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Purpose: This research intends to investigate the treatment of non-small cell lung cancer (NSCLC) using Toripalimab, focusing on its effectiveness and safety profile. Efficacy refers to the survival prognosis, while safety pertains to the occurrence of adverse events in our study. It also aims to provide reference information for neoadjuvant and postoperative therapies. Methods: Up to March 20, 2024, studies on randomized controlled trials and single-arm trials involving Toripalimab for NSCLC were sourced from the Cochrane Library, Embase, PubMed, and Web of Science databases. Data extraction and analysis were independently conducted by two researchers utilizing Stata 15.0 and R software. Results: A total of 8 studies were analyzed, including 6 single-arm studies and 2 randomized controlled trials (RCTs). Toripalimab treatment in the RCTs showed an overall survival (OS) of [HR=0.67, 95% CI (0.53, 0.85); p=0.71]. The objective response rate (ORR) from single-arm studies was reported as [ES=0.59, 95% CI (0.36, 0.81); p<0.01], and progression-free survival (PFS) was [ES=4.89, 95% CI (2.65, 9.02); p<0.01]. Furthermore, observed adverse effects included Anemia [OR=0.53, 95% CI (0.26, 0.79); p<0.01], Neutropenia [OR=0.43, 95% CI (0.20, 0.68); p<0.01], and Thrombocytopenia [OR=0.28, 95% CI (0.18, 0.43); p<0.01]. Conclusions: Toripalimab, being China's first domestically developed anti-tumor PD-1 antibody drug, shows potential advantages over traditional chemotherapy in possibly prolonging patients' survival times. However, the limited number of studies included indicates the need for additional single-arm and RCT studies to further validate these findings. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier (CRD42024519806). [ABSTRACT FROM AUTHOR]

Immunotherapy targeting immune checkpoints (ICPs), such as programmed death‐ligand‐1 (PD‐L1), is used as a treatment option for advanced or metastatic non‐small cell lung cancer (NSCLC). However, overall response rate to anti‐PD‐L1 treatment is limited due to antigen heterogeneity and the immune‐suppressive tumor microenvironment. Human leukocyte antigen‐G (HLA‐G), an ICP as well as a neoexpressed tumor‐associated antigen, is previously demonstrated to be a beneficial target in combination with anti‐PD‐L1. In this study, a nanobody‐based trispecific T cell engager (Nb‐TriTE) is developed, capable of simultaneously binding to T cells, macrophages, and cancer cells while redirecting T cells toward tumor cells expressing PD‐L1‐ and/or HLA‐G. Nb‐TriTE shows broad spectrum anti‐tumor effects in vitro by augmenting cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs). In a humanized immunodeficient murine NSCLC model, Nb‐TriTE exhibits superior anti‐cancer potency compared to monoclonal antibodies and bispecific T cell engagers. Nb‐TriTE, at the dose with pharmacoactivity, does not induce additional enhancement of circulating cytokines secretion from PMBCs. Nb‐TriTE effectively prolongs the survival of mice without obvious adverse events. In conclusion, this study introduces an innovative therapeutic approach to address the challenges of immunotherapy and the tumor microenvironment in NSCLC through utilizing the dual ICP‐targeting Nb‐TriTE. [ABSTRACT FROM AUTHOR]

Objective: The present study endeavors to furnish an exhaustive review of the research advancements on solid tumors harboring RET rearrangement within the Chinese context, particularly emphasizing the examination of real-world therapeutic strategies and clinical outcomes observed in individuals diagnosed with advanced non-small cell lung cancer (NSCLC). The review delves into a critical assessment of the therapeutic efficacy of targeted RET inhibitors, while also scrutinizing the diverse array of treatment modalities employed in the Chinese patient population. Methods: The study conducted a comprehensive review of the advancements made by Chinese scholars in the realm of RET driver genes. It delved into the analysis of the incidence of RET rearrangements in solid tumors, alongside an examination of the varied treatment paradigms and their current status within China. Utilizing the RECIST 1.1 criteria, the study evaluated the therapeutic efficacy achieved in RET-positive NSCLC patients undergoing diverse treatment modalities. Furthermore, treatment-related adverse events (TRAEs) were meticulously graded following the Common Terminology Criteria for Adverse Events (CTCAE). Results: A retrospective, multi-center, real-world analysis was conducted, encompassing 64 patients diagnosed with pathologically confirmed RET rearrangement advanced non-small cell lung cancer (NSCLC) between December 2015 and November 2023. Notably, KIF5B-RET emerged as the most prevalent RET fusion partner, accounting for 59.4% of cases. Therapeutic interventions among these patients included specific targeted inhibitors such as Pralsetinib (48.4%), chemotherapy (34.3%), multi-target inhibitors (15.6%), and one case (1.6%) involving immunotherapy combined with anti-angiogenic therapy. In terms of progression-free survival (PFS), Pralsetinib monotherapy demonstrated a median PFS of 16.03 months, outperforming chemotherapy (2.87 months; p < 0.0001), chemotherapy combined with anti-angiogenic therapy (6.90 months; p = 0.048), and multi-target inhibitors (2.50 months; p < 0.0001). Furthermore, the one-year and two-year overall survival (OS) rates for Pralsetinib monotherapy were 64.3% and 46.4%, respectively. Regarding safety, 71.0% of patients receiving Pralsetinib experienced at least one adverse event, with 45.2% classified as grade 3–4 in severity. Notably, no fatalities were attributed to adverse events. Common adverse events included hemoglobin reduction (35.5%) and neutropenia (32.3%), indicative of an overall favorable safety profile for Pralsetinib in this patient population. Conclusion: This study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC. [ABSTRACT FROM AUTHOR]

The immunosuppressive tumor microenvironment (TME) significantly inhibits the effective anti-tumor immune response, greatly affecting the efficacy of immunotherapy. Most tumor-associated macrophages (TAMs) belong to the M2 phenotype, which contributes significantly to the immunosuppressive effects in non-small cell lung cancer (NSCLC) TME. The interaction between signal regulatory protein α (SIRPα) expressed on macrophages and CD47, a transmembrane protein overexpressed on cancer cells, activates the "eat-me-not" signaling pathway, inhibiting phagocytosis. In this study, a folic acid (FA)-modified ultrasound responsive gene/drugs delivery system, named FA@ PFP @ Fe3O4 @LNB-SIRPα siRNA (FA-PFNB-SIRPα siRNA), was developed using 1,2-dioleoacyl-3-trimethylammonium-propane (DOTAP), FA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol)2000] (DSPE-PEG2000-FA), cholesterol, and perfluoropentane (PFP), for the delivery of siRNA encoding SIRPα mRNA and immune adjuvant Fe3O4 nanoparticles. Under ultrasound conditions, the nanobubbles effectively transfected macrophages, inhibiting SIRPα mRNA and protein expression, promoting the phagocytosis of TAMs, and synergistically reversing M2 polarization. This system promotes the infiltration of T cells, enhances the proliferation and activation of cytotoxic T cells, and inhibits the infiltration of immunosuppressive cells in tumor tissues. Administration of FA-PFNB-SIRPα siRNA combined with ultrasound significantly inhibits NSCLC progression. The study highlights the potential of ultrasound nanotechnology-enabled delivery of SIRPα siRNA and Fe3O4 as an effective strategy for macrophage-based immunotherapy to reshape the immunosuppressive TME for cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with immune-related adverse events (irAEs). This study analyzes the relationship between irAEs and treatment effectiveness in advanced non-small cell lung cancer (NSCLC) patients. Methods: We conducted a retrospective study of NSCLC patients treated with ICIs from March 2019 to October 2022 at Zhongshan Hospital (Xiamen). Patients were divided into irAE and non-irAE groups, and treatment outcomes were compared. Results: A total of 154 patients were included, with 36.4% in the irAE group and 63.6% in the non-irAE group. Most irAEs were Grade 1–2 (86.4%), with 13.6% being Grade 3 or higher. The irAE group had higher disease control rates (DCR: 94.6% vs. 76.5%, P = 0.004) and objective response rates (ORR: 42.9% vs. 26.5%, P = 0.037). Median progression-free survival (PFS) was longer in the irAE group (18 vs. 9 months, HR: 0.53, P = 0.001), as was overall survival (OS: 39.5 vs. 16 months, HR: 0.46, P = 0.001). Landmark analysis at 6 and 12 weeks confirmed that irAEs were associated with improved outcomes. Moreover, patients who experienced two or more adverse events during treatment had significantly longer OS compared to those who had only one or no adverse events (41.6 months vs. 34.0 vs. 23.6, P = 0.003). Conclusion: Patients with irAEs demonstrated better outcomes, including ORR, DCR, PFS, and OS. Further studies on biomarkers and irAE incidence are warranted to improve lung cancer management. [ABSTRACT FROM AUTHOR]

