Primary graft dysfunction (PGD) caused by ischemia-reperfusion injury (IRI) is a major complication after lung transplantation, yet its underlying mechanisms remain unclear. Triggering receptor expressed on myeloid cells 1 (Trem1) is an important mediator of inflammation, but its role in neutrophil function and metabolic reprogramming during lung IRI is not well understood. In this study, we used a murine orthotopic lung transplantation model with cold ischemia and reperfusion, and Trem1 knockout (Trem1-/-) and myeloid-specific Trem1 conditional knockout mice (LysmCreTrem1fl) to explore the role of Trem1 in neutrophil recruitment, neutrophil extracellular trap (NET) formation, and metabolism. Our results show that Trem1 expression increases in both mouse and human lungs after reperfusion and correlates with neutrophil infiltration and lung injury. Trem1 deficiency significantly reduced neutrophil and macrophage recruitment, NET formation, and tissue damage. Multi-omics analysis revealed that Trem1 deletion suppressed oxidative phosphorylation (OXPHOS) and induced a metabolic shift in neutrophils toward glycolysis. In clinical samples, the abundance of TREM1+ neutrophils was correlated with PGD severity and OXPHOS activity. These findings identify Trem1 as a key regulator of neutrophil metabolism and recruitment in lung IRI, and suggest that targeting Trem1 may provide a novel therapeutic strategy to mitigate PGD and improve lung transplant outcomes.

Colon cancer represents a global health challenge. The 3’-phosphoadenosine 5’-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. However, the correlation between PAPSS2 and diagnosis, prognosis, and immune cell infiltration in colon adenocarcinoma (COAD) has rarely been mentioned. We analyzed PAPSS2 expression levels in pan-cancer from The Cancer Genome Atlas (TCGA) database; and validated it in the Gene Expression Omnibus (GEO) database. RNA-seq data were analyzed using the R package to identify differentially expressed genes (DEGs) between COAD tissues with high and low PAPSS2 expression from multiple databases. The ssGSEA algorithm was used to analyze the correlation between PAPSS2 and immune cell infiltration in COAD. Tumor tissues and normal tissues were classified and assayed at the single-cell level to analyze differences in PAPSS2 expression. CCK8 and EdU assays were used to validate proliferative capacity; wound healing assays to validate migratory capacity; and Transwell assays to examine changes in invasive capacity. The PAPSS2 expression level was significantly lower in the tumor tissues and associated with worse clinical parameters and prognosis in COAD patients. And we constructed a transcriptional regulatory network involving FLI1 and hsa-miR-152-3p targeting PAPSS2 to support the role of PAPSS2.Enrichment analysis revealed that PAPSS2 is involved in O-glycan biosynthesis, TP53 pathway and extracellular matrix formation. PAPSS2 was found to be positively associated with the infiltration of numerous immune cells, immunomodulatory factors and chemokines. Cytological experiments demonstrated that PAPSS2 knockdown enhanced the proliferation, migration, and invasion of HCT116 and HT-29 cells. Our study suggests that PAPSS2 acts as a promising diagnostic and prognostic biomarker, which facilitates malignant progression in part through its regulation of the p53 signaling pathway.

BACKGROUND Anastomotic leakage (AL) is a serious complication following McKeown esophagectomy (MKE), associated with increased postoperative morbidity and mortality. The right gastroepiploic artery (RGEA) is the principal blood supply to the gastric conduit, yet its role in AL risk remains incompletely defined. This study aimed to evaluate the relationship between preoperative computed tomographic angiography (CTA) measured RGEA length and the incidence of AL following MKE while exploring whether RGEA length thresholds within our cohort could serve as risk-enrichment markers to support preoperative planning. AIM To evaluate the association between preoperative CTA-measured RGEA length and AL after MKE. METHODS A total of 679 patients who underwent MKE for esophageal cancer were included and stratified into two groups based on the presence or absence of AL (AL and Non-AL). The primary endpoint was to assess the association between AL incidence and the length of the RGEA as measured by CTA. Statistical analyses were performed using EmpowerStats and R software version 4.5.1. RESULTS Among the 679 patients, 109 (16.10%) developed AL. Patients in the AL group had significantly shorter RGEA lengths compared with the non-AL group (P < 0.001). Segmented regression analysis identified a cohort-specific threshold of 27.8 cm, below which the risk of AL increased. These findings suggest that shorter RGEA length is associated with elevated AL risk. CONCLUSION Shorter preoperative CTA-measured RGEA length is associated with a higher risk of AL. This cohort-specific threshold may serve as a risk-enrichment marker to inform perioperative planning and patient counseling.

