Liver metastasis is prevalent among patients with neuroendocrine prostate cancer (NEPC) and other types of neuroendocrine (NE) cancers, featuring with an aggressive clinical course and a dismal prognosis. However, the cellular and molecular mechanisms underlying liver-specific metastatic tropism in NE cancers remain poorly understood. Intriguingly, it is found that NEPC liver metastatic foci are frequently associated with thrombi. NEPC cells express an aberrantly elevated level of glycosyltransferase Galnt9. Notably, the Galnt9-mediated O-GalNAc glycosylation on the cell membrane of NE cancer cells, particularly on the adhesion molecule Annexin A2, activates the mannose-binding lectin (MBL) complement signaling in the liver. This cascade stimulates platelet activation and thrombus formation, ultimately facilitating hepatic metastasis of NEPC. Inhibition of O-GalNAc glycosylation or knockdown of Galnt9 demonstrates efficacy in restraining the liver metastasis of NEPC, small cell lung cancer (SCLC), and colorectal neuroendocrine cancer. These findings identify Galnt9-mediated O-GalNAc glycosylation as a targetable mechanism driving liver metastasis through activation of MBL complement and coagulation cascades across a broad spectrum of NE cancers.

The use of prophylactic cranial irradiation (PCI) in early stage small cell lung cancer (SCLC) patients post-surgery remains controversial. This meta-analysis aimed to evaluate the efficacy of PCI in resected early stage SCLC patients.

Relevant literature was reviewed through PubMed, Cochrane, and Embase databases. The pooled hazard ratios (HRs) for overall survival (OS) were analyzed for the overall population, as well as for pathologically node-negative (pN0) and pathologically node-positive (pN+) patients. We also assessed the pooled HRs for brain metastasis-free survival (BMFS) in all patients. Sensitivity analyses were conducted to validate these results.

A total of 13 retrospective studies were included, encompassing 3,530 postoperative SCLC patients, of whom 880 received PCI treatment. In the overall patient population, PCI significantly improved OS compared to non-PCI group (HR: 0.66, 95% CI 0.58-0.74, p < 0.001). For pN0 patients, there was no significant OS benefit from PCI (HR: 0.85, 95% CI 0.65-1.10, p = 0.22). In contrast, pN + patients showed a significant OS improvement with PCI (HR: 0.52, 95% CI 0.41-0.66, p < 0.001). Furthermore, PCI significantly improved BMFS in all patients (HR: 0.42, 95% CI 0.29-0.60, p < 0.001). Sensitivity analyses confirmed the stability of these results.

PCI was associated with a significant improvement in OS and BMFS in resected early stage SCLC patients. The benefits of PCI were particularly pronounced in pN + patients, whereas pN0 patients did not experience a significant OS benefit. These findings supported the selective use of PCI based on nodal status to optimize treatment outcomes in postoperative SCLC patients.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression, high metastatic potential, and limited therapeutic options. Lysine-specific demethylase 1 (LSD1) has been identified as a promising epigenetic target in SCLC. RG6016 (ORY-1001) is a selective LSD1 inhibitor currently under clinical investigation for its antitumor activity. In this study, publicly available RNA-Seq datasets from SCLC patient-derived xenograft (PDX) models treated with RG6016 were reanalyzed using bioinformatic approaches. Differential gene expression analysis was conducted to identify genes responsive to LSD1 inhibition. Candidate genes showing significant downregulation were further evaluated by molecular docking to assess their potential interaction with RG6016. The analysis identified a set of differentially expressed genes following RG6016 treatment, including notable downregulation of MYC, UCHL1, and TSPAN8. In silico molecular docking revealed favorable docking poses between RG6016 and the proteins encoded by these genes, suggesting potential direct or indirect targeting. These findings support a broader mechanism of action for RG6016 beyond its known interaction with LSD1. This study demonstrates that RG6016 may exert its antitumor effects through the modulation of additional molecular targets such as MYC, UCHL1, and TSPAN8 in SCLC. The combined bioinformatic and molecular docking analyses provide new insights into the potential multi-target profile of RG6016 and indicate the need for further experimental validation.