Background: Patients with programmed cell death‐ligand 1 (PD‐L1) ≥50% metastatic non‐small cell lung cancer (NSCLC) treated with first‐line immunotherapy showed heterogeneous tumor responses. In this study, we investigated the clinical and immune‐inflammatory markers distinguishing patients with metastatic NSCLC achieving high depth of tumor response (HDPR) from those with non‐high depth of response (NHDPR). The impact of clinical features on the prognosis of patients with PD‐L1 ≥50% were further clarified. Methods: The clinical characteristics and immune‐inflammatory markers of 17 patients with PD‐L1 ≥50% metastatic NSCLC at Beijing Tiantan Hospital between July 2020 and December 2023 were retrospectively analyzed. Results: Among the 17 patients, seven (41.2%) patients achieved HDPR (range: −50%, −72%) and 10 (58.8%) patients achieved NHDPR (range: −13%, −45%). Below normal CD4 + T lymphocytes/CD8 + T lymphocytes (CD4/CD8) ratio (p = 0.01) and oncogenes and/or tumor suppressor gene mutations (TP53/KRAS/EGFR) (p = 0.001) were found enriched for NHDPR compared with HDPR. With a median follow‐up of 26.0 months (range: 17.2–34.8 months), the median progression‐free survival (PFS) following first‐line immunotherapy and overall survival (OS) were 9.0 months (95% CI: 5.0–13.0) and not reached (NR), respectively. The neutrophil‐to‐lymphocyte ratio (NLR) was identified as an independent prognostic factor on first‐line PFS. Patients with an NLR ≥4 exhibited a shorter median PFS (7.0 months vs. NR; p = 0.033; 95% CI: 1.2–80.2) than those with an NLR <4 following first‐line immunotherapy. Conclusions: Among patients with PD‐L1 ≥50% metastatic NSCLC who received first‐line immunotherapy, a lower CD4/CD8 ratio and the presence of genes mutations showed a diminished tumor response and a higher NLR ratio exhibited a worse median PFS. [ABSTRACT FROM AUTHOR]

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Background: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets. Methods: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression. Results: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC. Conclusions: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Background: The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. Methods: The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. Results: Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38–0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26–0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25–0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31–0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28–0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. Conclusion: For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone. [ABSTRACT FROM AUTHOR]

Organic–inorganic hybrid nanocomposites (OIHN), with tailored surface chemistry, offer ultra-sensitive architecture capable of detecting ultra-low concentrations of target analytes with precision. In the present work, a novel nano-biosensor was fabricated, acquainting dynamic synergy of reduced graphene oxide (rGO) decorated hexagonal boron nitride nanosheets (hBNNS) for detection of carcinoembryonic antigen (CEA). Extensive spectroscopic and microscopic analyses confirmed the successful hydrothermal synthesis of cross-linked rGO-hBNNS nanocomposite. Uniform micro-electrodes of rGO-hBNNS onto pre-hydrolyzed ITO were obtained via electrophoretic deposition (EPD) technique at low DC potential (15 V). Optimization of antibody incubation time, pH of supporting electrolyte, and immunoelectrode preparation was thoroughly investigated to enhance nano-biosensing efficacy. rGO-modified hBNNS demonstrated 29% boost in electrochemical performance over bare hBNNS, signifying remarkable electro-catalytic activity of nano-biosensor. The presence of multifunctional groups on the interface facilitated stable crosslinking chemistry, increased immobilization density, and enabled site-specific anchoring of Anti-CEA, resulting in improved binding affinity. The nano-biosensor demonstrated a remarkably low limit of detection of 5.47 pg/mL (R2 = 0.99963), indicating exceptional sensitivity and accuracy in detecting CEA concentrations from 0 to 50 ng/mL. The clinical evaluation confirmed its exceptional shelf life, minimal cross-reactivity, and robust recovery rates in human serum samples, thereby unraveling the potential for early, highly sensitive, and reliable CEA detection. [ABSTRACT FROM AUTHOR]

With the outbreak of the coronavirus disease 2019 (COVID-19), reductions in T-cell function and exhaustion have been observed in patients post-infection of COVID-19. T cells are key mediators of anti-infection and antitumor, and their exhaustion increases the risk of compromised immune function and elevated susceptibility to cancer. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with high incidence and mortality. Although the survival rate after standard treatment such as surgical treatment and chemotherapy has improved, the therapeutic effect is still limited due to drug resistance, side effects, and recurrence. Recent advances in molecular biology and immunology enable the development of highly targeted therapy and immunotherapy for cancer, which has driven cancer therapies into individualized treatments and gradually entered clinicians' views for treating NSCLC. Currently, with the development of photosensitizer materials, phototherapy has been gradually applied to the treatment of NSCLC. This review provides an overview of recent advancements and limitations in different treatment strategies for NSCLC under the background of COVID-19. We discuss the latest advances in phototherapy as a promising treatment method for NSCLC. After critically examining the successes, challenges, and prospects associated with these treatment modalities, their profound prospects were portrayed. [ABSTRACT FROM AUTHOR]

The main bottleneck in training a robust tumor segmentation algorithm for non-small cell lung cancer (NSCLC) on H&E is generating sufficient ground truth annotations. Various approaches for generating tumor labels to train a tumor segmentation model was explored. A large dataset of low-cost low-accuracy panCK-based annotations was used to pre-train the model and determine the minimum required size of the expensive but highly accurate pathologist annotations dataset. PanCK pre-training was compared to foundation models and various architectures were explored for model backbone. Proper study design and sample procurement for training a generalizable model that captured variations in NSCLC H&E was studied. H&E imaging was performed on 112 samples (three centers, two scanner types, different staining and imaging protocols). Attention U-Net architecture was trained using the large panCK-based annotations dataset (68 samples, total area 10,326 [mm2]) followed by fine-tuning using a small pathologist annotations dataset (80 samples, total area 246 [mm2]). This approach resulted in mean intersection over union (mIoU) of 82% [77 87]. Using panCK pretraining provided better performance compared to foundation models and allowed for 70% reduction in pathologist annotations with no drop in performance. Study design ensured model generalizability over variations on H&E where performance was consistent across centers, scanners, and subtypes. [ABSTRACT FROM AUTHOR]

Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is rare and is associated with poor prognosis. However, the standard treatment protocols for patients with SCLC transformation remain unknown. Here, we report the case of a patient with advanced EGFR exon 19 deletion (19del) NSCLC who underwent SCLC transformation during targeted therapy. Biopsies and genetic testing were performed to adjust treatment regimens accordingly. The patient responded favorably to a combined treatment regimen comprising etoposide plus cisplatin chemotherapy and adebrelimab plus osimertinib. This case highlights the critical importance of acknowledging tumor heterogeneity in clinical decision-making and identifying potentially effective treatment options for patients with SCLC transformation. Additionally, we reviewed cases of the transformation of NSCLC to SCLC from 2017 to 2023. [ABSTRACT FROM AUTHOR]