e14572 Background: TSN222 is a novel stimulator of interferon genes (STING) agonist capable of being metabolized into a DNA synthesis inhibitor in vivo. This dual action affords sequential stimulation of the innate immune system and release of apoptotic DNA to further activate the STING pathway, and neoantigens to assist the emerging T-cell responses in the tumor microenvironment. TSN222 demonstrated potent antitumor effects via intratumoral (i.t.) injection on a variety of preclinical tumor models across solid tumors and lymphomas. Methods: This first-in-human phase 1/2 study was to determine the maximum tolerated dose (MTD), recommended tolerated phase 2 dose, pharmacokinetic (PK) profile, and preliminary antitumor activity of TSN222 in patients with advanced malignancies. In the phase 1 part, prespecified 7 sequential dose levels from 100 to 6400 μg of TSN222 were to be evaluated, using a "3+3" design for dose escalation. Patients received TSN222 via i.t. injection on Days 1, 8 and 15 of every 28-day cycle until disease progression or unacceptable toxicity. Here we report the data from the ongoing phase 1 part. Results: As of Jan 17, 2025, 16 patients were treated with 100-1600 μg of TSN222, including 5 patients with sarcoma (2 with liposarcoma, 1 each with myxoid fibrosarcoma, epithelioid sarcoma and perivascular epithelioid cell tumor), 4 melanoma and 1 each of 7 other tumors. Median age was about 56 years (range 35-70). Median lines of prior systemic therapy were 4 (range 1-8). No dose-limiting toxicity was observed and MTD not reached. The most common (≥ 10%) treatment related adverse events (TRAEs) were injection site pain (18.8%) and pyrexia (12.5%), with the rest TRAEs occurring in 1 patient each (6.3%), and all TRAEs were of grade 1-2. Among 9 patients assessed per RECIST 1.1, 2 patients with sarcoma had partial response (PR) and are still on treatment with TSN222 at 800 μg for 7.5 and 3.3 months, respectively; 5 had stable disease and 2 had disease progression. Paired biopsies of a PR patient demonstrated that TSN222 significantly induced STING activation, increased CD4 and CD8 positive T cells infiltration and programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment compared to baseline. The plasma T max of TSN222 and its cytotoxic metabolite was around 0.25 and 1 hour, and half-life was 0.8 and 7 hours, respectively. Both C max and AUC displayed dose-proportional increases, without obvious accumulation after multiple dosing. Conclusions: TSN222 was well tolerated with favorable PK profile and promising antitumor activity in patients with heavily pretreated advanced tumors. In addition to monotherapy, the differentiated safety profile of TSN222 supports the exploration of diverse combination therapies in clinical trials. Current data also informs the tolerance and efficacy potential of TSN222 as a promising payload for antibody drug conjugates (ADCs) development. Clinical trial information: NCT05842785 .

