Enhancing the differential diagnosis of small pulmonary nodules: a comprehensive model integrating plasma methylation, protein biomarkers, and LDCT imaging features.

BACKGROUND: Accurate differentiation between malignant and benign pulmonary nodules, especially those measuring 5-10 mm in diameter, continues to pose a significant diagnostic challenge. This study introduces a novel, precise approach by integrating circulating cell-free DNA (cfDNA) methylation patterns, protein profiling, and computed tomography (CT) imaging features to enhance the classification of pulmonary nodules. METHODS: Blood samples were collected from 419 participants diagnosed with pulmonary nodules ranging from 5 to 30 mm in size, before any disease-altering procedures such as treatment or surgical intervention. High-throughput bisulfite sequencing was used to conduct DNA methylation profiling, while protein profiling was performed utilizing the Olink proximity extension assay. The dataset was divided into a training set and an independent test set. The training set included 162 matched cases of benign and malignant nodules, balanced for sex and age. In contrast, the test set consisted of 46 benign and 49 malignant nodules. By effectively integrating both molecular (DNA methylation and protein profiling) and CT imaging parameters, a sophisticated deep learning-based classifier was developed to accurately distinguish between benign and malignant pulmonary nodules. RESULTS: Our results demonstrate that the integrated model is both accurate and robust in distinguishing between benign and malignant pulmonary nodules. It achieved an AUC score 0.925 (sensitivity = 83.7%, specificity = 82.6%) in classifying test set. The performance of the integrated model was significantly higher than that of individual methylation (AUC = 0.799, P = 0.004), protein (AUC = 0.846, P = 0.009), and imaging models (AUC = 0.866, P = 0.01). Importantly, the integrated model achieved a higher AUC of 0.951 (sensitivity = 83.9%, specificity = 89.7%) in 5-10 mm small nodules. These results collectively confirm the accuracy and robustness of our model in detecting malignant nodules from benign ones. CONCLUSIONS: Our study presents a promising noninvasive approach to distinguish the malignancy of pulmonary nodules using multiple molecular and imaging features, which has the potential to assist in clinical decision-making. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 01/01/2020 (NCT05432128). https://classic. CLINICALTRIALS: gov/ct2/show/NCT05432128 .

Lobectomy with Lymph Node Dissection Benefits N3 Stage Non-Small Cell Lung Cancer Patients: A Population-Based Study.

INTRODUCTION: There remain controversies about the role of surgery for N3 stage non-small cell lung cancer (NSCLC) patients. METHODS: N3 stage NSCLC patients were identified from the US National Cancer Institute Surveillance, Epidemiology, and End Results database (2010-2020). Survival analysis and multivariate regression models were used to adjust covariates and analyze factors associated with survival. Propensity score matching was used to balance selection bias. RESULTS: Of 6,473 included patients, 121 received treatment that included lobectomy with mediastinal lymph node dissection. Overall survival (OS) was significantly prolonged in the lobectomy group than in the nonsurgery group (median survival time [MST]: 57 vs. 16 months; log-rank p < 0.001). A total of 403 patients were matched, and OS was significant longer in the lobectomy group (MST: 51 vs. 16 months; log-rank p < 0.001). Multivariate regression analyses indicated that lobectomy was independently associated with improved OS (hazard ratio [HR] 0.398, 95% confidence interval [CI] 0.302-0.526; p < 0.001) and lung cancer-specific death (LCSD) (subhazard ratio [SHR] 0.343, 95% CI: 0.249-0.474; p < 0.001). CONCLUSION: Compared with nonsurgical treatment modalities, lobectomy with lymph node dissection was associated with improved OS and LCSD in selected N3 stage NSCLC patients.

FAM65A promotes the progression and growth of lung squamous cell carcinoma in vivo and vitro.

