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Background: Adenosquamous carcinoma of the lung (ASC) is a rare non-small-cell lung cancer (NSCLC) subtype combining components of squamous cell carcinoma (SCC) and adenocarcinoma (AC). Data on ASC, particularly in Caucasian populations, are limited. Methods: We reviewed clinicopathological and radiological characteristics of ASC patients diagnosed between 1996 and 2023. Patients were classified into AC-predominant ASC (AC-ASC) and SCC-predominant ASC (SCC-ASC) groups for analysis. Results: Among the 66 patients included, the median overall survival was 41.7 (95% CI, 25.0–54.4), while it was 48.1 (95% CI, 27.3–88.0) in patients treated with curative surgery (n = 44) and 15.3 (95% CI, 6.5–42.6) months for palliative patients (n = 22). The five-year survival rates were 39% and 26%, respectively. Recurrence occurred in 43% of stage I patients and was associated with worse survival (HR 3.303 (95% CI, 1.10–9.89) p = 0.033). AC-ASCs (n = 17) more frequently showed air-bronchogram (p = 0.002) and pleural effusions (p = 0.054) compared to SCC-ASCs (n = 26). SCC-ASCs exhibited more vascular invasion (p = 0.006) and PD-L1 values between 1 and 49% (TPS) (p = 0.032). The subtype did not influence survival. EGFR and ALK alterations were found in 17% and 2% of patients, respectively. Conclusions: Despite early-stage disease, ASC patients had a high recurrence rate, associated with worse survival. Clinicopathologic differences between AC-ASCs and SCC-ASCs did not influence survival. [ABSTRACT FROM AUTHOR]

Background: Cancer survival prediction is vital in improving patients' prospects and recommending therapies. Understanding the molecular behavior of cancer can be enhanced through the integration of multi-omics data, including mRNA, miRNA, and DNA methylation data. In light of these multi-omics data, we proposed a graph attention network (GAT) model in this study to predict the survival of non-small cell lung cancer (NSCLC). Methods: The different omics data were obtained from The Cancer Genome Atlas (TCGA) and preprocessed and combined into a single dataset using the sample ID. We used the chi-square test to select the most significant features to be used in our model. We used the synthetic minority oversampling technique (SMOTE) to balance the dataset and the concordance index (C-index) to measure the performance of our model on different combinations of omics data. Results: Our model demonstrated superior performance, with the highest value of the C-index obtained when we used both mRNA and miRNA data. This demonstrates that the multi-omics approach could be effective in predicting survival. Further pathway analysis conducted with KEGG showed that our GAT model provided high weights to the features that are associated with the viral entry pathways, such as the Epstein–Barr virus and Influenza A pathways, which are involved in lung cancer development. From our findings, it can be observed that the proposed GAT model leads to a significantly improved prediction of survival by exploiting the strengths of multiple omics datasets and the findings from the enriched pathways. Our GAT model outperforms other state-of-the-art methods that are used for NSCLC prediction. Conclusions: In this study, we developed a new model for the survival prediction of NSCLC using the GAT based on multi-omics data. Our model showed outstanding predictive values, and the KEGG analysis of the selected significant features showed that they were implicated in pivotal biological processes underlying pathways such as Influenza A and the Epstein–Barr virus infection, which are linked to lung cancer progression. [ABSTRACT FROM AUTHOR]

The non-canonical PD-L1 pathway revealed that programmed-death ligand 1 (PD-L1) expression in immune cells also plays a crucial role in immune response. Moreover, immune cell distribution in a tumour microenvironment (TME) is pivotal for tumour genesis. However, the results remain controversial and further research is needed. Distribution of PD-L1-positive (PD-L1+) tumour-infiltrating lymphocytes in the context of TME was assessed in 72 archival I–III stage surgically resected NSCLC tumour specimens. Predominant PD-L1+ lymphocyte distribution in the tumour stroma, compared to islets, was found (p = 0.01). Higher PD-L1+ lymphocyte infiltration was detected in smokers due to their predominance in the stroma. High PD-L1+ lymphocyte infiltration in tumour stroma was more common in tumours with higher CD4+ T cell infiltration in islets and stroma, Foxp3+CD4+ T cell infiltration in islets and lover M1 macrophage infiltration in the stroma (p = 0.034, p = 0.034, p = 0.005 and p = 0.034 respectively). Meanwhile, high PD-L1+ lymphocyte infiltration in islets was predominantly found in tumours with high levels of IL-17A+CD4+ T cells in islets and Foxp3+CD4+ T cells in islets and stroma (p = 0.032, p = 0.009 and p = 0.034, respectively). Significant correlations between PD-L1+ lymphocytes and tumour-infiltrating CD4+, Foxp3+CD4+, IL-17A+CD4+ T cells and M2 macrophages were found. An analysis of the tumour-immune phenotype revealed a significant association between PD-L1 expression and IL17+CD4+ and Foxp3+CD4+ immune phenotypes. PD-L1+ lymphocytes are associated with the distribution of CD4+, Foxp3+CD4+, IL17A+CD4+ T cells, M1 and M2 macrophages in TME of resected NSCLC. [ABSTRACT FROM AUTHOR]

