Finite element analysis and clinical study of chest wall reconstruction using carbon fiber artificial rib.

Carbon fiber composites are emerging as a promising new biomaterial for chest wall reconstruction implants due to their mechanical properties and biocompatibility. This work evaluates the biomechanics of carbon fiber artificial ribs using finite element analysis and clinical implementation. Static simulations of normal breathing process show the maximum stress on the implant is only 2.83 MPa, far below the material ultimate strength of 60 MPa, indicating the excellent fit for maintaining respiratory function. Dynamic collision simulations demonstrate the artificial rib model could withstand a 4 kg rigid object impact at 2 m/s without fracture. Reconstructing the artificial rib with a human rib in the finite element analysis model increases the overall stress tolerance. The impact force required for fracture increases 48% compared to the artificial rib alone, suggesting improved strength from rib integration. Clinically, 10 of 13 patients receiving the artificial rib implants show no significant loss of pulmonary function based on spirometry tests. Based on our findings, the combined simulations and clinical results validate the strong mechanical performance and biocompatibility of the carbon fiber artificial ribs for chest wall reconstruction under static and dynamic loading while maintaining normal respiratory function.

Efficacy and safety of microwave ablation and its synergistic potential in the treatment of early-stage non-small cell lung cancer.

Lung cancer remains the primary cause of cancer-related mortality globally. In the case of early-stage non-small cell lung cancer (NSCLC), surgical resection, such as lobectomy and sub-lobectomy, continues to be the established standard treatment. However, for patients with insufficient cardiopulmonary function and multiple comorbidities who are unable to undergo surgical resection, nonoperative local therapies, including radiotherapy and thermal ablation, are preferred. In recent years, microwave ablation (MWA) has gained popularity for treating early-stage NSCLC due to its high heating efficiency, good tissue conductance, and heat conduction capabilities. This review provides a comprehensive summary of the current efficacy and safety data regarding MWA for early-stage NSCLC and discusses the potential benefits of combining MWA with other therapies.

Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues.

Background: A better understanding of T cells in lung cancer and their distribution across tumor-adjacent lungs and peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients. Methods: Here, we performed CDR3ß TCR sequencing of 136 samples from 20 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumors, tumor edges (<1 cm from tumor), as well as adjacent lungs 1 cm, 2 cm, 5 cm, and 10 cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4, and CD8 expression was assessed using immunohistochemical staining, and genomic features were derived by targeted sequencing of 1,021 cancer-related genes. Multiplex immunohistochemistry against PD-1, CTLA4, LAG3, and TIM3 was performed on four patients to assess T cell exhaustion. Results: Our study reveals a decreasing gradient in TIL Tumor Infiltrating Lymphocytes homology with tumor edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression. Conclusions: Exclusion in T exhaustion cells at play across the lungs of patients with NSCLC may potentially be the mechanism for lung cancer occurrence.

hsa_circ_0000519 promotes the progression of lung adenocarcinoma through the hsa-miR-1296-5p/DARS axis.

Emerging research indicates that circRNAs serve a crucial role in occurrence and development of cancers. This study aimed to uncover the biological role of hsa_circ_0000519 in the progression of LUAD (lung adenocarcinoma). hsa_circ_0000519 was identified by bioinformatic analysis, and its differential expression was validated in LUAD tissues and cell lines. CCK8, colony formation, wound healing, transwell assays, and xenograft tumor models were used to observe the biological functions of hsa_circ_0000519. FISH, RIP, dual luciferase reporter assays, and recovery experiments were implemented to explore the underlying mechanisms of hsa_circ_0000519. hsa_circ_0000519 was significantly upregulated in LUAD tissues and cell lines. The expression of hsa_circ_0000519 was positively correlated with T grade and TNM stage in patients with LUAD. Downregulation of hsa_circ_0000519 remarkably reduced cell proliferation, migration, invasion in vitro, and tumor growth in vivo. Mechanistic investigation demonstrated that hsa_circ_0000519 directly sponged hsa-miR-1296-5p to reduce its repressive impact on DARS as well as activate the PI3K/AKT/mTOR signaling pathway. The malignant phenotypes of LUAD cells induced by upregulation of hsa_circ_0000519 could be rescued by hsa-miR-1296-5p overexpression or knockdown of DARS. In conclusion, hsa_circ_0000519 promotes LUAD progression through the hsa-miR-1296-5p/DARS axis and may be expected as a novel biomarker and therapeutic for LUAD.

