Search Results (60)

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

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

Background: Despite advances in immunotherapy, non-small-cell lung carcinoma (NSCLC)’s clinical success is limited, possibly due to substantial immunological alterations in advanced cancer patients. This study examines the immunomodulatory effects of sEVs derived from lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) on T cells. Methods: SEVs were isolated from lung cancer cell lines and Jurkat-E6.1. SEV size and morphology were analyzed by NTA and TEM, respectively, while Western blotting confirmed sEV markers. SEV uptake was assessed, followed by resazurin assay, RNA isolation, quantification, cDNA preparation, RT-PCR, nano LC-MS, and bioinformatic analysis, before and after treating Jurkat-E6.1 cells with sEVs from A549 and SKMES1. Results: Cancer-derived sEVs were efficiently internalized by immune cells, reducing T-cell viability. The real-time PCR analysis showed downregulation of KI67, BCL2, BAX, TNFA, IL6, TGFβ, and IL10, suggesting reduced proliferation, dysregulated apoptosis, and impaired inflammatory and immunosuppressive signaling, and the upregulation of GZMB and IL2 suggests retained cytotoxic potential but possibly dysfunctional T-cell activation. Proteomic analysis revealed 39 differentially abundant proteins (DAPs) in ADC-treated T cells and 276 in SCC-treated T cells, with 19 shared DAPs. Gene Ontology (GO) analysis of these DAPs highlighted processes such as sEV biogenesis, metabolic pathways, and regulatory functions, with ADC sEVs influencing NAD metabolism, ECM binding, and oxidoreductase activity, while SCC sEVs affected mRNA stability, amino acid metabolism, and cadherin binding. The cytoplasmic colocalization suggests the presence of these proteins in the cellular and extracellular lumen, indicating the potential of further release of these proteins in the vesicles by T cells. Conclusion: Lung cancer-derived sEVs regulate T-cell activities through immunoregulatory signaling. The molecular interactions between sEVs and immune cells can reveal novel tumor immune regulatory mechanisms and therapeutic targets. Full article

Globally, lung cancer is the most prevalent cause of cancer-related death. There are two large histological groups of lung cancer: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Based on histopathological and molecular features, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the two major histologic subtypes of NSCLC. Various epidemiological and environmental factors are linked with an increased risk of lung cancer. However, these risk factors show disparities in patients with divergent racial and ethnic backgrounds. Interestingly, different populations were found to harbor distinct molecular features as evidenced by variations in genetic mutation profiles. Moreover, diverse histological and molecular progression patterns are identified in lung cancer, which could be crucial in improving diagnosis, prognosis, and therapeutic planning. In concert with a plethora of nuclear genetic alterations, mitochondrial alteration, epigenetic reprogramming, microbial dysbiosis, and immune alteration signatures have been identified in various lung cancer types. This review article provides a comprehensive overview of screening tests and the treatment strategies for NSCLC and SCLC, including surgery, radiation therapy, chemotherapy, targeted therapies, and immunotherapies. Through the unification of these diverse aspects, this review article aspires to a complete understanding of lung cancer’s genomics, biology, microbial landscapes, and racial disparity and seeks to understand the essential role of racial and ethnic factors in lung cancer occurrence and treatment. Full article

Cisplatin combined with gemcitabine, a doublet regimen, is the first-line treatment for patients with advanced lung adenocarcinoma (ADC); however, the treatment response remains poor. This study aimed to identify potential biomarkers for predicting response to cisplatin and gemcitabine. Tissue transcriptome and blood proteome analyses were conducted on 27 patients with lung ADC. Blood-derived proteins that reflected tissue-specific biomarkers were obtained using Venn diagrams. The candidate proteins were validated by Western blotting. Lentivirus-mediated short hairpin RNA interference was used to verify the functional roles of the candidate proteins in human A549 cells. We identified 417 differentially expressed genes, including 52 upregulated and 365 downregulated genes, and 31 differentially expressed proteins, including 26 upregulated and 5 downregulated proteins. Integrative analysis revealed the presence of alpha-1-acid glycoprotein 1 (A1AG1) and fibrinogen alpha chain (FGA or FIBA) in both the tissue and serum. FGA levels were elevated in responders compared to non-responders, and reduced serum FGA levels were correlated with resistance to this regimen. Moreover, FGA knockdown in A549 cells resulted in resistance to the doublet regimen. Our findings indicate that FGA is a tissue-specific serum protein that may function as a blood-based biomarker to predict the response of patients with lung ADC to cisplatin plus gemcitabine chemotherapy. Full article