Acute lung injury, COVID-19, lung cancer, and asthma are a few of the respiratory conditions that are the main causes of morbidity and mortality worldwide. The increasing incidence and mortality rates have attracted significant attention to the prevention and treatment of these conditions. In recent years, there has been a renewed interest in utilizing naturally derived compounds as therapeutic agents for respiratory diseases. Luteolin (Lut), a flavonoid compound, possesses an extensive range of pharmacological characteristics, encompassing anti-inflammatory, antioxidative, antineoplastic, and antimicrobial activities. However, a comprehensive summary of Lut's therapeutic effects and mechanisms in respiratory diseases remains lacking. This review examines the physicochemical properties, toxicity, and avenues of Lut's action in respiratory ailments. Lut exerts therapeutic effects through pathways such as nuclear factor kappa-B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and pyroptosis, modulating key processes such as the suppression of inflammatory mediators, attenuation of oxidative assault, and induction of apoptosis in lung cancer cells. This review strives to provide critical realizations into respiratory disease therapeutics and contribute to the foundation for drug development.

Small cell lung cancer (SCLC) is initially highly sensitive to chemotherapy, which often leads to significant tumor reduction. However, the majority of patients eventually develop resistance, and the disease is further complicated by its "cold" tumor microenvironment, characterized by low tumor immunogenicity and limited CD8+ T cell infiltration. These factors contribute to the poor response to immunotherapy in many cases of extensive-stage SCLC (ES-SCLC). High-dose chemotherapy has shown potential in enhancing tumor cytoreduction, but its use is often limited by severe hematologic toxicity. Combining chemotherapy with immune checkpoint inhibitors (ICIs) can create a synergistic effect by promoting immunogenic cell death and enhancing immune activation. Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a means to support hematopoietic recovery, mitigate chemotherapy-induced myelosuppression, and contribute to immune reconstitution. In this context, the integration of auto-HSCT with dose-intensified chemotherapy and ICIs aims to both protect the bone marrow and enhance antitumor immune responses, potentially overcoming resistance to immunotherapy in ES-SCLC.

A phase I, single-center, single-arm trial was designed to evaluate the safety and efficacy of auto-HSCT-supported dose-intensified chemotherapy combined with adebrelimab in treatment-naive ES-SCLC patients. Participants will receive induction chemotherapy followed by stem cell mobilization, apheresis, and cryopreservation. After successful mobilization, consolidation chemotherapy with stem cell reinfusion and granulocyte colony-stimulating factor (G-CSF) support will be performed. Maintenance therapy with adebrelimab continues until disease progression or unacceptable toxicity. Safety and efficacy data, including adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), will be analyzed.

The study aims to enhance treatment outcomes by overcoming resistance to immuno-chemotherapy and promoting immune reconstitution. The trial is ongoing at the First Affiliated Hospital of Guangzhou Medical University.

ClinicalTrials.gov Identifier: NCT06597513.

Spinal metastases are a common and severe complication of lung cancer, particularly in small cell lung cancer (SCLC), and are associated with poor survival. Despite advancements in treatment, optimal management strategies remain unclear, with significant differences between non-small cell lung cancer (NSCLC) and SCLC. This study evaluates treatment patterns, survival outcomes, and prognostic factors in lung cancer patients with spinal metastases, integrating deep learning survival prediction models.

This retrospective cohort study analyzed the National Cancer Database (NCDB) to identify NSCLC and SCLC patients diagnosed with spinal metastases. Demographics and treatment modalities were analyzed and adjusted for age, sex, and comorbidities. Kaplan-Meier analysis and Cox proportional hazards models assessed overall survival (OS). Five advanced survival prediction models estimated 1-year and 10-year mortality, with feature importance determined via permutation analysis.

Among 428,919 lung cancer patients, 5.1% developed spinal metastases, with a significantly higher incidence in SCLC (13.6%) than in NSCLC (5.1%). SCLC patients had poorer OS. Radiation therapy alone was the predominant treatment, and stereotactic body radiation therapy (SBRT) predicted better short- and long-term survival compared to other radiation techniques. High-dose radiation (71-150 Gy BED) improved OS in NSCLC, while reirradiation benefited NSCLC but had a limited impact in SCLC. SurvTrace demonstrated the highest predictive accuracy for 1-year and 10-year mortality, identifying age, radiation dose, reirradiation, and race as key prognostic factors.

The management of spinal metastases requires a histology-specific approach. Radiation remains the primary treatment, with SBRT predicting better short- and long-term survival. High-dose radiation and reirradiation should be considered for NSCLC, while the benefits are limited in SCLC. These findings support histology-specific treatment strategies to improve survival of patients with metastatic lung cancer to the spine.

DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR, respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.

Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive subtype of lung cancer with limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) combined with chemotherapy have demonstrated significant efficacy in several clinical trials. This study aims to evaluate the efficacy of first-line chemotherapy combined with immunotherapy in patients with ES-SCLC and identify prognostic factors based on real-world data. This retrospective study analyzed the clinical data of 349 patients with ES-SCLC treated at Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine from January 2018 to August 2023. The patients were divided into a combination group (chemotherapy plus immunotherapy, n = 173) and a chemotherapy group (chemotherapy alone, n = 176) based on their treatment regimens. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was treatment-related adverse events. Kaplan-Meier survival analysis was performed, and Cox regression models were used to analyze the factors influencing OS and PFS. The median OS in the combination group was 14.9 months, significantly longer than 11.9 months in the chemotherapy group (P < 0.001). After applying Propensity Score Matching (PSM) to minimize selection bias, the survival advantage remained statistically significant. The 1-, 2-, and 3-year OS rates in the combination group were 62.4%, 42.8%, and 19.5%, respectively, compared to 50.2%, 20.8%, and 9.6% in the chemotherapy group. The median PFS in the combination group was 5.4 months, also significantly longer than the 3.8 months observed in the chemotherapy group (P < 0.001). Multivariate analysis identified chemotherapy alone, ECOG performance status, and number of metastatic sites as independent risk factors for poorer OS and PFS (P < 0.001). A separate analysis was conducted to evaluate the association between tumor response (CR/PR/SD/PD) and survival outcomes, which showed that patients with CR/PR had significantly better OS and PFS compared to those with SD/PD (P < 0.001). These findings reinforce the clinical importance of achieving tumor response. There were no significant differences in the incidence of adverse events between the two groups, with most adverse events being grade 1-2, and no grade 5 adverse events were reported. This study demonstrates that chemotherapy combined with immunotherapy significantly prolongs OS and PFS in patients with ES-SCLC without substantially increasing treatment-related adverse events. This combination therapy shows promising clinical value for improving long-term prognosis in ES-SCLC patients. Future studies should explore potential biomarkers to optimize individualized treatment strategies.

Assessing the role of radiotherapy on the long-term outcomes in patients with small cell lung cancer (SCLC).

A total of 6819 patients with SCLC diagnosed histologically from 2011 to 2020 were collected from the Surveillance, Epidemiology, and End Results database. The importance of radiation on overall survival (OS) and cancer-specific survival (CSS) was assessed by a random forest algorithm. The association of radiation with OS and CSS was evaluated by COX regression and subgroup analysis. The survival difference between radiation and non-radiation groups was analyzed by the Kaplan-Meier (KM) method. The conditional survival (CS) and competing risk analyses were performed to evaluate the influence of radiation on CSS.

Among all variables, the importance of tumor metastasis to OS and CSS ranked first. COX regression analysis indicated independent association (all P < 0.05) of radiation with OS and CSS in patients with metastasis in the liver, lymphatic, and other sites (not found in bone and brain). KM showed better OS and CSS in the radiation group (vs. non-radiation) in the 3 types of metastases (all P < 0.05). Among 5 metastasis patterns, liver metastasis (LM) was identified as the key pattern to OS and CSS. We found that LM patients with chemotherapy, female, and stage IV can significantly benefit from radiotherapy. However, radiation cannot decrease the incidence of cancer-specific death in male LM patients.

This study determined the importance of radiotherapy on the long-term outcomes of patients. In particular, male LM patients may not benefit from radiotherapy.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid proliferation and high metastatic potential. It is characterized by universal inactivation of and RB1, overexpression of the MYC family and dysregulation of multiple oncogenic signaling pathways. Among different patients, SCLCs are similar at the genetic level but exhibit significant heterogeneity at the molecular level. The classification of SCLC has evolved from a simple neuroendocrine (NE)/non-neuroendocrine (non-NE) classification system to a transcription factor-based molecular subtype system; lineage plasticity adds further complexity and poses challenges for therapeutic development. While SCLC is initially sensitive to platinum-based chemotherapy, resistance develops rapidly, leading to a dismal prognosis. Various antibodies, including PD-1/PD-L1 inhibitors and antibody‒drug conjugates, have been introduced into clinical practice or are being evaluated in clinical trials. However, their therapeutic benefits for SCLC patients remain limited. This review summarizes SCLC carcinogenic mechanisms, tumor heterogeneity, and the immune microenvironment of SCLC, with a focus on recent advances in metastasis and resistance mechanisms. Additionally, the corresponding clinical progress in tackling these challenges is discussed.

