Search Results (109)

Background/Objectives: The clinical value of KRAS mutations in lung adenocarcinoma, alone or in combination with other mutations, has been assessed especially in advanced stages. This study evaluates how KRAS and the presence of co-mutations could affect survival in early-stage lung. Methods: We analyzed a real-world cohort including all staged NSCLC patients diagnosed and treated from 2018 to 2022 at our Institute with availability of NGS molecular data. Statistical analyses were made using log-rank test, the two-tailed Fisher’s exact test and Kaplan-Meier survival curves. Results: KRAS mutations were observed in 179/464 cases (38.6%). The majority of KRAS co-mutations were in TP53 (74%) and STK11 (14.3%) genes. KRAS+TP53 co-mutations were more frequent compared to KRAS-only tumors in stage IV NSCLC (p = 0.01). In early stage and locally advanced cases (stage I-III), better prognosis was associated to KRAS-only mutated NSCLC and to KRAS+STK11 mutated cases compared to KRAS+TP53 (p = 0.008). In particular, patients carrying KRAS+TP53 in stage I and II displayed a shorter survival, similar to patients diagnosed at stage III. Conclusions: Routine NGS provides important information for potential actionable mutations but also for the prognostic and predictive role of the presence of co-occurring mutations. In particular, the presence of KRAS+TP53 in stage I and II NSCLC may be considered an unfavorable prognostic marker possibly leading to adapt the perioperative chemo-immunotherapy. Full article

Background/Objectives: The role of tertiary lymphoid structures (TLSs) in cancer prognosis is well established, yet their significance in early-stage EGFR-mutant lung adenocarcinoma remains unclear. While outcomes for early-stage lung cancer are generally better than those of late-stage disease, recurrence remains a significant challenge. This study investigates the prognostic value of TLSs and their molecular characteristics in early-stage EGFR-mutant lung adenocarcinoma. Methods: TLSs were identified in tumor samples using multiplex immunohistochemistry (IHC), and their density was quantified. The PD-L1 tumor proportion score (TPS) and TLS density were analyzed for associations with disease-free survival (DFS). Gene expression profiling was performed to compare tumor microenvironment signatures between high- and low-TLS-density groups. Results: High TLS density correlated with significantly longer DFS (43 vs. 20.5 months, p = 0.0082). No relationship was found between TLS density and PD-L1 TPS or EGFR mutation subtype. Transcriptomic analysis revealed upregulated immune response genes in the high-TLS-density group, including those involved in T and B cell activation. Low-TLS-density tumors exhibited gene signatures promoting tumor growth, such as cell cycle and WNT pathway activation. Conclusions: In summary, TLS density is a potential prognostic biomarker for DFS in early-stage EGFR-mutant lung adenocarcinoma, independent of PD-L1 TPS or EGFR mutation subtype. Enhanced immune activation in high-TLS-density tumors highlights TLSs as a potential target for improving outcomes in these patients. 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

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly enhance the median survival of patients with lung adenocarcinoma (ADC) that harbor EGFR-sensitive mutations. However, most patients inevitably experience tumor relapse owing to drug resistance. We aimed to identify potential serum biomarkers for predicting post-EGFR-TKI treatment relapse in patients with advanced-stage lung ADC. Methods: Among 27 patients, including 6 and 21 with early and late relapse, respectively, differentially expressed proteins between patients with early and late relapses were identified using liquid chromatography and tandem mass spectrometry and subsequently validated using Western blotting. Predictive ability was assessed using the receiver operating characteristic curve and area under the curve (AUC) analysis. The association between the clinical variables and treatment response was evaluated using the chi-square test. Results: The serum expression levels of the translocated promoter region (TPR), junction plakoglobin (JUP), and fibrinogen alpha chain (FGA) were significantly higher in patients with late rather than early relapse. The findings indicated that TPR and FGA exhibited good diagnostic performance, with AUCs of 0.946 (p = 0.002; 95% confidence interval [CI], 0.84–1.05) and 0.809 (p = 0.034; 95% CI, 0.65–0.97), respectively. Conclusions: Our results suggest that the TPR and FGA levels are potential predictors of post-EGFR-TKI treatment relapse. Full article

