Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease characterized by progressive dyspnea and decreased lung function, yet its exact etiology remains unclear. It is of great significance to discover new drug targets for IPF. METHODS: We obtained the cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium as exposure and the genome wide association study (GWAS) of IPF from the International IPF Genetics Consortium as outcomes to simulate the effects of drugs on IPF by employing mendelian randomization analysis. Then colocalization analysis was performed to calculate the probability of both cis-eQTL of druggable genes and IPF sharing a causal variant. For further validation, we conducted protein quantitative trait locus (pQTL) analysis to reaffirm our findings. RESULTS: The expression of 45 druggable genes was significantly associated with IPF susceptibility at FDR < 0.05. The expression of 23 and 15 druggable genes was significantly associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLco) in IPF patients, respectively. IPF susceptibility and two significant genes (IL-7 and ABCB2) were likely to share a causal variant. The results of the pQTL analysis demonstrated that high levels of IL-7 in plasma are associated with a reduced risk of IPF (OR = 0.67, 95%CI: 0.47-0.97). CONCLUSION: IL-7 stands out as the most promising potential drug target to mitigate the risk of IPF. Our study not only sheds light on potential drug targets but also provides a direction for future drug development in IPF.

Perioperative outcomes of uniportal versus three-port video-assisted thoracoscopic surgery in lung cancer patients aged ≥ 75 years old: a cohort study.

BACKGROUND: Increasing attention has been raised on the surgical option for lung cancer patients aged ≥75 years, however, few studies have focused on whether uniportal video-assisted thoracoscopic surgery (VATS) is safe and feasible for these patients. This study aimed to evaluate short-term results of uniportal versus three-port VATS for the treatment of lung cancer patients aged ≥75 years. METHODS: We retrospectively evaluated 582 lung cancer patients (≥75 years) who underwent uniportal or three-port VATS from August 2007 to August 2021 based on the Western China Lung Cancer Database. The baseline and perioperative outcomes between uniportal and three-port VATS were compared in the whole cohort (WC) and the patients undergoing lobectomy (lobectomy cohort, LC) respectively. Propensity score matching (PSM) was used to minimize confounding bias between the uniportal and three-port cohorts in WC and LC. RESULTS: Intraoperative blood loss was significantly less in the uniportal than three-port LC (50 mL vs. 83 mL, P = 0.007) before PSM and relatively less in the uniportal than three-port LC (50 mL vs. 83 mL, P = 0.05) after PSM. Significantly more lymph nodes harvested (13 vs. 9, P = 0.007) were found in the uniportal than three-port LC after PSM. In addition, in WC and LC, there were no significant differences between uniportal and three-port cohorts in terms of operation time, the rate of conversion to thoracotomy during surgery, nodal treatments (dissection or sampling or not), the overall number of lymph node stations dissected, postoperative complications, volume and duration of postoperative thoracic drainage, hospital stay after operation and hospitalization expenses before and after PSM (P > 0.05). CONCLUSIONS: There were no significant differences in short-term outcomes between uniportal and three-port VATS for lung cancer patients (≥75 years), except relatively less intraoperative blood loss (P < 0.05 before PSM and P = 0.05 after PSM) and significantly more lymph nodes harvested (P < 0.05 after PSM) were found in uniportal LC. It is reasonable to indicate that uniportal VATS is a safe, feasible and effective operation procedure for lung cancer patients aged ≥75 years.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

A Competing Risk Model Nomogram to Predict the Long-Term Prognosis of Lung Carcinoid.

BACKGROUND: The prediction of long-term, cancer-specific survival of lung carcinoid remains controversial. We aimed to build a prognostic model by using competing-risk analysis to predict the long-term, cancer-specific survival of lung carcinoid patients. METHODS: Patients were retrospectively enrolled from the SEER database, and clinicopathological data were collected. Univariable and multivariable competing-risk analyses were conducted to identify prognostic factors. A competing-risk model and a nomogram were developed by using independent prognostic factors. The model was assessed by using concordance index and calibration curves. RESULTS: A total of 2496 patients were enrolled, of which 267 (10.7%) died of diagnosed carcinoma; 316 (12.7%) died because of other reasons. The 5-year, 10-year, and 15-year cancer-specific survival of carcinoid patients were 91.35%, 86.60%, and 84.39%, respectively. Multivariable analysis demonstrated that increasing age, male, larger tumor size, higher N stage, M1, atypical carcinoid, and undergoing no surgery were independent risk factors. A competing-risk model based on the risk factors and a corresponding nomogram were developed. Concordance index of the developed model for 5-year, 10-year, and 15-year were 0.891, 0.856, 0.836 respectively in the training cohort and 0.876, 0.841, 0.819 respectively in the validation cohort after bootstrap adjustment. The calibration curves of 5-year, 10-year, and 15-year showed good agreement. CONCLUSIONS: Increasing age, male, larger tumor size, higher N stage, M1, atypical carcinoid, and undergoing no surgery were independent risk factors. A competing risk model of excellent performance in predicting long-term survival was developed, and a nomogram was established.

