MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway.

MTHFD1L, a key enzyme of folate metabolism, is seldom reported in cancer. In this study, we investigate the role of MTHFD1L in the tumorigenicity of esophageal squamous cell carcinoma (ESCC). ESCC tissue microarrays (TMAs) containing 177 samples from 109 patients were utilized to evaluate whether MTHFD1L expression, determined using immunohistochemical analysis, is a prognostic indicator for ESCC patients. The function of MTHFD1L in the migration and invasion of ESCC cells was studied with wound healing, Transwell, and three-dimensional spheroid invasion assays in vitro and a lung metastasis mouse model in vivo. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MTHFD1L. Elevated expression of MTHFD1L in ESCC tissues was significantly associated with poor differentiation and prognosis. These phenotypic assays revealed that MTHFD1L significantly promote the viability and metastasis of ESCC cell in vivo and in vitro. Further detailed analyses of the molecular mechanism demonstrated that the ESCC progression driven by MTHFD1L was through up-regulation ERK5 signaling pathways. These findings reveal that MTHFD1L is positively associated with the aggressive phenotype of ESCC by activating ERK5 signaling pathways, suggesting that MTHFD1L is a new biomarker and a potential molecular therapeutic target for ESCC.

Transcriptome analysis of well-differentiated laryngeal squamous cell carcinoma cells in below-background environment.

Background: Preliminary research has shown an inhibited growth rate of well-differentiated laryngeal squamous cell carcinoma cells (FD-LSC-1) in below-background radiation (BBR), but how the cells respond to this environmental stress and the potential mechanisms are yet unknown. The current study aimed to reveal the molecular differences in cells grown under BBR conditions and normal radiation at the transcriptional level. Methods: The expression profiles between FD-LSC-1 cells grown in a deep underground laboratory and above ground laboratory collected on day 4 were investigated by whole-transcriptome analysis, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). Functional analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were then implemented for differentially expressed (DE) mRNAs and target genes of lncRNAs and circRNAs. Co-expression levels and the Bayesian network of DE genes were subsequently constructed, and the reliability of expression patterns were validated by quantitative real-time polymerase chain reaction (PCR). Results: The study identified a total of 671 mRNAs, 286 lncRNAs, 489 circRNAs, and 6 miRNAs as significantly expressed in response to the environmental stress. The GO annotations regarding the biological processes category were mainly biological regulation, metabolic process, response to stimulus, cell cycle, and modification process. The KEGG enrichment analysis indicated that TGF-ß and Hippo signaling played a crucial role in the transcriptional regulation of FD-LSC-1 cell growth under background radiation. Further network construction suggested that the enriched KEGG pathways affected this process by regulating cell proliferation-related genes including SMAD, SMAD7, CDH1, EGR1, and BMP2. Conclusions: Below-background radiation can lead to transcriptional changes in FD-LSC-1 cells cultured in the deep underground. The inhibitory growth effect is associated with multiple biological processes as well as canonical pathways of proliferation.

Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway.

Background: Glycosylation is crucial for the stability and biological functions of proteins. The aberrant glycosylation of critical proteins plays an important role in multiple cancers, including lung adenocarcinoma (LUAD). STT3 oligosaccharyltransferase complex catalytic subunit A (STT3A) is a major isoform of N-linked glycosyltransferase that catalyzes the glycosylation of various proteins. However, the functions of STT3A in LUAD are still unclear. Methods: The expression profiles of STT3A were initially analyzed in public data sets and then validated by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry assays in clinical LUAD samples. The overall survival (OS) between patients with high and low STT3A expression was compared using a Kaplan-Meier curve with a log-rank analysis. STT3A was knocked-out using CRISPR/Cas9 and inhibited by NGI-1. Cell Counting Kit-8, colony formation assay, wound-healing, transwell assay, and flow cytometry were performed to assess the cellular functions of STT3A in vitro. A mice xenograft model was established to investigate the effects of STT3A on tumor growth in vivo. Further, the downstream signaling pathways of STT3A were screened by mass spectrometry with a bioinformatics analysis, and the activation of the target pathways were subsequently validated by Western blot. Results: The expression of STT3A was frequently upregulated in LUAD tissues than normal lung tissues. The high expression of STT3A was significantly associated with poor OS in LUAD patients. The knockout or inhibition of STT3A suppressed proliferation, migration, and invasion, and arrested the cell cycle of LUAD cell lines in vitro. Similarly, the knockout or inhibition of STT3A suppressed tumor growth in vivo. In terms of molecular mechanism, STT3A may promote LUAD progression by activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT) pathways and regulating the epithelial-mesenchymal transition. Conclusions: STT3A promotes LUAD progression via the MAPK and PI3K/AKT signaling pathways and could serve as a novel prognostic biomarker and potential therapeutic target for LUAD patients.