The treatment of non-small cell lung cancer (NSCLC) has evolved tremendously in recent decades as innovations in medical therapies advanced concomitantly with minimally invasive surgical techniques. Despite early skepticism regarding its benefits, video-assisted thoracoscopic surgery (VATS) techniques for the surgical resection of early-stage NSCLC have now become the standard of care. After being the subject of many studies since its inception, VATS has been shown to cause less postoperative pain, have shorter recovery time, and have fewer overall complications when compared to conventional open approaches. Furthermore, some studies have shown it to have comparable oncological outcomes, though more higher evidence studies are needed. Newer technologies and improved surgical instruments, advancements in nodule localization techniques, and improved preoperative staging procedures have allowed for the development of newer, less invasive techniques such as uniportal VATS and parenchymal-sparing sublobar resections, which might further improve postoperative rates of complications in specific cases. These minimally invasive approaches have allowed surgeons to offer surgery to high-risk patients and those who would otherwise not tolerate conventional thoracotomy, though some relative contraindications still exist. This review aims to describe the evolution of VATS lobectomy, current techniques, its indications, contraindications, preoperative testing, benefits, and outcomes in patients with stage I and II NSCLC. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a leading cause of cancer deaths in the United States. An increasing understanding of relevant non-small cell lung cancer (NSCLC) biomarkers has led to the recent development of molecular-targeted therapies and immune checkpoint inhibitors that have revolutionized treatment for patients with advanced and metastatic disease. The purpose of this review is to provide surgeons with a state-of-the-art understanding of the current medical and surgical treatment trends and their implications in the future of management of NSCLC. Materials and Methods: A systematic search of PubMed was conducted to identify English language articles published between January 2010 and March 2024 focusing on molecular markers, tumor targeting, and immunotherapy in the diagnosis and treatment of NSCLC. Case series, observational studies, randomized trials, guidelines, narrative reviews, systematic reviews, and meta-analyses were included. Results: There is now increasing data to suggest that molecular-targeted therapies and immune therapies have a role in the neoadjuvant setting. Advances in intraoperative imaging allow surgeons to perform increasingly parenchymal-sparing lung resections without compromising tumor margins. Liquid biopsies can noninvasively detect targetable mutations in cancer cells and DNA from a blood draw, potentially allowing for earlier diagnosis, personalized therapy, and long-term monitoring for disease recurrence. Conclusions: The management of NSCLC has advanced dramatically in recent years fueled by a growing understanding of the cancer biology of NSCLC. Advances in medical therapies, surgical techniques, and diagnostic and surveillance modalities continue to evolve but have already impacted current treatment strategies for NSCLC, which are encompassed in this review. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focuses on Stage IIIA-N2 non-small cell lung cancer (NSCLC), which occurs when lung cancer has spread to lymph nodes in the centre of the chest but not to distant parts of the body. This type of cancer is difficult to treat, and survival rates remain low despite advances in therapy. The research is based on real-world data from Guy's Thoracic Cancer Database and aims to enhance our understanding of patient outcomes and identify important factors that impact survival and disease progression. By examining various treatment strategies, the study aims to offer insights that could help tailor treatment approaches to individual patients. The findings underscore the need for personalised care and the potential benefits of incorporating newer therapeutic options, ultimately leading to better survival outcomes for patients with this challenging form of lung cancer. Background: Stage IIIA-N2 non-small cell lung cancer (NSCLC) poses a significant clinical challenge, with low survival rates despite advances in therapy. The lack of a standardised treatment approach complicates patient management. This study utilises real-world data from Guy's Thoracic Cancer Database to analyse patient outcomes, identify key predictors of overall survival (OS) and disease-free survival (DFS), and address the limitations of randomised controlled trials. Methods: This observational, single-centre, non-randomised study analysed 142 patients diagnosed with clinical and pathological T1/2 N2 NSCLC who received curative treatment from 2015 to 2021. Patients were categorised into three groups: Group A (30 patients) underwent surgery for clinical N2 disease, Group B (54 patients) had unsuspected N2 disease discovered during surgery, and Group C (58 patients) received radical chemoradiation or radiotherapy alone (CRT/RT) for clinical N2 disease. Data on demographics, treatment types, recurrence, and survival rates were analysed. Results: The median OS for the cohort was 31 months, with 2-year and 5-year OS rates of 60% and 30%, respectively. Group A had a median OS of 32 months, Group B 36 months, and Group C 25 months. The median DFS was 18 months overall, with Group A at 16 months, Group B at 22 months, and Group C at 17 months. Significant predictors of OS included ECOG performance status, lymphovascular invasion, and histology. No significant differences in OS were found between treatment groups (p = 0.99). Conclusions: This study highlights the complexity and diversity of Stage IIIA-N2 NSCLC, with no single superior treatment strategy identified. The findings underscore the necessity for personalised treatment approaches and multidisciplinary decision-making. Future research should focus on integrating newer therapeutic modalities and conducting multi-centre trials to refine treatment strategies. Collaboration and ongoing data collection are crucial for improving personalised treatment plans and survival outcomes for Stage IIIA-N2 NSCLC patients. [ABSTRACT FROM AUTHOR]

Phenotypical innovations during evolution are caused by novel mutations, which are usually heterozygous at the beginning. The gene expressions on two alleles of these mutation sites are not necessarily identical, leading to flexible allele-specific regulation in cell systems. We retrieve the transcriptome data of normal and non-small cell lung cancer (NSCLC) tissues from 47 African Americans (AA) and 50 European Americans (EA). We analyze the differentially expressed genes (DEGs) in NSCLC as well as the tumor-specific mutations. Expression and mutation profiles show convergent evolution in AA and EA populations. The tumor-specific mutations are poorly overlapped, but many of them are located in the same genes, mainly oncogenes and tumor suppressor genes. The DEGs in tumors are majorly caused by the mutated alleles rather than normal alleles. The relative expressions of mutated alleles are highly correlated between AA and EA. The differential expression in NSCLC is predominantly mediated by the mutated alleles on heterozygous sites. This molecular mechanism underlying NSCLC oncogenesis is conserved across different human populations, exhibiting convergent evolution. We present this novel angle that differential expression analysis should be performed separately for different alleles. Our ideas should greatly benefit the cancer community. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME) and can induce functional polarization of tumor macrophages. This study aimed to explore the effect of CAFs‐derived exosome LINC01833 on the malignant biological behavior of non‐small cell lung cancer (NSCLC) cells and its mechanism. Tumor tissues (n = 3) and adjacent noncancerous tissues (n = 3) were collected from patients with NSCLC, and fibroblasts (CAF, NF) were isolated from the two tissues. Expression of LINC01833/miR‐335‐5p/VAPA in NSCLC clinical tissues and cell lines was detected by RT‐qPCR. Exosomes of CAFs and NFs were isolated by ultracentrifugation. Cell proliferation, migration, invasion, and M2 macrophage polarization were detected by MTT, transwell, wound‐healing assay, and flow cytometry assay, while western blot was used to verify the expression of M2 macrophage polarization‐related proteins. Tumor volume weight and M2 macrophage polarization were detected by tumor xenografts in nude mice. LINC01833 was highly expressed in NSCLC tumor tissues and cells. Knockdown of LINC01833 exosomes could significantly inhibit proliferation, migration, invasion of NSCLC cells, and M2 macrophage polarization of THP‐1 cells, while simultaneous knockdown of miR‐335‐5p on the above basis could reverse the effect of knockdown of LINC01833. In vivo experiments also indicated that knockdown of LINC01833 exosomes suppressed tumor growth and M2 macrophage polarization. CAF‐derived LINC01833 exosomes can promote the proliferation, migration and invasion of NSCLC cells and M2 macrophage polarization by inhibiting miR‐335‐5p and regulating VAPA activity. [ABSTRACT FROM AUTHOR]

