 NSCLC sized ≤2 cm and who underwent sublobar resection with clear resection margins. We assigned them to two groups according to radiologic features: ground glass opacity (GGO)-predominant tumor and solid-predominant tumor. Clinicopathological characteristics and survival were analyzed in both groups. Risk factors for recurrence were analyzed in the solid-predominant tumor group., Results: Seventy-three patients had a GGO-predominant tumor, and 45 patients had a solid-predominant tumor. Five-year recurrence-free survival (RFS) in the solid-predominant tumor and GGO-predominant tumor groups was 64.9% and 95.5%, respectively. A multivariate analysis was performed to determine factors associated with recurrence after sublobar resection in the solid-predominant tumor group; it indicated that SUVmax [hazard ratio (HR) =1.482, 95% confidence interval (CI): 1.123-1.956, P=0.005] and histologic types other than adenocarcinoma (squamous cell carcinoma, HR =8.789, 95% CI: 1.572-49.134, P=0.013; other types, HR =53.569, 95% CI: 2.616-1096.849, P=0.010) were significant risk factors for recurrence., Conclusions: Risk factors in solid-predominant tumors sized ≤2 cm after sublobar resection are a high SUVmax and histologic types other than adenocarcinoma. Thus, lobectomy should be considered for solid-predominant NSCLC sized ≤2 cm with a high SUVmax or non-adenocarcinoma types., Competing Interests: The authors have no conflicts of interest to declare.

Background: Pure ground-glass opacity (GGO) on computed tomography (CT) is considered a diagnostic feature of noninvasive lung adenocarcinoma. However, pure GGO can sometimes be associated with invasive adenocarcinoma (IA). The purpose of this study was to determine the predictive factors for IA when pure GGO is present., Methods: Between 2011 and 2014, 83 patients with persistent pure GGO on chest CT underwent surgical treatment for lung cancer. We compared the clinical, surgical, and pathological characteristics of non-IA with those of IA., Results: A total of 66 patients (79.5%) were diagnosed with non-IA and 17 patients (20.5%) were diagnosed with IA. The mean axial diameter of the GGO lesions in IA was larger than that in non-IA (1.9 vs. 1.2 cm; P<0.001). The incidence of pleural retraction was higher in IA than in non-IA (76.5% vs. 15.2%; P<0.001). Multivariate logistic regression analysis identified GGO lesion size and the presence of pleural retraction as significant predictive factors for IA., Conclusions: Both preoperative GGO lesion size on CT and the computed-tomography or operative finding of pleural retraction are predictive factors for IA. In patients with these findings, curative lobectomy is preferable to limited resection.