Metastasis is a major cause of death in lung cancer. The aim of this study is to analyze the role and mechanism of PI3K catalytic subunit gamma (PIK3CG, also known as p110γ) in lung cancer cell migration and metastasis. Knockdown (KD) and overexpression (OE) of PIK3CG expression in lung cancer cell lines A549 and H1299 in vitro cultured was achieved. Two PIK3CG-specific inhibitors, Eganelisib and CAY10505, were used to treat A549 and H1299 cells. An experimental lung metastasis mouse model was constructed using tail vein injection of LLC cells. Finally, a co-culture system was established using Transwell chambers. Compared with the NC group, the number of cells that completed migration and the expression levels of matrix metalloproteinases (MMPs) were significantly reduced in the KD group and Eganelisib and CAY10505 treatment groups, while the number of cells that migrated successfully and the expression levels of MMPs were significantly increased in the OE group. Lung tissues of mice injected with PIK3CG-stabilized overexpressed LLC cells showed more pronounced lung cancer growth, lung metastatic nodules, neutrophil infiltration and MMPs expression. Co-culture with neutrophils, soluble extracts of neutrophils and cathepsin G all promoted the migration of lung cancer cells. PIK3CG overexpression in tumor cells significantly promoted the migration and metastasis of lung cancer cell.

Small-cell lung cancer (SCLC) is an aggressive tumor characterized by the frequent development of distant metastases. This study aimed to explore the mechanism of SCLC metastasis using an originally developed orthotopic transplantation model with DMS273 cells. An analysis of G3H cells, a highly metastatic subline of DMS273 cells, revealed that claudin-11 promotes the invasive and metastatic ability of the cells. Further analysis revealed that membrane type 1-matrix metalloproteinase (MT1-MMP), which degrades a wide range of extracellular matrix components, was coprecipitated with claudin-11. Gelatin zymography revealed that claudin-11 enhanced MT1-MMP activity, and MT1-MMP silencing suppressed the invasive and metastatic ability of G3H cells. Moreover, in MT1-MMP silencing DMS273 cells, the enhancement of invasion and metastatic potential induced by CLDN11 overexpression was abolished. These results demonstrate that claudin-11 enhances the invasive capacity of the cells by activating MT1-MMP, which promotes metastatic formation in the orthotopic transplantation model. Additionally, claudin-11 expression was detected in SCLC tumor samples, and higher expression of CLDN11 correlated with poor prognosis in patients with SCLC. These findings suggest that the claudin-11/MT1-MMP axis plays an important role in SCLC pathogenesis.

Serine/arginine-rich splicing factors (SRSFs) are a family of 12 RNA-binding proteins crucial for the precursor messenger RNA (pre-mRNA) splicing. SRSFs are involved in RNA metabolism events such as transcription, translation, and nonsense decay during the shuttle between the nucleus and cytoplasm, which are important components of genome diversity and cell viability. SRs recognize splicing elements on pre-mRNA and recruit the spliceosome to regulate splicing. In tumors, aberrant expression of SRSFs leads to aberrant splicing of RNA, affecting the proliferation, migration, and anti-apoptotic ability of tumor cells, highlighting the therapeutic potential of targeted SRSFs for the treatment of diseases. The body's immune system is closely related to the occurrence and development of tumor, and SRSFs can affect the function of immune cells in the tumor microenvironment by regulating the alternative splicing of tumor immune-related genes. We review the important role of SRSFs-induced aberrant gene expression in a variety of tumors and the immune system, and prospect the application of SRSFs in tumor. We hope that this review will inform future treatment of the disease.

The content of cancer stem cells and CD3+CD8+ T cells in the blood of a patient with small cell lung cancer (SCLC) and chronic obstructive pulmonary disease (COPD) was evaluated. In vitro analysis of tumorospheres allowed us to characterize circulating tumor stem cells in the blood of patients at risk. The fundamental possibility of reprogramming exhausted CD3+CD8+ T cells (rCD3CD8T) of a patient with SCLC and COPD using a mitogen-activated protein kinase inhibitor (iMEK) and human monoclonal antibody nivolumab was demonstrated. Target cell elimination by rCD3CD8T was achieved by treatment with autologous cancer cell and stem cancer cell lysate in vitro. Thus, blockade of the MAPK/ERK signaling pathway and the PD-1/PD-L1 checkpoints may be used to overcome exhaustion and enhance cytotoxicity of CD3+CD8+ T cells in patients with SCLC and COPD.

To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds 3g (IC50 = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and 3x (IC50 = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. 3g and 3x effectively prevent SCLC cell proliferation, invasion, and migration in vitro, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their in vivo tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.