Abstract Fundamental changes in intracellular processes, such as overactive growth signaling pathways, are common in carcinomas and are targets of many cancer therapeutics. GRIP and coiled-coil containing 2 (GCC2) is a trans-Golgi network (TGN) golgin maintaining Golgi apparatus structure and regulating vesicle transport. Here, we found an aberrant overexpression of GCC2 in non-small cell lung cancer (NSCLC) and conducted shRNA-mediated gene knockdown to investigate the role of GCC2 in NSCLC progression. shRNA-mediated GCC2 knockdown suppressed NSCLC cell growth, migration, stemness, and epithelial-mesenchymal transition (EMT) in vitro and tumor growth in vivo. In addition, GCC2 knockdown suppressed cancer cell exosome secretion and the oncogenic capacity of cancer cell-derived exosomes. Mechanistically, GCC2 inhibition decreased epidermal growth factor receptor (EGFR) expression and downstream growth and proliferation signaling. Furthermore, GCC2 inhibition compromised Golgi structural integrity in cancer cells, indicating a functional role of GCC2 in regulating intracellular trafficking and signaling to promote lung cancer progression. Together, these findings suggest GCC2 as a potential therapeutic target for the treatment of NSCLC.

Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Despite advancements in first-line treatments such as immunotherapy and targeted therapies, resistance to these treatments is common, creating a significant unmet need for effective second-line therapies. This review evaluates current and emerging second-line therapeutic options for advanced or metastatic NSCLC, focusing on their efficacy and potential to improve patient outcomes. Anti-angiogenic drugs like ramucirumab combined with chemotherapy, particularly docetaxel, have shown moderate success. Antibody-drug conjugates (ADCs) targeting specific tumor antigens offer a promising avenue for targeted therapy, while chimeric antigen receptor (CAR)-T cell therapy and T-cell receptor therapy leverage the patient’s immune system to combat cancer more effectively. mRNA vaccines, although in early stages, show potential for inducing robust immune responses against cancer-specific antigens. Building on this foundation, recent advancements in molecular testing and the exploration of the tumor microenvironment are opening new therapeutic avenues, further enhancing the potential for personalized second-line treatments in NSCLC. While ADCs and bispecific antibodies are gaining traction, more precise biomarkers are needed to optimize treatment response. Regular monitoring through techniques like liquid biopsies allows real-time tracking of mutations such as EGFR T790M, enabling timely therapeutic adjustments. Additionally, the role of neutrophils and macrophages in the tumor microenvironment is increasingly being recognized as a potential therapeutic avenue, with Smad3 emerging as a key target. Further research into drug sequencing, toxicity management, and biomarker development remains crucial to improving NSCLC treatment outcomes.

Abstract Objective The present study endeavors to furnish an exhaustive review of the research advancements on solid tumors harboring RET rearrangement within the Chinese context, particularly emphasizing the examination of real-world therapeutic strategies and clinical outcomes observed in individuals diagnosed with advanced non-small cell lung cancer (NSCLC). The review delves into a critical assessment of the therapeutic efficacy of targeted RET inhibitors, while also scrutinizing the diverse array of treatment modalities employed in the Chinese patient population. Methods The study conducted a comprehensive review of the advancements made by Chinese scholars in the realm of RET driver genes. It delved into the analysis of the incidence of RET rearrangements in solid tumors, alongside an examination of the varied treatment paradigms and their current status within China. Utilizing the RECIST 1.1 criteria, the study evaluated the therapeutic efficacy achieved in RET-positive NSCLC patients undergoing diverse treatment modalities. Furthermore, treatment-related adverse events (TRAEs) were meticulously graded following the Common Terminology Criteria for Adverse Events (CTCAE). Results A retrospective, multi-center, real-world analysis was conducted, encompassing 64 patients diagnosed with pathologically confirmed RET rearrangement advanced non-small cell lung cancer (NSCLC) between December 2015 and November 2023. Notably, KIF5B-RET emerged as the most prevalent RET fusion partner, accounting for 59.4% of cases. Therapeutic interventions among these patients included specific targeted inhibitors such as Pralsetinib (48.4%), chemotherapy (34.3%), multi-target inhibitors (15.6%), and one case (1.6%) involving immunotherapy combined with anti-angiogenic therapy. In terms of progression-free survival (PFS), Pralsetinib monotherapy demonstrated a median PFS of 16.03 months, outperforming chemotherapy (2.87 months; p

Abstract Purpose Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with immune-related adverse events (irAEs). This study analyzes the relationship between irAEs and treatment effectiveness in advanced non-small cell lung cancer (NSCLC) patients. Methods We conducted a retrospective study of NSCLC patients treated with ICIs from March 2019 to October 2022 at Zhongshan Hospital (Xiamen). Patients were divided into irAE and non-irAE groups, and treatment outcomes were compared. Results A total of 154 patients were included, with 36.4% in the irAE group and 63.6% in the non-irAE group. Most irAEs were Grade 1–2 (86.4%), with 13.6% being Grade 3 or higher. The irAE group had higher disease control rates (DCR: 94.6% vs. 76.5%, P = 0.004) and objective response rates (ORR: 42.9% vs. 26.5%, P = 0.037). Median progression-free survival (PFS) was longer in the irAE group (18 vs. 9 months, HR: 0.53, P = 0.001), as was overall survival (OS: 39.5 vs. 16 months, HR: 0.46, P = 0.001). Landmark analysis at 6 and 12 weeks confirmed that irAEs were associated with improved outcomes. Moreover, patients who experienced two or more adverse events during treatment had significantly longer OS compared to those who had only one or no adverse events (41.6 months vs. 34.0 vs. 23.6, P = 0.003). Conclusion Patients with irAEs demonstrated better outcomes, including ORR, DCR, PFS, and OS. Further studies on biomarkers and irAE incidence are warranted to improve lung cancer management.

Abstract The immunosuppressive tumor microenvironment (TME) significantly inhibits the effective anti-tumor immune response, greatly affecting the efficacy of immunotherapy. Most tumor-associated macrophages (TAMs) belong to the M2 phenotype, which contributes significantly to the immunosuppressive effects in non-small cell lung cancer (NSCLC) TME. The interaction between signal regulatory protein α (SIRPα) expressed on macrophages and CD47, a transmembrane protein overexpressed on cancer cells, activates the "eat-me-not" signaling pathway, inhibiting phagocytosis. In this study, a folic acid (FA)-modified ultrasound responsive gene/drugs delivery system, named FA@ PFP @ Fe3O4 @LNB-SIRPα siRNA (FA-PFNB-SIRPα siRNA), was developed using 1,2-dioleoacyl-3-trimethylammonium-propane (DOTAP), FA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol)2000] (DSPE-PEG2000-FA), cholesterol, and perfluoropentane (PFP), for the delivery of siRNA encoding SIRPα mRNA and immune adjuvant Fe3O4 nanoparticles. Under ultrasound conditions, the nanobubbles effectively transfected macrophages, inhibiting SIRPα mRNA and protein expression, promoting the phagocytosis of TAMs, and synergistically reversing M2 polarization. This system promotes the infiltration of T cells, enhances the proliferation and activation of cytotoxic T cells, and inhibits the infiltration of immunosuppressive cells in tumor tissues. Administration of FA-PFNB-SIRPα siRNA combined with ultrasound significantly inhibits NSCLC progression. The study highlights the potential of ultrasound nanotechnology-enabled delivery of SIRPα siRNA and Fe3O4 as an effective strategy for macrophage-based immunotherapy to reshape the immunosuppressive TME for cancer therapy. Graphical Abstract