Several microRNAs (miRNAs), including miR-221-5p, Let-7b-5p, miR-21-5p, miR-9-5p, miR-126-3p, and miR-222-3p, were recently found to be enriched in circulating exosomes of patients with non-small cell lung cancers (NSCLCs). These miRNAs distinguished cancer cases from controls with high precision and were predicted to modulate the expression of genes within the oncogenic LINE-1 regulatory network. To test this hypothesis, plasma exosomes from controls, early, and late-stage NSCLC patients were co-cultured with non-tumorigenic lung epithelial cells for 72 h and processed for measurements of gene expression. Exosomes from late-stage NSCLC patients markedly increased the mRNA levels of LINE-1 ORF1 and ORF2, as well as the levels of target miRNAs in naïve recipient cells compared to saline or control exosomes. Late-stage exosomes also modulated the expression of oncogenic targets within the LINE-1 regulatory network, namely, ICAM1, AGL, RGS3, RGS13, VCAM1, and TGFβ1. In sharp contrast, exosomes from controls or early-stage NSCLC patients inhibited LINE-1 expression, along with many of the genetic targets within the LINE-1 regulatory network. Thus, late-stage NSCLC exosomes activate LINE-1 and miRNA-regulated oncogenic signaling in non-tumorigenic, recipient lung bronchial epithelial cells. These findings raise important questions regarding lung cancer progression and metastasis and open the door for the exploration of new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Lung cancer continues to have one of the highest morbidity and mortality rates of any cancer. Although radiochemotherapy, in combination with immunotherapy, has significantly improved overall survival, new treatment options are urgently needed. However, preclinical radiotherapy testing is often performed in animal models, which has several drawbacks, including species-specific differences and ethical concerns. To replace animal models, this study used a micro-extrusion bioprinting approach to generate a three-dimensional (3D) human lung cancer model consisting of lung tumor cells embedded in human primary lung fibroblasts for radiotherapy research. The models were placed in a mouse phantom, i.e., a 3D-printed mouse model made of materials that mimic the X-ray radiation attenuation rates found in mice. In radiotherapy experiments, the model demonstrated a selective cytotoxic effect of X-rays on tumor cells, consistent with findings in 2D cells. Furthermore, the analysis of metabolic activity, cell death, apoptosis, and DNA damage-induced γH2AX foci formation revealed different results in the 3D model inside the phantom compared to those observed in irradiated models without phantom and 2D cells. The proposed setup of the bioprinted 3D lung model inside the mouse phantom provides a physiologically relevant model system to study radiation effects. [ABSTRACT FROM AUTHOR]

Objectives: This systematic review aimed to examine the efficacy and safety profile of amivantamab in patients with advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR mutations. Methods: Three scientific databases, PubMed, Cochrane library and ClinicalTrials.gov were searched for relevant articles up until 30 June 2024. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and ≥3 grade adverse events (AE) were the outcomes of interest. Results: Five clinical trials were included in this systematic review, reporting data from 1124 patients (safety population; n = 1091 efficacy population), who received amivantamab as a monotherapy or in combination with other treatments, both in a first-line and in a relapsed/refractory setting. The median PFS for groups of patients that received amivantamab ranged from 4.3 to 8.3 months, while the lowest observed OS was 10.2 months. The ORR ranged from 30% to 73%. The rate of grade 3 or higher AEs ranged from 35% to 92%, while serious AEs ranged from 29% to 52%. Infusion-related reactions (IRRs) ranged from 42% to 78% among patients that received amivantamab intravenously, while a 13% IRR rate was found in a group of patients that received amivantamab subcutaneously. Conclusions: Current evidence suggests that amivantamab is an effective treatment option for patients with advanced or metastatic NSCLC with EGFR mutations. Amivantamab-based combinations may prolong survival both in the treatment of naïve patients and those who have progressed on chemotherapy or tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease. [ABSTRACT FROM AUTHOR]

