Prognosis of spread through air spaces in invasive mucinous lung adenocarcinoma after curative surgery.

INTRODUCTION: The purpose of this study is to investigate the prognostic impact of spread through air spaces (STAS) in invasive mucinous adenocarcinoma (IMA). MATERIALS AND METHODS: From 2015 to 2019, patients who underwent complete resection of IMA were extracted from the prospective database. Multivariable Cox-regression analysis and inverse probability of treatment weight (IPTW) - adjusted log-rank test for 5-year recurrence-free survival (RFS) were performed. RESULTS: STAS was observed in 39.1% (53 out of 133). The STAS (+) group shows larger tumor size (2.9 ± 2.4 cm vs 3.8 ± 2.4 cm, p = 0.031) and higher incidence of lympho-vascular invasion (6 [7.5%] vs 18 [34.0%], p < 00.001) compared to the STAS (-) group. The 5-year RFS was 66.1% in the STAS (+) group and 91.8% in the STAS (-) group (p < 00.001), and the incidence of locoregional recurrence was significantly higher in the STAS (+) group than the STAS (-) group (1 [1.2%] vs 12 [22.6%], p < 00.001). Multivariable analysis revealed that STAS was associated with poor prognosis for all-recurrence (hazard ratio 2.81, 95% confidence interval 1.01-7.81, p = 0.048). After IPTW adjustment, 5-year RFS was 66.3% in the STAS (+) group and 92.9% in the STAS (-) group (p = 0.007), and risk for locoregional recurrence was greater in the STAS (+) group than the STAS (-) group (1.1 [0.9%] vs 20.8 [16.6%], p < 00.001). CONCLUSIONS: STAS showed negative prognostic impact on all-recurrence, especially due to locoregional recurrence, after curative resection of IMA.

The Optimal Treatment Strategy for Postoperative Anastomotic Leakage After Esophagectomy: a Comparative Analysis Between Endoscopic Vacuum Therapy and Conventional Treatment.

BACKGROUND: We compared the clinical outcomes between endoscopic vacuum therapy (EVT) and conventional treatment (CT) for the management of post-esophagectomy anastomotic leakage. METHODS: A retrospective review of the medical records of patients who underwent esophagectomy with esophagogastrostomy from November 2003 to August 2021 was conducted. Thirty-four patients who developed anastomotic leakage were analyzed according to whether they underwent CT (n = 13) or EVT (n = 21). RESULTS: The median time to complete healing was significantly shorter in the EVT group than in the CT group (16 [4-142] days vs. 70 [8-604] days; p = 0.011). The rate of clinical success was higher in the EVT group (90.5%) than in the CT group (66.7%, p = 0.159). A subgroup analysis showed more favorable outcomes for EVT in patients with thoracic leakage, including a higher clinical success rate (p = 0.037), more rapid complete healing (p = 0.004), and shorter hospital stays (p = 0.006). However, the results were not significantly different in patients with cervical leakage. Anastomotic strictures occurred in 3 EVT patients (14.3%) and 5 CT patients (50.0%) (p = 0.044), and the EVT group showed a trend towards improved freedom from anastomotic strictures (p = 0.105). CONCLUSIONS: EVT could be considered as an adequate treatment option for post-esophagectomy anastomotic leakage. EVT might have better clinical outcomes compared to CT for managing anastomotic leakage after transthoracic esophagogastrostomy, and further studies are needed to evaluate the effectiveness of EVT in patients who undergo cervical esophagogastrostomy.

Surgical outcomes of thoracoscopic thymectomy via the single-port subxiphoid approach versus the unilateral intercostal approach.