Abstract Background Patients with programmed cell death‐ligand 1 (PD‐L1) ≥50% metastatic non‐small cell lung cancer (NSCLC) treated with first‐line immunotherapy showed heterogeneous tumor responses. In this study, we investigated the clinical and immune‐inflammatory markers distinguishing patients with metastatic NSCLC achieving high depth of tumor response (HDPR) from those with non‐high depth of response (NHDPR). The impact of clinical features on the prognosis of patients with PD‐L1 ≥50% were further clarified. Methods The clinical characteristics and immune‐inflammatory markers of 17 patients with PD‐L1 ≥50% metastatic NSCLC at Beijing Tiantan Hospital between July 2020 and December 2023 were retrospectively analyzed. Results Among the 17 patients, seven (41.2%) patients achieved HDPR (range: −50%, −72%) and 10 (58.8%) patients achieved NHDPR (range: −13%, −45%). Below normal CD4 + T lymphocytes/CD8 + T lymphocytes (CD4/CD8) ratio (p = 0.01) and oncogenes and/or tumor suppressor gene mutations (TP53/KRAS/EGFR) (p = 0.001) were found enriched for NHDPR compared with HDPR. With a median follow‐up of 26.0 months (range: 17.2–34.8 months), the median progression‐free survival (PFS) following first‐line immunotherapy and overall survival (OS) were 9.0 months (95% CI: 5.0–13.0) and not reached (NR), respectively. The neutrophil‐to‐lymphocyte ratio (NLR) was identified as an independent prognostic factor on first‐line PFS. Patients with an NLR ≥4 exhibited a shorter median PFS (7.0 months vs. NR; p = 0.033; 95% CI: 1.2–80.2) than those with an NLR

Abstract The main bottleneck in training a robust tumor segmentation algorithm for non-small cell lung cancer (NSCLC) on H&E is generating sufficient ground truth annotations. Various approaches for generating tumor labels to train a tumor segmentation model was explored. A large dataset of low-cost low-accuracy panCK-based annotations was used to pre-train the model and determine the minimum required size of the expensive but highly accurate pathologist annotations dataset. PanCK pre-training was compared to foundation models and various architectures were explored for model backbone. Proper study design and sample procurement for training a generalizable model that captured variations in NSCLC H&E was studied. H&E imaging was performed on 112 samples (three centers, two scanner types, different staining and imaging protocols). Attention U-Net architecture was trained using the large panCK-based annotations dataset (68 samples, total area 10,326 [mm2]) followed by fine-tuning using a small pathologist annotations dataset (80 samples, total area 246 [mm2]). This approach resulted in mean intersection over union (mIoU) of 82% [77 87]. Using panCK pretraining provided better performance compared to foundation models and allowed for 70% reduction in pathologist annotations with no drop in performance. Study design ensured model generalizability over variations on H&E where performance was consistent across centers, scanners, and subtypes.

Objectives: EGFR tyrosine kinase inhibitor (EGFR-TKI) therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer (NSCLC). However, the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness. Piperlongumine (PPL), an extract from the long pepper fruit (Piper longum), has been shown to possess anticancer properties. The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells. Methods: Anticancer efficacy of PPL, erlotinib (ERL), gefitinib (GEF), and cisplatin (CIS) were investigated in H1299 and H1975 cell lines. Cells were treated with PPL, ERL, GEF, and CIS alone, and in combination, cell viability was determined after 72 h. The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species (ROS) induction, and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry. The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers. Results: PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL, GEF, and CIS. Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines, which were associated with apoptotic induction, but without significant ROS induction. Compared to control, PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry. Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level. Conclusion: PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations. [ABSTRACT FROM AUTHOR]

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease. Article highlights Advances in targeted therapy Covalent inhibitors like sotorasib, adagrasib and divarasib represent significant advancements in targeted therapy aimed specifically at tumors harboring the KRASG12C mutation. Clinical efficacy Clinical trials have shown that KRAS G12C inhibitors improved objective response rates and progression-free survival compared with standard treatments. These trials have obtained promising results in personalized cancer therapy for non-small cell lung cancer (NSCLC) patients harboring the KRASG12C mutation. Importance of co-mutations Co-mutations in genes like KEAP1, SMARCA4 and CDKN2A can significantly impact patient outcomes and response to KRAS G12C inhibitors, with certain co-mutations associated with poor prognosis. Pharmacokinetics & safety Each KRAS G12C inhibitor comes with its own pharmacokinetics profile. Sotorasib and adagrasib are both well tolerated, though gastrointestinal adverse events are common and can be managed with supportive care. Predictive biomarkers Liquid biopsies show promise in detecting KRAS mutations, monitoring treatment response and predicting overall survival, making them a valuable tool in managing NSCLC. Resistance mechanisms Development of resistance to KRAS inhibitors can occur through various genetic alterations and activation of alternative pathways. Combination therapies may help overcome these resistance mechanisms. Future directions Ongoing and future clinical trials aim to further explore the efficacy of KRAS G12C inhibitors, their combinations with immunotherapies, and other novel compounds to improve treatment outcomes in NSCLC. [ABSTRACT FROM AUTHOR]

Context: Coix [Coix lacryma-jobi L. var. mayuen (Roman.) Stapf (Poaceae)], a crop of medicinal and edible significance, contains coixol, which has demonstrated anticancer properties. however, the limited solubility of coixol restricts its potential therapeutic applications. Objective: this study prepared a water-soluble coixol-β-cyclodextrin polymer (CDP) inclusion compound and evaluated its anticancer effect. Materials and methods: the coixol-CDP compound was synthesized through a solvent-stirring and freeze-drying technique. its coixol content was quantified using HPLC, and its stability was tested under various conditions. the anticancer effects of the coixol-CDP compound (4.129, 8.259, 16.518, and 33.035 mg/L for 24, 48, and 72 h) on the proliferation of non-small cell lung cancer (NSCLC) a549 cells were evaluated using an MTT assay; cell morphology was examined by hoechst nuclear staining; apoptosis and cell cycle was detected by flow cytometry; and the expression of apoptosis-related proteins was assessed by Western blots. Results: the water-soluble coixol-CDP inclusion compound was successfully prepared with an inclusion ratio of 86.6% and an inclusion yield rate of 84.1%. the coixol content of the compound was 5.63% and the compound remained stable under various conditions. compared to coixol alone, all 24, 48, and 72 h administrations with the coixol-CDP compound exhibited lower IC50 values (33.93 ± 2.28, 16.80 ± 1.46, and 6.93 ± 0.83 mg/L) in a549 cells; the compound also showed stronger regulatory effects on apoptosis-related proteins. Discussion and conclusions: these findings offer a new perspective for the potential clinical application of Coix in NSCLC therapy and its future research. [ABSTRACT FROM AUTHOR]

Abstract Purpose The most appropriate time of primary tumor radiotherapy in non-small cell lung cancer(NSCLC) with EGFR-TKIs remains unclear. The aim of this study was to investigate the effect of the time factor of primary tumor radiotherapy on long-term overall survival(OS)and provide a theoretical basis for further clinical research. Patients and methods In total, 238 patients with EGFR-TKIs and OS ≥ 12 months were statistically analysed. Patients were grouped: the D group without primary tumor radiotherapy and the R group with it.The R group were divided into three groups according to the interval between the start of EGFR-TKIs and the start of primary tumor radiotherapy: R0 − 30(

Abstract The EphA family belongs to a large group of membrane receptor tyrosine kinases. Emerging evidence indicates that the EphA family participates in tumour occurrence and progression. Nonetheless, the expression patterns and prognostic values of the nine EphAs in non-small cell lung cancer (NSCLC) have rarely been studied before. In the current study, we comprehensively analysed the expression and prognostic role of EphA family members by different means. The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis databases were used to investigate the expression of EphAs in NSCLC. The cBioPortal database was applied to analyse the prognostic values and genetic mutations of EphAs.We discovered that the expression of EphA10 was significantly higher in NSCLC tissues than in adjacent noncancerous tissues, and survival analyses showed that a higher level of EphA10 predicted poor prognosis. Further exploration into the role of EphA10 by ESTIMATE, CIBERSORT, and ssGSEA analysis found that it was also related to immune infiltration and higher expression of targets of ICI targets. In conclusion, this study revealed that among the EphA family members, EphA10 played an oncogenic role and was a promising biomarker for poor prognosis and better immunotherapy response in NSCLC.