BACKGROUNDS: Currently, family with sequence similarity 65 member A (FAM65A) is reported as a pivotal regulator in various cancers. However, the effect of FAM65A in lung squamous cell carcinoma (LSCC) is still unclear, the prime objective of this research is to explore the role of FAM65A in LSCC. METHODS: Gene expression data and correlated clinical information were downloaded from the public database and the expression of FAM65A was detected. The expression of FAM65A was also detected in our collected clinical samples and LSCC cell lines. Survival package of R language was used to determine the survival significance of FAM65A. Proteins expression level was determined via western blot assay. Cell function experiments and in vivo experiments were performed to explore the effect of FAM65A on LSCC cell biological behaviors. RESULTS: FAM65A expression was significantly increased in LSCC clinical samples and cell lines. High FAM65A expression predicted poor prognosis in LSCC patients. After silencing FAM65A, the ability of LSCC cell proliferation, invasion and migration was decreased, and LSCC cell cycle was blocked. Moreover, in vivo experiments revealed that silencing FAM65A could inhibit LSCC cell proliferation. CONCLUSIONS: High FAM65A expression could enhance proliferative, invasive and migratory abilities of LSCC. FAM65A might be a novel biomarker of LSCC.

Network meta-analysis on the efficacy and safety of management for resectable stage IIIA-N2 non-small cell lung cancer.

BACKGROUND: There is controversy regarding the optimal treatment for stage IIIA-N2 non-small cell lung cancer (NSCLC). We aimed to address this crucial issue through a frequentist network meta-analysis. METHODS: We conducted a literature database search for randomized controlled trials comparing the following treatment modalities before March 1st, 2023: surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and various combinations of these treatments. Summary data on overall survival (OS) and treatment-related deaths (trDeath) were analyzed using frequentist methods. RESULTS: Twenty-two randomized controlled trials (RCTs) with 3269 participants were included, covering 17 treatment regimens. In terms of overall survival, surgery followed by adjuvant targeted therapy (S-T), neoadjuvant targeted therapy followed by surgery and adjuvant targeted therapy (T-S-T), and neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy (C-S-C) were relatively more advantageous than other treatment regimens. Overall, S-T is the most likely treatment option to prolong OS, with a 59.8% likelihood, while immunotherapy plus chemotherapy followed by surgery and adjuvant chemotherapy (IC-S-C) demonstrates good safety. CONCLUSION: S-T and T-S-T treatments have the greatest potential to be the optimal overall survival treatments for stage IIIA-N2 NSCLC patients with positive driver genes, demonstrating significant clinical application prospects. While for patients with negative driver genes, C-S-C treatments benefit the most. The protocol was registered in the Prospective Register of Systematic Reviews, PROSPERO (CRD42022372711).

Effects of lobectomy versus sub-lobar resection on the survival in adults with stage IA left upper lobe non-small cell lung cancer: a retrospective cohort study based on the SEER database.

INTRODUCTION: To compare the survival after lobectomy (LR) and sub-lobar resection (SLR) of left upper lobe (LUL) among non-small cell lung cancer (NSCLC) patients with stage IA. METHODS: This retrospective cohort research analyzed public data collected by the Surveillance, Epidemiology, and End Results (SEER) database. Tumor characteristics were determined based on the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3). Propensity score matching (PSM) analysis was performed with a ratio of 1:1. Univariate and multivariable Cox proportional regression analyses were used to assess the effects of LR and SLR on the survival of the patients, with hazard ratios (HRs) and 95% confidence intervals (95%CIs). The effects were further evaluated by different subgroups of age, gender, tumor grades, histologic types, T stages. RESULTS: Of the total 2,649 patients, 1,907 underwent the LR and 742 received SLR. Totally 998 patients died at the end of the follow-up. The median survival time of all patients were 66 (49, 87) months. After adjusting the age, gender, race, tumor grade, histologic type, T stage, examined lymph nodes, radiation, and chemotherapy, NSCLC patients with stage IA who received SLR had higher odds of death in comparison with these patients who received LR (HR=1.424, 95%CI: 1.227-1.652). After PSM, SLR was associated with higher odds of death in the patients (HR=1.35, 95%CI: 1.10-1.66). Similar results were discovered in different subpopulations. DISCUSSION/CONCLUSION: The SLR was inferior to LR on the survival of NSCLC patients with stage IA.

