Search Results (548)

Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, high-dimensional multi-omics data remains a major challenge due to heterogeneity and frequent missingness in patient profiles. To address this challenge, we present SeNMo, a self-normalizing deep neural network trained on five heterogeneous omics layers—gene expression, DNA methylation, miRNA abundance, somatic mutations, and protein expression—along with the clinical variables, that learns a unified representation robust to missing modalities. Trained on more than 10,000 patient profiles across 32 tumor types from The Cancer Genome Atlas (TCGA), SeNMo provides a baseline that can be readily fine-tuned for diverse downstream tasks. On a held-out TCGA test set, the model achieved a concordance index of 0.758 for OS prediction, while external evaluation yielded 0.73 on the CPTAC lung squamous cell carcinoma cohort and 0.66 on an independent 108-patient Moffitt Cancer Center cohort. Furthermore, on Moffitt’s cohort, baseline SeNMo fine-tuned for TLS ratio prediction aligned with expert annotations (p < 0.05) and sharply separated high- versus low-TLS groups, reflecting distinct survival outcomes. Without altering the backbone, a single linear head classified primary cancer type with 99.8% accuracy across the 33 classes. By unifying diagnostic and prognostic predictions in a modality-robust architecture, SeNMo demonstrated strong performance across multiple clinically relevant tasks, including survival estimation, cancer classification, and TLS ratio prediction, highlighting its translational potential for multi-omics oncology applications. Full article

Background/Objectives: CD318 (also known as CDCP1) is a transmembrane protein that is overexpressed in many cancers and contributes to tumor progression, invasion, and metastasis by activating SRC family kinases through phosphorylation. Emerging evidence also suggests that CD318 plays a role in modulating the tumor immune microenvironment, although its precise mechanism in tumor progression is still not well understood. Methods: To investigate this, we analyzed the expression and immune-related functions of CD318 using the publicly available data from The Cancer Genome Atlas (TCGA) across colorectal adenocarcinoma (COAD), cervical squamous cell carcinoma (CESC), lung adenocarcinoma (LUAD), and pancreatic adenocarcinoma (PAAD). Results: All four cancers exhibited a high level of CD318 expression. Notably, in CESC, LUAD, and PAAD, plasmin-mediated cleavage of CD318 leads to phosphorylation of SRC and protein kinase C delta (PKCδ), which activates HIF1α and/or p38 MAPK. These downstream effectors translocate to the nucleus and promote the transcriptional upregulation of TGFβ1, fostering an immunosuppressive tumor microenvironment through Treg cell recruitment. In contrast, this signaling cascade appears to be absent in COAD. Instead, our analysis indicate that intact CD318 in COAD interacts with the surface receptors CD96 and CD160, which are found on CD8⁺ T cells and NK cells. Conclusions: This interaction enhances cytotoxic immune responses in COAD by promoting CD8⁺ T cell and NK cell activity, offering a possible explanation for the favorable prognosis associated with high CD318 expression in COAD, compared to the poorer outcomes observed in CESC, LUAD, and PAAD. Full article

TP (tumor protein) 53 mutation status plays a critical role in cancer progression and may influence survival outcomes in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. This study investigates the impact of TP53 mutation status and immunotherapy treatment on survival in NSCLC patients. This retrospective study analyzed NSCLC patients treated with pembrolizumab or ipilimumab plus nivolumab, stratified by TP53 mutation status and PD-L1 (programmed death-ligand 1) expression (<1%, 1–49%, >50%). Survival outcomes (overall survival (OS) and progression free survival (PFS) were assessed using Kaplan–Meier curves and log-rank tests, with subgroup analysis by histological subtype. In squamous cell cancer (SCC) patients, no significant differences in OS or PFS were found based on TP53 mutation status or treatment type. A trend toward improved survival was observed with pembrolizumab (p = 0.088). In adenocarcinoma patients, significant differences in OS and PFS were observed based on TP53 mutation status. Pembrolizumab showed superior survival outcomes compared to ipilimumab plus nivolumab in TP53 wild-type patients (p < 0.001). PD-L1 ≥ 1% also predicted better outcomes, especially in adenocarcinoma patients. TP53 mutation status and immunotherapy type significantly influence survival outcomes in NSCLC, particularly in adenocarcinoma patients. Pembrolizumab demonstrated superior efficacy in TP53 wild-type patients, with PD-L1 expression further refining survival predictions. These findings underscore the importance of personalized treatment strategies based on TP53 status and PD-L1 expression in NSCLC. Further studies are needed to validate these results and optimize treatment approaches. Full article