Abstract Background Activator protein-1 (AP-1) represents a transcription factor family that has garnered growing attention for its extensive involvement in tumor biology. However, the roles of the AP-1 family in the evolution of lung cancer remain poorly characterized. FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB), a classic AP-1 family member, was previously reported to play bewilderingly two-polarized roles in non-small cell lung cancer (NSCLC) as an enigmatic double-edged sword, for which the reasons and significance warrant further elucidation. Methods and Results Based on the bioinformatics analysis of a large NSCLC cohort from the TCGA database, our current work found the well-known tumor suppressor gene TP53 served as a key code to decipher the two sides of FOSB – its expression indicated a positive prognosis in NSCLC patients harboring wild-type TP53 while a negative one in those harboring mutant TP53. By constructing a panel of syngeneically derived NSCLC cells expressing p53 in different statuses, the radically opposite prognostic effects of FOSB expression in NSCLC population were validated, with the TP53-R248Q mutation site emerging as particularly meaningful. Transcriptome sequencing showed that FOSB overexpression elicited diversifying transcriptomic landscapes across NSCLC cells with varying genetic backgrounds of TP53 and, combined with the validation by RT-qPCR, PREX1 (TP53-Null), IGFBP5 (TP53-WT), AKR1C3, and ALDH3A1 (TP53-R248Q) were respectively identified as p53-dependent transcriptional targets of FOSB. Subsequently, the heterogenous impacts of FOSB on the tumor biology in NSCLC cells via the above selective transcriptional targets were confirmed in vitro and in vivo. Mechanistic investigations revealed that wild-type or mutant p53 might guide FOSB to recognize and bind to distinct promoter sequences via protein-protein interactions to transcriptionally activate specific target genes, thereby creating disparate influences on the progression and prognosis in NSCLC. Conclusions FOSB expression holds promise as a novel prognostic biomarker for NSCLC in combination with a given genetic background of TP53, and the unique interactions between FOSB and p53 may serve as underlying intervention targets for NSCLC.

Abstract Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.

Abstract Background Cisplatin (DDP) chemotherapy is commonly used in therapy for non-small cell lung cancer (NSCLC), but increased drug resistance has become a huge obstacle. Baicalin (BA) contributed to the sensitivity of NSCLC to DDP. Here, we aimed to further probe the pathophysiological mechanisms of BA in NSCLC. Methods A549 and A549/DDP cells and xenograft mice were treated with BA and DDP. Xenograft mice were treated additionally with the NRF2 inducer (Bardoxolone methyl, BM) and KEAP1 knockdown. The levels of ferritinophagy-related proteins and biomarkers were determined. The autophagosomes were observed. M1 macrophage polarization and the contents of related indicators were analyzed. The involvement of KEAP1/NRF2/HO-1 was determined. Results BA inhibited cell development, and the effect of BA and DDP on cell development was additive. The abundance of ferritinophagy-related proteins and the number of autophagosomes were induced by BA. BA also promoted the transition of GSH to GSSH. BA favored M1 macrophage polarization and affected the expression of related proteins. When BA and DDP combined, these molecular phenomena were further exacerbated. BA induced accumulation of KEAP1 and reduction of NRF2 and HO-1. However, BM and KEAP1 knockdown disrupted the synergistic effects of BA and DDP on inhibiting NSCLC growth. BM and KEAP1 knockdown reversed DDP and BA-promoted protein expression activity and M1 macrophage polarization. Conclusion Our findings suggest that BA is involved in ferritinophagy and macrophage immunity through the KEAP1-NRF2/HO-1 axis, thereby improving the DDP sensitivity in NSCLC, which could provide new candidates for treatment strategies.

Abstract The success of chemotherapy regimens in patients with non-small cell lung cancer (NSCLC) could be restricted at least in part by cancer stem cells (CSC) niches within the tumor microenvironment (TME). CSC express CD133, CD44, CD47, and SOX2, among other markers and factors. Analysis of public data revealed that high expression of hyaluronan (HA), the main glycosaminoglycan of TME, correlated positively with CSC phenotype and decreased disease-free interval in NSCLC patients. We aimed to cross-validate these findings on human and murine lung cancer cells and observed that CD133 + CSC differentially expressed higher levels of HA, HAS3, ABCC5, SOX2, and CD47 (p

Abstract Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic.

Abstract Background This study compared the survival outcomes after thermal ablation versus wedge resection in patients with stage I non-small cell lung cancer (NSCLC) ≤ 2 cm. Methods Data from the United States (US) National Cancer Institute Surveillance Epidemiology and End Results (SEER) database from 2004 to 2019 were retrospectively analyzed. Patients with stage I NSCLC and lesions ≤ 2 cm who received thermal ablation or wedge resection were included. Patients who received chemotherapy or radiotherapy were excluded. Propensity-score matching (PSM) was applied to balance the baseline characteristics between patients who underwent the two procedures. Results Univariate and Cox regression analyses were performed to determine the associations between study variables, overall survival (OS), and cancer-specific survival (CSS). After PSM, 328 patients remained for analysis. Multivariable Cox regression analysis revealed, compared to wedge resection, thermal ablation was significantly associated with a greater risk of poor OS (adjusted HR [aHR]: 1.34, 95% CI: 1.09–1.63, p = 0.004) but not CSS (aHR: 1.28, 95% CI: 0.96–1.71, p = 0.094). In stratified analyses, no significant differences were observed with respect to OS and CSS between the two procedures regardless of histology and grade. In patients with tumor size 1 to 2 cm, compared to wedge resection, thermal ablation was significantly associated with a higher risk of poor OS (aHR: 1.35, 95% CI: 1.10–1.66, p = 0.004). In contrast, no significant difference was found on OS and CSS between thermal ablation and wedge resection among those with tumor size

Abstract Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients. As the nonselective nature of these inhibitors, patients have off-target adverse effects. The discovery of highly potent selective RET inhibitors such as pralsetinib and selpercatinib improve the clinic efficiency and more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) become a new challenge for selective RET inhibitor therapies. In this review, we highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.

Abstract Background Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum‐based chemotherapy in patients with stage II–IIIA non‐small cell lung cancer with 1% or more programmed death ligand‐1 (PD‐L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non‐small cell lung cancer. Therefore, our study aimed to compare two PD‐L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. Methods We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD‐L1 expression between SP263 and 22C3 assays. Results The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522–0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639–0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p

Purpose: The most appropriate time of primary tumor radiotherapy in non-small cell lung cancer(NSCLC) with EGFR-TKIs remains unclear. The aim of this study was to investigate the effect of the time factor of primary tumor radiotherapy on long-term overall survival(OS)and provide a theoretical basis for further clinical research. Patients and methods: In total, 238 patients with EGFR-TKIs and OS ≥ 12 months were statistically analysed. Patients were grouped: the D group without primary tumor radiotherapy and the R group with it.The R group were divided into three groups according to the interval between the start of EGFR-TKIs and the start of primary tumor radiotherapy: R0 − 30(<30 days), R30 − PD(≥ 30 days and disease stable), and RPD(radiotherapy after disease progression). The Kaplan-Meier method and log-rank test were used for survival analyses. Exploratory landmark analyses were investigated. Results: The OS rates at 1, 2, 3, 5 years for the R group and D group were 96.8%, 62.9%, 38.3%, 17.1%, and 95.6%, 37.7%, 21.8%, 2.9%, respectively; the corresponding MST was 29 months(95% CI: 24.3–33.7) for the R group and 22 months(95% CI: 20.4–23.6) for the D group (χ2 = 13.480, p<0.001). Multivariate analysis revealed that primary tumor radiotherapy was independent predictors of prolonged OS.Among the four groups, The R30 − PD appeared to have the best OS (D, χ2 = 19.307, p<0.001;R0 − 30, χ2 = 11.687, p = 0.01; RPD, χ2 = 4.086, p = 0.043). Landmark analyses(22 months) showed the R30 − PD group had a significant long-term OS.The incidence of radiation pneumonitis ≥ grade 2 was17.3%(n = 19)and radiation esophagitis ≥ grade 2 was observed in 32 patients(29.1%). Conclusions: Our results showed that primary tumour radiotherapy may prolong long-term OS with acceptable toxicities. Appropriate delay(R30 − PD)of primary tumour radiotherapy may be the best choice.Premature radiotherapy(R0 − 30) and radiotherapy after disease progression (RPD)may not be reasonable for long-term OS. [ABSTRACT FROM AUTHOR]