Lung cancer is one of the deadliest malignancies worldwide, with distant metastasis being a major cause of death. However, the specific mechanisms of lung cancer metastasis remain unclear. NcRNAs, a widely present type of non-coding RNAs in the body, constitute about 98% of the human genome, lacking protein-coding capacity but involved in various cellular processes such as proliferation, apoptosis, invasion, and migration. Studies have shown that ncRNAs play a crucial role in the metastasis of lung cancer, although research in this area is limited. This review summarizes the biological origins and functions of ncRNAs, their specific roles and mechanisms in lung cancer metastasis, and discusses their potential for early screening and therapeutic applications in lung cancer. Furthermore, it outlines the challenges in translating basic advancements of ncRNAs in lung cancer metastasis into clinical practice.

The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components-collagens, fibronectin, and laminin-and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases.

Lung cancer stands prominently among the foremost contributors to human mortality, distinguished by its elevated fatality rate and the second-highest incidence rate among malignancies. The metastatic dissemination of lung cancer stands as a primary determinant of its elevated mortality and recurrence rates, underscoring the imperative for comprehensive investigation into its metastatic pathways. Circular RNAs (circRNAs), a subclass of non-coding RNA (ncRNA) molecules, have garnered attention for their pivotal involvement in the genesis and advancement of lung cancer. Emerging evidence highlights the indispensable functions of circRNAs in orchestrating the metastatic cascade of lung cancer. This review primarily discusses the mechanisms by which circRNAs act as competitive endogenous RNAs (ceRNAs) and modulate various signaling pathways to regulate lung cancer metastasis. CircRNAs influence critical cellular processes including angiogenesis, autophagy, and glycolysis, thereby exerting influence over the metastatic cascade in lung cancer. These discoveries offer innovative perspectives and therapeutic avenues for the diagnosis and management of lung cancer.

The presence of metastases in mediastinal lymph nodes (LNs) is essential for planning lung cancer treatment and assessing anticancer immune responses. The aim of the study was to assess LNs for the presence of neoplastic cells and evaluate lung cancer-selected antigen expression. LN aspirates were obtained during an EBUS/TBNA procedure. The cells were analyzed using a hematological analyzer and flow cytometry. It was possible to indicate the presence of cells characterized by high fluorescence connected with high metabolic activity using a hematological analyzer and to determine their non-hematopoietic origin using flow cytometry. Using these methods together, we detected very quickly a high proportion of cancer cells in LNs. We noticed that it was possible to determine a high expression of EpCAM, TTF-1, Ki67, cytokeratin, HER, and differences between non-small-cell (NSCLC) and small-cell lung cancer (SCLC) for the antigens MUC-1, CD56, HLA-DR, CD39, CD184, PD-L1, PD-L2 and CTLA-4 on tumor cells. We report, for the first time, that the detection of tumor cells in LNs with the expression of specific antigens is easy to evaluate using a hematological analyzer and flow cytometry in EBUS/TBNA samples. Such precise characteristics of non-hematopoietic cells in LNs may be of great diagnostic importance in the detection of micrometastases.

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

Metastasis is currently becoming a major clinical concern, due to its potential to cause therapeutic resistance. Its development involves a series of phases that describe the metastatic cascade: preparation of the pre-metastatic niche, epithelial-mesenchymal transition, dissemination, latency and colonization of the new tissue. In the last few years, new therapeutic targets, such as integrins, are arising to face this disease. Integrins are transmembrane proteins found in every cell that have a key role in the metastatic cascade. They intervene in adhesion and intracellular signaling dependent on the extracellular matrix and cytokines found in the microenvironment. In this case, integrins can initiate the epithelial-mesenchymal transition, guide the formation of the pre-metastatic niche and increase tumor migration and survival. Integrins also take part in the tumor vascularization process necessary to sustain metastasis. This fact emphasizes the importance of inhibitory therapies capable of interfering with the function of integrins in metastasis.

Non-small cell lung cancer (NSCLC), which accounts for about 85 % of all lung cancers, currently exhibits insensitivity to most treatment regimens. Therefore, the identification of new and effective biomarkers for NSCLC is crucial for the development of treatment strategies. Immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immune responses and generating long-term immune memory, holds promise for enhancing anti-tumor immunity and offering promising prospects for immunotherapy strategies in NSCLC.

Clinical information and expressive profiles of NSCLC genes were retrieved from the GEO and TCGA databases. By combining these databases, the researchers were able to identify the appropriate genes for use in forecasting outcomes of patients with this type of cancer. We further performed functional enrichment, gene variants and immune privilege correlation analysis to determine the underlying mechanisms. This was followed by univariate and multivariate Cox regression and LASSO regression analyses, we developed a prognostic risk model based on the TCGA cohort, which included 17 gene labels. The results of the external validation were then used to identify the appropriate genes for use in predicting the survival outcome of patients with this type of cancer. In addition, a nomogram was created to help visualise the clinical presentation of the patients. For the analyses, we performed 50 functional and immunoinfiltration assessments for two risk groups.