OBJECTIVES: The purpose of this study was to explore the safety and feasibility of video-assisted thoracic surgery (VATS) total thymectomy via the single-port subxiphoid approach compared with the intercostal approach. METHODS: From January 2018 to May 2022, patients who underwent VATS total thymectomy via the subxiphoid or unilateral intercostal approach and diagnosed with Masaoka-Koga stage I-II, non-myasthenic thymoma were included in this study. Perioperative outcomes, immediate and long-term pain evaluations were compared in a propensity score-matching analysis. RESULTS: In total, 95 patients were included and underwent the subxiphoid approach (n = 37) and the intercostal approach (n = 58). Propensity score yielded 2 well-matched cohorts of 30 patients and there was no significant demographical imbalance between the 2 groups. Compared with the intercostal approach, the subxiphoid group demonstrated favourable perioperative outcomes including the intraoperative blood loss (P = 0.025) and the median duration of hospital stay (P = 0.083). The immediate and long-term pain evaluations revealed that the subxiphoid group reported lower visual analogue scales at postoperative 24 h and lower total doses of fentanyl bolus infusions during hospitalization (P = 0.004 and 0.018, respectively), along with lower long-term neuropathic pain scale scores (P = 0.005) than patients in the intercostal group. CONCLUSIONS: VATS thymectomy via the single-port subxiphoid approach showed favourable perioperative outcomes compared to the intercostal approach. Moreover, the subxiphoid approach seemed both to cause minimal immediate postoperative pain and to have advantages in reducing long-term neuropathic pain compared with the intercostal approach.

A single-cell atlas of in vitro multiculture systems uncovers the in vivo lineage trajectory and cell state in the human lung.

We present an in-depth single-cell atlas of in vitro multiculture systems on human primary airway epithelium derived from normal and diseased lungs of 27 individual donors. Our large-scale single-cell profiling identified new cell states and differentiation trajectories of rare airway epithelial cell types in human distal lungs. By integrating single-cell datasets of human lung tissues, we discovered immune-primed subsets enriched in lungs and organoids derived from patients with chronic respiratory disease. To demonstrate the full potential of our platform, we further illustrate transcriptomic responses to various respiratory virus infections in vitro airway models. Our work constitutes a single-cell roadmap for the cellular and molecular characteristics of human primary lung cells in vitro and their relevance to human tissues in vivo.

Role of prognostic nutritional index in postoperative radiotherapy for non-small cell lung cancer.

BACKGROUND: The prognostic nutritional index (PNI) is known to be correlated with clinical outcomes in non-small cell lung cancer (NSCLC) patients. However, its role has not been studied in patients who have undergone postoperative radiotherapy (PORT). This study aimed to investigate the relationship between PNI and survival and recurrence in NSCLC patients with PORT. METHODS: We reviewed 97 stage I-III NSCLC patients who received PORT between January 2006 and December 2016 at our institution. We obtained PNI values for both pre-RT (within 1 month before PORT) and post-RT (within 2 months after PORT) by using serum albumin and lymphocyte count. A cutoff value for PNI was determined by the receiver operating characteristic curve (ROC). The median follow-up period was 52.8 months. RESULTS: The ROC curve of post-RT PNI exhibited a higher area under the curve (AUC 0.68, cut-off: 47.1) than that of pre-RT PNI (AUC 0.55, cutoff: 50.3), so the group was divided into high post-RT PNI (> 47.1) and low post-RT PNI ( ≤ 47.1). The five-year overall survival rate (OS) was 66.2% in the high post-RT group, compared with 41.8% in the low post-RT PNI group (p = 0.018). Those with both low pre-RT and low post-RT PNI had the worst five-year OS of 31.1%. Post-RT PNI (HR 0.92, p = 0.003) was an independent risk factor for mortality. CONCLUSIONS: PNI after PORT was significantly associated with survival. This finding suggests that PNI can be used as a prognostic marker.

Differential Prognostic Value of Vascular Invasion in Resected Lung Adenocarcinomas According to Epidermal Growth Factor Receptor Mutational Status.