Background/Objectives: Lung cancer screening with low-dose computed tomography (LDCT) has reduced lung cancer mortality in high-risk smokers. However, the evidence on LDCT screening in the elderly is limited, with there being few older participants in major trials and ongoing debate about the benefits, risks, and appropriate age limits of LDCT. This study aimed to investigate the prevalence of pulmonary nodules and lung cancer detection rates in men aged 70 and above who underwent a single round of LDCT screening. Methods: We retrospectively analyzed data from elderly male participants aged 70 years or older who underwent a single low-dose CT lung cancer screening at the Veterans Health Service Medical Center between 2010 and 2023. The participants included those who requested screening or were asymptomatic but recommended by physicians. Individuals with prior lung cancer, symptoms suggestive of lung cancer, or suspicious findings on previous imaging were excluded. The nodule prevalence, lung cancer diagnoses, pathological subtypes, and clinical stages were reviewed. Results: A total of 1409 individuals with a mean age of 74.2 years were included. The median follow-up duration was 3.6 years. Among the included individuals, 1304 (92.6%) had a history of smoking. Positive nodules were detected in 179 patients (12.7%, 95% CI: 11.0–14.5%), and lung cancer was diagnosed in 31 patients (2.2%, 95% CI: 1.5–3.1%). Of the diagnosed cases, 14 (45.2%) were adenocarcinomas and 12 (38.7%) were squamous cell carcinomas. Nineteen patients (51.3%) were diagnosed with stage I or II cancer, while seven (22.6%) were diagnosed at stage IV. Conclusions: A single round of LDCT screening in elderly men resulted in a relatively high lung cancer detection rate, with over half of the diagnosed cases being identified at an early stage. This highlights the potential clinical benefit of even one-time screening in enabling timely treatment, which may still be feasible in older adults. However, potential harms such as overdiagnosis should also be considered. Full article

In recent years, an increasingly important role in the etiopathogenesis of lung cancer has been attributed to genetic predisposition. Current genetic research suggests that the increased risk of this cancer may be due to gene polymorphism within repair genes. In the case of lung cancer, observations about genes involved in the DNA repair system by cutting bases of nitrogen—base excision repair (BER)—seem to be interesting. Most attention has been devoted to the XRCC1 gene, which coordinates the various stages of BER. The aim of this study was to assess the role of the single nucleotide polymorphism Arg399Gln in the XRCC1 gene as a factor influencing the risk of lung cancer. The study involved 118 patients with non-small cell lung cancer (NSCLC). The control group consisted of 60 people who did not have cancer. The study proved that the polymorphism of the XRCC1 gene is characterized by a statistically significant relationship with the onset of cancer. There were no statistically significant differences between the Arg399Gln polymorphism of the XRCC1 gene and risk factors for non-small cell lung cancer, such as age, sex, smoking and its duration, or place of residence, as well as between the histological type of the tumor or its severity. Detailed analysis of three genotypes—Arg/Arg, Arg/Gln, and Gln/Gln—showed that the incidence of particular genotypes in the group of patients was, respectively, 16.10%, 27.12%, and 58.78%. In the case of the Gln/Gln genotype, the most common associated histopathological type was squamous cell carcinoma, and in the case of adenocarcinoma, the most common genotype was Arg/Arg. It was estimated that each Arg allele reduced the chance of tumor occurrence to 0.48 times the reference value, i.e., the Gln/Gln genotype class for the Arg/Gln genotype and the Arg/Gln genotype for the Arg/Arg genotype. The relationship between the male sex and the occurrence of cancer remained insignificant, in contrast to the presence of nicotinism. Studies suggest that the Arg399Gln polymorphism of the XRCC1 gene has limited prognostic significance in non-small cell lung cancer. Full article

Background: Lung cancer, predominantly NSCLC (80%), has a poor prognosis due to late diagnosis and limited treatment efficacy. DMRTA2 (DMRT5), a transcription factor linked to neural/germ cell development, is overexpressed in NSCLC per TCGA data, indicating its potential role in tumorigenesis and as a therapeutic target. Methods: Conduct a comprehensive search of the relevant theoretical foundations. Based on this, differential expression analysis will be performed using the DESeq2 package in R on RNA-seq data from lung adenocarcinoma and lung squamous cell carcinoma in the TCGA database. The research will then employ various methods, including CRISPR genome editing, MTS assay, flow cytometry, Western blot, co-immunoprecipitation, immunofluorescence, and qRT-PCR. Results: Through experimental validation, we found that DMRTA2 mRNA is highly expressed in non-small-cell lung cancer (NSCLC) tissues and is negatively correlated with poor prognosis. DMRTA2 binds to HSP90β, inhibiting the interaction between HSP90β and p53, thereby suppressing p53 ubiquitination and nuclear export. This activates the p53 pathway, inhibiting the proliferation and invasion of lung cancer cells. Conclusions: In NSCLC, DMRTA2 acts as a context-dependent regulator, stabilizing wild-type p53 through competitive HSP90β binding to suppress tumors, while in p53-compromised cells, potentially engaging HSP90β or alternative pathways to promote malignancy. Its dual localization and transport interactions reveal multifunctional, stress-responsive roles beyond transcription. Full article