Association of phthalate exposure with pulmonary function in adults: NHANES 2007-2012.

BACKGROUND: Epidemiological evidence for the adverse effect of phthalate exposure on respiratory health is on the rise, but cross-sectional studies regarding its effects on lung function are limited and contradictory, especially in adults. OBJECTIVE: To assess the associations between individual and a mixture of urinary phthalate metabolites and adult pulmonary function in the United States, and to identify which ones were primarily responsible for impaired respiratory function. METHODS: We obtained a cross-sectional data on 3788 adults aged 20 years and older from the National Health and Nutrition Examination Survey (2007-2012). Respiratory function was evaluated using spirometry, and phthalate exposure was assessed by measuring the levels of ten urinary phthalate metabolites. The effects of individual and mixed phthalate metabolites exposure on lung function were assessed using multivariate linear regression models and the repeated holdout weighted quantile sum (WQS) regression models, respectively, after adjusting for potential confounders including age, gender, family poverty income ratio, body mass index, and serum cotinine. RESULTS: When modeled as continuous variables or quantiles, urinary phthalate metabolites, including mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-iso-butyl phthalate, mono-benzyl phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(3-carboxypropyl) phthalate, and mono-carboxyoctyl phthalate, were identified to be negatively associated with forced vital capacity in percent predicted values (ppFVC) and forced expiratory volume in the first second in percent predicted values (ppFEV1). In addition, per each decile increase in the WQS index, ppFVC (ß = -2.87, 95% CI: -3.56, -2.08) and ppFEV1 (ß = -2.53, 95% CI: -3.47, -1.54) declined significantly, primarily due to the contribution of MEP and MECPP. Furthermore, there were no significant interactions between co-exposure to urinary phthalate metabolites and each covariate. CONCLUSION: Our findings reveal that urinary phthalate metabolites are significantly associated with adult respiratory decrements, with diethyl and di-(2-ethylhexyl) phthalate contributing the most to the impaired lung function.

Mutation of TP53 Confers Ferroptosis Resistance in Lung Cancer Through the FOXM1/MEF2C Axis.

Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules in early lung cancer, but whether ferroptosis may also be involved in determining this biological process has not yet been determined. Using in vivo and in vitro gain- and loss-of-function approaches, this study used clinical tissue for mutation analysis and pathological research to show that wild-type TP53 inhibited the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis. This function was absent in mutant cells, resulting in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 activated the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role of TP53 in the malignant progression of lung cancer.

Real-world comprehensive diagnosis and "Surgery + X" treatment strategy of early-stage synchronous multiple primary lung cancer.

BACKGROUND: Diagnosing and treating synchronous multiple primary lung cancers (sMPLC) are complex and challenging. This study aimed to report real-world data on the comprehensive diagnosis and treatment of patients with early-stage sMPLC. MATERIALS AND METHODS: A single-center cohort study was carried out and a large number of patients with early-stage sMPLC were included. A single- or two-stage surgery was performed to remove the primary and co-existing lesions. The "X" strategies, including ablation, SBRT, and EGFR-TKIs treatment, were applied to treat the high-risk residual lesions. Wide panel-genomic sequencing was performed to assess the genetic heterogeneity of the co-existing lesions. RESULTS: A total of 465 early-stage sMPLC patients with 1198 resected lesions were included. Despite most patients being histologically different or harboring different genetic alternations, about 7.5% of the patients had the same histological type and driver gene mutation changes, comprehensive re-evaluation is thus needed. The "Surgery + X" strategy showed remarkable efficacy and safety in treating multiple lesions. Follow-up data revealed that the T2 stage (p = 0.014) and the solid presence of a primary lesion (p < 0.001) were significantly related to tumor recurrence. And a T2-stage primary tumor had a significantly higher rate of developing new lesions after the initial surgery (p < 0.001). CONCLUSIONS: In real-world practice, histopathological and radiological evaluation combined with genetic analyses could be a robust diagnostic approach for sMPLC. The "Surgery + X" treatment strategy showed remarkable efficacy, superiority, and safety in the clinical treatment of early-stage sMPLC.