[MinerVa: A high performance bioinformatic algorithm for the detection of minimal residual disease in solid tumors].

How to improve the performance of circulating tumor DNA (ctDNA) signal acquisition and the accuracy to authenticate ultra low-frequency mutation are major challenges of minimal residual disease (MRD) detection in solid tumors. In this study, we developed a new MRD bioinformatics algorithm, namely multi-variant joint confidence analysis (MinerVa), and tested this algorithm both in contrived ctDNA standards and plasma DNA samples of patients with early non-small cell lung cancer (NSCLC). Our results showed that the specificity of multi-variant tracking of MinerVa algorithm ranged from 99.62% to 99.70%, and when tracking 30 variants, variant signals could be detected as low as 6.3 × 10 -5 variant abundance. Furthermore, in a cohort of 27 NSCLC patients, the specificity of ctDNA-MRD for recurrence monitoring was 100%, and the sensitivity was 78.6%. These findings indicate that the MinerVa algorithm can efficiently capture ctDNA signals in blood samples and exhibit high accuracy in MRD detection.

Uniportal Thoracoscopic Single-Direction Basal Subsegmentectomy (Left S10a+ci): Trans-Inferior-Pulmonary-Ligament Approach.

Thoracoscopic segmentectomy and subsegmentectomy have been widely accepted for the treatment of peripheral small lung cancers. Thoracoscopic basal subsegmentectomy, especially when performed through a uniportal procedure, is extremely technically challenging, and therefore there are seldom reports of its technical details. In this article, we present a uniportal thoracoscopic left S10a+ci subsegmentectomy following the single-direction strategy through the inferior pulmonary ligament approach.

Clinicopathological characteristics and prognosis of resectable lung adenosquamous carcinoma: a population-based study of the SEER database.

OBJECTIVE: Adenosquamous carcinoma is a rare subtype of non-small cell lung cancer characterized by aggressive behavior, with combination of adenocarcinoma and squamous cell carcinoma components. The clinicopathological characteristics and prognosis of resectable adenosquamous carcinoma are incompletely understood and this study aimed to depict those in a large population. METHODS: A total of 805 adenosquamous carcinoma, 7875 squamous cell carcinoma and 23 957 adenocarcinoma patients who underwent lobectomy or sublobectomy were queried from the Surveillance, Epidemiology, and End Results database (2010-17). Clinicopathological characteristics of adenosquamous carcinoma patients were compared with those of squamous cell carcinoma and adenocarcinoma patients. Prognostic factors were identified by univariable and multivariable Cox regression analyses. Propensity score matching was applied to reduce confounding effects. RESULTS: Adenosquamous carcinoma was associated with higher pleural invasion incidence and poorer differentiation compared with squamous cell carcinoma or adenocarcinoma (P values < 0.001). The independent risk factors of cancer-specific survival of adenosquamous carcinoma patients were increasing age, male sex, invading through visceral pleura, poor differentiation and higher stage. Stage IB adenosquamous carcinoma patients whose tumor invaded through visceral pleura had significantly worse survival than those not (P = 0.003). Adenosquamous carcinoma patients had worse survival compared with squamous cell carcinoma (5-year-survival: 64.55 vs. 69.09%, P = 0.003) and adenocarcinoma (5-year-survival: 64.55 vs. 76.79%, P < 0.001) patients before match. And this difference persisted after match. CONCLUSIONS: Resectable adenosquamous carcinoma patients had higher pleural invasion incidence, poorer differentiation and worse survival compared with squamous cell carcinoma and adenocarcinoma patients. Visceral pleural invasion status and differentiation grade were vital prognostic factors of adenosquamous carcinoma patients on the basis of stage.