Bardoxolone methyl, also known as CDDO-Me or RTA 402, is a synthetic oleanane triterpenoid that has garnered significant attention as a potent pharmacological activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a master regulator of cellular redox homeostasis, controlling the expression of genes involved in antioxidant defense, detoxification, and mitochondrial function. By inducing Nrf2 and promoting the transcription of downstream antioxidant response element (ARE)-driven genes, bardoxolone methyl enhances cellular resilience to oxidative stress and inflammation. This mechanism is central not only to its cytoprotective effects but also to its emerging role in oncology. A number of studies investigated the effects of bardoxolone methyl in several malignancies including breast cancer, lung cancer, pancreatic ductal adenocarcinoma, prostate cancer, colorectal cancer, oral and esophageal squamous cell carcinoma, ovarian cancer and glioblastoma. Studies in the literature indicate that bardoxolone methyl exhibits anticancer activity through several mechanisms, including the suppression of cell proliferation, induction of cell cycle arrest and apoptosis, inhibition of epithelial–mesenchymal transition (EMT), and impairment of cancer cell stemness. Additionally, bardoxolone methyl modulates mitochondrial function, reduces glycolytic and oxidative phosphorylation capacities, and induces reactive oxygen species (ROS)-mediated stress responses. In this review, we summarize the available literature regarding the studies which investigated the effects of bardoxolone methyl as anticancer agent. Full article

Background/Objectives: In 2024, Lithuania developed a national lung cancer screening program (the Program), targeting individuals aged 50 to 70 years, regardless of their smoking history, with screenings conducted once every three years. The Program aims not only to actively detect lung nodules (lung cancer) but also to identify clinically significant concomitant findings. The pilot study aimed to evaluate the screening process’s feasibility and organizational efficiency of the screening process, as well as its potential clinical effectiveness. Methods: Three family medicine centers were selected for participation. The Coordinating Center contacted individuals aged 50 to 70 sequentially and invited them to participate, regardless of smoking status. In total, 1014 individuals were prospectively enrolled and underwent low-dose chest computed tomography (LDCT) screening between 26 September 2024 and 14 February 2025. Results: Of the individuals invited, 76.1% agreed to participate. Lung-RADS v2022 category 4 nodules were identified in 1.4% of participants (n = 14), including six smokers and eight non-smokers. Additionally, one participant with a Lung-RADS category 2 nodule was diagnosed with squamous cell carcinoma originating from peripheral lung changes. Newly identified significant incidental findings were detected in 25.9% of participants: 5.1% had pulmonary or mediastinal findings (most commonly emphysema, interstitial lung changes, and bronchiectasis), 18.7% had cardiovascular findings (usually coronary artery calcification, aortic valve calcification, and aorta dilation), and 2.1% had other clinically relevant conditions (e.g., thyroid nodules, diaphragmatic changes). Following assessment by family physicians, 17.6% of all participants were referred to medical specialists, including pulmonologists, cardiologists, and others. Conclusions: This pilot study demonstrated that the Lithuanian lung cancer screening model is feasible, well-organized, and clinically valuable. The findings support the Program’s readiness for broader implementation at the national level. Full article

Background: Organoid cultures have received much attention in recent years due to the promise of patient-derived organoid cultures for exploration of personalized cancer treatment strategies. Organoid cultures have been established from a variety of malignancies; however, lack of a thorough histopathological analysis has limited the acceptance of organoid models as translational tools. Methods: Here, we aimed to establish patient-derived tumor-organoid (PDTO) models from human non-small-cell lung cancer (NSCLC) resection specimens and provide a thorough histopathological evaluation of the cultures. Results: We show that we were able to establish organoid cultures of lung adenocarcinomas (LUADs) and lung squamous cell carcinomas (LUSCs) successfully, and that the organoid cultures of different subtypes of NSCLC preserved the histoarchitecture and growth pattern of the tumors they derive from. Immunohistochemistry and AB-PAS staining confirmed the subtype-specific protein expression pattern and preserved mucin production in LUAD organoids. The genetic abnormalities of the tumors assessed by immunohistochemistry (IHC-P) were preserved in the organoid cultures. Conclusions: Our thorough study reveals conserved PDTO histopathology, supports further exploration, and encourages using PDTO models in translational research projects. PDTO models hold remarkable promise as patient-specific models and may be applied to predict therapy response in cases where molecular–pathological analyses pose significant management dilemmas, and they also may provide a platform for exploring the molecular mechanisms of therapy resistance in a biologically relevant model system. Full article