The EphA family belongs to a large group of membrane receptor tyrosine kinases. Emerging evidence indicates that the EphA family participates in tumour occurrence and progression. Nonetheless, the expression patterns and prognostic values of the nine EphAs in non-small cell lung cancer (NSCLC) have rarely been studied before. In the current study, we comprehensively analysed the expression and prognostic role of EphA family members by different means. The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis databases were used to investigate the expression of EphAs in NSCLC. The cBioPortal database was applied to analyse the prognostic values and genetic mutations of EphAs.We discovered that the expression of EphA10 was significantly higher in NSCLC tissues than in adjacent noncancerous tissues, and survival analyses showed that a higher level of EphA10 predicted poor prognosis. Further exploration into the role of EphA10 by ESTIMATE, CIBERSORT, and ssGSEA analysis found that it was also related to immune infiltration and higher expression of targets of ICI targets. In conclusion, this study revealed that among the EphA family members, EphA10 played an oncogenic role and was a promising biomarker for poor prognosis and better immunotherapy response in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Tertiary lymphoid structures (TLS), ordered structure of tumorinfiltrating immune cells in tumor immune microenvironment (TIME), play an important role in the development and anti-tumor immunity of various cancers, including liver, colon, and gastric cancers. Previous studies have demonstrated that the presence of TLS in intra-tumoral (IT), invasive margin (IM), and peritumoral (PT) regions of the tumors at various maturity statuses. However, the density of TLS in different regions of non-small cell lung cancer (NSCLC) has not been extensively studied. Methods: TLS and tumor-infiltrating immune cells were assessed using immunohistochemistry (IHC) staining in 82 NSCLC patients. Tumor samples were divided into three subregions as IT, IM and PT regions, and TLS were identified as early/primary TLS (E-TLS) or secondary/follicular TLS (F-TLS). The distribution of TLS in different maturity statuses, along with their correlation with clinicopathological characteristics and prognostic value, was assessed. Nomograms were used to predict the probability of 1-, 3-, and 5-year overall survival (OS) in patients with NSCLC. Results: The density of TLS and proportion of F-TLS in the IT region (90.2%, 0.45/mm², and 61.0%, respectively) were significantly higher than those in the IM region (72.0%, 0.18/mm2, and 39.0%, respectively) and PT region (67.1%, 0.16/mm², and 40.2%, respectively). A lower density of TLS, especially E-TLS in the IM region, was correlated with better prognosis in NSCLC patients. CD20+ B cells, CD3+ T cells, CD8+ cytotoxic T cells, and CD68+ macrophages were significantly overexpressed in the IM region. CD20+ B cells and CD3+ T cells in the IM region were significantly correlated with the density of E-TLS, while no statistically significant correlation was found with F-TLS. The E-TLS density in the IM region and TNM stage were independent prognostic factors for NSCLC patients. The nomogram showed good prognostic ability. Conclusions: A higher density of E-TLS in the IM region was associated with a worse prognosis in NSCLC patients, potentially due to the inhibition of TLS maturation caused by the increased density of suppressive immune cells at the tumor invasion front. [ABSTRACT FROM AUTHOR]

Background: Activator protein-1 (AP-1) represents a transcription factor family that has garnered growing attention for its extensive involvement in tumor biology. However, the roles of the AP-1 family in the evolution of lung cancer remain poorly characterized. FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB), a classic AP-1 family member, was previously reported to play bewilderingly two-polarized roles in non-small cell lung cancer (NSCLC) as an enigmatic double-edged sword, for which the reasons and significance warrant further elucidation. Methods and Results: Based on the bioinformatics analysis of a large NSCLC cohort from the TCGA database, our current work found the well-known tumor suppressor gene TP53 served as a key code to decipher the two sides of FOSB – its expression indicated a positive prognosis in NSCLC patients harboring wild-type TP53 while a negative one in those harboring mutant TP53. By constructing a panel of syngeneically derived NSCLC cells expressing p53 in different statuses, the radically opposite prognostic effects of FOSB expression in NSCLC population were validated, with the TP53-R248Q mutation site emerging as particularly meaningful. Transcriptome sequencing showed that FOSB overexpression elicited diversifying transcriptomic landscapes across NSCLC cells with varying genetic backgrounds of TP53 and, combined with the validation by RT-qPCR, PREX1 (TP53-Null), IGFBP5 (TP53-WT), AKR1C3, and ALDH3A1 (TP53-R248Q) were respectively identified as p53-dependent transcriptional targets of FOSB. Subsequently, the heterogenous impacts of FOSB on the tumor biology in NSCLC cells via the above selective transcriptional targets were confirmed in vitro and in vivo. Mechanistic investigations revealed that wild-type or mutant p53 might guide FOSB to recognize and bind to distinct promoter sequences via protein-protein interactions to transcriptionally activate specific target genes, thereby creating disparate influences on the progression and prognosis in NSCLC. Conclusions: FOSB expression holds promise as a novel prognostic biomarker for NSCLC in combination with a given genetic background of TP53, and the unique interactions between FOSB and p53 may serve as underlying intervention targets for NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: This retrospective observational study recruited 380 patients, 115 with lung cancer and 265 in the control group. Both the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) were significantly higher in cancer patients than in the control group. The correlation of PLR with the probability of lung cancer differs between men and women. CRP values did not differ according to histological types of lung cancer (p = 0.242) and were not associated with the presence of mutations in EGFR (p = 0.679). CRP values were significantly lower in NSCLC patients with PD-L1 mutations than in those without PD-L1 mutations (22.7 [IQR: 10.4;40.3] vs. 76.7 [IQR: 32.6;140] mg/L, p = 0). Background and objective: Analysis of inflammatory biomarkers, along with the neutrophil/lymphocyte ratio (NLR) or platelet/lymphocyte ratio (PLR), supports the connection between inflammation and carcinogenesis. Methods: We conducted a retrospective observational study at the Clinical County Hospital Mureș involving patients with lung cancer. The parameters analyzed included histopathological type (NSCLC: squamous cell carcinoma or adenocarcinoma; SCLC), molecular mutations (EGFR, ALK, PD-L1), parameters from the complete blood count, inflammatory parameters, and associated comorbidities. Results: A total of 380 patients were included: 115 patients in the cancer group and 265 patients in the control group. Among patients in the lung cancer group, 88 were diagnosed with NSCLC (44 adenocarcinomas, 44 squamous cell carcinomas) and 27 with SCLC. Both NLR and PLR were significantly higher in cancer patients than in the control group (5.30 versus 2.60, p < 0.001; 217 versus 136, p < 0.001, respectively). NLR and PLR differ between men and women (p = 0.005 and p = 0.056, respectively). C-reactive protein was not correlated with either NLR (p-value: 0.0669) or PLR (p-value: 0.6733) in lung cancer patients. Conclusions: The NLR and PLR values may serve as new predictive biomarkers for the diagnosis of disease in patients with lung cancer, especially those with NSCLC. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to explore the abilities of atezolizumab plus chemotherapy in preventing brain metastases (BMs) among metastatic non–small cell lung cancer (NSCLC) without initial BMs, as well as the risk factors of BMs. Methods: Individual patient data from three trials involving first‐line atezolizumab for metastatic NSCLC (IMpower130, IMpower131, and IMpower150) were pooled. Among patients without baseline BMs and without epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutations, those receiving atezolizumab + chemotherapy ± bevacizumab were classified as the atezolizumab plus chemotherapy group and those receiving placebo + chemotherapy ± bevacizumab were classified as the chemotherapy group. The cumulative incidences of BM (CI‐BMs) between the two groups were compared. Other factors associated with the CI‐BM were analyzed by Cox regression analyses. Results: With a median follow‐up of 17.6 months (range, 0.03–33.64 months), 74 (3.1%) of the 2380 enrolled patients developed BMs, including 50 (3.1%) and 24 (3.0%) in the atezolizumab plus chemotherapy group (n = 1589) and the chemotherapy group (n = 791), respectively. The CI‐BMs at 6, 12, and 24 months were 1.7%, 2.8%, and 3.3%, respectively. After taking competing risk events into account, there was no significant difference in the CI‐BMs between the two groups (p =.888). Nevertheless, the use of bevacizumab and the histology of nonsquamous NSCLC were found to be independently associated with the risk of BMs. Conclusions: In patients with metastatic EGFR/ALK wild‐type NSCLC without baseline BMs, adding atezolizumab in the first‐line treatment might not reduce the CI‐BM. However, the administration of bevacizumab may reduce the risk of BMs. In patients with metastatic EGFR/ALK wild‐type non–small cell lung cancer without baseline brain metastases (BMs), adding atezolizumab in the first‐line treatment could not reduce the cumulative incidence of BM. However, administration of bevacizumab may reduce the risk of BMs. [ABSTRACT FROM AUTHOR]