Shenlingcao oral liquid for patients with non-small cell lung cancer receiving adjuvant chemotherapy after radical resection: A multicenter randomized controlled trial.

BACKGROUND: Low quality of life (QoL) in patients with non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy after radical resection is a major global health issue. High-quality evidence for the effectiveness of Shenlingcao oral liquid (SOL) as a complementary treatment in this patients is lacking at present. PURPOSE: To determine whether complementary SOL treatment in NSCLC patients receiving adjuvant chemotherapy would yield greater improvements in QoL than chemotherapy alone. STUDY DESIGN: We conducted a multicenter, randomized controlled trial of stages IIA-IIIA NSCLC patients undergoing adjuvant chemotherapy in seven hospitals. METHODS: Using stratified blocks, participants were randomized in a 1:1 ratio to receive SOL combined with conventional chemotherapy or conventional chemotherapy alone. The primary outcome was the change in global QoL from baseline to the fourth chemotherapy cycle, and intention-to-treat analysis was applied with a mixed-effect model. Secondary outcomes were functional QoL, symptoms, and performance status scores at the 6-month follow-up. Missing data were handled with multiple imputation and a pattern-mixture model. RESULTS: Among 516 randomized patients, 446 (86.43%) completed the study. After the fourth chemotherapy cycle, in comparison with the control group, patients receiving SOL showed a lower reduction in mean global QoL (-2.76 vs. -14.11; mean difference [MD], 11.34; 95% confidence interval [CI], 8.28 to 14.41), greater improvement in physical function (MD, 11.61; 95% CI, 8.57 to 14.65), role function (MD, 10.15; 95% CI, 5.75 to 14.54), and emotional function (MD, 4.71; 95% CI, 1.85 to 7.57), and greater improvements in lung cancer-related symptoms (e.g., fatigue, nausea/vomiting, and appetite loss) and performance status during the 6-month follow-up period (treatment main effect, p < 0.05). CONCLUSION: SOL treatment for NSCLC patients receiving adjuvant chemotherapy can significantly improve QoL and performance status within 6 months after radical resection. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03712969.

Genetic, DNA methylation, and immune profile discrepancies between early-stage single primary lung cancer and synchronous multiple primary lung cancer.

BACKGROUND: To explore the possible carcinogenesis and help better diagnose and treat patients with synchronous multiple primary lung cancers (sMPLC), we systematically investigated the genetic and DNA methylation profiles of early-stage sMPLC and single primary lung cancer (SPLC) and explored the immune profiles in the tumor microenvironment. METHODS: Hundred and ninety-one patients with 191 nodules in the SPLC group and 132 patients with 295 nodules in the sMPLC group were enrolled. All the samples were subjected to wide panel-genomic sequencing. Genome-wide DNA methylation was assessed using the Infinium Human Methylation 850 K BeadChip. RNA-seq and CIBERSORT analyses were performed to identify the immune characteristics in these two groups. RESULTS: Lesions from sMPLC patients had lower TMB levels than that from SPLC patients. sMPLC had a similar genetic mutational landscape with SPLC, despite some subgroup genetic discrepancies. Distinct DNA methylation patterns were identified between the two groups. The differentially methylated genes were related to immune response pathways. RNA-seq analyses revealed more immune-related DEGs in sMPLC. Accordingly, more immune-related biological processes and pathways were identified in sMPLC. Aberrant DNA methylation was associated with the abnormal expression of immune-related genes. CIBERSORT analysis revealed the infiltration of immune cells was different between the two groups. CONCLUSION: Our study for the first time demonstrated genetic, epigenetic, and immune profile discrepancies between sMPLC and SPLC. Relative to the similar genetic mutational landscape, the DNA methylation patterns and related immune profiles were significantly different between sMPLC and SPLC, indicating their essential roles in the initiation and development of sMPLC.

Thermal ablation versus radiotherapy for inoperable stage III non-small cell lung cancer: a propensity score matching analysis.