Uniportal video-assisted anatomical segmentectomy: an analysis of the learning curve.

BACKGROUND: This study aimed to demonstrate the learning curve of anatomical segmentectomy performed by uniportal video-assisted thoracoscopic surgery (U-VATS). METHOD: We conducted a retrospective study of U-VATS segmentectomies performed by the same surgeon between September 2019 and August 2022. The learning curve was demonstrated using risk-adjusted cumulative sum (RA-CUSUM) analysis in terms of perioperative complications, which reflected surgical quality and technique proficiency. The surgical outcomes were also compared between different phases. RESULT: The complication-based learning curve of U-VATS segmentectomy could be divided into two phases based on RA-CUSUM analysis: phase I, the initial learning phase (cases 1-50) and phase II, the proficiency phase (cases 51-141). Significantly higher complication rates (24.0 vs. 8.8%, p=0.013), longer surgical times (119.8±31.9 vs. 106.2±23.8 min, p=0.005), and more blood loss (20 [IQR, 20-30] vs. 20 [IQR, 10-20] ml, p=0.003) were observed in phase I than in phase II. CONCLUSION: The learning curve of U-VATS segmentectomy consists of two phases, and at least 50 cases were required to gain technique proficiency and achieve high-quality surgical outcomes.

A small-sized tube versus traditional closed thoracic drainage in uniportal thoracoscopic surgery.

Introduction: To assess the feasibility and safety of placing a small-sized tube as drainage in patients after uniportal thoracoscopic lung resection. Patients and Methods: Patients who received uniportal video-assisted thoracoscopic surgery (U-VATS) lung resection were identified in our database. Patients placed small-sized tube drainage were compared with those placed conventional chest tube in terms of characteristics, operation modality, post-operative pulmonary complications, post-operative pain, chest tube duration and post-operative hospital stay. Propensity score matching was performed. Results: Of the 217 enrolled patients, 173 were assigned to the conventional tube group and 44 were assigned to the small-sized tube group. Rates of post-operative pulmonary complications were relatively low and similar between the two groups. After propensity score matching, operation duration was shorter (1 h vs. 1.21 h, P = 0.01) was shorter, and the maximum value of the Visual Analogue Scale (VAS) score after operation (1 vs. 1.5, P = 0.02) and the overall average value of VAS score after operation (0.33 vs. 0.88, P = 0.006) was lower in small-sized tube group. No significant difference was observed in chest tube duration (2 vs. 2, P = 0.34) and post-operative hospital stay (3 vs. 3, P = 0.34). Conclusions: Compared to conventional chest tubes, small-sized tubes for post-operative drainage after U-VATS lung resection may be a safe and promising approach for reducing post-operative pain.

Long-term results of postoperative unsuspected small cell lung cancer on real-world data.