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer and is frequently diagnosed at advanced stages with metastasis, contributing to its poor prognosis. Identifying key metastasis-related biomarkers is critical for improving early diagnosis and therapeutic targeting. Methods: We analyzed four GEO microarray datasets (GSE32863, GSE27262, GSE40275, and GSE33356) and TCGA data to identify differentially expressed genes (DEGs) in LUAD. Functional enrichment of DEGs was analyzed using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and a Cancer Hallmark Enrichment Plot. Hub gene analysis was conducted using Cytoscape. Hub genes were evaluated for their expression, prognostic significance (via the Kaplan–Meier plotter), and clinical correlation using additional platforms (TCGA, Lung Cancer Explorer, TNMplot, and the Human Protein Atlas). Results: A total of 333 consistently dysregulated DEGs were identified, enriched in pathways related to metastasis, including angiogenesis, immune escape, and ECM interaction. Ten hub genes (AURKA, TOP2A, CCNB2, CENPF, MCM4, TPX2, KIF20A, ASPM, MELK, and NEK2) were identified through network analysis. Among these, MCM4 showed strong upregulation in LUAD and was significantly associated with poor overall survival. Notably, MCM4 expression also correlated with post-progression survival and markers of invasiveness. Immunohistochemistry and transcriptomic analyses confirmed MCM4 overexpression at both mRNA and protein levels. Additionally, MCM4 expression was positively correlated with various matrix metalloproteinases, supporting its role in promoting tumor invasiveness. Conclusions: MCM4 is a novel potential biomarker for LUAD metastasis and prognosis. Its consistent upregulation, association with metastatic markers, and clinical significance suggest it may serve as a candidate target for diagnostic use or therapeutic intervention in advanced LUAD. Full article

Background/Objectives: The early detection of high levels of CBC-derived inflammatory biomarkers and cellular lines, as well as their variations across different histological subtypes of lung cancer, may aid in the early identification of high-risk lung cancer patients and further guide their clinical approach. Methods: A retrospective descriptive study was conducted and included 202 patients diagnosed with lung carcinoma at the Clinical County Hospital Mureș. The main analyzed parameters were the histological subtype and the stage of the tumor at diagnosis, white blood cell counts, and platelet counts, as well as nine CBC-derived inflammatory indexes like neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-neutrophil ratio (ENR), eosinophil-to-monocyte ratio (EMR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI). The statistical analysis was performed using the MedCalc software, version 23.0.2. Logarithmic ANOVA was used to compare groups. Normality was tested using the Shapiro–Wilk test. The Chi-square test compared categorical variables, while the independent Mann-Whitney test was used for continuous variables. Results: The inflammatory response increased as disease severity progressed, with NSCLC-NOS being the histological subtype with the most numerous patients outside the normal ranges. Eosinophil count differed significantly across the histologic subtypes of NSCLC, with adenocarcinoma and adenosquamous patients exhibiting the highest values. In adenocarcinoma patients, we observed that NLR and MLR levels increased progressively as the tumor stage advanced. Based on severity, differences were observed across the histological subtypes of lung cancer in stage III patients for ENR, EMR, AISI, eosinophil count, and platelet count, as well as in stage IV patients for AISI, SIRI, and SII. Disease severity impacts the associated inflammatory response in all histologic subtypes of lung cancer to varying degrees. Conclusions: Histological subtype might have a decisive role in shaping the systemic inflammatory profile of lung cancer patients. CBC-derived indices serve as accessible, cost-effective biomarkers for early risk assessment, aiding in the prognosis evaluation and monitoring of therapeutic response. Future studies are needed to further evaluate the histology-specific inflammatory profiles as adjunctive tools in precision oncology. Full article

Lung cancer is responsible for 2.21 million annual cancer cases and is the leading worldwide cause of cancer-related deaths. Specifically, lung adenocarcinoma (LUAD) is the most prevalent lung cancer subtype resulting from genetic causes; LUAD has a 15% patient survival rate due to it commonly being detected in its advanced stages. This study aimed to identify a novel biomarker signature of early-stage LUAD utilizing gene expression analysis of human lung tissue samples. Using 22 pairs of LUAD and matched normal lung microarrays, 229 differentially expressed genes were identified. These genes were networked for their protein–protein interactions, and 44 hub genes were determined from protein essentiality. Survival analysis of 478 LUAD patient samples identified four statistically significant candidates. These candidate genes’ expression profiles were validated from GTEx and TCGA (347 normal, 483 LUAD samples); immunohistochemistry validated the subsequent protein presence. Through intensive bioinformatic identification and multiple validations of the four-biomarker gene signature, AGER, MGP, and PECAM1 were identified as downregulated in LUAD; SLC2A1 was identified as upregulated in LUAD. These four biologically significant genes are involved in tumorigenesis and poor LUAD prognosis, meriting their use as a clinical biomarker signature and therapeutic targets for early-stage LUAD. 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