Background: Epstein–Barr virus (EBV) is involved in the development of lymphomas, nasopharyngeal carcinomas (NPC), and a subgroup of gastric carcinomas (GC), and has also been detected in lung carcinomas, even though the role of the virus in this malignancy has not yet been established. BamH1-A Rightward Frame 1 (BARF1), a suggested exclusive epithelial EBV oncoprotein, is detected in both EBV-associated GCs (EBVaGC) and NPC. The expression and role of BARF1 in lung cancer is unknown. Methods: A total of 158 lung carcinomas including 80 adenocarcinomas (AdCs) and 78 squamous cell carcinomas (SQCs) from Chilean patients were analyzed for EBV presence via polymerase chain reaction (PCR), Immunohistochemistry (IHC), or chromogenic in situ hybridization (CISH). The expression of BARF1 was evaluated using Reverse Transcription Real-Time PCR (RT-qPCR). Additionally, A549 and BEAS-2B lung epithelial cells were transfected with a construct for ectopic BARF1 expression. Cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) were evaluated. Results: We found that EBV was present in 37 out of 158 (23%) lung carcinomas using PCR. Considering EBV-positive specimens using PCR, IHC for Epstein–Barr nuclear antigen 1 (EBNA1) detected EBV in 24 out of 30 (80%) cases, while EBERs were detected using CISH in 13 out of 16 (81%) cases. Overall, 13 out of 158 (8%) lung carcinomas were shown to be EBV-positive using PCR/IHC/CISH. BARF1 transcripts were detected in 6 out of 13 (46%) EBV-positive lung carcinomas using RT qPCR. Finally, lung cells ectopically expressing BARF1 showed increased migration, invasion, and EMT. Conclusions. EBV is frequently found in lung carcinomas from Chile with the expression of BARF1 in a significant subset of cases, suggesting that this viral protein may be involved in EBV-associated lung cancer progression. Full article

Background and Objective: The aim of this study is to evaluate the effectiveness of apparent diffusion coefficient (ADC) values in predicting pathologic subtypes and grade in non-small-cell lung cancer (NSCLC). Materials and Methods: From January 2018 to March 2020, 48 surgically diagnosed NSCLC cases were included in this study. To obtain ADC values, ADC maps were constructed, and a region of interest was put on the tumor. The values were measured three times from different places of the lesion, and the mean value of these measurements was recorded. All MRI scans were evaluated by two radiologists in consensus. Results: A total of 14 cases were squamous cell cancer, 32 cases were adenocarcinoma, and 2 cases were large cell carcinoma. The mean ADC values of adenocarcinoma, squamous cell carcinoma, and large cell cancer were 1.51 ± 0.19 × 10⁻³ mm²/s, 1.32 ± 0.15 × 10⁻³ mm²/s, and 1.39 ± 0.25 × 10⁻³ mm²/s, respectively. There were 11 grade 1, 27 grade 2, and 10 grade 3 NSCLC cases. The mean ADC value was 1.44 ± 0.14 × 10⁻³ mm²/s in grade 1 tumors, 1.25 ± 0.10 × 10⁻³ mm²/s in grade 2 tumors, and 1.07 ± 0.15 × 10⁻³ mm²/s in grade 3 tumors. The cut-off value to discriminate grade 2 from grade 1 tumors was 1.31 ± 0.11 × 10⁻³ mm²/s (85% sensitivity, 75% specificity). The cut-off value to discriminate grade 3 from grade 2 tumors was 1.11 ± 0.15 × 10⁻³ mm²/s (87% sensitivity, 69% specificity). Conclusions: ADC values can accurately predict NSCLC histopathologic subtypes and tumor grade. Full article

Few effective treatments are available for small cell lung cancer (SCLC), indicating the need to explore new therapeutic options. Here, we focus on an antibody–drug conjugate (ADC) targeting the L1 cell adhesion molecule (L1CAM). Several publicly available databases reveal that (1) L1CAM is expressed at higher levels in SCLC cell lines and tissues than in those of lung adenocarcinoma and (2) the expression levels of L1CAM are slightly higher in SCLC tissues than in adjacent normal tissues. We conducted a series of in vitro experiments using an anti-L1CAM monoclonal antibody (termed HSL175, developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. Our HSL175-DT3C conjugates theoretically kill cells only when the conjugates are internalized by the target (L1CAM-positive) cells through antigen–antibody interaction. The conjugates (an ADC analog) were effective against two SCLC-N (NEUROD1 dominant) cell lines, Lu-135 and STC-1, resulting in decreased viability. In addition, L1CAM silencing rendered the two cell lines resistant to HSL175-DT3C conjugates. These findings suggest that an ADC consisting of a humanized monoclonal antibody based on HSL175 and a potent anticancer drug would be effective against SCLC-N cells. Full article