Background: In some patients, clinical N0 (cN0) lung adenocarcinoma diagnosed by preoperative computed tomography scanning and positron emission tomography scanning was staged as pathologic N1 (pN1) or N2 (pN2) postoperatively. The aim of this study was to determine the preoperative and postoperative clinicopathologic factors related to nodal upstaging after a surgical operation., Methods: We conducted a retrospective chart review of 350 patients treated for cN0 lung adenocarcinoma by curative resection. We analyzed clinicopathologic findings, comparing pN0 patients with the nodal upstaging group., Results: Of 350 patients treated for cN0 tumors, 305 (87.1%) were confirmed postoperatively as having pN0 tumors, and 45 (12.9%) were confirmed as having pN1 or pN2 tumors. The mean maximum standardized uptake value (SUVmax) was higher in the nodal upstaging group than in the pN0 group (6.9 versus 3.8, p = 0.004); the upstaging group also included more cases in which SUVmax was greater than 5 (70.5% versus 24.8%, p < 0.001). Pleural invasion, lymphatic invasion, and vascular invasion were all more frequently seen in the nodal upstaging group than in the pN0 group (all p < 0.001). The presence of tumors with a micropapillary component was higher in the nodal upstaging group (p < 0.001). Multivariate logistic regression analysis identified SUVmax greater than 5, lymphatic invasion, vascular invasion, and a micropapillary component as significant risk factors for nodal upstaging., Conclusions: In lung adenocarcinoma diagnosed as clinical N0 by chest computed tomography and positron emission tomography scanning, the possibility of occult lymph node metastasis increases with SUVmax greater than 5 and when lymphatic invasion, vascular invasion, and a micropapillary component are present., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis., Methods: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated., Results: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%)., Conclusions: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Minimally invasive esophagectomy (MIE) has the potential to reduce the morbidity and mortality of esophageal cancer surgery. Esophageal squamous cell carcinoma (ESCC) has a high incidence of earlier lymphatic spread and is usually located more proximal to the incisor than esophageal adenocarcinoma; consequently, the anastomosis should be made more proximal in the thorax or in the neck. We adopted the proximal intrathoracic anastomotic technique using thoracoscopy for mid-to-lower ESCC., Methods: From October 2010 to August 2014, fifty-eight consecutive patients underwent MIE for ESCC. After laparoscopic gastric tubing, thoracoscopic esophageal resection and reconstruction were performed using a 28-mm circular stapler following radical mediastinal lymph node dissection. We tried to make an anastomosis at the apex of the chest. Postoperative outcomes, including overall survival and recurrence, were assessed., Results: The mean patient age was 64.3±9 years. The mean operative time was 371.8±51.6 minutes, and the duration of the thorax procedure was 254.8±38.3 minutes. The mean number of lymph nodes dissected was 31±11.7. The mean intensive care unit (ICU) stay and hospital stay were 3.5±8.2 hours and 13.6±7.4 days, respectively. The level of anastomosis was 22.3±1.8cm from the incisor. One patient died of uncontrolled sepsis due to necrosis of the gastric graft. Two patients developed small contained leakage. Nine patients exhibited distant metastasis during the follow-up period., Conclusion: Thoracoscopic intrathoracic anastomosis at the proximal esophagus is feasible and safe.

Background: Stage I pulmonary adenocarcinoma (PA) can offer an unfavorable prognosis. The aim of this study was to classify the prognosis of stage I PA on the basis of the lepidic component and to confirm whether the lepidic component can be used as a criterion for predicting the prognosis of stage I PA., Methods: We conducted a retrospective study of patients who underwent curative surgery for stage I and IIA PA. Stage I disease was divided into three groups on the basis of the lepidic component: group 1, ≤10%; group 2, >10 to 50%; and group 3, >50%. We compared recurrence-free survival (RFS) rates among groups 1, 2, and 3, and stage IIA disease. We also evaluated risk factors for disease recurrence with multivariate analysis., Results: A total of 224 patients were included in our study; most patients (n=201) had stage I disease. Three-year RFS rates in group 1 (n=73), group 2 (n=75), and group 3 (n=53) were 74.1, 90.4, and 90.0%, respectively. There was a significant difference in RFS between group 1 and group 2 (p=0.009). The 3-year RFS rate in stage IIA disease was 61.4%. There were no significant differences in RFS between group 1 and stage IIA disease (p=0.163). In multivariate analysis, group 1 had the highest risk of recurrence (HR 5.806, p=0.006) in stage I PA., Conclusions: Stage I PA with a lepidic component≤10% was associated with an unfavorable prognosis that was similar to the prognosis of stage IIA disease. The prognosis for stage I PA should not be based on general criteria, but instead, the lepidic component should be evaluated and considered when determining disease prognosis.