Lymph node colonization induces tumor-immune tolerance to promote distant metastasis.

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

Perioperative Outcomes of Minimally Invasive Esophagectomy After Neoadjuvant Immunotherapy for Patients With Locally Advanced Esophageal Squamous Cell Carcinoma.

Background: Immunotherapy has become a pillar of advanced solid tumors treatment. Patients are more likely to benefit from neoadjuvant immunotherapy compared with traditional neoadjuvant therapy. However, the safety and efficacy of neoadjuvant immunotherapy for the treatment of locally advanced, surgically resectable Esophageal squamous cell carcinoma (ESCC) remain unknown. Method: ESCC patients who received neoadjuvant treatment following minimally invasive esophagogastrostomy were enrolled from June 2020 to September 2021. The characteristics of neoadjuvant treatment and surgery were investigated to determine the safety and efficacy of the neoadjuvant combination of chemotherapy and immunotherapy (NCI). Results: A total of 149 patients were included in the study. Patient ratio was 40:109 between NCI and neoadjuvant chemotherapy plus radiotherapy (NCR) groups. No significant difference was found in terms of pathological characteristics, including ypN stage, ypTNM stage, differentiation, lymphovascular invasion, perineural invasion, pathological complete regression and tumor regression score, and these parameters were not correlated with NCI or NCR (all p>0.05). Regarding to the operation, the NCI group had less blood loss (49.25 ± 13.47 vs. 57.02 ± 47.26, p<0.001), and shorter operation time (247.75 ± 28.28 vs. 285.83 ± 52.43, p<0.001) than the NCR group. Additionally, the NCI group demonstrated a lower rate of overall perioperative complications (p=0.003) and grade >2 perioperative complications (p=0.042) than the NCR group. Conclusion: Overall, the findings reported here indicate NCI could result in better outcome and less complications to locally advanced ESCC patients compared with NCR therapy. As a novel therapeutic option, the efficacy and safety of NCI appears to be feasible and safe, while long-term survival data is still needed.

Comparative N-Glycoproteomics Analysis of Clinical Samples Via Different Mass Spectrometry Dissociation Methods.

Site-specific N-glycosylation characterization requires intact N-glycopeptide analysis based on suitable tandem mass spectrometry (MS/MS) method. Electron-transfer/higher-energy collisional dissociation (EThcD), stepped collision energy/higher-energy collisional dissociation (sceHCD), higher-energy collisional dissociation-product-dependent electron-transfer dissociation (HCD-pd-ETD), and a hybrid mass spectrometry fragmentation method EThcD-sceHCD have emerged as valuable approaches for glycoprotein analysis. However, each of them incurs some compromise, necessitating the systematic performance comparisons when applied to the analysis of complex clinical samples (e.g., plasma, urine, cells, and tissues). Herein, we compared the performance of EThcD-sceHCD with those previous approaches (EThcD, sceHCD, HCD-pd-ETD, and sceHCD-pd-ETD) in the intact N-glycopeptide analysis, and determined its applicability for clinical N-glycoproteomic study. The intact N-glycopeptides of distinct samples, namely, plasma from prostate cancer (PCa) patients, urine from immunoglobulin A nephropathy (IgAN) patients, human hepatocarcinoma cell line (HepG2), and thyroid tissues from thyroid cancer (TC) patients were analyzed by these methods. We found that EThcD-sceHCD outperformed other methods in the balance of depth and accuracy of intact N-glycopeptide identification, and sceHCD and EThcD-sceHCD have good complementarity. EThcD-sceHCD holds great potential for biomarker discovery from clinical samples.

Tumor-Infiltrating PD-1hiCD8+-T-Cell Signature as an Effective Biomarker for Immune Checkpoint Inhibitor Therapy Response Across Multiple Cancers.