The combination of chemotherapy and targeted therapy has been validated in non-small-cell lung cancer (NSCLC) patients with EGFR mutations. We therefore investigated whether this type of combined approach could be more widely used by targeting other genetic alterations present in NSCLC. PDXs were generated from patients with NSCLC adenocarcinomas (ADCs) and squamous-cell carcinomas (SCCs). Targeted NGS analyses identified various molecular abnormalities in the MAPK and PI3K pathways and in the cell cycle process in our PDX panel. The antitumor efficacy of targeted therapies alone or in combination with chemotherapy was then tested in vivo. We observed that trametinib, BKM120, AZD2014 and palbociclib increased the efficacy of each chemotherapy in SCC PDXs, in contrast to a non-insignificant or slight improvement in ADCs. Furthermore, we observed high efficacy of trametinib in KRAS-, HRAS- and NRAS-mutated tumors (ADCs and SCCs), suggesting that the MEK inhibitor may be useful in a wider population of NSCLC patients, not just those with KRAS-mutated ADCs. Our results suggest that the detection of pathogenic variants by NGS should be performed in all NSCLCs, and particularly in SCCs, to offer patients a more effective combination of chemotherapy and targeted therapy. Full article

Lung cancer ranks as the second most prevalent cancer globally and is the primary contributor to neoplastic-related deaths. The approach to its treatment relies on both tumour staging and histological type determination. Data indicate that the prognosis of lung cancer is strongly linked to its clinical stage, underscoring the importance of early diagnosis in enhancing patient outcomes. Consequently, the choice of an appropriate diagnostic method holds significant importance in elevating both the early detection rate and prognosis of lung cancer. This paper aims to assess computer tomography features specific to the most common lung cancer types (adenocarcinoma, squamous cell carcinomas and small cell lung cancer). Data were collected retrospectively from CT scans of 58 patients pathologically diagnosed with lung cancer. The following CT features were evaluated and recorded for each case: location, margins, structure, lymph node involvement, cavitation, vascular bundle-thickening, bronchial obstruction, and pleural involvement. Squamous cell carcinoma (SQCC) and small cell lung cancer (SCLC) showed a higher incidence of central location, while adenocarcinoma (ADC) showed a significant predilection for a peripheral location. Internal cavitation was mostly observed in SQCC, and a solid structure was observed in almost all cases of ADC. These features can provide information about the prognosis of the patient, considering that NSCLCs are more frequent but tend to demonstrate positive results for targetable driver mutations, such as EGFR, thereby increasing the overall survival. In addition, SCLC presents with early distant spreads, which limits the opportunity to investigate the evolution of tumorigenesis and gene alterations at early stages but can have a rapidly positively response to chemotherapy. The location of the lung cancer exhibits distinct forecasts, with several studies suggesting that peripheral lung tumours offer a more favourable prognosis. Cavity formation appears correlate with a poorer prognosis. Histopathological analysis is the gold standard for diagnosing the type of lung cancer; however, using CT scanning for the purpose of a rough, but fast, preliminary diagnosis has the potential to shorten the waiting time for treatment by helping clinicians and patients to know more about the diagnosis and prognosis. Full article

Non-small-cell lung cancer (NSCLC) poses a challenge due to its heterogeneity, necessitating precise histopathological subtyping and prognostication for optimal treatment decision-making. Molecular markers emerge as a potential solution, overcoming the limitations of conventional methods and supporting the diagnostic–therapeutic interventions. In this study, we validated the expression of six genes (MIR205HG, KRT5, KRT6A, KRT6C, SERPINB5, and DSG3), previously identified within a 53-gene signature developed by our team, utilizing gene expression microarray technology. Real-time PCR on 140 thoroughly characterized early-stage NSCLC samples revealed substantial upregulation of all six genes in squamous cell carcinoma (SCC) compared to adenocarcinoma (ADC), regardless of clinical factors. The decision boundaries of the logistic regression model demonstrated effective separation of the relative expression levels between SCC and ADC for most genes, excluding KRT6C. Logistic regression and gradient boosting decision tree classifiers, incorporating all six validated genes, exhibited notable performance (AUC: 0.8930 and 0.8909, respectively) in distinguishing NSCLC subtypes. Nevertheless, our investigation revealed that the gene expression profiles failed to yield predictive value regarding the progression of early-stage NSCLC. Our molecular diagnostic models manifest the potential for an exhaustive molecular characterization of NSCLC, subsequently informing personalized treatment decisions and elevating the standards of clinical management and prognosis for patients. Full article