Background: Previously, we found that an uncharacterized protein CXorf38 is significantly downregulated in human ZIP8-knockout (KO) cells. Given that ZIP8 regulates essential micronutrients linked to diseases including cancer, this study aims to characterize CXorf38 and evaluate its role in lung adenocarcinoma. Methods: iTRAQ-based proteomics was previously used to identify the abundance of proteins in ZIP8-KO cells. Cell proliferation and colony formation assays were used to examine the function of CXorf38 by overexpressing the gene in lung adenocarcinoma cell lines. Kaplan–Meier survival analysis was used to assess the prognostic value of CXorf38, while TCGA clinical database analysis was used to evaluate its expression in lung cancer tissues, particularly in smokers. Bioinformatics analyses (GO, KEGG, PPI, and ICI) were performed on CXorf38-coexpressed genes derived from patients with lung cancer. Results: CXorf38 overexpression suppressed lung cancer cell proliferation and colony formation, suggesting a tumor-suppressive role. Higher CXorf38 expression correlated with improved survival in patients with lung adenocarcinoma, but not in lung squamous cell carcinoma. Clinical data showed CXorf38 downregulation with lung cancer tissues of smokers, indicating a potential role in smoking-induced cancer progression and treatment. Functional analysis using bioinformatics linked CXorf38 to immune response regulation, suggesting involvement in the tumor immune microenvironment. Conclusions: Our study reveals for the first time that CXorf38 is a potential tumor suppressor, prognostic biomarker, and/or tumor immune regulator in lung adenocarcinoma—further research is warranted to explore its role in tumor immunity and its therapeutic potential. Full article

Lung cancer is the leading cause of cancer-related death worldwide, ranking first among men and second among women for both incidence and mortality. Surgery remains the primary treatment for early-stage, resectable non-small cell lung cancer (NSCLC), encompassing stages I and selected cases of stage IIIB. For patients with stage II to III disease, as well as some stage IB tumors, neoadjuvant or adjuvant systemic therapies are recommended. It is well recognized that specific driver gene mutations play a critical role in tumor progression and aggressiveness, and patients with these genetic alterations may benefit from targeted treatment approaches. These alterations are referred to as “druggable”, “targetable”, or “actionable”, representing specific targets for personalized treatments. Tyrosine kinase inhibitors (TKIs) are now the preferred first-line treatment for patients harboring mutations in EGFR, ALK, ROS1, and BRAF. Additionally, targeted therapies exist for patients with alterations in RET, ERBB2, KRAS, MET, and NTRK, either for those who have received prior treatments or as part of ongoing clinical trials. The success of targeted therapies is reshaping treatment approaches for NSCLC with targetable driver gene alterations, both in early-stage and locally advanced settings. This review focuses on current therapeutic strategies that combine targeted therapies with surgical resection in patients with resectable non-small cell lung cancer (NSCLC) harboring actionable driver gene alterations. Full article