Clinical Significance of Station 3A Lymph Node Dissection in Patients with Right-Side Non-Small-Cell Lung Cancer: A Retrospective Propensity-Matched Analysis.

PURPOSE: To investigate the prognostic impact of station 3A lymph node (LN) dissection in patients with right-side non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively reviewed data of 1906 patients with primary right-side NSCLC who underwent lobectomy between January 2005 and December 2017 (570 patients underwent station 3A LN dissection and 1336 patients did not). Propensity score matching was conducted to minimize the effects of potential confounding factors. Disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The metastasis rate of station 3A LN was 15.3% (87/570), which was second only to station 4 (17.3%). Only stations 10 and 11 LN metastases were found to be independent risk factors for station 3A LN metastasis (odds ratio = 19.43, 95% CI 1.21-311.12; P = 0.036 and odds ratio = 53.28, 95% CI 2.02-1404.90; P = 0.016, respectively). After propensity score matching, patients with dissection of station 3A LNs showed higher DFS (5-year DFS, 52.4% vs. 37.1%; P = 0.001) and OS (5-year OS, 58.8% vs. 48.7%; P = 0.007) than those without dissection. Subgroup analysis indicated that station 3A LN dissection was associated with significantly higher DFS and OS in patients with stage II and III disease. In multivariate survival analysis, dissection of 3A LNs retained its independent favorable effect on both DFS (hazard ratio = 0.76, 95% CI 0.64-0.90; P = 0.001) and OS (hazard ratio = 0.73, 95% CI 0.60-0.88; P = 0.001). CONCLUSION: Station 3A LN involvement was not rare and station 3A LN dissection was associated with a more favorable prognosis in patients with right-side NSCLC.

Primary Mediastinal Nonseminomas: A Population-Based Surveillance, Epidemiology, and End Results Analysis.

BACKGROUND: This study aimed to determine the disease characteristics and prognosis of patients with primary mediastinal nonseminomas (PMNS) in a Surveillance, Epidemiology, and End Results (SEER) analysis. MATERIALS AND METHODS: Demographic, treatment, and survival outcome data of cases with PMNS from 1975 to 2016 were retrieved. Cases with unknown variables mentioned in the analysis were excluded. Relative statistical methods were applied to analyze clinical characteristics and prognosis. RESULTS: A total of 587 PMNS patients met the selection criteria, 526 of whom were men. The mean age of patients was 28 (1-85) y. A total of 511 PMNS patients had validated subtypes, including 172 mixed germ cell tumors, 117 yolk sac tumors, 111 malignant teratomas, 70 choriocarcinomas, and 41 embryonal carcinomas. Patients with yolk sac tumors had the highest 3-y cancer-specific survival (CSS) rate (66.9%), while those with choriocarcinoma and embryonal carcinoma showed the worst prognosis. Surgery + chemotherapy (46.2%) was the most common and effective treatment for each subtype of PMNS. Multivariate Cox proportional hazards analysis identified embryonal carcinoma, malignant teratoma, choriocarcinoma, tumor size >15 cm, nodal metastasis, and distant stage as risk factors. In contrast, surgery-based care and younger age were protective factors. Propensity score matching analysis revealed significant improvement in the 5-y CSS rate from 35.8% to 60.3% with surgery (P < 0.001). However, radiotherapy (P = 0.436) and chemotherapy (P = 0.978) showed no survival benefits. CONCLUSIONS: 10 percent of the PMNS patients were female. Choriocarcinomas and embryonal carcinomas had the worst prognosis. Surgery was demonstrated to be the only way to prolong survival time. Chemotherapy and radiotherapy had minimal effects on prognosis.

Results of video-assisted thoracic surgery versus thoracotomy in surgical resection of pN2 non-small cell lung cancer in a Chinese high-volume Center.