BACKGROUND: In traditional opinion, solid pulmonary nodule suspected lung cancer should be confirmed by pathology before the operation to exclude small cell lung cancer (SCLC), considering SCLC tends to be aggressive and surgical effect in the management of SCLC remains controversial. The aim of this study was to evaluate the survival result and risk factors of postoperative unsuspected SCLC. METHODS: A total of 120 patients with postoperative unsuspected SCLC who were confirmed by pathology and referred to Chinese PLA General Hospital between 2000 and 2021 were retrospectively analyzed (surgery group). Additionally, 120 patients with limited-stage SCLC who underwent chemotherapy and radiotherapy in the same period were enrolled in the chemoradiotherapy group.. Kaplan-Meier method was used to estimate survival; the Log-Rank test was used to compare survival rates between different groups; a COX stepwise regression model was used for multivariate analysis. RESULTS: Among 120 patients in the surgery group, 28 were with central type and other 92 with peripheral type. The median survival (OS) was 44.85 months, and the 5-year survival rate was 46%. The 5-year survival rates for stage I, II, and III were 52.1%, 45.4%, and 27.8%, respectively. The mean disease-free survival time (DFS) was 30.63 ± 4.38 months, and the 5-year DFS rate was 31.5%. In the chemoradiotherapy group, the mean OS was 21.4 ± 4.26 months, and the 5-year survival rate was 28.3%. The 5-year survival rates for clinical stage I, II, and III were 42.5%, 39.8%, and 20.5%, respectively. The mean progression-free survival (PFS) was 10.63 ± 3.6 months. In the surgery group, one-way ANOVA revealed that the gender, symptoms, smoking history, tumor location, and postoperative radiotherapy were not associated with OS (P ≥ 0.05), while age, surgical approach, surgical method, N stage, TNM stage, and vascular tumor thrombus were related to OS (P < 0.05). Multivariate analysis indicated that the N stage was associated with OS (HR = 1.86 P = 0.042). CONCLUSION: Surgery and adjuvant therapy were found to have encouraging outcomes in postoperative unsuspected SCLC. Patients with stage I, stage II and part of stage IIIA SCLC could benefit from surgery and the standard lobectomy, and systematic lymph node dissection, is also recommended for these patients.

LncRNA PCGEM1 induces proliferation and migration in non-small cell lung cancer cells through modulating the miR-590-3p/SOX11 axis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers. As reported, long non-coding RNAs (lncRNAs) induce various biological behaviors in cancers. LncRNA PCGEM1 prostate-specific transcript (PCGEM1) is reported to exert carcinogenic effect on certain cancers. Our research aimed to explore the role of PCGEM1 in NSCLC. METHODS: We enrolled forty NSCLC patients to explore PCGEM1 expression in clinical NSCLC tissues. Colony formation assay, CCK-8, Transwell assay were conducted to reveal cell proliferation, viability, migration and invasion. Luciferase reporter assay, RNA pull down, and RIP assay were performed to investigate the downstream axis of PCGEM1. RESULTS: PCGEM1 was significantly upregulated in NSCLC cells and tissues. Subsequently, in vitro loss-of-function experiments illustrated the carcinogenic role of PCGEM1 in NSCLC through promoting viability, proliferation, migration, and invasion. MiR-590-3p was confirmed to be a downstream gene of PCGEM1. Furthermore, SRY-box transcription factor 11 (SOX11) was verified to be a target of miR-590-3p. Additionally, rescue experiments indicated that miR-590-3p inhibitor or pcDNA3.1/SOX11 rescued the impacts of downregulated PCGEM1 on NSCLC cell proliferation, viability, migration and invasion. CONCLUSIONS: LncRNA PCGEM1 aggravated proliferative and migrative abilities in NSCLC via the miR-590-3p/SOX11 axis.

Prognostic value of neuron-specific enolase for small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Neuron-specific enolase (NSE) has become a widely used and easily attainable laboratory assay of small cell lung cancer (SCLC). However, the prognostic value of NSE for SCLC patients remains controversial. The aim of the study was to evaluate the correlation between elevated serum NSE before therapy and survival of SCLC patients. METHODS: We performed a systematic review and meta-analysis. A systematic literature search was conducted in PubMed, Embase, and the Cochrane Central Register from the inception dates to December 2019. Eligible articles were included according to inclusion and exclusion criteria; then, data extraction and quality assessment were performed. The primary outcome was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). RESULTS: We identified 18 studies comprising 2981 patients. Pooled results revealed that elevated NSE was associated with worse OS (HR = 1.78, 95% CI 1.55-2.06, p < 0.001) and PFS (HR = 1.50, 95% CI 1.16-1.93, p = 0.002). In subgroup analysis, elevated NSE did not predict worse OS in patients who received only chemotherapy (HR 1.22, 95% CI 0.96-1.55, p = 0.10) or part of whom received surgical resection before chemotherapy and radiotherapy (HR = 2.16, 95% CI 0.82-5.69, p = 0.12). CONCLUSION: Elevated serum NSE before any therapy of SCLC patients may be a negative prognostic factor for OS and PFS. The prognostic value of NSE for OS was particularly observed in patients treated by standard management.