Background: Idiopathic pulmonary fibrosis (IPF) and emphysema often coexist in patients with lung cancer (LC), forming a syndrome with combined pulmonary fibrosis and emphysema (CPFE). The three share the pathogenic mechanisms of smoking, chronic inflammation, and oxidative stress. The clinical management of CPFE patients is challenging, but its impact on tumor characteristics, acute exacerbation (AE), and prognosis is still controversial. The purpose of this study was to clarify the effect of CPFE on tumor biological behavior, AE risk, and survival outcome in patients with IPF-LC so as to optimize individualized treatment strategies. Methods: This was a retrospective and single-center study. Newly diagnosed LC patients with IPF, COPD, and normal lungs were recruited in the west China hospital. Patients with IPF were further categorized into CPFE-LC and isolated IPF-LC groups based on the presence of emphysema. Clinical and tumor features, lung function parameters, and prognosis were obtained and compared. Results: Patients with IPF and LC were more common in older men and heavy smokers. IPF-associated tumors had a higher proportion of carrying EGFR wild-type, occurring in the lower lobe of the lung and developing adenocarcinoma and squamous cell carcinoma. Among IPF-LC patients, 68.2% (103/151) met CPFE criteria. Pulmonary function tests demonstrated preserved VC% but significantly reduced FEV1/FVC in CPFE versus non-emphysema IPF (76.3% vs. 80.7%, p = 0.004), alongside elevated CPI and impaired DLCO. CPI ≥ 40 (HR = 2.087, 95%CI: 1.715–6.089, p = 0.012), combined with COPD (HR = 2.281, 95%CI: 1.139–4.569, p = 0.040), isolated IPF (HR = 5.703, 95%CI: 2.516–12.925, p < 0.001), and CPFE (HR = 6.275, 95%CI: 3.379–11.652, p < 0.001), were independent prognostic risk factors in LC patients. The incidence of treatment-induced AEs (49.5% vs. 29.2%, p = 0.038) and AE-related mortality (28.0% vs. 11.8%, p = 0.045) were significantly higher in the CPFE group than in the isolated IPF group. Logistic regression analysis showed that CPFE (OR: 3.494, 95%CI: 2.014–6.063, p = 0.001) was independently associated with the risk of AE-related mortality in patients with LC and IPF. Conclusions: Compared to LC patients with solely IPF, the presence of emphysema had no significant impact on overall survival, but CPFE increased the risk of treatment-triggered AE and was associated with AE-related mortality. In patients with LC, CPFE with AEs had a worse prognosis than IPF with AEs. Full article

DNA methylation changes, especially hypermethylation of SOX1 and HOXA9, may serve as biomarkers for diagnosis and prognosis in non-small cell lung carcinoma (NSCLC). This study analyzed the methylation status of SOX1 and HOXA9 in 63 primary NSCLC tumor samples, corresponding normal lung tissues, and circulating blood, using bisulfite pyrosequencing. The relationship between methylation patterns and clinicopathologic features was also explored. SOX1 and HOXA9 promoter methylation levels were significantly higher in tumor tissues compared to normal lung tissues and blood samples. Histological subtypes influenced methylation patterns, with squamous cell carcinomas (SCC) showing higher hypermethylation rates at both loci compared to other NSCLC subtypes. HOXA9 hypermethylation was associated with advanced tumor stage (stages II and III). Gender and smoking status did not correlate with methylation status. These findings highlight the cancer-specific nature of SOX1 and HOXA9 hypermethylation in NSCLC. Further investigation into demographic and molecular factors influencing methylation could enhance the clinical utility of SOX1 and HOXA9 in NSCLC diagnosis and management. Full article

Background: Ambient air pollution is a modifiable determinant of lung cancer survival, affecting early-stage Non-Small Cell Lung Cancer (NSCLC) incidence and mortality. Methods: This retrospective cohort study examined the association between all-cause mortality and exposure to air pollution among stage 1A NSCLC-treated patients from the U.S. National Cancer Registry from 1988 to 2015. The Cox hazard model and Kaplan–Meier survival plots were provided. Air pollutants were included separately and together in the models, accounting for spatiotemporal weather variability affecting air pollution exposure levels pre and post lung cancer diagnosis. Results: NO₂ (above the median sample mean = 25.66 ppb; 12.97 ppb below median), SO₂ (above median sample mean = 3.98 ppb; 1.81 ppb below median), and CO (above median sample mean = 1010.84 ppb; 447.91 ppb below median) air pollutant levels and weather conditions were calculated for county-day units. The median months of survival for those exposed to above-median NO₂ were 27 months (SD = 17.61 months), while the median was 30 months (SD = 15.93 months) for those exposed to below-median levels. Multipollutant analyses indicated that an average monthly NO₂ increase of 1 part per billion (ppb) in the county of NSCLC diagnosis was associated with increases of 4%, 6%, and 9% in the all-cause mortality rate one, three, and five years after diagnosis, respectively; an equivalent increase in SO₂ was associated with increases of 16%, 17%, and 17%; and an increase in CO was associated with increases of 53%, 51%, and 42% Conclusion: It is vital to implement environmental policies that control emissions to reduce preventable deaths in stage 1A NSCLC patients with adenocarcinoma or squamous cell carcinoma histology types who reside in metropolitan areas. Full article

Epidermal growth factor receptor (EGFR) mutations are described in 10–15% of Caucasian patients and in 50% of Asian patients with non-squamous non-small cell lung cancer (NSCLC). The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapeutic scenario and has changed the natural history of the disease. Despite the results obtained with osimertinib, a third-generation TKI, most patients experience disease progression. The search for new therapeutic strategies both to enhance first-line treatment and to ensure adequate second-line therapies represents an unmet medical need, towards which all efforts are being concentrated. In this review, we describe the main strategies identified to improve the prognosis of patients with EGFR-mutated NSCLC. Full article