PURPOSE: To investigate the short-term outcomes and long-term oncological efficacy of video-assisted thoracic surgery (VATS) for surgical treatment of pN2 non-small cell lung cancer (NSCLC) compared with open thoracotomy (OT). PATIENTS AND METHODS: We retrospectively collected data from 1034 patients who underwent pulmonary resection and systemic lymph node dissection for pathological N2 NSCLC from September 2005 to December 2017 (536 patients in VATS group and 498 patients in OT group). Propensity score matching was applied to reduce the confounding effects. Factors affecting survival were assessed by Kaplan-Meier estimates and Cox regression analysis. RESULTS: The VATS procedure was associated with shorter operative time compared with the OT procedure (147.96 ± 58.91 min vs. 165.34 ± 58.91 min, P < 0.001). No significant difference was identified between the two groups in the number of dissected mediastinal lymph nodes (MLNs) and number of dissected MLNs stations. More patients after VATS procedure received postoperative adjuvant therapy (83.4% vs. 75.5%, P = 0.002). At a median follow-up of 36 (range 4-150) months, comparing VATS procedure and OT procedure, no significant differences were noted in 5-year DFS (20.7% vs. 22.5%, P = 0.89) and 5-year OS (30.7% vs. 34.5%, P = 0.821). The VATS procedure was not found to be an independent predictor of DFS (hazard ratio, 0.986; 95% CI, 0.809 to 1.202) or OS (hazard ratio, 0.977; 95% CI 0.802 to 1.191). CONCLUSION: In this large propensity-matched comparison, the VATS procedure offered comparable short-term outcomes and long-term oncological efficacy for patients with pN2 NSCLC when compared with OT procedure.

Predictive value of pretreatment PD-L1 expression in EGFR-mutant non-small cell lung cancer: a meta-analysis.

OBJECTIVE: To investigate the predictive value of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). METHODS: We conducted a systemic search of PubMed, EMBASE, and the Cochrane Library from 1 January 2000 to 30 August 2020, to identify related studies. We combined the hazard ratio (HR) and 95% confidence interval (CI) to assess the correlation of PD-L1 expression with progression-free survival (PFS) and overall survival (OS). We assessed the quality of the included studies by the Newcastle-Ottawa Scale (NOS). We performed subgroup analyses based on immunohistochemistry (IHC) scoring system, IHC antibodies, sample size, countries, and survival analysis mode. Sensitivity analysis and evaluation of publication bias were also performed. RESULTS: Twelve studies including 991 patients met the criteria. The mean NOS score was 7.42 ± 1.19. Patients with high PD-L1 expression was associated with poorer PFS (HR = 1.90; 95% CI = 1.16-3.10; P = 0.011), while there was no association between PD-L1 expression and OS (HR = 1.19; 95% CI = 0.99-1.43; P = 0.070). Subgroup analysis prompted IHC scoring systems, IHC antibodies, and sample size have important effects on heterogeneity. The pooled results were robust according to the sensitivity analysis. CONCLUSIONS: The result of this meta-analysis suggested that PD-L1 expression might be a predictive biomarker for EGFR-mutant non-small cell lung cancer treated with EGFR-TKIs.

Trans-Inferior-Pulmonary-Ligament Single-Direction Thoracoscopic RS9 Segmentectomy: Application of Stem-Branch Method for Tracking Anatomy.