Background: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK‐positive cancer and in murine models. Methods: In this study, three groups, including an experimental group of male patients with ALK‐positive, advanced non–small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK‐positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK‐negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. Results: Ninety‐five patients were consecutively enrolled onto the study. Among sixty‐eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p =.0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p =.0002) were significantly lower in ALK‐positive ANSCLC patients in cohort A compared with ALK‐negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p =.0059) and LH levels (4.72 vs. 7.49 mUI/ml; p =.0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK‐positive male patients (74.3 vs. 44.24 pg/ml; p =.0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. Conclusions: Symptoms of androgen deficiency should be tracked in male patients with ALK‐positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate. Male patients with ALK‐positive advanced non–small cell lung cancer treated with first‐line alectinib had lower median total testosterone (p =.0001) and free testosterone (p =.0002) levels compared with male patients who had ALK‐negative disease and were receiving other anticancer treatments. Symptoms of hypogonadism were more frequent in ALK‐positive patients compared with ALK‐negative patients (62% vs 26.8% rates of positive score at ADAM questionnaire, respectively), suggesting the need for hormone assessment and referral to an andrologist, as appropriate. [ABSTRACT FROM AUTHOR]

Purpose: The hyperactivation of epidermal growth factor receptor (EGFR) plays a crucial role in non-small cell lung cancer (NSCLC). Hedgehog (Hh) signaling has been implicated in the tumorigenesis and progression of various cancers, however, its function in NSCLC cells remains controversial. Herein, we present a novel finding that challenges the current understanding of Hh signaling in tumor growth. Methods: Expression of Hh ligands and receptor were assessed using TCGA datasets, immunoblotting and immunohistochemical. Biological function of Hh ligands and receptor in NSCLC were tested using colony formation, cell count kit-8 (CCK-8) and xenograft assays. Biochemical effect of Hh ligands and receptor on regulating EGFR stability and activity were checked via immunoblotting. Results: Expression of Hh ligands and receptor was suppressed in NSCLC tissues, and the lower expression levels of these genes were associated with poor prognosis. Ptch1 binds to EGFR and facilitates its poly-ubiquitylation and degradation independent of downstream transcriptional signaling. Moreover, Hh ligands cooperate with Ptch1 to regulate the protein stability and activity of EGFR. This unique mechanism leads to a suppressive effect on NSCLC tumor growth. Conclusion: Non-canonical Hh signaling pathway, involving cooperation between Hh ligands and their receptor Ptch1, facilitates the degradation of EGFR and attenuates its activity in NSCLC. These findings provide novel insights into the regulation of EGFR protein stability and activity, offer new diagnostic indicators for molecular typing of NSCLC and identify potential targets for targeted therapy of this challenging disease. [ABSTRACT FROM AUTHOR]

Background: Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitor (TKI) and an available therapy for patients with non‐small cell lung cancer (NSCLC) that have an EGFR or T790M mutation. It has become the preferred TKI in this patient group as it is superior to first‐generation TKIs; however, osimertinib may be discontinued due to various toxicities or reactions. Aim: We report two instances of successful osimertinib desensitisation in a 70‐year‐old woman requiring treatment for NSCLC following two hypersensitivity reactions presenting as angioedema and urticaria. Clinical details: Osimertinib desensitisation started at 5 mg/day and was gradually increased to 80 mg/day over a period of 30 days. Outcomes: The patient continued osimertinib 80 mg daily for over a year until treatment was withheld for 4 weeks due to thrombocytopenia and diverticulitis. She restarted osimertinib, completing a second desensitisation to a reduced dose of 40 mg daily without serious adverse effect. The patient continues reduced‐dose osimertinib with stable disease. Conclusion: This case report proposes an osimertinib desensitisation strategy useful for select patients experiencing osimertinib‐induced hypersensitivity reactions. It also demonstrates that if there is prolonged disruption to treatment, a second desensitisation can be completed successfully in the same patient so effective treatment in NSCLC may be continued. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). Materials and methods: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). Results: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0–53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40–0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30–0.79, p < 0.0001). Conclusion: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Among NSCLCs, squamous cell carcinoma (SqCC) is strongly associated with smoking. However, lung cancer in never smokers (LCINS) represents approximately 25% of lung cancer cases globally and shows increasing incidence, particularly in East Asia. LCINS-SqCC is less well-characterized, especially regarding its genomic alterations and their impact on clinical outcomes. We conducted a retrospective analysis over a 20-year period (July 2003–July 2023) at two major tertiary centers in the UK. The cohort included 59 patients with LCINS-SqCC who underwent radical surgical resection. Data collected included demographic information, comorbidities, histopathological details, and outcome metrics such as disease-free and overall survival. Molecular sequencing of tumor specimens was performed to identify genomic aberrations. The cohort had a median age of 71 years (IQR 62–77) and a median BMI of 25.4 (IQR 22.8–27.8), with a slight male predominance (53%). The majority of patients (93%) had a preoperative MRC of 1–2. Recurrent disease was observed in 23 patients (39%), and 32 patients (54%) had died at a median follow-up of 3 years. Median disease-free survival was 545 days (IQR 132–1496), and overall survival was 888 days (IQR 443–2071). Preoperative creatinine levels were higher in patients who experienced recurrence (p = 0.037). Molecular analysis identified biallelic SMARCB1 loss in two younger patients, associated with rapid disease progression despite R0 resection. These patients' tumors were PDL1-negative, TTF-1-negative, and positive for cytokeratin, CD56, and p40. SMARCB1-deficient SqCC in never smokers represents a highly aggressive variant with poor disease-free survival, highlighting the importance of integrating advanced molecular diagnostics in clinical practice. This study underscores the necessity for personalized treatment strategies, including targeted therapies such as EZH2 inhibitors and immune checkpoint blockade, to address the unique molecular pathways in SMARCB1-deficient cancers. Further clinical trials are essential to optimize therapeutic approaches for this challenging subgroup of lung cancer. [ABSTRACT FROM AUTHOR]