Using 17 genes (AIRE, APOH, CDKN2A, CEACAM4, COL4A3, CPA, DBH, F10, FCGRB, FGFR4, MMP1, PGLYRP1, SCGB2A2, SLC9A3, UGT2B17 and VIP), The researchers then created a gene signature that could be used to identify patients with an increased risk of contracting cancer. They divided the patients into two groups based on their risk score. The low-risk group exhibited a better prognosis (P < 0.01). The survival curve demonstrated that ICD-related models could accurately predict patient prognosis. Conversely, high-risk subgroups were closely associated with immune-related signaling pathways. The analysis of immune infiltration also showed that the infiltration levels of most immune cells were higher in the high risk sub-group than in the low risk sub-group. In comparison to the low-risk group, the high-risk group was more susceptible to the immune-checkpoint blockade (ICB) treatment.

Our researchers utilized a gene model to analyze the immune inflammation and prognosis of patients with non-small-cell lung cancer (NSCLC). The discovery of new ICD-related genes could lead to the development of new targeted treatments for this condition.

Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, contributing to its aggressive progression and therapy resistance. Autophagy, a conserved cellular process, is implicated in many cancers, but its role in SCLC remains unclear.

Using a genetically engineered mouse model (Rb1fl/fl ; Trp53fl/fl ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to investigate its effects on SCLC biology. Additional in vitro experiments were conducted to modulate autophagic flux in NE and non-NE SCLC cell lines.

Tumor subpopulations with high autophagic flux displayed increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics. Conversely, low-autophagic flux subpopulations exhibited immune-related signals and non-NE traits. In vitro, increasing autophagy induced NE features in non-NE cell lines, while autophagy inhibition in NE cell lines promoted non-NE characteristics.

This study provides a novel model for investigating autophagy in vivo and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights.

To investigate the clinicopathological features of individuals who have cervical lymph node metastasis (CLNM) from non-head and neck primary carcinomas.

The data of 1448 patients diagnosed with CLNM from non-head and neck primary carcinomas at the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, China, from January 2013 to December 2023 were collected. The patients' general information, imaging data, and pathological information were retrospectively analyzed.

There were 780 men and 668 women among the 1448 patients, for a male-to-female ratio of 1.17:1. The median age was 56 years (range 21-81 years). The most prevalent primary sites in males were the lung (n = 508, 65.1%) and, in females, the breast (n = 276, 41.3%). The most prevalent pathological kind (n = 949), or 65.5% of cases, was adenocarcinoma. There was a significant difference in the proportion of adenocarcinoma between males (n = 385, 49.4%) and females (n = 564, 84.4%). The common sites of CLNM from non-head and neck primary carcinomas were level V (1,236 cases, 85.4%). In a subgroup of 1133 patients with primary cancer located in symmetrical or unilateral organs, 60.3% exhibited ipsilateral lymph node metastasis, 27.6% had bilateral lymph node metastasis, and 12.1% showed contralateral lymph node metastasis exclusively.

For patients with CLNM, especially those with metastasis to cervical areas IV-V and those with adenocarcinoma pathology, it is particularly important to screen for primary foci in the lungs, breast, urogenital system, and digestive system after excluding head and neck primary cancers.

Small cell lung cancer (SCLC) is highly aggressive with poor prognosis. Despite a relative prevalence of circulating tumour DNA (ctDNA) in SCLC, liquid biopsies are not currently implemented, unlike non-SCLC where cell-free DNA (cfDNA) mutation profiling in the blood has utility for guiding targeted therapies and assessing minimal residual disease. cfDNA methylation profiling is highly sensitive for SCLC detection and holds promise for disease monitoring and molecular subtyping; cfDNA fragmentation profiling has also demonstrated clinical potential. Extrachromosomal DNA (ecDNA), that is often observed in SCLC, promotes tumour heterogeneity and chemotherapy resistance and can be detected in blood. We discuss how these cfDNA profiling modalities can be harnessed to expand the clinical applications of liquid biopsy in SCLC.

Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.