Abnormal expression of ACSL members 1, 3, 4, 5, and 6 is frequently seen in human cancer; however, their clinical relevance is unclear. In this study, we analyzed the expression of ACSLs and investigated the effects of the ACSL inhibitor Triacsin C (TC) in lung cancer. We found that, compared to normal human bronchial epithelial (NHBE) cells, ACSL1, ACSL4, and ACSL6 were highly expressed, while ACSL3 and ACSL5 were lost in the majority of lung cancer cell lines. ACSL activity was associated with the expression levels of the ACSLs. In primary lung tumors, a higher expression of ACSL1, ACSL4, and ACSL5 was significantly correlated with adenocarcinoma (ADC). Moreover, ACSL5 was significantly reversely related to the proliferation marker Ki67 in low-grade tumors, while ACSL3 was positively associated with Ki67 in high-grade tumors. Combination therapy with TC and Gemcitabine enhanced the growth-inhibitory effect in EGFR wild-type cells, while TC combined with EGFR-TKIs sensitized the EGFR-mutant cells to EGFR-TKI treatment. Taken together, the data suggest that ACSL1 may be a biomarker for lung ADC, and ACSL1, ACSL4, and ACSL5 may be involved in lung cancer differentiation, and TC, in combination with chemotherapy or EGFR-TKIs, may help patients overcome drug resistance. Full article

Thrombocytosis is a risk marker for lung cancer in primary care. We investigated whether thrombocytosis presents pre-diagnostically for all the histological subtypes of lung cancer and its association with the stage at diagnosis. A matched cohort study used English electronic primary care data linked to the national cancer registry. Patients diagnosed with lung cancer aged ≥40 years with no prior history of malignancy were matched by age, sex, and general practice to five controls without lung cancer. Multivariable logistic regression models quantified the incidence of pre-diagnostic thrombocytosis and advanced-stage diagnoses, adjusting for COPD diagnosis, smoking status, and anti-platelet drug prescriptions. A total of 9504 cases were matched to 45,647 controls, consisting of 3260 (34%) adenocarcinomas (ADC), 2020 (21%) squamous cell carcinomas (SCC), 70 (<1%) large-cell carcinomas (LCC), and 1089 (12%) small-cell lung cancers (SCLC). The patients with lung cancer were 8.9 (95% CI 8.0–9.9) times more likely to exhibit pre-diagnostic thrombocytosis than the controls. The odds ratios were highest for the comparison between SCC and ADC (1.8, 95% CI 1.5–2.1). Thrombocytosis is associated with advanced-stage ADC and SCC but presented equally for early- and advanced-stage SCLC. Pre-diagnostic thrombocytosis may aid in the detection of all the histological subtypes in primary care. Full article

Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (n = 10) and MIA (n = 18) and compared the number of genetic mutations with advanced ADC (n = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (p < 0.001) than in advanced ADC (53.7%). In contrast to the high number of mutations in Kirsten rat sarcoma virus gene (KRAS) in advanced ADC (34.6%), there was only one case of AIS with KRAS G12C mutation (3.5%; p < 0.001) and no cases of MIA with KRAS mutation (p < 0.001). In contrast to the modest prevalence of epidermal growth factor receptor (EGFR) mutations in advanced ADC (15.0%), the fraction of EGFR mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; p < 0.001). The EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA. Full article

We investigated the survival and patterns of failure in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) in early stage non-small cell lung cancer (NSCLC) treated with single-fraction stereotactic body radiation therapy (SF-SBRT) of 27–34 Gray. A single-institution retrospective review of patients with biopsy-proven early stage ADC or SCC undergoing definitive SF-SBRT between September 2008 and February 2023 was performed. The primary outcomes were overall survival (OS) and disease-free survival (DFS). The secondary outcomes included local failure (LF), nodal failure (NF), and distant failure (DF). Of 292 eligible patients 174 had adenocarcinoma and 118 had squamous cell carcinoma. There was no significant change in any outcome except distant failure. Patients with ADC were significantly more likely to experience distant failure than patients with SCC (p = 0.0081). In conclusion, while SF-SBRT produced similar LF, NF, DFS, and OS, the higher rate of distant failure in ADC patients suggests that ongoing trials of SBRT and systemic therapy combinations should report their outcomes by histology. Full article