BACKGROUND: Stratification of patients who could benefit from immune checkpoint inhibitor (ICI) therapy is of much importance. PD-1hiCD8+ T cells represent a newly identified and effective biomarker for ICI therapy response biomarker in lung cancer. Accurately quantifying these T cells using commonly available RNA sequencing (RNA-seq) data may extend their applications to more cancer types. METHOD: We built a transcriptome signature of PD-1hiCD8+ T cells from bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data of tumor-infiltrating immune cells. The signature was validated by flow cytometry and in independent datasets. The clinical applications of the signature were explored in non-small-cell lung cancer, melanoma, gastric cancer, urothelial cancer, and a mouse model of breast cancer samples treated with ICI, and systematically evaluated across 21 cancer types in The Cancer Genome Atlas (TCGA). Its associations with other biomarkers were also determined. RESULTS: Signature scores could be used to identify the PD-1hiCD8+ T subset and were correlated with the fraction of PD-1hiCD8+ T cells in tumor tissue (Pearson correlation, R=0.76, p=0.0004). Furthermore, in the scRNA-seq dataset, we confirmed the capability of PD-1hiCD8+ T cells to secrete CXCL13, as well as their interactions with other immune cells. In 581 clinical samples and 204 mouse models treated with ICIs, high signature scores were associated with increased survival, and the signature achieved area under the receiver operating characteristic curve scores of 0.755 (ranging from 0.61 to 0.91) in predicting therapy response. In TCGA pan-cancer datasets, our signature scores were consistently correlated with therapy response (R=0.78, p<0.0001) and partially explained the diverse response rates among different cancer types. Finally, our signature generally outperformed other mRNA-based predictors and showed improved predictive performance when used in combination with tumor mutational burden (TMB). The signature score is available in the R package "PD1highCD8Tscore" (https://github.com/Liulab/PD1highCD8Tscore). CONCLUSION: Through estimating the fraction of the PD-1hiCD8+ T cell, our signature could predict response to ICI therapy across multiple cancers and could serve as a complementary biomarker to TMB.

Identifying the prognostic significance of B3GNT3 with PD-L1 expression in lung adenocarcinoma.

BACKGROUND: As a novel treatment, programmed cell death protein 1 (PD-1) inhibitor appears to be less effective in tumors of lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) has reported to be associated with programmed death ligand 1 (PD-L1)/PD-1 interaction. However, the relationship between B3GNT3 and PD-L1 and its prognostic significance in. EGFR: mutant status are still unknown. METHODS: B3GNT3 was identified through transcriptome sequencing and The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) database. Flow cytometry and real-time polymerase chain reaction were performed to investigate the association between B3GNT3, PD-L1, and EGFR. Then, B3GNT3 and PD-L1 expression were evaluated by immunohistochemical analysis in 145 surgically resected primary lung adenocarcinomas. The relationships between survival and B3GNT3, PD-L1, and EGFR status were assessed, and the potential prognostic factors in patients with B3GNT3 expression were identified. RESULTS: We found that EGFR activation induced PD-L1 expression, and EGFR tyrosine kinase inhibitor (TKI) could reduce PD-L1 protein in EGFR-TKI-sensitive HCC827 and PC9 cell lines. Subsequent analysis showed that EGFR inhibitor could also lead to both decreased PD-L1 and B3GNT3 mRNA expression. A total of 145 lung adenocarcinoma patients were included. PD-L1 >1% and B3GNT3-positive expression in patients might contribute to worse prognosis in both overall survival (OS) [hazard ratio (HR), 2.63; 95% confidence interval (CI), 0.98-7.06; P=0.048] and disease-free survival (DFS) (HR, 3.04; 95% CI, 1.13-8.14; P=0.019), especially in the PD-L1 ≥50% group. However, when patients were negative for B3GNT3, PD-L1, and EGFR (or "triple negative"), there were significant decreases in OS (HR, 5.44; 95% CI, 0.99-29.83; P=0.029) and DFS (HR, 7.24; 95% CI, 1.32-39.73; P=0.008). Positive B3GNT3 expression was a significant risk factor associated with lower DFS (HR, 3.30; P=0.043). CONCLUSIONS: Our results indicate that the B3GNT3 expression is tightly correlated with PD-L1 expression and EGFR mutation status. B3GNT3 is associated with poor prognosis in lung adenocarcinoma patients. Collectively, these findings may offer new insight into enhancing immune therapy efficacy for lung adenocarcinoma patients.