BACKGROUND:Our previous findings have underscored the role of innate immunity in obliterative bronchiolitis (OB). However, despite the central importance of the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway in innate immune responses, its specific contribution to OB progression remains largely unexplored. METHODS:A murine orthotopic tracheal transplantation model was established to replicate OB pathogenesis. RNA sequencing and single-cell RNA sequencing data were analysed to investigate mechanisms underlying OB. Key molecules of the cGAS/STING pathway were assessed using immunofluorescence staining. Macrophage-specific Sting1 knockout mice were generated to investigate the role of the cGAS/STING pathway in OB. Haematoxylin and eosin staining and Masson's trichrome staining were utilised to evaluate allograft stenosis and fibrosis. Immune cell infiltration and cytokine expression were analysed using immunofluorescence staining and qRT-PCR. Flow cytometry was used to characterise splenic T-cell subsets and assess co-stimulatory molecule expression in macrophages. RESULTS:The cGAS/STING pathway was upregulated in macrophages infiltrating allografts. Macrophage-specific Sting1 knockout significantly attenuated alloreactive T-cell responses and alleviated OB. Furthermore, Sting1 deletion reduced the expression of inflammatory marker NOS2, antigen-presenting molecule MHC class II and co-stimulatory molecules (CD80 and CD86) in macrophages. Mechanistically, Sting1 knockout inhibited the production of interferon-α2 (IFN-α2), while the protective effect of macrophage-specific Sting knockout was reversed by IFN-α2 administration. Importantly, STING inhibition enhanced the allograft tolerance-promoting effects of cytotoxic T-lymphocyte-associated antigen 4-Ig (CTLA4-Ig), leading to the preservation of the airway epithelium. CONCLUSIONS:Our study demonstrated that cGAS/STING signalling pathway exacerbated allograft rejection in an IFN-α2-dependent manner. These findings provide insights into potential novel strategies for prolonging allograft survival. KEY POINTS:cGAS/STING signalling pathway was activated in macrophages infiltrating allografts. cGAS/STING signalling pathway in macrophages exacerbated allograft rejection, promoted antigen-presenting ability of macrophages and enhanced alloreactive T-cell responses in an IFN-α2-dependent manner. STING inhibition potentiated the therapeutic efficacy of CTLA4-Ig in OB.

8024 Background: Ensartinib has been approved as ALK-positive locally advanced/metastatic NSCLC, but its role in adjuvant therapy remains unknown. This real-world study aimed to evaluate the efficacy and safety of ensartinib as adjuvant therapy in ALK-positive NSCLC. Methods: Data were retrospectively collected from “Ensacove Patient Assistance Program" held by Betta pharmaceutical company. The patients who were ≥18 years-old and had completely resected, histologically confirmed stage I-III NSCLC as classified according to the eighth edition of AJCC/UICC, were documented ALK-positive, and had at least one post-baseline CT scan. The primary endpoint is 2-year disease-free survival (DFS) rate. Secondary endpoints include DFS, safety and OS. Results: From November 19, 2020, to May 31, 2024, a total of 296 patients were screened. 222 patients were enrolled. The median age was 55 years-old. 128 females. 98 (44.1%) were stage I, 42 (18.9%) were stage II, 82 (36.9%) were stage III. 98.2% were lung adenocarcinoma. Thirty-two patients (14.4%) received postoperative chemotherapy. The median duration of ensartinib treatment was 25.3 (95% confidence intervals [CI], 3.1-47.2) months. At the data-cutoff date of December 29, 2024, median follow-up time was 23.5 months (95% CI, 21.7-26.2). The median DFS was immature. The 2-year DFS rate was 92.1% (95% CI, 86.6%-95.5%) for all patients, and 89.3% (95% CI, 77.9%-95.0%), 100.0% (95% CI, NR-NR) and 91.0% (95% CI, 80.6%-95.9%) for patients with stage I, stage II, and stage III, respectively. 16 patients had disease recurrence or death, including 7 patients with local recurrence and 9 patients with distant metastasis. The OS data was immature with only 2 deaths occurred. The treatment-related adverse events (TRAEs) of any grade occurred in 169 patients (76.1%), and 11 patients (5.0%) experienced ≥grade 3 TRAEs. The most common TRAEs were rash (60.8%). Serious TRAEs were 8 (3.6%) patients. TRAEs led to dose reductions, dose interruptions and permanent discontinuation were 21.2%, 9.0% and 3.2% of the patients, respectively. No deaths due to TRAEs were reported. Conclusions: To our knowledge, this real-world study has the largest sample size on postoperative adjuvant therapy with ALK inhibitors. In this real-world setting, ensartinib demonstrated encouraging efficacy and well-tolerated safety profile among stage IA1-IIIB ALK-positive NSCLC, providing a potential adjuvant therapy option in this patient population.