A growing number of studies have shown that microRNAs (miRNAs) can exert oncogenic or tumor suppressor activities in a variety of cancers, including lung cancer. Given their presence in exosome preparations, microRNA molecules may in fact participate in exosomal intercellular transfers and signaling. In the present study, we examined the profile of 25 circulating exosomal microRNAs in ostensibly healthy controls compared to patients with squamous cell lung cancers (SQCLC) or lung adenocarcinomas (LUAD). Eight miRNAs, namely, miR-21-5p, miR-126-3p, miR-210-3p, miR-221-3p, Let-7b-5p, miR-146a-5p, miR-222-3p, and miR-9-5p, were highly enriched in the cohort and selected for further analyses. All miRNAs were readily detected in non-small cell lung cancer (NSCLC) patients of both sexes at all cancer stages, and their levels in exosomes correlated with the clinicopathological characteristics of tumors. Thus, the presence of these miRNAs in circulating exosomes may contribute to the regulation of oncogenic activity in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine lung adenocarcinomas are malignant tumors generally treated by surgical excision. When inoperable, chemotherapy can be performed with limited benefit. For this reason, the use of targeted drugs can be attempted, as has already happened in human medicine. In this retrospective study, 19 canine lung adenocarcinomas were investigated with three different methods to evaluate the expression of HER2. This transmembrane receptor for the human epidermal growth factor is often altered in human epithelial tumors, for which many targeted drugs have recently been produced. Using immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing, we found 3 cases out of 19 with protein overexpression, 2 cases with amplification, and only 1 case with a specific type of mutation (V659E), probably sensitive to tyrosine kinase inhibitory drugs. Due to the similar HER2 molecular changes in dogs and humans, this study provides preliminary information regarding the possible future use of targeted therapies in canine pulmonary adenocarcinomas. Recently, human epidermal growth factor receptor 2 (HER2) has emerged as a therapeutic target of interest for non-small-cell lung cancer in humans. The role of HER2 in canine pulmonary adenocarcinomas is poorly documented. To address this gap, this study employed three methodologies: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) to investigate the protein expression, gene amplification, and mutation of HER2 in 19 canine primary pulmonary adenocarcinomas. By IHC, 3 out of 19 cases were overexpressed 3+, 6 were 2+, and 10 were negative. With FISH, 2 cases were amplified (12.5%), 3 were inadequate for the analyses, and the others were non-amplified. With NGS, seven cases were inadequate. All other cases were wild-type, except for one IHC 3+ case, which was amplified with FISH and with a specific mutation already described in human pulmonary adenocarcinoma, V659E. This mutation is probably sensitive to tyrosine kinase inhibitory drugs. These results are similar to those in human medicine and to the few data in the literature on canine lung carcinomas; the presence of 12.5% of amplified cases in dogs lays the foundation for future targeted drugs against HER2 alterations. [ABSTRACT FROM AUTHOR]

Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge as promising therapeutic targets, including KRAS non-G12C, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5. In this review, we summarize the emerging molecular targets with a potential clinical impact in advanced NSCLC, elaborating on their clinical characteristics and specific mechanisms and molecular pathways for which targeted treatments are currently available. Additionally, we present an aggregate of ongoing clinical trials investigating the available treatment options targeting such alterations, in addition to their current recruitment status and preliminary efficacy data. These advancements may guide further research endeavors and inform future treatment strategies to improve the management of and transform outcomes for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) have emerged as a leading targeted cancer therapy, reducing the side effects often seen with non-targeted treatments, especially the damage to healthy cells. To tackle resistance, typically caused by epidermal growth factor receptor (EGFR) mutations, four generations of TKIs have been developed. Each generation has shown improved effectiveness and fewer side effects, resulting in better patient outcomes. For example, patients on gefitinib, a first-generation TKI, experienced a progression-free survival (PFS) of 10 months compared to 5 months with conventional chemotherapy. Second-generation TKI afatinib outperformed erlotinib and extended PFS to 11.1 months compared to 6.9 months with cisplatin. Third-generation TKIs further increased survival to 38.6 months, compared to 31.8 months with first-generation TKIs. This progress demonstrates the ability of newer TKIs to overcome resistance, particularly the T790M mutation, while reducing adverse effects. Ongoing research focuses on overcoming resistance from newer mutations like C797S to further improve patient survival. These developments highlight the significant progress in TKI therapy and the continued effort to refine cancer treatment. Recent research in South Korea shows that third-generation TKIs are ineffective against non-small cell lung cancer (NSCLC) with the C797S mutation. Several trials have started showing promising in vitro and in vivo results, but more trials are needed before clinical approval. This review underscores notable advancements in the field of EGFR TKIs, offering a comprehensive analysis of their mechanisms of action and the progression of various TKI generations in response to resistance. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) are detected in approximately 30% of metastatic non-small-cell lung cancer (NSCLC) cases using the CellSearch system, which relies on EpCAM immunomagnetic enrichment and Cytokeratin detection. This study evaluated the effectiveness of immunomagnetic enrichment targeting oncofetal chondroitin sulfate (ofCS) using recombinant VAR2CSA proteins (rVAR2) to improve the recovery of different NSCLC cell lines spiked into lysed blood samples. Four NSCLC cell lines—NCI-H1563, A549, NCI-H1792, and NCI-H661—were used to assess capture efficiency. The results demonstrated that the combined use of anti-EpCAM antibody and rVAR2 significantly enhanced the capture efficiency to an average of 88.2% compared with 40.6% when using only anti-EpCAM and 56.6% when using only rVAR2. These findings suggest that a dual-marker approach using anti-EpCAM and rVAR2 can provide a more robust and sensitive method for CTC enrichment in NSCLC, potentially leading to better diagnostic and prognostic outcomes. [ABSTRACT FROM AUTHOR]

Background: While adoption of personalized medicine (PM) continues to increase in clinical oncology, there is limited data connecting the level of PM adoption at a given institution to improved clinical outcomes for patients. The purpose of this study was to analyze the correlation between health care providers' scores on a previously described PM integration framework and two outcome measures: the use of targeted therapy and clinical trial enrollment. Methods: This study was conducted using real-world data (RWD) from the Syapse® Learning Health Network (LHN). The PM integration score for six community hospital systems in the LHN was calculated and subsequently correlated with the two outcome measures. Results: Across six institutions, a strong correlation between PM integration score and targeted therapy use was observed in metastatic non-small cell lung cancer (mNSCLC) (R2 = 0.81), an indication with a significant number of approved targeted agents. Conversely, a strong correlation between PM integration score and clinical trial enrollment was observed in metastatic triple-negative breast cancer (TNBC) (R2 = 0.63), an indication with fewer marketed targeted therapies but an active targeted therapy pipeline. Conclusion: The results in these cases suggest that PM integration is a strong indicator of high-quality care practices for both utilization of targeted therapy in more mature PM indications (e.g., mNSCLC) and clinical trial enrollment in more emerging PM indications (e.g., TNBC). [ABSTRACT FROM AUTHOR]