BACKGROUND: Video-assisted thoracoscopic segmentectomy has become a safe and effective surgical approach for stage IA non-small cell lung cancer.1,2 Therein, thoracoscopic segmentectomy for the lateral basal segment (S9) is the most technically challenging anatomical segmentectomy.3-6 Because the target vessels and bronchus are commonly variable and deeply located in the lung parenchyma, it is difficult to expose and correctly identify them through either an interlobar fissure approach or a posterior approach. Meanwhile, tailoring the intersegmental plane is another challenge that is encountered in a VATS S9 segmentectomy. METHODS: In this multimedia article, we present a thoracoscopic right S9 segmentectomy following the single-direction strategy through an inferior pulmonary ligament approach, using a novel method named stem-branch to track the target segmental branches along the stem (video).7 The positional relations of the basal segmental vessels and bronchi were preliminarily identified mainly through the high-resolution computed tomography (HRCT). The surgery was initiated through an inferior pulmonary ligament approach. The stems of the basal segmental vein and bronchus were first dissected, followed by dissection of their branches. Then, the target branches were tracked and identified according to the positional relations known via HRCT. Lung parenchyma between S10 and S7 should be divided to facilitate dissection and identification of the basal segmental venous and bronchus branches. After the target vein, bronchus and artery was transected in sequence. The method of inflation-deflation was used to identify the intersegmental plane. Then, stapler-based, three-dimensional tailoring was performed. RESULTS: The operative time was 1.5 h with an estimated blood loss of 30 ml. The chest tube was removed on postoperative Day 3. The patient was discharged on postoperative Day 4 without any complication. The final pathological finding was minimally invasive adenocarcinoma (pTmiN0M0). The chest X-ray on postoperative Day 1 and HRCT scan on postoperative Month 4 revealed that the residual right lung expended well. DISCUSSION: We identified the stem of the basal segmental bronchus, the number of its branches, and the relative locations of them according the preoperative HRCT. During the surgery, we started with dissection of the inferior pulmonary ligament. From the inferior view, the basal bronchus and its branches are located behind the veins. Division of the lung parenchyma between S10 and S7 would facilitate dissection and identification of the basal segmental venous branches during S9 segmentectomy. Because we already know the positional relations of the stem and its branches, the target segmental bronchus can easily be tracked. For the segmental veins, we should follow the principles of reserving uncertain veins, especially the intersegmental veins. The segmental arteries, which are usually accompanied by the segmental bronchus, could be found after transection of the bronchus. Stapling was started from the peripheral and thin parts of the lung and continued, reaching the segmental hilum and thick parts of the lung step-by-step during the intersegmental plane tailoring. For such a complex curved border, tailoring with the stapler alone was not affecting the expansion of the residual lung and causing atelectasis. CONCLUSIONS: Thoracoscopic segmentectomy for S9 can be performed successfully through the inferior pulmonary ligament approach by using the method of stem-branch for tracking anatomy based on HRCT and method of complete stapler-based tailoring for the intersegmental plane management.

Comparison of the Short- and Long-term Outcomes of Video-assisted Thoracoscopic Surgery versus Open Thoracotomy Bronchial Sleeve Lobectomy for Central Lung Cancer: A Retrospective Propensity Score Matched Cohort Study.

PURPOSE: The purpose of this study was to evaluate the short- and long-term outcomes of video-assisted thoracoscopic surgery (VATS) versus open thoracotomy bronchial sleeve lobectomy (BSL) for patients with central lung cancer. METHODS: This is a retrospective cohort study. Perioperative outcomes and long-term survival of patients who underwent VATS versus open thoracotomy BSL for central lung cancer from June 2010 and June 2018 in the Western China Lung Cancer Database were compared using propensity score matching (PSM) between the two surgical approaches. RESULTS: The retrospective study included 187 patients who divided into VATS group (n = 44) and open group (n = 143) according to surgical approach, and PSM resulted in 43 patients in each group, which were well matched by 11 potential prognostic factors. The VATS group was associated with lower overall incidence of postoperative complications (20.3% vs. 30.2%, P = 0.029), less postoperative drainage (875 ml [250-3960] vs. 1280 ml [100-4890], P = 0.039). The 5-year overall survival (OS) and disease-free survival (DFS) were comparable between the VATS and open groups (55.9% vs. 65.2% P = 0.836 and 54.1% vs. 60.2% P = 0.391, respectively) after matching. Multivariable adjusted analysis demonstrated that the surgical approach was not an independent favorable prognostic factor for OS (hazard ratio [HR] = 0.922; 95% confidence interval [CI], 0.427-1.993; P = 0.836) but just the pTNM stage (HR = 2.003; 95% CI 1.187-3.382; P = 0.009). CONCLUSIONS: VATS BSL may achieve equivalent long-term outcomes for central lung cancer patients when comparing with open thoracotomy. Although slightly longer duration of surgery, VATS approach may be a feasible option for lung cancer patients requiring BSL.

Survival Benefit of Left Lower Paratracheal (4L) Lymph Node Dissection for Patients with Left-Sided Non-small Cell Lung Cancer: Once Neglected But of Great Importance.