Lung cancer remains a major global health problem because of its high cancer-related mortality rate despite advances in therapeutic approaches. Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is more amenable to surgical intervention in its early stages. However, the prognosis for advanced NSCLC remains poor, owing to limited treatment options. This underscores the growing need for novel therapeutic strategies to complement existing treatments and improve patient outcomes. In recent years, pentacyclic triterpenoids, a group of natural compounds, have emerged as promising candidates for cancer therapy due to their anticancer properties. Pentacyclic triterpenoids, such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid, have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models. These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK. Furthermore, advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids. However, despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy. This review explores the role of triterpenoids in NSCLC and therapeutic potential in preclinical models, focusing on their molecular mechanisms of action.

The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs).

Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model's performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA).

Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p < 0.05). In the meantime, PNI was considerably lower in the PD group than in the PR group (both p < 0.01). Kaplan-Meier curves demonstrated that patients with a low SII-PNI had prolonged progression-free survival (PFS) and overall survival (OS) compared to those with a high SII-PNI (all p < 0.01). Multivariate Cox analysis showed that PS = 1, bone metastasis, brain metastasis, and SII-PNI = 1,2 after four treatment cycles were independent risk factors for shorter OS and were included in the nomogram model. The ROC curves, C-index, and DCA curves confirm that the SII-PNI scores-based nomograms have strong predictive accuracy for OS.

There was a significant correlation between pre- and post-treatment SII-PNI and treatment effect in ES-SCLC. The SII-PNI score after four treatment cycles is a useful prognostic indicator for ES-SCLC patients receiving chemotherapy combined with immune checkpoint inhibitors (ICIs).

Small cell lung cancer (SCLC) is one of the highly metastatic malignancies that contributes to ∼15 % of all lung cancers. Most SCLC patients (50-60 %) develop osteolytic bone metastases, significantly affecting their quality of life. Among several factors, environmental pollutant 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) and kynurenine (Kyn), an endogenous ligand derived from tryptophan (Trp) metabolism, activate the aryl hydrocarbon receptor (AhR) and are responsible for SCLC progression and metastasis. Further, elevated AhR expression in bone cells intensifies bone resorption, making the Kyn/AhR axis a potential target for the bone metastatic propensity of SCLC. We first assessed the expression profile of AhR in human SCLC cell lines and found a significantly increased expression compared to normal lung cells. Additionally, we also evaluated the clinical significance of AhR expression in the patient samples of SCLC along with the relevance of the same in the Rb1fl/fl; Trp53fl/fl; MycLSL/LSL (RPM) mouse model using immunohistochemistry and found the higher AhR expression in the patient samples and RPM mouse tumor tissues. Using computational simulations, we found that clofazimine (CLF) binds at the activator (Kyn) binding site by forming a stable complex with AhR. The CLF binding with AhR was favored by Van der Waals and hydrophobic forces, and the proteins retained their secondary structure. Furthermore, we found that Kyn treatment potentiates the migration and clonogenic ability of SCLC cell lines by activating Erk/Akt oncogenic signaling. Treatment with CLF reduces AhR expression, which inhibits Kyn-mediated proliferation of SCLC cells, induces apoptosis, and cell cycle arrest in the G2/M phase. Further, our examination indicates that Kyn treatment also promotes osteoblast-mediated osteoclast differentiation through RANKL. The treatment with CLF impedes RANKL expression and osteoclastogenesis, suggesting that CLF has the potential to be used as the therapeutic for SCLC patients having bone metastasis.

Lung cancer remains one of the most prevalent and lethal malignancies globally, characterized by high incidence and mortality rates among all cancers. The delayed diagnosis of lung cancer at intermediate to advanced stages frequently leads to suboptimal treatment outcomes. To improve the management of this disease, it is imperative to identify new, highly sensitive prognostic and diagnostic biomarkers. Exosomes, extracellular vesicles with a lipid-bilayer structure and a size range of 30-150 nm, are pivotal in intercellular communication and play significant roles in lung cancer progression. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are highly prevalent within exosomes and play a crucial role in various pathophysiological processes mediated by these extracellular vesicles. Beyond their established functions in miRNA and protein sequestration, these ncRNAs are involved in regulating translation and interactions within exosomes. Numerous studies have highlighted the importance of exosomal lncRNAs and circRNAs in influencing epithelial-mesenchymal transition (EMT), angiogenesis, proliferation, invasion, migration, and metastasis in lung cancer. Due to their unique functional characteristics, these molecules are promising therapeutic targets and biomarkers for diagnosis and prognosis. This review provides a succinct summary of the formation of exosomal lncRNAs and circRNAs, clarifies their biological roles, and thoroughly explains the mechanisms by which they participate in the progression of lung cancer. Finally, we discuss the potential clinical applications and challenges associated with exosomal lncRNAs and circRNAs in lung cancer.