Background Accurate localization of small-to-medium pulmonary nodules before video-assisted thoracoscopic surgery (VATS) is essential for success. Traditional imaging methods face challenges in the thoracic cavity. This study compares electromagnetic navigational bronchoscopic (ENB), computed tomography (CT)-guided localization effectiveness and safety with methylene blue marker dye. Materials and Methods This study, approved on May 4, 2024 by the Institutional Review Board of Wuhan Union Hospital (IRB ID UHCT240340) affiliated with Tongji Medical College, included patients with pulmonary nodules scheduled for VATS. Methylene blue was used as a marker dye and injected via CT-guided percutaneous or ENB techniques. The study compared clinical parameters, success rates, and complications between the two localization methods. Results Out of 378 patients who underwent preoperative localization, 254 received electromagnetic navigational bronchoscopy (ENB) and 124 had CT-guided percutaneous marker dye injections. Nodules were significantly larger in the ENB group (p < 0.001). Success rates were similar: ENB at 97.24% and CT-guided at 97.58%. ENB was more effective in the upper lobes than the lower lobes (p = 0.005), with no lobar preference for CT-guided localization (p = 0.073). ENB also had significantly fewer complications than CT-guided procedures (p < 0.001). Conclusions ENB localization success rates are comparable to CT-guided methods, but ENB carries lower risks, particularly for puncture-related complications. CT-guided localization is more effective than ENB for lower lobe nodules.

Post-transplant obliterative bronchiolitis (OB) is a major cause of lung graft dysfunction and failure, with the epithelial–mesenchymal transition (EMT) process playing a pivotal role in driving extracellular matrix (ECM) deposition and fibrosis. A mouse heterotopic tracheal allograft model was established to replicate the clinical manifestations of post-transplant OB. Histopathological alterations of tracheal grafts were assessed using Hematoxylin and Eosin (HE) staining. Gene expression was quantified through enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry (IHC), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western blot assays. Differentially expressed genes (DEGs) in heterotopic tracheal grafts were identified by RNA sequencing (RNA-Seq). Chromatin accessibility was evaluated using assay for transposase-accessible chromatin with sequencing (ATAC-Seq). Histological analysis revealed progressive luminal occlusion (7–14 days), with significant inflammatory infiltration at day 7 and ECM deposition at day 14. Elevated IL-1β/IL-6 levels and reduced IL-10 confirmed immune activation. High mobility group at-hook 1 (HMGA1) was upregulated in allografts and mediated TGF-β1-driven EMT in vitro. Integration of ATAC-seq and RT-qPCR in pulmonary epithelial cells demonstrated that HMGA1 orchestrates extensive chromatin remodeling during OB pathogenesis. HMGA1 directly enhanced chromatin accessibility at EMT-promoting loci, including specificity protein 1 (SP1), dedicator of cytokinesis 4 (DOCK4), serum response factor (SRF), and anillin (ANLN). Epigenetic reprogramming of these regulatory regions induced TGF-β1-mediated EMT. HMGA1 promotes EMT in OB by facilitating chromatin accessibility at EMT-associated loci, highlighting its potential as a therapeutic target for post-transplant intervention.