Background/Objectives: Epidermal growth factor receptor (EGFR) plays a vital role in cell proliferation and survival, with its overexpression linked to various malignancies, including non-small cell lung cancer (NSCLC). Although EGFR tyrosine kinase inhibitors (TKIs) are a key therapeutic strategy, acquired resistance and relapse remain challenges. This study aimed to synthesize and evaluate novel rhenium-based complexes incorporating EGFR TKIs to enhance anticancer efficacy, particularly in radiosensitization. Methods: We synthesized a rhenium tricarbonyl complex (Complex 2) and its 99mTc analog (Complex 2') by incorporating triphenylphosphine instead of bromine as the monodentate ligand and P F 6 − as the counter-ion, resulting in a positively charged compound that forms cationic structures. Cytotoxicity and EGFR inhibition were evaluated in A431 cells overexpressing EGFR using MTT assays, Western blotting, and flow cytometry. Radiosensitization was tested through MTT and clonogenic assays. The 99mTc complex's radiochemical yield, stability, and lipophilicity were also assessed. Results: Complex 2 exhibited significant cytotoxicity with an IC50 of 2.6 μM and EGFR phosphorylation inhibition with an IC50 of 130.6 nM. Both complex 1 and 2 induced G0/G1 cell cycle arrest, with Complex 2 causing apoptosis. Radiosensitization was observed at doses above 2 Gy. Complex 2' demonstrated high stability and favorable lipophilicity (LogD7.4 3.2), showing 12% cellular uptake after 30 min. Conclusions: Complexes 2 and 2' show promise as dual-function anticancer agents, offering EGFR inhibition, apoptosis induction, and radiosensitization. Their potential as radiopharmaceuticals warrants further in-depth investigation in preclinical models. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading cause of cancer-related death worldwide that needs updated therapies to contrast both the serious side effects and the occurrence of drug resistance. A panel of non-small cell lung cancer (NSCLC) cells were herein employed as cancer models. Eight structurally related gold(I) and gold(III) complexes with NHC and halides or triphenylphosphane ligands were investigated as lung cancer cell growth inhibitors. As expected, gold compounds with PPh3 were found to be more cytotoxic than homoleptic [(NHC)2-Au(I)]X or heteroleptic NHC-Au(I)X or NHC-Au(III)X3 complexes. Mixed ligand gold(I) compounds exhibiting the linear NHC-AuPPh3 (compound 7) or the trigonal NHC-Au(Cl)PPh3 (compound 8) arrangements at the central metal were found to be the best lung cancer cytotoxic compounds. Analysis of the TrxR residual activity of the treated cells revealed that these compounds efficiently inhibit the most accredited molecular target for gold compounds, the TrxR, with compound 8 reaching more than 80% activity reduction in lung cells. Some of the current cancer lung therapy protocols consist of specific lung cancer cell cytotoxic agents combined with antifolate drugs; interestingly, the herein gold compounds are both TrxR and antifolate inhibitors. The human DHFR was inhibited with IC50 ranging between 10–21 µM, depending on substrate concentrations, proceeding by a likely allosteric mechanism only for compound 8. [ABSTRACT FROM AUTHOR]

Targeting epidermal growth factor receptor (EGFR) mutants is a promising strategy for treating non-small cell lung cancer (NSCLC). This study focused on the computational identification and characterization of potential EGFR mutant-selective inhibitors using pharmacophore design and validation by deep learning, virtual screening, ADMET (Absorption, distribution, metabolism, excretion and toxicity), and molecular docking-dynamics simulations. A pharmacophore model was generated using Pharmit based on the potent inhibitor JBJ-125, which targets the mutant EGFR (PDB 5D41) and is used for the virtual screening of the Zinc database. In total, 16 hits were retrieved from 13,127,550 molecules and 122,276,899 conformers. The pharmacophore model was validated via DeepCoy, generating 100 inactive decoy structures for each active molecule and ADMET tests were conducted using SWISS ADME and PROTOX 3.0. Filtered compounds underwent molecular docking studies using Glide, revealing promising interactions with the EGFR allosteric site along with better docking scores. Molecular dynamics (MD) simulations confirmed the stability of the docked conformations. These results bring out five novel compounds that can be evaluated as single agents or in combination with existing therapies, holding promise for treating the EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