Small cell lung cancer (SCLC) represents an aggressive neuroendocrine (NE) tumor within the pulmonary region, characterized by very poor prognoses. Druggable targets for SCLC remain limited, thereby constraining treatment options available to patients. Immuno-chemotherapy has emerged as a pivotal therapeutic strategy for extensive-stage SCLC (ES-SCLC), yet it fails to confer significant efficacy in cases involving liver metastases (LMs) originating from SCLC. Therefore, our attention is directed towards the challenging subset of SCLC patients with LMs. Disease progression of LM-SCLC patients is affected by various factors in the tumor microenvironment (TME), including immune cells, blood vessels, inflammatory mediators, metabolites, and NE substances. Beyond standard immuno-chemotherapy, ongoing efforts to manage LMs in SCLC encompass anti-angiogenic therapy, radiotherapy, microwave ablation (MWA) / radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), and systemic therapies in conjunction with local interventions. Prospective experimental and clinical investigations into SCLC should prioritize precise and individualized approaches to enhance the prognosis across distinct patient cohorts.

Background: Lung cancer is an aggressive disease with rapid progression and a high rate of metastasis, leading to a significantly poor prognosis for many patients. While chemotherapy continues to serve as a cornerstone treatment for a large proportion of lung cancer patients, expanding preclinical and clinical evidence indicates that chemotherapy may promote tumor metastasis and cause side effects. Methods: We develop an injectable bait-and-hook hydrogel (BH-gel) for targeted tumor cell eradication, which embedded doxorubicin liposomes as cytotoxic agents and CXCL12 as a chemoattractant to capture and kill tumor cells. The hydrogel backbone was formed through covalent cross-linking between PVA and borax. In vitro, we investigated tumor recruitment and the antitumor effects in A549 cells. In vivo, we explored the anti-metastatic and antitumor activities against lung cancer. Results: BH-gel retained CXCL12 within its three-dimensional porous architecture for gradual release, effectively recruiting tumor cells. In contrast, blank hydrogel failed to achieve this. After encapsulation in BH-gel, the therapeutic efficacy of doxorubicin liposomes for tumor eradication was markedly improved, significantly reducing metastatic tumor presence to near-undetectable levels, while also resulting in notable reductions in cardiotoxicity and hepatotoxicity. Notably, BH-gel adhered well to tissues and exhibited exceptional electrical conductivity, which may be further developed into a real-time tumor monitoring system, facilitating timely therapeutic adjustments. Conclusions: BH-gel utilizes CXCL12 as a bait to recruit and entrap tumor cells in a three-dimensional porous matrix and subsequently kill them with embedded doxorubicin liposomes, thereby tackling the issue of metastatic spread. This bait-and-hook strategy has significant implications for the field of anti-metastasis medicine and shows considerable potential for clinical application.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Small cell lung cancer (SCLC) harbours the most aggressive phenotype of all lung cancers to correlate with its bleak prognosis. The aggression of SCLC is partially attributable to its strong metastatic tendencies. The biological processes facilitating the metastasis in SCLC are still poorly understood and garnering a deeper understanding of these processes may enable the exploration of additional targets against this cancer hallmark in the treatment of SCLC.

This narrative review will discuss the proposed molecular mechanisms by which the cancer hallmark of activating invasion and metastasis is featured in SCLC through important steps of the metastatic pathway, and address the various molecular targets that may be considered for therapeutic intervention. The tumour immune microenvironment plays an important role in facilitating immunotherapy resistance, whilst the poor infiltration of natural killer cells in particular fosters a pro-metastatic environment in SCLC. SCLC vasculogenesis is achieved through VEGF expression and vascular mimicry, and epithelial-mesenchymal transition is facilitated by the expression of the transcriptional repressors of E-cadherin, the suppression of the Notch signalling pathway and tumour heterogeneity. Nuclear factor I/B, selectin and B1 integrin hold important roles in SCLC migration, whilst various molecular markers are expressed by SCLC to assist organ-specific homing during metastasis. The review will also discuss a recent article observing miR-1 mRNA upregulation as a potential therapeutic option in targeting the metastatic activity of SCLC.

Treatment of SCLC remains a clinical challenge due to its recalcitrant and aggressive nature. Amongst the many hallmarks used by SCLC to enable its aggressive behaviour, that of its ability to invade surrounding tissue and metastasise is particularly notable and understanding the molecular mechanisms in SCLC metastasis can identify therapeutic targets to attenuate SCLC aggression and improve mortality.