OBJECTIVE: The aim of this study was to compare survival outcomes between non-small cell lung cancer (NSCLC) patients with or without 4L node dissection (4LND) and to evaluate the potential patient population who will particularly benefit from 4LND. METHODS: Between January 2009 and December 2015, a total of 2063 patients with primary left-sided NSCLC in the Western China Lung Cancer Database were initially reviewed. After exclusion, 1064 patients were enrolled in this study. A total of 460 patients with 4LND (4LND+ group) were matched with 460 patients without 4LND (4LND- group) using propensity-matched analysis. Disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The metastasis rate of station 4L was 14.6%. Patients with 4LND showed higher DFS (5-year DFS 52.6% vs. 46.7%; hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.03-1.50; p = 0.022) and OS (5-year OS 65.8% vs. 56.3%; HR 1.36, 95% CI 1.10-1.69; p = 0.006) than patients without 4LND. In the multivariate analysis, patients without 4LND (HR 1.33, 95% CI 1.07-1.66; p = 0.011), tumor size > 3 cm, lymph node metastasis, and pathologic stage higher than stage I were independent prognostic factors for poor OS. Subgroup analysis according to pathologic TNM stage and N stage showed that stage II, IIIA, and N2 disease indicated better survival outcomes in the 4LND+ group (p = 0.050, p = 0.016, and p = 0.008, respectively). CONCLUSIONS: Performing 4LND may bring survival benefits to patients with left-sided NSCLC. We suggest 4LND as a standard procedure for left-sided NSCLC patients with stage II or advanced stage disease.

[The Development of Huaxi Intelligent Endoscopic Skill Training and Assessment System].

OBJECTIVE: To develop a novel objective standardized endoscopic skill training and assessment system based on artificial intelligence technology. METHODS: By designing five basic skill parts of endoscopic operation including vision location, clamping, delivering, shearing and suturing, we achieved objective standardized indexes which gained automatically with image recognition and refined perception. RESULTS: With Huaxi intelligent endoscopic skill training system, the accurate rates of vision location, clamping, delivering, shearing and suturing were 90%, 95%, 99%, 90%, and 89%, respectively. The response and performance time were 8-10 s, <1 s, <1 s, 1-3 s, and <1 s, respectively. CONCLUSION: Huaxi intelligent endoscopic skill training and assessment system has preliminarily possessed the capability to assess the endoscopic skills of surgeons objectively.

Posttranscriptional Control of PD-L1 Expression by 17ß-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines.

OBJECTIVE: Estrogen is a well-known oncogenic driver in endometrial (ECs) and breast cancers (BCs). Programmed cell death protein 1 (PD-1) and its ligands PD-1 Ligand 1 (PD-L1) and PD-L2 have been shown to mediate immune evasion of the tumor cells. The purpose of the present study was to assess the effects of estrogen on PD-L1 and PD-L2 expression in EC and BC cell lines. METHODS: 17ß-Estradiol (E2)-induced expression of PD-L1 and PD-L2 and possible signaling pathway were investigated in EC and BC cells. Coculture of T cells and cancer cells with E2 stimulation was performed to assess the functions of T cells. RESULTS: We found that E2 increased expression of PD-L1, but not PD-L2, protein via activation of phosphoinositide 3-kinase (PI3K)/Akt pathway in Ishikawa and Michigan Cancer Foundation-7 (MCF-7) cells. Phosphoinositide 3-kinase and Akt inhibitors could block E2's effects. 17ß-Estradiol did not increase PD-L1 mRNA transcription, but stabilized PD-L1 mRNA. 17ß-Estradiol's effects were only observed in estrogen receptor α (ERα)-positive Ishikawa and MCF-7 cells, but not in ERα-negative MDA-MB-231 cells. Coculture of Ishikawa or MCF-7 cells with T cells inhibited expression of interferon-γ and interleukin-2 and increased BCL-2-interacting mediator of cell death expression in the presence of E2. CONCLUSIONS: This study provides the first evidence that estrogen upregulates PD-L1 protein expression in ERα-positive EC and BC cells to suppress immune functions of T cells in the tumor microenvironment, demonstrating a new mechanism of how estrogen drives cancer progression.

[Diagnosis and Surgical Treatment of Lung Ground-glass Opacities:a Review of 663 Cases].