BACKGROUND: It is unclear whether all patients with stage IB to IIIA epidermal growth factor receptor (EGFR)-mutant adenocarcinoma should receive adjuvant osimertinib. We investigated the prognostic value of vascular invasion for risk stratification according to EGFR mutational status. MATERIALS AND METHODS: This retrospective study evaluated patients with stage IB to IIIA lung adenocarcinoma resected between 2011 and 2016 at a tertiary care center. The study outcome was overall survival (OS). The prognostic value of vascular invasion was analyzed using the adjusted log-rank test and multivariable Cox regression with clinico-pathological factors as covariates. A sensitivity analysis, which included the presence of ground-glass opacity on CT scans as an additional covariate, and subgroup analyses according to the pathological stage were performed. RESULTS: In total, 272 patients were included (146 women; median age, 66 years [interquartile range: 58, 72 years]; 128 EGFR-mutant adenocarcinomas). The 5-year OS rate was 90.8% (95% CI: 84.0%, 98.1%) in EGFR-mutant, vascular invasion-absent lung adenocarcinomas, which was higher than in other subgroups (P < .05). Vascular invasion was an independent, negative prognostic factor in EGFR-mutant lung adenocarcinomas (adjusted log-rank test, P = .02; adjusted hazard ratio, 3.01; 95% CI: 1.30, 7.02; P = .01). However, the prognosis of EGFR wild-type adenocarcinomas was not associated with the presence of vascular invasion (adjusted log-rank test, P = .95; adjusted hazard ratio, 1.32; 95% CI: 0.74, 2.34; P = .35). Similar results were observed in the sensitivity analysis and subgroup analyses. CONCLUSIONS: Vascular invasion-absent, EGFR-mutant, resected lung adenocarcinomas showed a very good prognosis, and vascular invasion had a differential prognostic value according to EGFR mutational status.

Multi-targeted therapy resistance via drug-induced secretome fucosylation.

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.

Impact of Preoperative Diagnostic Biopsy Procedure on Spread Through Airspaces and Related Outcomes in Resected Stage I Non-Small Cell Lung Cancer.

BACKGROUND: Tumor spread through airspaces (STAS) is a recently determined pathologic phenomenon of lung cancer with significant prognostic impact. This study aimed to analyze the unexplored correlation between preoperative biopsy procedure and a higher risk of STAS and its impact on STAS-related outcomes in resected stage I non-small cell lung cancer (NSCLC). RESEARCH QUESTION: Does preoperative biopsy procedure affect the risk of STAS and STAS-related outcomes in surgically treated stage I NSCLC? STUDY DESIGN AND METHODS: We examined 2,169 patients who underwent surgery for pathologic stage I NSCLC from January 2011 through December 2019 at the Seoul National University Bundang Hospital, a tertiary center in South Korea. Factors including percutaneous needle biopsy (PCNB) and bronchoscopic biopsy were assessed for determining the association between preoperative biopsy procedure and an elevated risk of STAS. In addition, the impact of preoperative biopsy on STAS-related prognosis (recurrence and lung cancer-specific mortality) was evaluated with multivariate Cox regression analyses. RESULTS: STAS findings were positive in 638 of 2,169 patients (29.4%). An insignificant association was found between preoperative biopsy (both PCNB and bronchoscopic biopsy) and STAS. After adjustments for preoperative tumor biopsy, STAS was a significant risk factor for cancer recurrence (hazard ratio [HR], 1.72; 95% CI, 1.20-2.48). Additionally, sublobar resection remained a significant risk factor for recurrence (HR, 3.20; 95% CI, 1.65-6.21) and lung cancer-specific mortality (HR, 12.71; 95% CI, 3.68-43.92) in patients with positive STAS findings. However, this association was insignificant for patients without STAS. Preoperative biopsy was not a significant risk factor for either recurrence and mortality, regardless of STAS positivity. INTERPRETATION: Preoperative biopsy in stage I NSCLC neither was associated with an elevated risk of STAS nor influenced the prognosis related to STAS. Physicians can be less apprehensive about performing preoperative biopsy in relationship to STAS.

Expression-based species deconvolution and realignment removes misalignment error in multispecies single-cell data.