BACKGROUND:Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) plays an important role in innate immune system. However, whether and how TREM-1 contributes to obliterative bronchiolitis (OB) progression remains unclear. METHODS:A murine orthotopic tracheal transplantation model was constructed to mimic the pathogenesis of OB. qPCR and immunoblotting were used to measure TREM-1 expression. RNA sequencing was used to investigate the impact of TREM-1 on proinflammatory phenotype of macrophages. Trem-1 knockout mice and Nlrp3 knockout mice were generated to investigate the role of the TREM-1/NLRP3 pathway in the proinflammatory phenotype of macrophages. The infiltration of immune cells within the grafts was quantified using immunofluorescence staining. Flow cytometry was used to detect the proportion of different immune cells in mice spleen and the expression levels of iNOS and co-stimulatory molecules in macrophages. RESULTS:The expression of TREM-1 was upregulated in the mouse OB model. Genetic ablation or pharmacological inhibition of TREM-1 ameliorated OB, whereas the stimulation of TREM-1 using anti-TREM-1 agonistic antibody exacerbated OB. Moreover, Trem-1 ablation reduced the infiltration of iNOS+ macrophages and limited the T cell responses. In vitro studies revealed that Trem-1 deletion impaired the proinflammatory function and antigen presentation ability of macrophages. Additionally, Trem-1 knockout inhibited the activation of NLRP3 signaling pathway. NLRP3 overexpression restored the proinflammatory phenotype of Trem-1 knockout macrophages. CONCLUSIONS:These findings indicated that TREM-1 could promote the proinflammatory phenotype of macrophages through NLRP3 inflammasome activation, thereby exacerbating OB progression. These findings indicated that TREM-1 may serve as a therapeutic target for OB treatment.

TPS8117 Background: Patients with stage II-III A non-small cell lung cancer (NSCLC) can benefit from adjuvant targeted therapy. ADAURA study shows a remarkable advantage of disease-free survival (DFS). However, there are still unresolved clinical issues. Firstly, the control group in the trial is received placebo, making it impossible to directly compare the efficacy of adjuvant targeted therapy with the traditionally recommended adjuvant chemotherapy in guidelines. Thus, it cannot address the direct comparison of third-generation TKIs with the current standard therapy (chemotherapy). Secondly, the necessity of combining chemotherapy with adjuvant targeted therapy need to explored. Aumolertinib is a third-generation epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR sensitizing and EGFR T790M resistance mutations. This study aims to evaluate the efficacy and safety of aumolertinib combined with or without chemotherapy as adjuvant treatment for EGFR-sensitive mutations stage II-III A non-squamous NSCLC patients. Methods: This is a multicenter, randomized, open label, phase III study. Patients with histologically confirmed stage II-III A non-squamous NSCLC harboring EGFR mutations without prior EGFR TKI treatment and R0 resection are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 606 patients, will be randomized (3:2:1) to receive either aumolertinib alone (110mg, po, once daily) or aumolertinib (110mg, po, once daily) plus pemetrexed (500mg/m2, iv) and cisplatin (500mg/m2, iv) or pemetrexed (500mg/m2, iv) plus cisplatin (500mg/m2, iv). The first patient was enrolled on August 2, 2021. The primary end point is DFS, The secondary endpoints include 2, 3, 4, 5-year DFS rates, 5-year overall survival (OS), OS, safety and quality of life. Adverse effects were graded per CTCAE v.4.0. This trial is registered as NCT04762459. Clinical trial information: NCT04762459 .

Neoadjuvant chemoimmunotherapy has demonstrated significant benefit for resectable non-small-cell lung cancer (NSCLC) excluding known EGFR/ALK genetic alterations. Recent evidence has shown that neoadjuvant chemoimmunotherapy could be clinically valuable in resectable localized driver gene-mutant NSCLC, though the data still lack robust support, especially for rare oncogenic mutations. Here, we report a patient with stage IIIA lung adenocarcinoma with a RET fusion gene and high expression of PD-L1 who underwent neoadjuvant chemoimmunotherapy and successfully attained a pathologic complete response. The patient has survived for 12 months with no recurrence or metastases after surgery. Our case suggests that this treatment strategy may be an alternative therapeutic option for resectable RET fusion-positive NSCLC patients.

Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.