Skip metastasis in mediastinal lymph node is a favorable prognostic factor in N2 lung cancer patients: a meta-analysis.

BACKGROUND: Skip metastasis is a common lymph node metastatic pattern in non-small cell lung cancer (NSCLC). The relationship between skip metastasis and specific clinicopathologic factors and the prognostic value of skip metastasis are controversial. METHODS: A systematic search and analysis of skip metastasis in NSCLC was conducted in the databases of PubMed, EMBASE, and Web of Science up to Dec 2019. Summarized hazard ratio (HR), mean difference (MD), and odds ratio (OR) with associated 95% confidence intervals (CI) were evaluated to investigating the relationship between skip metastasis and overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and clinicopathological features in NSCLC. RESULTS: 29 studies with a total of 1,806 skip and 4,670 non-skip N2 patients were included. The upper lobe tumor showed a higher rate of skip metastasis compared with lower lobe one (RR =1.16, 95% CI: 1.00-1.34, P=0.044, I2=39.8%). The presence of skip metastasis correlated with superior overall survival (HR =0.74, 95% CI: 0.66-0.83, P<0.001, I2=48.2%) and DFS or RFS (HR =0.71, 95% CI: 0.61-0.84, P<0.001, I2=18.2%). Further subgroup analyses indicated similar results in articles that reported intrapulmonary lymph node dissection (HR =0.67, 95% CI: 0.57-0.77, P<0.001, I2=0). CONCLUSIONS: The results indicate that the presence of skip metastasis is associated with a marked increase in survival of NSCLC patients compared to patients with non-skip N2 metastasis. These results suggest that skip metastasis might be a distinct subgroup for purposes of N staging of NSCLC patients, and intrapulmonary lymph node assessment is needed.

Metabolomic analysis of lung cancer patients with chronic obstructive pulmonary disease using gas chromatography-mass spectrometry.

Chronic obstructive pulmonary disease (COPD), characterized by intermittent exacerbations and clinical subphenotypes like emphysema and chronic bronchitis, poses a significant risk of lung cancer (LC) development. Metabolomic studies of COPD are scarce, and those of LC patients with COPD subphenotypes have not been investigated. To study metabolite profile alteration in LC patients with different COPD subphenotypes, lung paracancer tissue from 10 LC (CON) patients, 10 LC patients with emphysema (E), and 9 LC patients with chronic bronchitis (CB) were analyzed using gas chromatography-mass spectrometry. Multivariate analysis indicated a distinct separation between LC patients with COPD subphenotypes and LC patients. Overall, 60, 55, 33 and 63 differential metabolites (DM) were identified in comparisons between CB vs CON, E vs CON, CB vs E, and CB + E vs CON, respectively, and of these, 8 DM were shared in all comparisons. Among the high altered metabolites, E samples showed higher 'acetol' than CON samples, and lower 'azelaic acid', '3-methylglutaric acid' and 'allose'. CB samples showed higher 'turanose' and 'o-phosphoserine' and lower 'anandamide' than CON and E samples. In CB and E samples, 'galactonic acid', '2-mercaptoethanesulfonic acid', 'D-alanyl-D-alanine' '3-methylglutaric acid', 'glycine', 'L-4-Hydroxyphenylglycine' and 'O-phosphonothreonine' had common alteration trends compared with those of CON samples. 'Glycine', 'L-4-Hydroxyphenylglycine' and 'O-phosphonothreonine' were significantly enriched in glycine, serine and threonine metabolism pathways. The total differential metabolites detected were remarkably altered in pyrimidine, beta-alanine and purine metabolism. Our study provided altered DM patterns of lung paracancer tissue, the key metabolites and their enriched metabolic pathways in LC patients with different COPD subphenotypes.

Efficacy of switching therapy to aflibercept for patients with persistent diabetic macular edema: a systematic review and meta-analysis.