A Pilot Study of Pulmonary Segmentectomy With Indocyanine Green Near-Infrared Angiography.

OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) pulmonary segmentectomy is commonly used in treating small ground-glass opacity (GGO) nodules in lung. The identification of the intersegmental plane is one of the challenges. In this pilot study, we aimed to evaluate the feasibility of indocyanine green (ICG) angiography in VATS segmentectomy. METHODS: Nineteen GGO patients were enrolled, and VATS segmentectomy with ICG near-infrared angiography were performed between July 2017 and December 2017. Conventional 3-port VATS was used. ICG was injected intravenously after dominant arties were ligated. Intersegmental plane was identified and divided by stapler and electrocautery. RESULTS: All patients had perfect intersegmental plane visualization. The mean operation time was 140.8 minutes, and the mean blood loss was 23.7 mL. No complications due to ICG occurred. The mean chest tube duration was 4.6 days. No severe complications occurred in the perioperative period. The mean chest tube drainage duration was 4.6 days. Prolonged postoperative air leak (>5 days), which required no surgical intervention, occurred in 2 cases. There were no severe complications or in-hospital deaths. CONCLUSIONS: VATS segmentectomy with ICG near-infrared angiography is a reasonable treatment option to treat small GGO in lung, especially due to its good surgical view maintenance.

Promoter methylation of APC and RAR-ß genes as prognostic markers in non-small cell lung cancer (NSCLC).

Aberrant promoter hypermethylations of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine methylation status at APC and RAR-ß promoters in primary NSCLC, and whether they have any relationship with survival. APC and RAR-ß promoter methylation status were determined in 41 NSCLC patients using methylation specific PCR. APC promoter methylation was detectable in 9 (22.0%) tumor samples and 6 (14.6%) corresponding non-tumor samples (P=0.391). RAR-ß promoter methylation was detectable in 13 (31.7%) tumor samples and 4 (9.8%) corresponding non-tumor samples (P=0.049) in the NSCLC patients. APC promoter methylation was found to be associated with T stage (P=0.046) and nodal status (P=0.019) in non-tumor samples, and with smoking (P=0.004) in tumor samples. RAR-ß promoter methylation was found associated with age (P=0.031) in non-tumor samples and with primary tumor site in tumor samples. Patients with APC promoter methylation in tumor samples showed significantly longer survival than patients without it (Log-rank P=0.014). In a multivariate analysis of prognostic factors, APC methylation in tumor samples was an independent prognostic factor (P=0.012), as were N1 positive lymph node number (P=0.025) and N2 positive lymph node number (P=0.06). Our study shows that RAR-ß methylation detected in lung tissue may be used as a predictive marker for NSCLC diagnosis and that APC methylation in tumor sample may be a useful marker for superior survival in NSCLC patients.

[The prognostic impact of preoperative PET-CT on postoperative recurrence for completely resected stage I non-small cell lung cancer].