Background: Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), has been authorized for use in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to evaluate the effectiveness and safety of neoadjuvant osimertinib in individuals with resectable locally advanced NSCLC harboring EGFR mutation.Methods: Ten centers located in mainland China took part in a single-arm, real-world, multicenter retrospective study (registration number: ChiCTR2100049954). Enrollment included individuals with lung adenocarcinoma who had EGFR mutations. Following the administration of osimertinib, the patients underwent a surgical procedure for resection. The main endpoint was the objective response rate (ORR). The subsequent endpoint analyzed was the joint assessment of overall survival (OS) and disease-free survival (DFS).Results: From July 31, 2018 to April 28, 2023, a total of 38 individuals were involved and received neoadjuvant osimertinib treatment. The ORR was 60.5% (23/38). Thirty-eight patients underwent surgery, and 36 (94.7%) underwent successful R0 resection. Out of 38 patients, sixteen (42.1%) experienced adverse events (AEs) due to treatment in the neoadjuvant phase, with none of them reaching grade 3. Skin irritation [14 (36.8%)], stomach upset [5 (13.2%)], mouth sores [1 (2.6%)] and increased liver enzyme levels [1 (2.6%)] were the common AEs of treatment. The follow-up period lasted an average of 24.9 months. The 1-year OS rate is 94.2%, while the 2-year OS rate is 89.2%. The 1-year DFS rate is 87.9%, and the 2-year DFS rate remains at 87.9% Conclusions: In the actual clinical setting, osimertinib displays encouraging possibilities as a neoadjuvant therapy for individuals with operable EGFR-mutated NSCLC, exhibiting adequate efficacy and an acceptable safety record. The phase III clinical trial of NeoADAURA is expected to provide further efficacy and safety results

IntroductionThoracic aortic aneurysm (TAA) is a severe vascular disease that threatens human life, characterized by focal dilatation of the entire aortic wall, with a diameter 1.5 times larger than normal. PIEZO1, a mechanosensitive cationic channel, monitors mechanical stimulations in the environment, transduces mechanical signals into electrical signals, and converts them into biological signals to activate intracellular signaling pathways. However, the role of PIEZO1 in TAA is still unclear.MethodsWe analyzed a single-cell database to investigate the expression level of PIEZO1 in TAA. We constructed a conditional knockout mouse model of Piezo1 and used the PIEZO1 agonist Yoda1 to intervene in the TAA model mice established by co-administration of BAPN and ANG-II. Finally, we explored the effect of Yoda1 on TAA in vitro.Results and discussionWe observed decreased PIEZO1 expression in TAA at both RNA and protein levels. Single-cell sequencing identified a specific reduction in Piezo1 expression in endothelial cells. Administration of PIEZO1 agonist Yoda1 prevented the formation of TAA. In PIEZO1 endothelial cell conditional knockout mice, Yoda1 inhibited TAA formation by interfering with PIEZO1. In vivo and in vitro experiments demonstrated that the effect of Yoda1 on endothelial cells involved macrophage infiltration, extracellular matrix degradation, and neovascularization. This study highlights the role of PIEZO1 in TAA and its potential as a therapeutic target, providing opportunities for clinical translation.