Docetaxel is a commonly used taxane chemotherapeutic agent in the treatment of a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer. Docetaxel exerts its anti-cancer effects through inhibition of the cell cycle and induction of proapoptotic activity. However, docetaxel also impacts rapidly proliferating normal cells in the scalp hair follicles (HFs), rendering the HFs vulnerable to docetaxel-induced cell death and leading to chemotherapy-induced alopecia (CIA). In severe cases, docetaxel causes persistent or permanent CIA (pCIA) when hair does not grow back completely six months after chemotherapy cessation. Hair loss has severe negative impacts on patients' quality of life and may even compromise their compliance with treatment. This review discusses the notable prevalence of docetaxel-induced CIA and pCIA, as well as their prevention and management. At this moment, scalp cooling is the standard of care to prevent CIA. Treatment options to promote hair regrowth include but are not limited to minoxidil, photobiomodulation (PBMT), and platelet-rich plasma (PRP). In addition, a handful of current clinical trials are exploring additional agents to treat or prevent CIA. Research models of CIA, particularly ex vivo human scalp HF organ culture and in vivo mouse models with human scalp xenografts, will help expedite the translation of bench findings of CIA prevention and/or amelioration to the clinic. [ABSTRACT FROM AUTHOR]

Since the initial US FDA approval of an immune checkpoint inhibitor (ICI) for the treatment of non-oncogene-driven non-small-cell lung cancer (NSCLC) nine years ago, this therapeutic strategy has been cemented as a crucial component of treatment for most of these patients. However, there is a clear efficacy–effectiveness gap whereby patients in the 'real world' seem to have more modest clinical outcomes compared to those enrolled in landmark clinical trials. This gap may be driven by the under-representation of important patient populations, including populations defined by clinical or molecular characteristics. In this review, we summarize the data outlining the evidence of ICIs in patients with poor Eastern Cooperative Oncology Group performance status (ECOG PS), underlying autoimmune disease (AID), older age, active brain metastases (BMs), and molecular aberrations such as EGFR mutations, ALK fusions, BRAF mutations and ROS1 fusions. [ABSTRACT FROM AUTHOR]

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB–IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)–IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease. [ABSTRACT FROM AUTHOR]

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide with non-small cell lung cancer (NSCLC) accounting for the majority of cases. The stage of detection significantly influences survival rates with early-stage diagnosis offering the best prognosis. This study investigates the prognostic impact of the omega-6/omega-3 ratio and tumor infiltration by CD8+ lymphocytes and CD68+ macrophages on overall survival (OS) and disease-free survival (DFS) in NSCLC patients undergoing pulmonary resection. Methods: We conducted a retrospective analysis of 53 patients with early-stage NSCLC who underwent pulmonary resection between September 2017 and January 2020. The omega-6/omega-3 ratio was quantified using gas chromatography and spectrometry. Tumor infiltration by CD8 and CD68 was assessed through immunohistochemistry. Survival outcomes were evaluated using Kaplan-Meier and Cox regression analyses. Results: An increased omega-6/omega-3 ratio and higher CD68+ macrophage infiltration were associated with a trend towards worse OS and DFS in NSCLC patients, though these results did not reach statistical significance. CD8+ T-cell infiltration was associated with improved survival outcomes, confirming its role as a favorable prognostic marker. Comparative analysis with existing datasets revealed similar demographic and clinical characteristics, reinforcing the generalizability of our findings. Conclusions: The omega-6/omega-3 ratio and CD68+ macrophage infiltration serve as important factors potentially influencing prognosis in NSCLC patients undergoing pulmonary resection. These findings highlight the need for further research to refine the prognostic utility of these biomarkers and to explore therapeutic strategies targeting inflammation and immune cell infiltration. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to investigate a series of complete blood cell count-based biomarkers of systemic inflammation as predictors of clinical outcomes in patients who underwent first-line chemoimmunotherapy for advanced NSCLC. Methods: Consecutive patients with pathologically diagnosed stage III/IV NSCLC and PD-L1 < 50% who underwent first-line chemoimmunotherapy were retrospectively enrolled. The clinical outcomes used for biomarker evaluation were Objective Response Rate (ORR) and Overall Survival (OS). Results: Non-responders had significantly higher values of neutrophil to lymphocyte ratio (NLR, median: 5.36; IQR: 2.78–10.82 vs. 3.31; IQR: 2.15–4.12, p = 0.019), neutrophil to monocyte ratio (NMR, median: 14.00; IQR: 8.82–21.20 vs. 9.20; IQR: 7.45–11.20, p = 0.013), and systemic inflammation index (SII, median: 1395; IQR: 929–3334 vs. 945; IQR: 552–1373, p = 0.025), but only NLR and NMR remained independently associated with clinical response in multivariate logistic regression. In the univariate analysis, white blood cells (OR:1.2202; 95% CI: 1.0339–1.4400, p = 0.019), neutrophils (OR:1.2916; 95% CI: 1.0692–1.5604, p = 0.008), NLR (OR:1.3601: 95% CI: 1.0949–1.6896, p = 0.005) and NMR (OR:1.2159; 95% CI: 1.00396–1.4221, p = 0.015) were significantly associated with survival; Cox regression models confirmed that neutrophils, NLR, and MLR were independently associated with survival; NLR, at a cut-off value of 4.0, showed the better AUC (0.749) in predicting OS. Conclusions: Baseline complete blood cell count biomarkers, especially the NLR, can predict clinical outcomes in patients with advanced NSCLC treated with first-line chemoimmunotherapy. [ABSTRACT FROM AUTHOR]

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies. [ABSTRACT FROM AUTHOR]