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings., (Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Pulmonary adenocarcinoma is largely peripheral in location but often does occur centrally. In the course of this study, clinicopathologic features of pulmonary adenocarcinoma, including the prognosis of early-stage disease, were assessed and compared by tumor location., Methods: A retrospective chart review was conducted, examining 308 patients treated for pulmonary adenocarcinoma by curative resection. Clinicopathologic findings were analyzed, comparing central and peripheral primary locations. Recurrence-free survival (RFS) rates were determined for tumor subsets (central vs. peripheral)., Results: At all disease stages (N=308), 41 patients (13.3%) with central adenocarcinoma were documented. In central (vs. peripheral) adenocarcinoma, mean tumor size was larger (3.1 vs. 2.3 cm, P=0.014), nodal metastasis was more frequent (P=0.012), and the likelihood of advanced disease (stages II and III) was greater (P=0.007). Microscopically, central adenocarcinoma displayed more acinar (53.3% vs. 38.9%; P=0.006) and less lepidic (20.9% vs. 37.5%; P=0.001) growth. At stage I disease [N=329; central, 25 (10.5%)], group similarities were sustained. As with disease overall, central adenocarcinoma contained more acinar (51.8% vs. 37.1%; P=0.025) and fewer lepidic (26.2% vs. 44.1%; P=0.006) areas. Three-year RFS rates for central and peripheral adenocarcinoma at all disease stages were 63.2% and 82.5% (P=0.024), respectively, compared with 70.4% and 91.0% (P=0.023), respectively at stage I. Lepidic growth was identified as a statistically significant risk factor for early recurrence by multivariate analysis., Conclusions: Central pulmonary adenocarcinoma is generally detected at an advanced stage. In early (stage I) disease, the prognosis is comparatively worse for central adenocarcinoma, owing to significant micromorphologic differences in central and peripheral tumors.

We aimed to establish whether the expression of microRNA-34a (miR-34a) is correlated with that of c-MET and G1 phase regulators such as cyclin dependent kinase (CDK) 4, CDK6, and cyclin D (CCND) 1 in non-small cell lung cancer (NSCLC), and whether a relationship exists between miR-34a expression and both clinicopathologic factors and recurrence-free survival (RFS). For 58 samples archived from NSCLC patients, we measured the expression of miR-34a and c-MET, CDK4/6, and CCND1 by quantitative RT-PCR and assessed the relationship between miR-34a expression, clinicopathological factors, and RFS. The expression of miR-34a was significantly lower in squamous cell tumors (P < 0.001) and in tumors associated with lymphatic invasion (P = 0.001). We found significant inverse correlations between miR-34a and c-MET (R = -0.316, P = 0.028) and CDK6 expression (R = -0.4582, P = 0.004). RFS were longer in adenocarcinoma patients with high miR-34a expression than in those with low miR-34a expression (55.6 vs. 21.6 months; P = 0.020). With univariate analysis, statistically significant prognostic factors for RFS in adenocarcinoma patients were miR-34a expression (Relative risk (RR), 8.14; P = 0.049), TNM stage (RR, 13.55; P = 0.001), LN metastasis (RR, 4.19; P = 0.043), and the presence of lymphatic invasion (RR, 7.05; P = 0.015). In multivariate analysis, only miR-34a was prognostic for RFS (RR, 11.5; P = 0.027). miR-34a expression was inversely correlated with that of c-MET and CDK6 in NSCLC, and had prognostic significance for RFS, especially in adenocarcinoma patients.

Background: Bis, also known as BAG3, has been identified as a Bcl-2-interacting protein that enhances cellular anti-apoptotic activity. It is involved in cellular differentiation, angiogenesis, migration, and invasion in various tumors. The purpose of this study was to investigate the Bis expression pattern, and the clinical significance thereof, in patients with resected lung cancer., Methods: We studied 121 lung cancer patients who underwent curative surgical resection. Patient clinicopathological characteristics were reviewed retrospectively from medical records, including tumor recurrence and survival. The expression of Bis protein in lung cancer tissues was evaluated by immunohistochemical staining and was assessed using a four-tiered intensity score system (negative, weak, moderate, strong). Enhanced Bis expression at the periphery of a tumor facing the adjacent nontumor region was referred as "marginal activity.", Results: Although Bis expression was higher in squamous cell carcinoma than in adenocarcinoma, marginal activity was higher in adenocarcinoma than in squamous cell carcinoma. All of the small cell carcinomas and lung cancer with neuroendocrine differentiation examined were negative for Bis expression. Compared with stage I lung cancer, patients with stage II and IIIA lung cancer exhibited higher Bis protein levels in lung tissues. Recurrence and survival rates did not differ significantly according to Bis expression intensity score or marginal activity., Conclusions: Our study demonstrated that Bis expression differed according to the histological type and pathological stage of the lung cancer. Further studies are needed to assess its use as a biomarker and its role in the molecular pathogenesis of lung cancer.