BACKGROUND:Immuno-chemotherapy has demonstrated significant anti-tumor effects in patients with resectable nonsmall cell lung cancer (NSCLC). Additionally, for patients initially diagnosed with unresectable stage III NSCLC, induction immuno-chemotherapy may achieve tumor downstaging, enabling conversion to resectable disease allowing for by R0 resection. This study aimed to assess the effectiveness and safety of induction immuno-chemotherapy followed by conversion surgery in unresectable stage III NSCLC. PATIENTS AND METHODS:A total of 113 patients with unresectable stage Ⅲ NSCLC who received induction immuno-chemotherapy at three institutions in China from March 2019 to April 2022 were retrospectively identified. After 2-4 cycles of immuno-chemotherapy, a multisiciplinary team (MDT) reassessed the tumor response and resectability in each case. Surgical resection was performed for patients who achieved tumor downstaging to resectable disease. Surgical and oncological outcomes of the patients were analyzed. RESULTS:Of the 113 patients treated with immuno-chemotherapy, 79 (69.9%) achieved conversion to resectable state and underwent surgery. Surgical procedures included lobectomy in 55 (69.6%) patients, sleeve lobectomy in 14 (17.7%) patients, bilobectomy in 6 (7.6%) patients, and pneumonectomy in 4 (5.1%) patients, achieving an R0 resection rate of 98.7% (78/79). No surgical-related 30-day or 90-day mortalities were recorded, although 17 patients (21.5%) experienced postoperative complications. In terms of pathological response, 44 (55.7%) patients achieved major pathologic response and 25 (31.6%) patients achieved complete pathologic response. Median progression-free survival (PFS) and overall survival (OS) was not reached. The 12- and 24-month PFS rates were 82.3% and 72.2%, while OS rates were 94.9% and 84.5%, respectively. CONCLUSION:Conversion surgery following immuno-chemotherapy is feasible and safe, yielding promising pathological responses and favorable survival outcomes for patients with unresectable stage III NSCLC.

BackgroundInhibition of Serum Amyloid A-like 1 (SAAL1) expression could inhibit cancer progression and improve the prognosis of cancer patients. At present, the correlation between SAAL1 and lung adenocarcinoma (LAC) remains unclear. Therefore, this study surveyed the worth and pathway of SAAL1 in LAC progression and immunity.MethodsBioinformatics and immunohistochemistry were used to identify the SAAL1 expression in LAC. The roles of SAAL1 expression in the existence values of LAC patients were explored, and the nomograms were constructed. Clinical values of SAAL1 co-expressed genes were evaluated by COX regression, survival, and Receiver operating characteristic (ROC) analysis. EDU and western blotting methods were used to inquiry the functions and pathways of the SAAL1 in cell growths. The correlation between the SAAL1 level and immune microenvironment was visualized using correlation research.ResultsSAAL1 level was elevated in LAC tissues, and was observed in cancer tissues of dead patients. SAAL1 overexpression had something to do with shorter overall survival, progression-free interval, and disease-specific survival in LAC. The area under the curve of SAAL1 was 0.902 in normal tissues and cancer tissues. Inhibition of SAAL1 expression could inhibit cancer cell proliferation, which may be related to the decreased expression of cyclin D1 and Bcl-2 proteins. In LAC, SAAL1 level had something to do with stromal, immune, and estimate scores, and correlated with macrophages, T cells, Th2 cells, CD8 T cells, NK CD56dim cells, DC, eosinophils, NK CD56bright cells, pDC, iDC, cytotoxic cells, Tgd, aDC cells, B cells, Tcm, and TFH levels. SAAL1 overexpression had something to do with existence values and the immunity in LAC.ConclusionsInhibition of SAAL1 expression could regulate cancer growth via cyclin D1 and Bcl-2. SAAL1 is a promising prognostic biomarker in LAC patients.

The roles and mechanisms of T-cell receptor (TCR)-associated transmembrane adaptor 1 (TRAT1) in lung adenocarcinoma (LAC) have not yet been reported in the relevant literature. Therefore, this study aimed to understand the roles and mechanisms of TRAT1 in LAC using bioinformatics and in vitro experiments. TRAT1 expression levels in LAC samples were analysed using various databases. TRAT1 co-expressed genes were acquired by the correlation analysis of LAC tissues. The functional mechanisms and protein network of TRAT1 co-expressed genes were analysed using bioinformatics analysis. The expression of TRAT1 was activated in LAC cells, and the roles of TRAT1 overexpression in the growth and migration of cancer cells was investigated using flow cytometry, Cell Counting Kit-8 (CCK-8), and migration and invasion assays. The relationship between TRAT1 overexpression, the immune microenvironment, and RNA modification was evaluated using correlation analysis. TRAT1 expression levels were significantly abnormal at multiple mutation sites and were related to the prognosis of LAC. TRAT1 co-expressed genes were involved in cell proliferation, adhesion, and differentiation, and TRAT1 overexpression significantly inhibited cell viability, migration, and invasion and promoted apoptosis of A549 and H1299 cells, which might be related to the TCR, B cell receptor (BCR), MAPK, and other pathways. TRAT1 expression levels were significantly correlated with the ESTIMATE, immune, and stromal scores in the LAC microenvironment. Additionally, TRAT1 expression levels were significantly correlated with the populations of B cells, CD8 T cells, cytotoxic cells, and other immune cells. TRAT1 overexpression was significantly correlated with the expression of immune cell markers (such as PDCD1, CD2, CD3E) and genes involved in RNA modification (such as ALKBH1, ALKBH3, ALKBH5). In conclusions, TRAT1 overexpression inhibited the growth and migration of LAC cells, thereby delaying cancer progression, and was correlated with the LAC microenvironment and RNA modifications.