BACKGROUND: To evaluate functional and anatomical consequences of switching anti-vascular endothelial growth factor (anti-VEGF) therapy from bevacizumab and/or ranibizumab to aflibercept intravitreal injection for the treatment of persistent diabetic macular edema (DME). METHODS: Analysis of switching treatment in patients with persistent DME was performed using a literature search across multiple databases (PubMed, Medline, EMBASE, Cochrane Library and Web of Science) prior to May 2019. Therapeutic effect parameters, including mean change of best-corrected visual acuity (BCVA) and central macular thickness (CMT), were extracted from baseline to different follow-up times post initial injections. The quality of studies was assessed with the Downs and Black checklist. Data pertaining to ocular and systemic safety adverse events (SAEs) were collected as well as subgroup analysis stratified by pre-switch anti-VEGF reagents. All results were analyzed and pooled using random-effects models with 95% confidence intervals (CI). RESULTS: Fourteen studies involving 489 eyes met the inclusion criteria. The mean differences in BCVA were significantly improved at 1, 2 and 3 months with -0.11 logMAR (P=0.016), -0.22 logMAR (P<0.001) and -0.24 logMAR (P<0.01), respectively. Vision gain was also assessed following the aflibercept injection with a mean change of -0.10 logMAR (P<0.001) at 6 months and -0.08 logMAR (P=0.01) at 12 months. CMT reduction was significant from baseline with a mean decrease of 80.52 µm (P<0.001) at 1 month, 89.6 µm (P<0.013) at 2 months, 113.88 µm (P<0.001) at 3 months and 125.12 µm (P<0.001) at 6 months. Mean CMT continued to decline by 75.70 µm (P<0.001) at 12 months as well. CONCLUSIONS: This meta-analysis indicated the comparable efficacy and safety of a conversion treatment to aflibercept in cases of unsatisfactory responses to other anti-VEGF drugs. Switching treatment produces significant advantage for vision acuity recovery and macular edema improvement among persistent DME patients.

Lung adenocarcinoma initially mimicking localized emphysema.

Here we report an exceedingly rare case of gradual continuous radiographic changes in lung cancer over five years. Over this period, the lesion was initially diagnosed as localized emphysema, yet in the final year, revealed itself to be a solid malignant nodule. Then the patient underwent thoracoscopic left upper lobectomy, followed by systematic lymphadenectomy when the nodule was confirmed as adenocarcinoma. This study demonstrates that slowly localized emphysema should be continuously monitored closely given its potential for malignant transformation in high-risk patients.

Video-assisted thoracoscopic surgery versus muscle-sparing thoracotomy for non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: It has been widely accepted that video-assisted thoracoscopic surgery (VATS) lobectomy is superior to conventional open thoracotomy lobectomy in many aspects. However, the direct comparison between VATS and Muscle-sparing thoracotomy (MST) has not been widely conducted. We aimed to compare the perioperative outcomes in non-small cell lung cancer (NSCLC) patients following VATS and MST. METHODS: PubMed, EMBASE, the Cochrane Library and Web of Science were searched for relevant studies. The retrieval time was up to April 24, 2019. Studies investigating the comparison of video-assisted thoracoscopy and muscle-sparing thoracotomy were included in our meta-analysis. Odds ratio and mean differences with 95% confidential interval were applied to determine the effectiveness of dichotomous or continuous variables respectively. RESULTS: A total of 10 studies were included with 1514 patients. Compared with MST, the incidence of postoperative complications in VATS [OR = 0.54; 95%CI(0.4, 0.73); P < 0.001] and the hospital stay [MD = -1.5; 95%CI(- 2.28, - 0.73); P = 0.0001] decreased significantly, chest tube drainage time [MD = -0.71; 95%CI(- 1.18, - 0.24); P = 0.003] were shorter and the intraoperative blood loss [MD = - 43.87; 95%CI(- 73.66, - 14.08); P = 0.004] were less in VATS group. VATS also showed a relatively longer operative time [MD = 17.11; 95%CI(2.38, 31.85); P = 0.02]. However, no significant differences were observed in numbers of resected lymph nodes, postoperative mortality, postoperative pneumonia and postoperative bleeding. CONCLUSION: Compared with MST, VATS was associated with lower incidence of postoperative complications, shorter length of hospital stay, less intraoperative blood loss and less chest tube drainage, which showed that VATS was a comparable method to MST. Meanwhile, these results should be further conformed by more randomized control trials.

Effect of Vein-First vs Artery-First Surgical Technique on Circulating Tumor Cells and Survival in Patients With Non-Small Cell Lung Cancer: A Randomized Clinical Trial and Registry-Based Propensity Score Matching Analysis.