OBJECTIVE: To compare the survival benefits of thermal ablation (TA) and radiotherapy in inoperable patients with stage III non-small cell lung cancer (NSCLC). METHOD: A retrospective analysis was conducted using the data from the Surveillance, Epidemiology, and End Results (SEER) program. Propensity score matching (PSM) was conducted to balance potential baseline confounding factors. Survival analyses were conducted using Kaplan-Meier and Cox regression methods. RESULTS: The present study included 33,393 inoperable patients with stage III NSCLC, including 106 patients treated with TA and 33,287 patients treated with radiotherapy. No statistical difference in overall survival (OS) (p = .065) or cancer-specific survival (CSS) (p = .996) was found between the patients treated with TA and those treated with radiotherapy. Using 1:3 matching, a matched cohort of 420 patients (105 patients treated with TA, 315 patients treated with radiotherapy) was identified. The differences in OS (p = .177) and CSS (p = .605) were still not significant between the radiotherapy and TA groups after PSM. According to subgroup analyses, TA showed comparable survival benefits in almost all subgroups compared to radiotherapy. CONCLUSION: For inoperable stage III NSCLC, the survival benefit of TA was comparable to radiotherapy. TA may be a potential therapeutic modality for inoperable stage III NSCLC.

Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles.

Ligamentum flavum (LF) hypertrophy (LFH) has been recognised as one of the key contributors to lumbar spinal stenosis. Currently, no effective methods are available to ameliorate this hypertrophy. In this study, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hUCMSC-EVs) were introduced for the first time as promising vehicles for drug delivery to treat LFH. The downregulation of miR-146a-5p and miR-221-3p expressions in human LF tissues negatively correlated with increased LF thickness. The hUCMSC-EVs enriched with these two miRNAs significantly suppressed LFH in vivo and notably ameliorated the progression of transforming growth factor ß1(TGF-ß1)-induced fibrosis in vitro after delivering these two miRNAs to mouse LF cells. The results further demonstrated that miR-146a-5p and miR-221-3p directly bonded to the 3'-UTR regions of SMAD4 mRNA, thereby inhibiting the TGF-ß/SMAD4 signalling pathway. Therefore, this translational study determined the effectiveness of a hUCMSC-EVs-based approach for the treatment of LFH and revealed the critical target of miR-146a-5p and miR-221-3p. Our findings provide new insights into promising therapeutics using a hUCMSC-EVs-based delivery system for patients with lumbar spinal stenosis.

Overexpression of LINC00551 promotes autophagy-dependent ferroptosis of lung adenocarcinoma via upregulating DDIT4 by sponging miR-4328.

According to mounting evidence, long noncoding RNAs (lncRNAs) play a vital role in regulated cell death (RCD). A potential strategy for cancer therapy involves triggering ferroptosis, a novel form of RCD. Although it is thought to be an autophagy-dependent process, it is still unclear how the two processes interact. This study characterized a long intergenic noncoding RNA, LINC00551, expressed at a low level in lung adenocarcinoma (LUAD) and some other cancers. Overexpression of LINC00551 suppresses cell viability while promoting autophagy and RSL-3-induced ferroptosis in LUAD cells. LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes LUAD autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner. This study provided an insight into the molecular mechanism regulating ferroptosis and highlighted LINC00551 as a potential therapeutic target for LUAD.

Survival benefit of thermal ablation therapy for patients with stage II-III non-small cell lung cancer: A propensity-matched analysis.

Background: Thermal ablation (TA) is considered a safe alternative to surgical resection for the treatment of non-small cell lung cancer (NSCLC). While previous studies have shown that TA is beneficial for stage I NSCLC patients, however, few have reported on TA efficacy in patients with stage II-III NSCLC. The current study investigated the impact of TA on the overall survival (OS) and cancer-specific survival (CSS) of patients with stage II-III NSCLC. Methods: Data on patients with stage II-III NSCLC who did not undergo surgical resection between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM), Kaplan-Meier survival curves, and Cox regression were used for statistical analyses. Results: A total of 57,959 stage II-III NSCLC patients who did not undergo surgical resection were included in this study, 261 of whom received TA. Overall, TA was associated with a longer OS (p = 0.035) and CSS (p = 0.005) than non-ablation. After 1:3 PSM, 252 patients receiving TA and 732 patients not receiving ablation were enrolled in the matched cohort. The OS (p = 0.047) and CSS (p = 0.029) remained higher in the TA group than in the non-ablation group after PSM. Cox regression analysis showed that age, sex, primary tumor site, pathological type, tumor size, radiotherapy, chemotherapy, and thermal ablation were independently associated with OS and CSS (p <0.05). Subgroup analysis found that the advantages of TA were more pronounced among individuals ≥70 years of age, with tumor size ≤3.0 cm, or who did not receive radiotherapy. Conclusion: TA could be an effective alternative treatment for stage II-III NSCLC patients unsuitable for surgical resection, particularly those ≥70 years of age, with tumor size ≤3.0 cm, or who have not received radiotherapy.