Immune activation status determines non-small cell lung cancer (NSCLC) prognosis, with reported positive/negative associations for T helper type 2 (TH2) responses, including allergen-specific IgE and eosinophils. Our study seeks to explore the potential impact of these comorbid immune responses on the survival rates of patients with NSCLC. Our retrospective study used data from the Data Warehouse of the German Center for Lung Research (DZL) and Lung Biobank at Thoraxklinik Heidelberg. We estimated the association of blood eosinophilia and neutrophilia on survival rates in an inflammatory cohort of 3143 patients with NSCLC. We also tested sensitization to food and inhalants and high-sensitivity C-reactive protein (hs-CRP) in a comorbidity cohort of 212 patients with NSCLC. Finally, we estimated the infiltration of immune-relevant cells including eosinophils, T-cells, and mast cells in a tissue inflammatory sub-cohort of 60 patients with NSCLC. Sensitization to at least one food or inhalant (sIgE) was higher in patients with adenocarcinoma (adeno-LC) than the non-adenocarcinoma (non-adeno-LC). Furthermore, hs-CRP was higher in non-adeno-LC compared with adeno-LC. Peripheral inflammation, particularly eosinophilia and neutrophilia, was associated with poor survival outcomes in NSCLC with a clear difference between histological subgroups. Finally, blood eosinophilia was paralleled by significant eosinophil infiltration into the peritumoral tissue in the lung. This study provides novel perspectives on the crucial role of peripheral inflammation, featuring eosinophilia and neutrophilia, with overall survival, underscoring distinctions between NSCLC subgroups (adeno-LC vs. non-adeno-LC). Peripheral eosinophilia enhances eosinophil infiltration into tumors. This sheds light on the complex interplay between inflammation, eosinophil infiltration, and NSCLC prognosis among various histological subtypes. Further studies are required to underscore the role of eosinophils in NSCLC among different histological subgroups and their role in shaping the tumor microenvironment. [ABSTRACT FROM AUTHOR]

The objective of this study was to enhance the membrane permeability and anticancer effectiveness of (20S)-protopanaxadiol (PPD) by introducing triphenylphosphonium into the OH group at the C-3 site. This study shows that the anti-proliferation activity of CTPPPPD, with an IC50 value of 1.65 ± 0.10 μmol/L, was 33-times better than that of PPD (with an IC50 value of 54.56 ± 4.56 μmol/L) and superior to that of cisplatin (with an IC50 value of 1.82 ± 0.25 μmol/L) against A549 cells. Biological examinations suggested that CTPPPPD treatment reduced the growth rate of A549 cells, increased the permeability of cell membranes, and changed the structure of chromosomal DNA in a concentration-dependent manner. Annexin V/PI assay and flow cytometry were employed to detect the effect of CTPPPPD on the apoptosis of A549 cells. The results showed that CTPPPPD could induce the apoptosis of A549 cells, and the apoptosis rate of A549 cells treated with 0, 1.0, 2.0, and 4.0 μM of CTPPPPD for 24 h was 0%, 4.9%, 12.7%, and 31.0%, respectively. The integration of transcriptomics and metabolomics provided a systematic and detailed perspective on the induced antitumor mechanisms. A combined analysis of DEGs and DAMs suggested that they were primarily involved in the central carbon metabolism pathway in cancer, as well as the metabolism of aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate. Central carbon metabolism in cancer-related genes, i.e., SLC16A3, FGFR3, LDHA, PGAM1, and SLC2A1, significantly reduced after treatment with CTPPPPD. In particular, the dominant mechanism responsible for total antitumor activity may be attributed to perturbations in the PI3K-AKT, MAPK, and P53 pathways. The findings derived from transcriptomics and metabolomics were empirically confirmed through q-PCR and molecular docking. Further analyses revealed that CTPPPPD could be a promising lead for the development of protopanaxadiol for non-small-cell lung cancer (NSCLC) drugs. [ABSTRACT FROM AUTHOR]

The results of a prospective, multi-institutional randomized trial developed to assess the equality of sublobar resection versus standard lobectomy were first published in 1995. They concluded that, compared with lobectomy, sublobar resections did not show any significant improvement either in terms of postoperative morbidity and mortality nor in terms of late post-resectional cardiorespiratory function. Moreover, due to the higher mortality and local recurrence rate related to sublobar resection, lobectomy had to be judged as the best surgical option for patients diagnosed with peripheral early-stage non-small-cell lung cancer. Since then, lobectomy has been considered the best surgical option for fit patients suffering from early-stage non-small cell lung cancer. In 2022 and 2023, three non-inferiority randomized trials were published, comparing lobectomy with the sublobar resection in T1a N0 patients whose tumors were up to 2 cm in size. Although presenting some important differences, all three trials met their primary endpoints, disclosing the non-inferiority of sublobar resections in terms of overall and disease-free survival. This narrative review aims to compare the newly published results of these trials as well as to report results from recent non-randomized studies on this topic. [ABSTRACT FROM AUTHOR]