Abstract Objective: Tumor spread through air spaces(STAS) is a poor prognostic factor for early-stage non-small-cell cancers. This investigation sought to determine the correlations of preoperative peripheral blood parameters with STAS and survival outcomes in pathological stage I lung adenocarcinoma (ADC). Methods: We retrospectively reviewed 633 stage I ADC patients who underwent radical surgical resection for the presence of STAS using HE-stained pathological sections. The baseline clinicopathological features, preoperative peripheral blood indexes and follow-up data were analysed. Independent indicators of STAS were identified using multivariate logistic regression. Kaplan‒Meier analyses were used to examine overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox regression analysis wasused to identifyindependent prognostic variables. Results: STAS was discovered in 285 (45.0%) of the 633 patients. STAS positivity was related to gender, smoking status, disease stage, predominant histological pattern, and differentiation. The multivariate logistic regression identified a level of carcinoembryonic antigen (CEA) ≥5 ug/L and absolute monocyte count (AMC) ≥0.38 G/L as an independent predictor of STAS (p=0.005; p=0.013) among the hematological parameters. STAS positivity was an independent poor prognostic factor for RFS and OS in the CEA <5 µg/L subgroup but not in the CEA ≥5 µg/L subgroup (RFS: HR=2.616, 95% CI=1.414-4.839, p=0.002; OS: HR=5.534, 95% CI=1.186-25.816, p=0.029). In STAS-negative patients but not in STAS-positive patients, CEA demonstrated an independent predictive influence for recurrence and death (RFS: HR=6.488, 95% CI=2.475-17.010, p=0.005; OS: HR=19.569, 95% CI=2.487-153.983, p=0.005). Conclusions: Preoperative hematological examination can be prioritised in predicting the presence of STAS, and CEA ≥5 ug/L and AMC ≥ 0.38 G/L were independent risk predictors for STAS in pathological stage I lung adenocarcinoma. Combining preoperative hematological markers with STAS can optimize the prediction of cancer mortality or recurrence following patient subclassification.

OBJECTIVE:T cell receptor-associated transmembrane adaptor 1 (TRAT1) is one of the hub genes regulating T cell receptors (TCRs). Herein, the roles of TRAT1 in the prognosis and immune microenvironment of non-small cell lung cancer (NSCLC) were investigated.METHODS:The expression and prognosis values of TRAT1 in NSCLC, and the relationship between TRAT1 expression levels and cancer immune cell infiltration was identified via the TIMER, UALCAN, TISIDB, and other databases. The mechanism of TRAT1 in NSCLC was analyzed using gene set enrichment analysis (GSEA).RESULTS:The expression level of TRAT1 was decreased in NSCLC tissues. Low TRAT1 expression was associated with shorter overall survival of patients with NSCLC and was related to gender, smoking, and tumor grade. TRAT1 was involved in regulating immune response, TCR signaling pathway, PI3K/AKT, and other processes. TRAT1 expression levels were positively correlated with immune cell infiltration in NSCLC.CONCLUSION:Down-regulation of TRAT1 expression was associated with an unfavorable prognosis and immune infiltration of NSCLC.