Comprehensive characterization of genomic and radiologic features reveals distinct driver patterns of RTK/RAS pathway in ground-glass opacity pulmonary nodules.

Ground-glass opacity (GGO)-associated pulmonary nodules have been known as a radiologic feature of early-stage lung cancers and exhibit an indolent biological behavior. However, the correlation between driver genes and radiologic features as well as the immune microenvironment remains poorly understood. We performed a custom 1021-gene panel sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients. A total of 130 multiple pulmonary nodules were sampled from 58 patients. Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry (IHC) and multiplex immunofluorescent staining (mIF) were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Compared with pure GGO nodules, mixed GGO nodules were enriched for invasive adenocarcinoma (IAC) (182/216 vs 73/118, P < .001). Eighty-eight percent (294/334) of GGO-associated nodules carried at least one mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway, and the alterations in these driver genes were mutually exclusive. The analysis of multifocal pulmonary nodules from the same patient revealed evidence of functional convergence on RTK/RAS pathways. Nodules with ERBB2/BRAF/MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations. IHC and mIF staining showed that KRAS-mutant GGO nodules displayed higher infiltration of CD4+ T cell and CD8+ T cell as well as stronger proliferation and immune inhibitory signals. Our study demonstrates a driver landscape of radiologically detectable GGO-associated pulmonary nodules in Chinese patients and supports that different driver patterns in RTK/RAS pathway are corresponding to different radiologic features.

Case Report: Pathological Complete Response to Neoadjuvant Alectinib in a Patient With Resectable ALK-Positive Non-Small Cell Lung Cancer.

Background: Alectinib, a highly selective inhibitor of ALK, is currently used in the first-line setting of untreated advanced ALK-positive NSCLC and in the second-line setting of crizotinib-resistant ALK-positive NSCLC. Despite promising efficacy and tolerability in the treatment of advanced ALK-positive NSCLC, the activity of alectinib as neoadjuvant therapy in resectable ALK-positive NSCLC remains to be investigated. Case presentation: Herein, we report a case of a 58-year-old female patient presented to our hospital with hemoptysis for 1 month. Contrast-enhanced computerized tomography (CT) of the chest showed an approximately 4.2 × 3.4 cm mass in the right hilum with localized obstructive pneumonia in the right lower lobe and multiple enlarged lymph nodes in the right hilum and mediastinum. Serum oncological markers results showed elevated levels of CA19-9, CEA, CA125, and CA242. Bronchoscopic biopsy of the mass showed poorly differentiated pulmonary adenocarcinoma and immunohistochemical testing results confirmed ALK positivity. Neoadjuvant alectinib was given at a dosage of 600 mg twice per day for two cycles (56 days), achieving a partial response of the disease with 90% shrinkage of the mass at the subsequent whole-body positron emission tomography. Repeat serum oncological markers results showed that only CA125 was elevated, but lower than before therapy. A bilobectomy of the right middle and lower lobes and systemic lymphadectomy under video-assisted thoracoscopic approach was successfully performed 7 days after the last dose of alectinib. Postoperative pathology showed pathological complete response (pCR). The patient experienced an uneventful postoperative course and continued to receive alectinib and did not report any specific discomfort at her 8-month follow-up. Thoracoabdominal CT at 8 months postoperatively showed no recurrence and repeated examination of serum oncological markers were negative. Conclusion: We report a case of resectable ALK-positive NSCLC treated with neoadjuvant aletinib achieving pCR. Our case highlights the feasibility of alectinib as neoadjuvant therapy for the treatment of resectable ALK-positive NSCLC. Undoubtedly, the safety and efficacy of this novel treatment modality needs to be explored in future large clinical trials.