Background/Objectives: The prolonged time to reach investigation and management decisions in non-small cell lung cancer (NSCLC) patients can negatively impact long-term outcomes. This retrospective cohort study aims to assess the impact of a multidisciplinary team conference (MDT) on NSCLC care quality and outcomes. Methods: This retrospective study included resectable NSCLC patients who underwent pulmonary resection at Chiang Mai University Hospital, Thailand, from 1 January 2009 to 31 December 2021. Patients were divided into two groups: non-MDT and MDT groups, based on the initiation of MDT on 1 March 2018. The study compared overall survival, disease-free survival, and waiting times for investigation and surgery between the two groups. The effect of MDT on these outcomes was analyzed using multivariable analysis with inverse-probability weighting propensity scores. Results: The study included 859 patients, with 583 in the non-MDT group and 276 in the MDT group. MDT groups had a higher proportion of stage I and II NSCLC patients undergoing pulmonary resection (78.6% vs. 59.69%, p < 0.001). In multivariable analysis, patients in the MDT group had a significantly higher likelihood of longer survival compared to the non-MDT group (adjusted HR 0.23, 95% CI 0.09–0.55). Median waiting times for bronchoscopy (3 days vs. 12 days, p = 0.012), pathologic report (7 days vs. 13 days, p < 0.001), and surgery scheduling (18 days vs. 25 days, p = 0.001) were significantly shorter in the MDT group. Conclusions: An MDT has a survival benefit in NSCLC care and improves waiting times for investigation and treatment steps. Further studies are needed to validate these results. [ABSTRACT FROM AUTHOR]

Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC. [ABSTRACT FROM AUTHOR]

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC. [ABSTRACT FROM AUTHOR]

Identifying biomarkers in non-small cell lung cancer (NSCLC) can improve diagnosis and patient stratification. We evaluated plasmas and sera for interleukins (IL)-11, IL-6, IL-8, IL-17A, and IL-33 as biomarkers in primary NSCLC patients undergoing surgical treatment against normal volunteers. Exhaled-breath condensates (EBCs), a potential source without invasive procedures, were explored in normal individuals. Due to separate recruitment criteria and intrinsic cohort differences, the NSCLC and control cohorts were not well matched for age (median age: 65 vs. 40 years; p < 0.0001) and smoking status (p = 0.0058). Interleukins were first assessed through conventional ELISA. IL-11 was elevated in NSCLC plasma compared to controls (49.71 ± 16.90 vs. 27.67 ± 14.06 pg/mL, respectively, p < 0.0001) but undetectable in sera and EBCs by conventional ELISA. Therefore, high-sensitivity PCR-based IL-11 ELISA was repeated, albeit with concentration discrepancies. IL11 gene and protein upregulation by RT-qPCR and immunohistochemistry, respectively, were validated in NSCLC tumors. The lack of detection sensitivity across IL-6, IL-8, IL-17A, and IL-33 suggests the need for further, precise assays. Surprisingly, biomarker concentrations can be dissimilar across paired plasmas and sera. Our results identified a need to optimize detection limits for biomarker detection and caution against over-reliance on just one form of blood sample for biomarker assessment. [ABSTRACT FROM AUTHOR]