Background: Lung adenocarcinoma in Taiwan has unique characteristics, such as a high EGFR mutation rate. While CEAs are a commonly used serum tumor marker (STM), the prognostic value of CA-125, CA-153, and CA-199 remains unclear. This study evaluates their clinical utility in predicting disease progression and prognosis. Methods: A multicenter retrospective study of 1133 patients with lung adenocarcinoma from three hospitals in Taiwan was conducted (2014–2021). Clinical data and STM levels (CEA, CA-125, CA-153, CA-199) were collected. Cox proportional hazards models were used to identify independent predictors of disease-free survival (DFS) and progression-free survival (PFS). Results: CEA, CA-125, CA-153, and CA-199 levels increased with lung adenocarcinoma stage (p < 0.001). In the early stages, CEA was an independent predictor of DFS (HR = 2.58, p < 0.001). In stage IV patients, CA-125 and CA-199 predicted poor PFS (CA-125: HR = 1.17, p = 0.004; CA-199: HR = 1.09, p = 0.049). Among those treated with EGFR tyrosine kinase inhibitors (TKIs), CA-125 remained a significant predictor (HR = 1.33, p < 0.001). Conclusions: CA-125 and CA-199 may be superior to CEAs in predicting poor PFS in stage IV lung adenocarcinoma, especially for EGFR TKI-treated patients. These easily accessible markers could aid prognosis and treatment decisions, although further validation is required. Full article

Background/Objectives: The analysis of the complete blood count (CBC)-derived inflammatory indexes across different histological subtypes of lung cancer supports the early detection of tumor-induced inflammation and has a good predictive value for severity in cancer patients. The main objective of this article was to assess the variations in CBC-derived inflammatory markers across different histologic subtypes of lung cancer, with the final goal of identifying specific predictors of severity for each histologic subtype of lung cancer. Methods: We conducted a retrospective descriptive study that included 202 patients diagnosed with lung carcinoma at the Clinical County Hospital Mureș. The analyzed parameters were as follows: the histological type, the stage of the tumor, patients’ general data, and associated comorbidities. In addition, nine CBC-derived inflammatory indexes, like the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-neutrophil ratio (ENR), eosinophil-to-monocyte ratio (EMR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI), were analyzed as predictors of severity and correlated with histologic findings. Results: The predictors of severity differed across the histologic subtypes. SIRI, d-NLR, and age were predictors of severity in adenocarcinoma patients, while the d-NLR, ENR, leukocyte, and neutrophil count predicted severity in squamous cell carcinoma. For SCLC patients, AISI, SIRI, SII, d-NLR, EMR, ENR, MLR, leukocyte count, lymphocyte count, neutrophil count, platelets count, COPD, smoking, and male gender were predictors for severity. Conclusions: Understanding the complexity and variations in the inflammatory response across different histologic types of lung cancer can personalize treatment regimens and target specific abnormal cellular lines, thus improving the outcome of this highly deadly condition. Full article

Background: In metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, osimertinib is the cornerstone treatment able to prolong overall survival (OS). Evidence around osimertinib being effective in leptomeningeal metastasis (LM) is scarce. Methods: We conducted a retrospective cohort study of patients with metastatic NSCLC-EGFR mutation treated with osimertinib at Sunnybrook Hospital. Results: We identified a total of 56 patients. Of these, 45 (79.4%) were never smokers, 53 (94.6%) had adenocarcinoma histology, and 26 (46.42%) had either the EGFR exon 21-L858R mutation or exon 19 deletion. The estimated median OS was 51 months (43.5–58.5). All eight patients with LM died during the study period. From the time of NSCLC diagnosis, the OS of patients without LM was 53 months (95% CI 47.2–58.7), and with LM was 21 months (95% CI 3.0–39), p = 0.001. However, the median OS from LM diagnosis was 2 months (95% CI, 1.0–26). Conclusions: In our population of patients with metastatic NSCLC-EGFR mutation who received osimertinib, there was a significant reduction in life expectancy in the group with LM. Patients who had advanced stage at diagnosis and were more likely to develop LM exhibited poorer survival compared to those who had early-stage cancer at diagnosis and developed metastases later on. Full article

Radiomic feature (RF) analysis of computed tomography (CT) images may aid the diagnosis and staging of ovine pulmonary adenocarcinoma (OPA). We assessed the RF characteristics of OPA tumours in JSRV-infected sheep compared to non-tumour lung tissues, examined their stability over time, and analysed RF variations in the nascent tumour field (NTF) and nascent tumour margin field (NTmF). In monthly CT scans, lung tissues were automatically segmented by density, and lung tumours were manually segmented. RFs were calculated for each imaging session, selected according to stability and reproducibility, and adjusted for volume dependence where appropriate. Comparisons between scans within sheep were facilitated through fiducial registration and spatial transformations. Initially, 9/36 RFs differed significantly from non-tumour lung tissue of similar density. Predominant RF changes included ngtdm_Complexity, glrlm_RunLNUnif_VN, and gldm_SmDHGLE. RFs in lung tumour segments showed time-dependent changes, whereas non-tumour lung tissue of similar density remained consistent. OPA lung tumour RF characteristics are distinct from those of other lung tissues of similar density and evolve as the tumour develops. Such characteristics suggest that radiomic analysis offers potential for the early detection and management of JSRV-related lung tumours. This research enhances the understanding of OPA imaging, potentially informing better diagnosis and control measures for naturally occurring infections. Full article