OBJECTIVES: To retrospectively investigate the clinical characteristics, surgical treatments of the patients with lung ground-glass opacities (GGO). METHODS: All the patients, who underwent surgical resection of GGO in our department from Jan. 2013 to Dec. 2016 were retrospectively reviewed. The clinicpathological features were analyzed. RESULTS: A total of 663 patients were included in this study. The rate of malignancy was 92.6% (614/663). The diameter of GGO in benign group [(0.8±0.2) cm] was significant smaller than that in malignant group [ (1.5±0.8) cm](P<0.001). The rate of irregular margin in malignant group was far higher than that in benign group (93.8% vs. 20.4%, P<0.001), but other CT signs such as vacuole sign, plural retraction, speculation and lobulation did not show significant difference between the two groups. A total of 652 (98.3%) cases were resected by video-assisted thoracoscopic surgery (VATS), and only 11 (1.7%) cases were resected by thoracotomy. A total of 336 (50.7%) patients underwent lobectomy, 226 (34.1%) underwent segmentectomy and 101 (15.2%) undewent wedge resection. The rate of surgery-related complications was 9.0% (60/663), and one (0.2%) patient died. CONCLUSIONS: With careful selection of GGO by experienced surgeons, the rate of malignancy is very high. Surgical resection may be recommended for highly suspected malignant cases. Sublobar resection or lobcotomy by VATS can achieve good treatment effect.

Monomethyl Auristatin E Phosphate Inhibits Human Prostate Cancer Growth.

BACKGROUND: Bone metastasis from primary prostate cancer leads to markedly diminished quality of life with poor long-term survival. Bone seeking treatment options are limited with adverse consequences on rapidly proliferating tissues such as bone marrow. In the present study, we seek to determine the bone-enriching capabilities of monomethyl auristatin E phosphate (MMAEp), a derivative of the potent antimitotic monomethyl auristatin E (MMAE). METHODS: The in vitro actions and mechanisms of cytotoxicity were assessed using cell viability, immunofluorescence, flow cytometry, and Western blot analysis. In vivo efficacy was determined using an intratibial xenograft mouse model of human prostate cancer and live animal imaging. RESULTS: The half maximal inhibitory concentration (IC50) of MMAE and MMAEp was determined to be approximately 2 and 48 nM, respectively, in PC-3 and C4-2B cell lines. MMAEp retained the mechanism of action of MMAE in reducing microtubule polymerization and stalling cell cycle progression at the G2/M transition. MMAEp was able to bind hydroxyapatite in in vitro assays. MMAEp significantly reduced intratibial tumor growth compared to the vehicle control treatment. CONCLUSIONS: MMAEp is an antimitotic compound that binds to calcium ions in the bone and inhibits prostate tumor growth in the bone. Prostate 76:1420-1430, 2016. © 2016 Wiley Periodicals, Inc.

IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44-VCAM-1 interaction.

BACKGROUND: Extravasation is a critical step in cancer metastasis, in which adhesion of intravascular cancer cells to the vascular endothelial cells is controlled by cell surface adhesion molecules. The role of interleukin-17 (IL-17), insulin, and insulin-like growth factor 1 (IGF1) in adhesion of prostate cancer cells to the vascular endothelial cells is unknown, which is the subject of the present study. METHODS: Human umbilical vein endothelial cells (HUVECs) and human prostate cancer cell lines (PC-3, DU-145, LNCaP, and C4-2B) were analyzed for expression of vascular cell adhesion molecule 1 (VCAM-1), integrins, and cluster of differentiation 44 (CD44) using flow cytometry and Western blot analysis. The effects of IL-17, insulin, and IGF1 on VCAM-1 expression and adhesion of prostate cancer cells to HUVECs were examined. The interaction of VCAM-1 and CD44 was assessed using immunoprecipitation assays. RESULTS: Insulin and IGF1 acted with IL-17 to increase VCAM-1 expression in HUVECs. PC-3, DU-145, LNCaP, and C4-2B cells expressed ß1 integrin but not α4 integrin. CD44 was expressed by PC-3 and DU-145 cells but not by LNCaP or C4-2B cells. When HUVECs were treated with IL-17, insulin or IGF1, particularly with a combination of IL-17 and insulin (or IGF1), adhesion of PC-3 and DU-145 cells to HUVECs was significantly increased. In contrast, adhesion of LNCaP and C4-2B cells to HUVECs was not affected by treatment of HUVECs with IL-17 and/or insulin/IGF1. CD44 expressed in PC-3 cells physically bound to VCAM-1 expressed in HUVECs. CONCLUSIONS: CD44-VCAM-1 interaction mediates the adhesion between prostate cancer cells and HUVECs. IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through increasing VCAM-1 expression in the vascular endothelial cells. These findings suggest that IL-17 may act with insulin/IGF1 to promote prostate cancer metastasis.