OBJECTIVE: To analyze the prognostic impact of preoperative (18)F-fluorodeoxyglucose (FDG) PET-CT on postoperative recurrence in patients with completely resected stage I non-small cell lung cancer (NSCLC). METHODS: The clinic data of 182 patients with stage I NSCLC who underwent (18)F-FDG PET-CT scan before surgical resection between June 2005 and June 2012 were reviewed retrospectively. There were 121 male and 61 female patients, with an average age of 68 years (range from 34 to 85 years). The pathological stage was I A in 98 patients, I B in 84 patients; the histology were adenocarcinoma in 137 patients, squamous cell carcinoma in 35 patients, and others in 10 patients. Clinicopathological factors including gender, age, smoking history, SUV(max), surgical procedure, pathological features and adjuvant chemotherapy were evaluated to identify the independent factors predicting postoperative recurrences by univariate and multivariate analysis. The survivals were calculated by the Kaplan-Meier method and differences in variables were analyzed by the Log-rank test. RESULTS: The postoperative recurrence rate was 15.9%. The univariate analysis identified that the SUV(max) (t=3.278, P<0.001), p-stage (χ² =5.204, P=0.026), blood vessel invasion (χ² =5.333, P=0.027) and visceral pleural invasion (χ² =7.697, P=0.009) are factors for predicting postoperative recurrence. Only SUV(max) was found to be a significant independent factor according to multivariate analysis (HR=1.068, 95%CI: 1.015 to 1.123, P=0.001). The study population was stratified into three groups by SUV(max), patients with SUV(max) > 5.0 had significantly higher risk of recurrence (23.9%) than those with 2.5 < SUV(max) ≤ 5.0 (15.0%) and SUV(max) ≤ 2.5 (7.3%) (P=0.043); patients with SUV(max) ≤ 2.5 had significantly better 5-year recurrence-free survival rate (90.9%) than those with 2.5 < SUV(max) ≤ 5.0 (82.7%) and SUV(max) ≤ 2.5 (71.0%) (P=0.030). There was a trend toward higher probability of blood vessel invasion (χ² =20.267, P < 0.001), visceral pleural invasion (χ² =6.185, P=0.045) and pathological stage I B (χ² =13.589, P=0.001) with increased SUV(max). CONCLUSIONS: Preoperative SUV(max) of primary tumor is a predictor of postoperative relapse for stage I NSCLC after surgical resection. Therefore, it can contribute to the risk stratification for patients with the same pathological stage and selecting the optimal postoperative follow-up and therapeutic strategy.

Choice of therapeutic strategies in intrathoracic anastomotic leak following esophagectomy.

BACKGROUND: The aim of this study was to analyze our experience with management of intrathoracic anastomotic leak after esophagectomy. METHODS: Clinical data from 33 patients who developed intrathoracic anastomotic leak were evaluated retrospectively. These patients were selected from 1867 patients undergoing resection carcinoma of the esophagus and reconstruction between January 2003 and December 2012. RESULTS: Surgical intervention and the reformed "three-tube method" were applied in 13 and 20 patients, respectively. The overall incidence of intrathoracic anastomotic leakage was 1.8%. The median time interval from esophagectomy to diagnosis of leak was 9.7 days. Sixteen patients were confirmed as having leakage by oral contrast computed tomography (CT). Age and interval from surgery to diagnosis of leak were identified as statistically significant parameters between contained and uncontained groups. Moreover, patients with hypoalbuminemia had a longer time to leak closure than patients without hypoalbuminemia. Six patients died from intrathoracic anastomotic leak, with a mortality rate of 18.2%. There was no statistically significant difference in the time to leak closure between patients who underwent surgical exploration and those who received conservative treatment. CONCLUSIONS: Intrathoracic anastomotic leak after esophagectomy was associated with significant mortality. Once intrathoracic anastomotic leakage following esophagectomy was diagnosed or highly suspected, individualized management strategies should be implemented according to the size of the leak, extent of the abscess, and status of the patient. In the majority of patients with anastomotic leak, we preferred the strategy of conservative treatment.

miR-143 inhibits NSCLC cell growth and metastasis by targeting Limk1.

MicroRNAs (miRNAs) have essential roles in carcinogenesis and tumor progression. Here, we investigated the roles and mechanisms of miR-143 in non-small cell lung cancer (NSCLC). miR-143 was significantly decreased in NSCLC tissues and cell lines. Overexpression of miR-143 suppressed NSCLC cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. Integrated analysis identified LIM domain kinase 1 (Limk1) as a direct and functional target of miR-143. Overexpression of Limk1 attenuated the tumor suppressive effects of miR-143 in NSCLC cells. Moreover, miR-143 was inversely correlated with Limk1 expression in NSCLC tissues. Together, our results highlight the significance of miR-143 and Limk1 in the development and progression of NSCLC.