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites., Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers., Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures., Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Purpose: To analyze the benefit and feasibility of this procedure compared with those of open method., Methods: Abdominal procedure includes laparoscopic gastric mobilization, celiac axis lymph node dissection, formation of the gastric tube, and pyloromyotomy. The actual procedure performed during open surgery is the same as those of laparoscopic surgery except for the main incision. Minimally invasive esophagectomy (MIE) was performed on 54 patients with esophageal cancer. The short-term outcomes, including postoperative complications were analyzed and compared with 44 cases of open method., Results: Although the total operative time was not different between 2 groups (349.8 minutes vs. 374.8 minutes, P = 0.153), the operation time of abdominal procedure was shorter in laparoscopic group (90.6 minutes vs. 162.1 minutes, P < 0.001). Operation related complications and hospital stay were not significantly different between the 2 groups. The number of transfused patients was significantly smaller in laparoscopic group (11.1% vs. 27.9%, P = 0.030)., Conclusion: Laparoscopic gastric tubing with pyloromyotomy is a feasible and safe treatment option for patients with esophageal cancer.

Background: The KIF5B-RET rearrangement is detected with the frequency of 1 ~ 2% in 'triple marker'-negative lung adenocarcinomas, i.e., EGFR, KRAS and EML4-ALK wild type. These mutational changes are known to be mutually exclusive, but the co-existence of ALK rearrangement with activating mutations of EGFR is rarely found., Methods: We examined the KIF5B-RET fusion gene in frozen tissues from 154 surgically resected lung tumors using RT-PCR with direct sequencing and the mutation status of EGFR and KRAS genes using PNA clamping. We tested KIF5B-RET translocation in Formalin Fixed Paraffin Embedded using fluorescence in situ hybridization. We also measured RET mRNA and protein expression by RT-PCR and immunohistochemistry, respectively., Results: The existence of KIF5B-RET fusion gene was identified in 9 patients. The mean age was 67.2 and M: F ratio 4:5. Of 9 patients, 3 patients harbored wild type of EGFR and KRAS gene. However, KIF5B-RET fusion gene coincided with EGFR or KRAS mutation in 6 patients. These six pts were also positive for both RET break-apart probes (23.9%) and KIF5B-RET fusion (44.4%). However, there were no correlations between RET mRNA and protein expression in the KIF5B-RET-positive patients. The median disease free survival and overall survival were 23.9 months and 29.5 months, respectively., Conclusions: Taken together, our data suggest one-step screening platform for KIF5B-RET as well as EGFR, K-RAS, ALK oncogenic mutations be necessary for lung adenocarcinoma patients because EGFR or KRAS mutation are not infrequently found in KIF5B-RET-positive patients.

Background: Recent studies demonstrated that miR-137 is downregulated in various tumors, and that it functions as a tumor suppressor. miR-137 could be silenced by its aberrant promoter hypermethylation. The purpose of this study was to investigate the significance of MIR137 promoter methylation on its expression in lung cancer., Methods: Lung cancer cell lines were treated with either a DNA methyltransferase inhibitor (5-azacytidine, AZA) and/or an HDAC inhibitor (trichostatin A, TSA) to determine whether miR-137 expression was reactivated. Paired lung tumor and adjacent non-tumor lung tissues were obtained (n=50). Quantitative methylation-specific PCR and bisulfite sequencing were used to analyze the methylation status of MIR137, and real-time RT-PCR was performed to analyze miR-137 expression., Results: miR-137 was reactivated by treatment with either AZA and/or TSA in lung cancer cell lines. Methylation-specific PCR showed increased MIR137 promoter methylation in lung tumors compared with adjacent non-tumor tissues, which was further validated by bisulfite sequencing. The expression of miR-137 was downregulated significantly in lung tumors, which was correlated with level of MIR137 promoter methylation inversely., Conclusions: miR-137 downregulation was related to its promoter hypermethylation in lung cancer. Further studies are needed to assess its value as a prognostic factor and potential therapeutic applications in lung cancer., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)