BACKGROUND: Although single-cell RNA sequencing of xenograft samples has been widely used, no comprehensive bioinformatics pipeline is available for human and mouse mixed single-cell analyses. Considering the numerous homologous genes across the human and mouse genomes, misalignment errors should be evaluated, and a new algorithm is required. We assessed the extents and effects of misalignment errors and exonic multi-mapping events when using human and mouse combined reference data and developed a new bioinformatics pipeline with expression-based species deconvolution to minimize errors. We also evaluated false-positive signals presumed to originate from ambient RNA of the other species and address the importance to computationally remove them. RESULT: Error when using combined reference account for an average of 0.78% of total reads, but such reads were concentrated to few genes that were greatly affected. Human and mouse mixed single-cell data, analyzed using our pipeline, clustered well with unmixed data and showed higher k-nearest-neighbor batch effect test and Local Inverse Simpson's Index scores than those derived from Cell Ranger (10 × Genomics). We also applied our pipeline to multispecies multisample single-cell library containing breast cancer xenograft tissue and successfully identified all samples using genomic array and expression. Moreover, diverse cell types in the tumor microenvironment were well captured. CONCLUSION: We present our bioinformatics pipeline for mixed human and mouse single-cell data, which can also be applied to pooled libraries to obtain cost-effective single-cell data. We also address misalignment, multi-mapping error, and ambient RNA as a major consideration points when analyzing multispecies single-cell data.

Prognostic Role of Circulating Tumor Cells in the Pulmonary Vein, Peripheral Blood, and Bone Marrow in Resectable Non-Small Cell Lung Cancer.

Background: Studies of the prognostic role of circulating tumor cells (CTCs) in early-stage non-small cell lung cancer (NSCLC) are still limited. This study investigated the prognostic power of CTCs from the pulmonary vein (PV), peripheral blood (PB), and bone marrow (BM) for postoperative recurrence in patients who underwent curative resection for NSCLC. Methods: Forty patients who underwent curative resection for NSCLC were enrolled. Before resection, 10-mL samples were obtained of PB from the radial artery, blood from the PV of the lobe containing the tumor, and BM aspirates from the rib. A microfabricated filter was used for CTC enrichment, and immunofluorescence staining was used to identify CTCs. Results: The pathologic stage was stage I in 8 patients (20%), II in 15 (38%), III in 14 (35%), and IV in 3 (8%). The median number of PB-, PV-, and BM-CTCs was 4, 4, and 5, respectively. A time-dependent receiver operating characteristic curve analysis showed that PB-CTCs had excellent predictive value for recurrence-free survival (RFS), with the highest area under the curve at each time point (first, second, and third quartiles of RFS). In a multivariate Cox proportional hazard regression model, PB-CTCs were an independent risk factor for recurrence (hazard ratio, 10.580; 95% confidence interval, 1.637-68.388; p<0.013). Conclusion: The presence of ≥4 PB-CTCs was an independent poor prognostic factor for RFS, and PV-CTCs and PB-CTCs had a positive linear correlation in patients with recurrence.

Poor Prognosis of Grade 2 Spread Through Air Spaces in Neuroendocrine Tumors.

BACKGROUND: Spread through air spaces (STAS) has recently emerged as a prognostic factor in lung adenocarcinoma, but little is known about the association of STAS and its grade with recurrence in neuroendocrine tumors (NETs). This study investigated the prognostic effect of STAS grade in NETs after curative resection. METHODS: Seventy-seven patients were retrospectively reviewed, including 9 with typical carcinoid (TC), 6 with atypical carcinoid (AC), 26 with large cell neuroendocrine carcinoma (LCNEC), and 36 with small cell carcinoma (SCC). STAS was defined as the presence of floating tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. STAS was classified as grade 1 or 2 depending on whether it was found within or beyond one ×10 objective lens field away from the main tumor margin, respectively. RESULTS: Fifty-four patients (70%) had STAS, including 22% with TC, 50% with AC, 69% with LCNEC, and 86% with SCC. Patients with STAS had more nodal metastasis, lymphatic and vascular invasion, tumor necrosis, and tumor subtypes other than TC. Among STAS cases, grade 2 STAS was present in 33% of AC, 78% of LCNEC, and 87% of SCC. The 5-year recurrence-free survival (RFS) rate was 81%, 63%, and 35% in patients with no STAS, grade 1, and grade 2 STAS, respectively. Multivariate analysis found that grade 2 STAS was an independent negative prognostic factor for RFS. CONCLUSION: Although STAS itself was not associated with a poor prognosis, grade 2 STAS was an independent negative prognostic factor for RFS.

Serum protein profiling of lung, pancreatic, and colorectal cancers reveals alcohol consumption-mediated disruptions in early-stage cancer detection.