Single-Cell RNA Sequencing Unravels Distinct Tumor Microenvironment of Different Components of Lung Adenocarcinoma Featured as Mixed Ground-Glass Opacity.

Lung adenocarcinoma featured as mixed ground-glass opacity (mGGO) doubled its volume half of the time in comparison with that featured as pure ground-glass opacity (pGGO). The mechanisms underlying the heterogeneous appearance of mGGO remain elusive. In this study, we macro-dissected the solid (S) components and ground-glass (GG) components of mGGO and performed single-cell sequencing analyses of six paired components from three mGGO patients. A total of 19,391 single-cell profiles were taken into analysis, and the data of each patient were analyzed independently to obtain a common alteration. Cancer cells and macrophages were the dominant cell types in the S and GG components, respectively. Cancer cells in the S components, which showed relatively malignant phenotypes, were likely to originate from both the GG and S components and monitor the surrounding tumor microenvironment (TME) through an intricate cell interaction network. SPP1hi macrophages were enriched in the S components and showed increased activity of chemoattraction, while macrophages in the GG components displayed an active antimicrobial process with a higher stress-induced state. In addition, the CD47-SIRPA axis was demonstrated to be critical in the maintenance of the GG components. Taken together, our study unraveled the alterations of cell components and transcriptomic features between different components in mGGOs.

A Machine-Learning Approach to Developing a Predictive Signature Based on Transcriptome Profiling of Ground-Glass Opacities for Accurate Classification and Exploring the Immune Microenvironment of Early-Stage LUAD.

Screening for early-stage lung cancer with low-dose computed tomography is recommended for high-risk populations; consequently, the incidence of pure ground-glass opacity (pGGO) is increasing. Ground-glass opacity (GGO) is considered the appearance of early lung cancer, and there remains an unmet clinical need to understand the pathology of small GGO (<1 cm in diameter). The objective of this study was to use the transcriptome profiling of pGGO specimens <1 cm in diameter to construct a pGGO-related gene risk signature to predict the prognosis of early-stage lung adenocarcinoma (LUAD) and explore the immune microenvironment of GGO. pGGO-related differentially expressed genes (DEGs) were screened to identify prognostic marker genes with two machine learning algorithms. A 15-gene risk signature was constructed from the DEGs that were shared between the algorithms. Risk scores were calculated using the regression coefficients for the pGGO-related DEGs. Patients with Stage I/II LUAD or Stage IA LUAD and high-risk scores had a worse prognosis than patients with low-risk scores. The prognosis of high-risk patients with Stage IA LUAD was almost identical to that of patients with Stage II LUAD, suggesting that treatment strategies for patients with Stage II LUAD may be beneficial in high-risk patients with Stage IA LUAD. pGGO-related DEGs were mainly enriched in immune-related pathways. Patients with high-risk scores and high tumor mutation burden had a worse prognosis and may benefit from immunotherapy. A nomogram was constructed to facilitate the clinical application of the 15-gene risk signature. Receiver operating characteristic curves and decision curve analysis validated the predictive ability of the nomogram in patients with Stage I LUAD in the TCGA-LUAD cohort and GEO datasets.

Establishment of Thoracic Surgical Difficulty Assessment Scale based on Delphi method. / 基于德尔菲法构建胸外科手术难度评价量表.