Importance: It is important to develop a surgical technique to reduce dissemination of tumor cells into the blood during surgery. Objective: To compare the outcomes of different sequences of vessel ligation during surgery on the dissemination of tumor cells and survival in patients with non-small cell lung cancer. Design, Setting, and Participants: This multicenter, randomized clinical trial was conducted from December 2016 to March 2018 with patients with non-small cell lung cancer who received thoracoscopic lobectomy in West China Hospital, Daping Hospital, and Sichuan Cancer Hospital. To further compare survival outcomes of the 2 procedures, we reviewed the Western China Lung Cancer database (2005-2017) using the same inclusion criteria. Interventions: Vein-first procedure vs artery-first procedure. Main Outcomes and Measures: Changes in folate receptor-positive circulating tumor cells (FR+CTCs) after surgery and 5-year overall, disease-free, and lung cancer-specific survival. Results: A total of 86 individuals were randomized; 22 patients (25.6%) were younger and 64 (74.4%) older than 60 years. Of these, 78 patients were analyzed. After surgery, an incremental change in FR+CTCs was observed in 26 of 40 patients (65.0%) in the artery-first group and 12 of 38 (31.6%) in the vein-first group (P = .003) (median change, 0.73 [interquartile range (IQR), -0.86 to 1.58] FU per 3 mL vs -0.50 [IQR, -2.53 to 0.79] FU per 3 mL; P = .006). Multivariate analysis confirmed that the artery-first procedure was a risk factor for FR+CTC increase during surgery (hazard ratio [HR], 4.03 [95% CI, 1.53-10.63]; P = .005). The propensity-matched analysis included 420 patients (210 with vein-first procedures and 210 with artery-first procedures). The vein-first group had significantly better outcomes than the artery-first group for 5-year overall survival (73.6% [95% CI, 64.4%-82.8%] vs 57.6% [95% CI, 48.4%-66.8%]; P = .002), disease-free survival (63.6% [95% CI, 55.4%-73.8%] vs 48.4% [95% CI, 40.0%-56.8%]; P = .001), and lung cancer-specific survival (76.4% [95% CI, 67.6%-85.2%] vs 59.9% [95% CI, 50.5%-69.3%]; P = .002). Multivariate analyses revealed that the artery-first procedure was a prognostic factor of poorer 5-year overall survival (HR, 1.65 [95% CI, 1.07-2.56]; P = .03), disease-free survival (HR, 1.43 [95% CI, 1.01-2.04]; P = .05) and lung cancer-specific survival (HR = 1.65 [95% CI, 1.04-2.61]; P = .03). Conclusions and Relevance: Ligating effluent veins first during surgery may reduce tumor cell dissemination and improve survival outcomes in patients with non-small cell lung cancer. Trial Registration: ClinicalTrials.gov identifier: NCT03436329.

Left destroyed lung caused by a pen cap in the left lower lobe bronchus "swallowed" 25 years ago.

A delayed diagnosis of tracheobronchial foreign body aspiration (FBA) may result in severe respiratory complications such as pneumonia, bronchiectasis, and atelectasis. Here, we present a rare case of a left lung destruction caused by a pen cap that remained in the left lower lobe bronchus for 25 years and was previously misdiagnosed as cavitary tuberculosis. The foreign body was not detected in bronchoscopic examination prior to surgery due to severe stenosis of the left main bronchus. The foreign body was found incidentally while the patient was undergoing left pneumonectomy. To the best of our knowledge, this the second longest delay to diagnosis of FBA reported. This case also exemplifies the grave consequences of misdiagnosis of FBA.

Successful trans-apical aortic valve implantation for a high risk patient with aortic stenosis using a new second-generation TAVI device - J-Valve system.

Transcatheter aortic valve implantation (TAVI) has evolved as a routine procedure to treat selected high-risk patients with severe aortic stenosis. The new J-Valve prosthesis is designed for antegrade transapical implantation, it is characterized by a porcine aortic prosthesis attaching to a self-expandable Nitinol stent. The key feature of the device are three U-shape anatomically oriented devices - "graspers" which could facilitate intuitive 'self-positioning' valve implantation. Hereby, we report a successful case of trans-apical TAVI in an elderly high-risk patient with severe aortic stenosis using J-Valve system.