While the link between serum proteins and cancer has been studied in an effort to enable early-stage cancer detection, factors that might perturb this link has been poorly understood. To ask this question, we performed serum protein profiling on a prospective cohort of 601 individuals with or without lung, pancreatic, or colorectal cancers and identified ten distinct serum protein signatures with distinct link to the patient metadata. Importantly, we discovered that a positive history of alcohol consumption is a major factor that diminishes the sensitivity of serum protein-mediated liquid biopsy in early-stage malignancies, resulting in a 44% decline in the sensitivity of detecting American Joint Committee on Cancer (AJCC) stage I malignancies. Our data provide evidence that patient lifestyle can affect the sensitivity of liquid biopsy and suggest the potential need for abstinence from alcohol before measurement during serum protein-based cancer screening.

Epigenetic readers and lung cancer: the rs2427964C>T variant of the bromodomain and extraterminal domain gene BRD3 is associated with poorer survival outcome in NSCLC.

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression. We investigated whether variants in BET genes are associated with survival outcomes for lung cancer. To do this, the associations between 77 variants in BET family genes and survival outcomes were analyzed in 773 non-small-cell lung cancer (NSCLC) patients who underwent surgery (349 and 424 patients in the discovery and validation cohorts, respectively). We found that six variants were significantly associated with overall survival (OS) in the discovery cohort, and one variant (rs2506711C>T) was replicated in the validation cohort. BRD3 rs2506711C>T is located in the repressed area and has a strong linkage disequilibrium with rs2427964C>T in the promoter region. BRD3 rs2427964C>T was significantly associated with worse OS in the discovery cohort, validation cohort, and combined analysis. In a luciferase assay, promoter activity in the BRD3 rs2427964 T allele was significantly higher than that in the BRD3 rs2427964 C allele, which selectively bound with the transcriptional repressor SIN3A. Knockdown of BRD3 with BRD3-specific siRNA decreased the proliferation and migration of lung cancer cells while also increasing the rate of apoptosis. These results suggest that BRD3 rs2427964C>T increases BRD3 expression through increased promoter activity, which is associated with poor prognosis for lung cancer.

Randomized Trial of Poloxamer 407-Based Ropivacaine Hydrogel After Thoracoscopic Pulmonary Resection.

BACKGROUND: We conducted a comparative study to evaluate the efficacy of poloxamer 407-based ropivacaine hydrogel at the wound site (Gel) and continuous thoracic paravertebral block using On-Q PainBuster (On-Q; B. Braun Medical) for postoperative pain after thoracoscopic pulmonary resection. METHODS: This prospective, randomized, noninferiority study included 89 patients randomized to the Gel group (poloxamer 407-based 0.75% ropivacaine, 22.5 mg) or the On-Q group (0.2% ropivacaine, 4 mg/h for 48 hours). The primary outcome measure was total fentanyl consumption, and secondary outcome measures were the need for rescue analgesia and pain intensity using the numeric rating scale (NRS). RESULTS: There was no significant difference in total fentanyl consumption between the Gel group and the On-Q group (1504.29 ± 315.72 µg vs 1560.32 ± 274.81 µg, P = .374). Pain intensity using the NRS between the Gel group and the On-Q group demonstrated no statistical differences at 6 hours (3.56 vs 3.55, P = .958), 24 hours (3.21 vs 3.00, P = .25), 48 hours (2.75 vs 2.49, P = .233), and 72 hours (2.39 vs 2.33, P = .811), and there was no significant difference in the frequency of analgesic rescue medication use (3.70 vs 3.33, P = .417). CONCLUSIONS: We confirm the noninferiority of Gel compared with On-Q for acute postoperative pain after thoracoscopic pulmonary resection. Considering a technical simplicity and low systemic toxicity of the local injection of Gel, this analgesic modality may be worthy of further research and is thus considered to have potential as a viable alternative to On-Q for regional analgesia.

Definitions of Central Tumors in Radiologically Node-Negative, Early-Stage Lung Cancer for Preoperative Mediastinal Lymph Node Staging: A Dual-Institution, Multireader Study.