OBJECTIVES: The difficulty of surgery, which is related to surgical safety, has only been mentioned as a subjective perception for a long time. There are few studies to quantitatively and systematically evaluate the difficulty of thoracic surgery. This study aims to establish a quantitative evaluation index system for thoracic surgical difficulty, and to evaluate its reliability and validity. METHODS: During the 2 national thoracic surgery academic conferences, the factors that may affect the difficulty of thoracic surgery were evaluated by the thoracic surgeons via semi open questionnaires, and then the evaluation item pool of thoracic surgery difficulty was established. The importance of each indicator in the evaluation item pool was graded by 2 rounds of Delphi method. The average score, full score rate and coefficient of variation of each index were calculated, and the composite index method was used to decide whether to delete the indicator.Finally, the difficulty evaluation scale of thoracic surgery was constructed. The surgical data of patients with thoracic tumors were collected. The scale was used to evaluate the difficulty of thoracic surgery for lung, esophageal, and mediastinal tumors. The reliability and validity of the scale were evaluated by the commonly used difficulty evaluation indexes: Operation time, intraoperative estimated blood loss, Visual Analog Scale (VAS), side injury rate, and blood transfusion rate as standards. RESULTS: A total of 230 questionnaires were distributed in the 2 rounds of survey, and 149 valid questionnaires were collected after eliminating duplicate questionnaires. Through 2 rounds of Delphi consultation with 20 experts, the difficulty evaluation indexes were scored and screened, and the difficulty evaluation scale of thoracic surgery was established. It included 5 main indexes (surgical decision-making, operation space, separation interface, reconstruction method, and surgical materials) and 16 secondary indexes [American Society of Anesthesiologists (ASA) classification, surgical trauma, operator experience, space size, space depth, space source, space adjacent, interface content, anatomical gap, visual field, interface size, reconstruction complexity, reconstruction scope, autologous materials, artificial biomaterials and instruments]. After weighting, the total score of Thoracic Surgery Difficulty Evaluation Scale was from 1 to 3. A Score at 1 standed for simplicity, and score at 3 standed for difficulty. Further data were collected for 127 cases of thoracic tumor surgery. The difficulty scores of surgery for lung, esophageal, and mediastinal tumor were 1.69±0.26, 1.86±0.18, and 1.56±0.31, respectively, and the Cronbach's α coefficients of the scale in 3 tumor surgeries were 0.993, 0.974, and 0.989, repectively, and the Spearman Brown coefficients were 0.996, 0.984, and 0.996, respectively. The Spearman correlation coefficients of operation difficulty score with operation time, estimated blood loss, and VAS were 0.360 and 0.634, 0.632 and 0.578, 0.696 and 0.875, respectively (all P<0.05). The incidence of postoperative complications in the difficult operation group (difficulty score >1.85) was higher than that in the non-difficult operation group (P=0.02). CONCLUSIONS: The quantitative Thoracic Surgical Difficulty Assessment Scale has been successfully established, which shows good reliability and validity in thoracic tumor surgery. The Thoracic Surgical Difficulty Assessment Scale has broad application prospects in reducing the difficulty of the surgery, controlling surgical complications, and training surgeons.

Osimertinib as Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: A Case Series.

Background: Evidence of osimertinib as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) are currently lacking. This case series study aimed to assess the safety and feasibility of neoadjuvant osimertinib therapy followed by surgery for resectable NSCLC. Materials and methods: Patients with resectable NSCLC with epidermal growth factor receptor (EGFR) mutation who received osimertinib as neoadjuvant therapy followed by surgery at our center were included. Demographic features, radiologic and pathological assessment of response, surgery-related details and complications, toxicity profiles, and prognostic outcomes were extracted. Results: A total of 13 patients were included in this study. The median age at the time of surgical resection was 57 years (interquartile range: 52-64 years), and eight (61.5%) patients were female. The objective response rate (ORR) was 69.2% (9/13), and the complete resection rate was 100%. The rates of pathologic downstaging and lymph node downstaging were 100% (13/13) and 66.7% (6/9), respectively. There were no perioperative deaths and only three (23.1%) patients had postoperative complications. Seven (53.8%) and 13 (100%) patients experienced grade 1 treatment-related adverse reactions and laboratory abnormalities, respectively. No patients experienced drug withdrawal or surgical delays due to the adverse events. No patients showed grade 2 or worse toxicity profiles. One patient was lost to follow-up. The other 12 patients were alive and free of disease recurrence with a median follow-up time of 9.5 months. Conclusion: Neoadjuvant osimertinib therapy seemed to be safe and feasible for resectable EGFR-mutated NSCLC. Future large prospective studies are warranted to confirm whether osimertinib as neoadjuvant therapy outperforms standard tyrosine kinase inhibitors (TKIs) or chemotherapy for resectable EGFR-mutated NSCLC.