Background: Liquid biopsy using plasma cfDNA has been established as a tool for informing the management of advanced-stage NSCLC. However, its effectiveness in early lung cancer detection, including the identification of high-risk cases, remains to be determined. Methods: We analyzed plasma cfDNA and matched tumors from 117 stage I–IV lung adenocarcinoma cases and compared the variants identified across all stages using the Oncomine Precision Assay on the Genexus^TM next-generation sequencing platform. Results: Cancer-specific mutations were detected in plasma from approximately 72% (84/117) of cases (all stages), with detection rates increasing by stage. Concordance between cfDNA and tumor tissue also increased with stage 0% (stage I), 19% (stage II), 45% (stage III), and 75% (stage IV). KRAS mutations were concordant in approximately 22% (6/27) of stage II and 46% (11/24) of stage III cases. Clinically important EGFR variants showed concordance in 11% (1/9) of stage II and 80% (8/10) in stage III/IV cases. Actionable mutations, targetable with FDA-approved drugs, were detected in 11% (4/37) of stage II, 27% (12/45) of stage III, and 55% (4/9) of stage IV cases, underscoring the potential of liquid biopsy for early detection of therapeutic targets. Moreover, co-occurring mutations with varying actionability were identified more frequently in plasma than in tumor tissues. Plasma detection of clinically important KRAS and EGFR variants was mostly associated with advanced-stage disease, suggesting the presence of these variants in plasma as a potential indication of disease progression. Conclusions: Liquid biopsy holds promise for identifying high-risk lung adenocarcinoma cases and serves as a complementary diagnostic tool in advanced stages, enhancing disease management strategies. Full article

Despite significant advancements in early detection and treatment, non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Specifically, in early-stage cases, recurrence after surgery continues to be the principal cause of death for these patients. The urgent need for novel diagnostic and prognostic biomarkers has directed attention towards PIWI-interacting RNAs (piRNAs), a group of small RNAs that regulate genomic stability and epigenetics. Some piRNAs, including hsa_piR_022710, hsa_piR_019822, and hsa_piR_020840, have been described as deregulated in various cancers. This study investigated the expression of these three piRNAs by RT-qPCR in 277 NSCLC patients and developed survival and CART classification models to predict recurrence risk, overall survival (OS), and disease-free survival (DFS). hsa_piR_019822 and hsa_piR_020840 were able to discriminate between tumor and normal tissue, as well as between adenocarcinoma and squamous cell carcinoma (LUSC) patients. Elevated expression of hsa_piR_019822 and hsa_piR_022710 was correlated with an increased risk of recurrence and poorer DFS and OS in LUSC patients. Patients with high hsa_piR_022710 expression more greatly benefited from adjuvant treatment. In summary, higher piRNA levels were associated with an increased risk of recurrence and poorer survival outcomes, especially in LUSC patients, where they may help guide personalized treatment strategies. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) benefit some lung cancer patients, but their efficacy is limited in advanced lung adenocarcinoma (LUAD) with EGFR mutations (EGFRm), largely due to a non-immunogenic tumour microenvironment (TME). Furthermore, EGFRm LUAD patients often experience increased toxicity with ICIs. CD73, an ectonucleotidase involved in adenosine production, promotes tumour immune evasion and could represent a novel therapeutic target. This study investigates CD73 expression in LUAD with EGFR alterations and its clinico-pathological correlations. Methods: CD73 expression in tumour (CD73_TC) and stromal (CD73_SC) cells was assessed in 76 treatment-naive LUAD patients using immunohistochemistry (IHC) (D7F9A clone) alongside IHC PD-L1 (22C3 clone). EGFR alterations were identified by molecular sequencing and FISH. Event-free survival (EFS) was analysed based on CD73_TC expression. Results: CD73_TC expression was observed in 66% of cases, with high expression (Tumour Proportion Score > 50%) correlating with improved EFS (p = 0.045). CD73_TC and PD-L1 expression were not significantly correlated (p = 0.44), although a weak inverse trend was observed. CD73_SC expression was detected in 18% of cases, predominantly in early-stage (p = 0.037), PD-L1-negative (p = 0.030), and non-EGFR-amplified (p = 0.0018) tumours. No significant associations were found with disease stage, histological subtype, EGFR mutation type, and amplification. Conclusions: CD73 expression in EGFRm LUAD is heterogeneous and associated with diverse TME profiles. These findings support the potential of CD73 as a predictive biomarker and therapeutic target, highlighting its clinical relevance in EGFRm LUAD. Full article