BACKGROUND: Definitions for central lung cancer (CLC) have been ambiguous in guidelines, causing difficulty in selecting candidates for invasive mediastinal staging among patients with radiologically node-negative, early-stage lung cancer. RESEARCH QUESTION: What is the optimal definition for CLC that is robust to interreader and institutional variation to select candidates for invasive mediastinal staging among those with clinical T1N0M0 lung cancer? STUDY DESIGN AND METHODS: Two retrospective cohorts were evaluated for the associations of central lung cancer according to 13 definitions based on chest CT scan with occult nodal metastasis. Univariate and multivariate ordinal logistic regression analyses were performed with the pathologic N category as an ordinal outcome. Robust definitions, which retained statistical significance across multireader, dual-institutional datasets, were identified. For these definitions, binary diagnostic performance and interreader agreement were investigated. RESULTS: In the two cohorts, 807 patients (median age, 63 years; interquartile range [IQR], 56-71 years; 410 women; 33 pN1, 48 pN2, and 1 pN3) and 510 patients (median age, 65 years; IQR, 58-71 years; 267 women; 33 pN1, 20 pN2, and no pN3) were included, respectively. Three definitions robust to interreader variation and dataset heterogeneity were identified: definition 7 (concentric lines arising from the midline, inner one-third, medial margin; adjusted OR, 2.01; 95% CI, 1.13-3.51; P = .02), definition 10 (location index-based inner one-third, center; adjusted OR, 3.60; 95% CI, 1.49-8.25; P = .003), and definition 12 (location index-based inner one-third, medial margin; adjusted OR, 3.57; 95% CI, 1.91-6.52; P < .001). Definition 12 showed higher interreader agreement than definition 7 (Cohen κ, 0.80 vs 0.66; P = .005). Nevertheless, the sensitivity and positive predictive value of the three definitions were < 50%. INTERPRETATION: Three definitions exhibited robust associations with occult nodal metastasis. However, selecting candidates for invasive mediastinal staging solely based on a central tumor location would be suboptimal.

The differential prognostic impact of spread through air spaces in early-stage lung adenocarcinoma after lobectomy according to the pT descriptor.

OBJECTIVES: We evaluated the differential prognostic impact of spread through air spaces (STAS) in early-stage lung adenocarcinoma after lobectomy according to the pT descriptor. METHODS: The study population included 506 patients who underwent lobectomy with mediastinal lymph node dissection for pT1b, pT1c, and pT2a adenocarcinoma between 2011 and 2016. We divided the study population into 2 groups according to STAS status, ie, STAS (+) versus STAS (-), and stratified them according to the pT descriptor. A Cox proportional hazard model and inverse probability of treatment weight-adjusted Kaplan-Meier curves were used to evaluate the prognostic impact of STAS on recurrence-free survival (RFS) and its independency in each stratum. RESULTS: Multivariable Cox proportional hazard regression analysis demonstrated that in pT1b and pT1c strata, STAS (+) patients had a 7.02-fold and 2.89-fold greater risk of recurrence than STAS (-) patients, respectively. However, in the pT2a stratum, STAS did not affect RFS. And the RFS of the STAS (+) pT1b/c strata was similar to that of the pT2a stratum. In the pT1b/c strata, inverse probability of treatment weighting-adjusted Kaplan-Meier curves also showed that RFS was significantly worse when STAS was present. Furthermore, the risks for locoregional and distant recurrence were both greater when STAS was present. CONCLUSIONS: The presence of STAS increased the risk of recurrence independently from other poor prognostic factors in patients with pT1b/cN0M0 adenocarcinoma who underwent lobectomy, but not in pT2a patients. The presence of STAS in pT1b/cN0M0 adenocarcinoma was associated with a similar risk of recurrence to that of pT2aN0M0 adenocarcinoma.

Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma.

Many studies support a stepwise continuum of morphologic changes between atypical adenomatous hyperplasia (AAH) and lung adenocarcinoma (ADC). Here we characterized gene expression patterns and the association of differentially expressed genes and immune tumor microenvironment behaviors in AAH to ADC during ADC development. Tumor tissues from nine patients with ADC and synchronous multiple ground glass nodules/lesions (GGN/Ls) were analyzed using RNA sequencing. Using clustering, we identified genes differentially and sequentially expressed in AAH and ADC compared to normal tissues. Functional enrichment analysis using gene ontology terms was performed, and the fraction of immune cell types was estimated. We identified up-regulated genes (ACSL5 and SERINC2) with a stepwise change of expression from AAH to ADC and validated those expressions by quantitative PCR and immunohistochemistry. The immune cell profiles revealed increased B cell activities and decreased natural killer cell activities in AAH and ADC. A stepwise change of differential expression during ADC development revealed potential effects on immune function in synchronous precursors and in tumor lesions in patients with lung cancer.

Genetic variants in histone modification regions are associated with the prognosis of lung adenocarcinoma.

We investigated the association between genetic variants in the histone modification regions and the prognosis of lung adenocarcinoma after curative surgery. Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The SNPs were analyzed in a discovery set (n = 166) and a validation set (n = 238). The associations of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. A total of 279 SNPs were selected for genotyping. Among these, CAPN1 rs17583C>T was significantly associated with better OS and DFS (P = 0.001 and P = 0.007, respectively), and LINC00959 rs4751162A>G was significantly associated with worse DFS (P = 0.008). Luciferase assays showed a significantly lower promoter activity of CAPN1 in the rs17583 T allele than C allele (P = 0.008), and consistently the CT + TT genotypes had significantly lower CAPN1 expression than CC genotype (P = 0.01) in clinical samples. The rs4751162 G allele had higher promoter activity of GLRX3 than A allele (P = 0.05). The motif analyses and ChIP-qPCR confirmed that the variants are located in the active promoter/enhancer regions where transcription factor binding occurs. This study showed that genetic variants in the histone modification regions could predict the prognosis of lung adenocarcinoma after surgery.

Video-assisted thoracic surgery sleeve resection and bronchoplasty using 3D imaging system: its safety and efficacy.

BACKGROUND: Video-assisted thoracic surgery sleeve resection with bronchial anastomosis or bronchoplasty is a technically demanding procedure. Three-dimensional endoscopic surgery has been reported to be helpful in decreasing operation time and improving spatial perception with less surgical errors, but there have been rare reports about relatively difficult thoracoscopic procedures utilizing 3D thoracoscope. We performed this study to evaluate early clinical outcomes of thoracoscopic sleeve resection and bronchoplasty utilizing 3D thoracoscope. METHODS: Data from a total of 36 patients who underwent thoracoscopic sleeve lobectomy or bronchoplasty at our institution from December 2015 to October 2017 were retrospectively reviewed. Three-port approach with one utility incision was used with a 10 mm, 30° three-dimensional thoracoscope. Twenty-three patients (81%) were male, and mean age was 65.9 ± 9.4 years. Fourteen patients (38.9%) underwent sleeve resection with bronchial anastomosis, 22 (61.1%) underwent wedge or simple bronchoplasty, and one patient received concomitant PA procedure. Bronchial anastomosis sites were not covered with viable tissue flaps. RESULTS: There was no (0%) suture needle injury from spatial misperception during bronchoplasty or sleeve anastomosis. There was no (0%) operative mortality. The pathologic report revealed squamous cell carcinoma (63.9%), adenocarcinoma (19.4%), carcinoid (6.9%), adenosquamous carcinoma (3.4%), and sarcomatoid carcinoma (2.8%). One (2.8%) late mortality was due to systemic recurrence of sarcomatoid carcinoma. There was no (0.0%) anastomotic failure. The mean number of dissected lymph nodes were 27.4 ± 13.2, and mean operation time was 216.8 ± 60.0 min. Median postoperative 24-h drain amount was 315 mL. Median chest tube days and hospital days were 4 and 6, respectively. Two patients (5.6%) had complications greater than Clavien-Dindo grade II-one case of ARDS, and the other case of a delayed bronchopleural fistula. CONCLUSIONS: Thoracoscopic sleeve resection and bronchoplasty utilizing HD 3D thoracoscope is a safe and effective procedure with excellent early clinical outcomes. Further investigation for long-term outcomes will be needed.