Lung cancer mortality rates, particularly non-small cell lung cancer (NSCLC), continue to present a significant global health challenge, and the adoption of lung cancer screening remains limited, often influenced by inequities in access to healthcare. Despite clinical evidence demonstrating the efficacy of annual screening with low-dose computed tomography (LDCT) and recommendations from medical organizations including the U.S. Preventive Services Task Force (USPSTF), the national lung cancer screening uptake remains around 5% among eligible individuals. Advancements in the clinical management of NSCLC have recently become more personalized with the implementation of blood-based biomarker testing. Extensive research into tumor-derived cell-free DNA (cfDNA) through fragmentation offers a novel method for improving early lung cancer detection. This review assesses the screening landscape, explores obstacles to lung cancer screening, and discusses how a plasma whole genome fragmentome test (pWGFrag-Lung) can improve lung cancer screening participation and adherence. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal–epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer markers are measurable molecules in blood or tissues that are produced by tumor cells or immune cells in response to cancer progression. They play an important role in clinical diagnosis, prognosis, and therapy monitoring. Splicing factor proline- and glutamine-rich (SFPQ) plays an important role in cancer growth and metastasis. SFPQ is not only more highly expressed in non-small-cell lung cancer (NSCLC) cells than it is in controls, but also highly expressed in cancer cells in patients with other solid cancers. Thus, a new enzyme-linked immunosorbent assay (ELISA) for detecting SFPQ was developed, in which the SFPQ protein is trapped by the first specific mAb coated on a microplate, and then recognized by a second specific mAb. This assay allows for the specific detection of SFPQ in the serum of patients with solid cancer. Regarding NSCLC, the serum SFPQ levels distinguished the non-cancer controls from the patients with NSCLC, with an area under the curve of 0.876, a sensitivity of 87%, and a specificity of 94%. The serum SFPQ levels were significantly elevated in the patients with NSCLC or other solid cancers. In conclusion, serum SFPQ could be a promising novel diagnostic biomarker for NSCLC and other malignancies. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) leads as a primary cause of cancer-related premature mortality in Western populations. This study leverages cutting-edge gene-expression-profiling technologies to perform an in-depth molecular characterization of NSCLC specimens, with the objective of uncovering tumor-specific genomic alterations. By employing DNA microarray analysis, our research aims to refine the classification of NSCLC for early detection, guide molecular-targeted treatment approaches, enhance prognostication, and broaden the scientific understanding of the disease's biology. We identified widespread genomic abnormalities in our samples, including the recurrent loss of chromosomal regions 3p, 5q, 13q, and 21q and the gain of 12p. Furthermore, utilizing Metascape for bioinformatic analysis revealed critical biological pathways disrupted in NSCLC, offering promising leads for novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Machine learning (ML) is commonly used to develop survival-predictive radiomic models in non-small cell lung cancer (NSCLC) patients, which helps assist treatment decision making. Radiomic features derived from computer tomography (CT) lung images aim to capture quantitative tumor characteristics. However, these features are determined by humans, which poses a risk of including irrelevant or redundant variables, thus reducing the model's generalization. To address this issue, we propose using genetic programming (GP) to automatically construct new features with higher discriminant power than the original radiomic features. To achieve this goal, we introduce a fitness function that measures the classification performance ratio of output to input. The constructed features are then input for various classifiers to predict the two-year survival of NSCLC patients from two public CT datasets. Our approach is compared against two popular feature selection methods in radiomics to choose relevant radiomic features, and two GP-based feature construction methods whose fitness functions are based on measuring the constructed features' quality. The experimental results show that survival prediction models trained on GP-based constructed features outperform feature selection methods. Also, maximizing the classification performance gain output-to-input ratio produces features with higher discriminative power than only maximizing the classification accuracy from constructed features. Furthermore, a survival analysis demonstrated statistically significant differences between survival and non-survival groups in the Kaplan–Meier curves. Therefore, the proposed approach can be used as a complementary method for oncologists in determining the clinical management of NSCLC patients. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases and poor prognosis in advanced stages. This study explored shifts in circulating metabolite levels in NSCLC patients versus healthy controls and examined the effects of conventionally fractionated radiation therapy (CFRT) and stereotactic body radiation therapy (SBRT). We enrolled 91 NSCLC patients (38 CFRT and 53 SBRT) and 40 healthy controls. Plasma metabolite levels were assessed using semi-targeted metabolomics, revealing 32 elevated and 18 reduced metabolites in patients. Key discriminatory metabolites included ethylmalonic acid, maltose, 3-phosphoglyceric acid, taurine, glutamic acid, glycocolic acid, and d-arabinose, with a combined Receiver Operating Characteristics curve indicating perfect discrimination between patients and controls. CFRT and SBRT affected different metabolites, but both changes suggested a partial normalization of energy and amino acid metabolism pathways. In conclusion, metabolomics identified distinct metabolic signatures in NSCLC patients with potential as diagnostic biomarkers. The differing metabolic responses to CFRT and SBRT reflect their unique therapeutic impacts, underscoring the utility of this technique in enhancing NSCLC diagnosis and treatment monitoring. [ABSTRACT FROM AUTHOR]

Introduction: One of the most important prognostic factors in non-small cell lung cancer (NSCLC), a condition with a high mortality rate, is the presence of mediastinal lymph node metastases alongside distant metastases. The aim of this study was to evaluate the prognostic value of selected parameters of N2 stage NSCLC with a special focus on lymph node ratio (LNR). Material: The study included 163 patients (61 women and 102 men) operated on due to NSCLC, postoperatively diagnosed as stage N2. The age of the patients ranged from 38 to 82 years (mean age: 62.4 years). The effects of the following factors on clinical data and survival rate were assessed: N1 stage, total number of all metastatic nodes, LNR and LNR N2 ratios, and the presence of skip, single- or multistation metastases. Results: Univariate analysis showed patient survival to be correlated with LNR and LNR N2 ratios, single/multistation metastases, and the number of nodes involved in metastasis. A multivariate model based on patient clinical data found nicotine dependence (p = 0.013), LNR > 0.26 (p = 0.004), and Charlson Comorbidity Index (CCI) value > 3 (p = 0.014) to be independent adverse prognostic factors in this group. Conclusions: LNR ratio is a significant cancer disease-derived independent prognostic factor for patients with postoperative N2 stage NSCLC. In addition, smoking and comorbidities also appear to have prognostic value. [ABSTRACT FROM AUTHOR]

Background: Actionable driver mutations account for 40–50% of NSCLC cases, and their identification clearly affects treatment choices and outcomes. Conversely, non-actionable mutations are genetic alterations that do not currently have established treatment implications. Among co-occurring alterations, the identification of concurrent actionable genomic alterations is a rare event, potentially impacting prognosis and treatment outcomes. Methods: We retrospectively evaluated the prevalence and patterns of concurrent driver genomic alterations in a large series of NSCLCs to investigate their association with clinicopathological characteristics, to assess the prognosis of patients whose tumor harbors concurrent alterations in the genes of interest and to explore their potential therapeutic implications. Results: Co-occurring driver alterations were identified in 26 out of 1520 patients with at least one gene alteration (1.7%). Within these cases, the incidence of concurrent actionable gene alterations was 39% (0.7% of the overall cohort). Among compound actionable gene mutations, EGFR was the most frequently involved gene (70%). The most frequent association was EGFR mutations with ROS1 rearrangement. Front-line targeted treatments were the preferred approach in patients with compound actionable mutations, with dismal median PFS observed (6 months). Conclusions: Advances in genomic profiling technologies are facilitating the identification of concurrent mutations. In patients with concurrent actionable gene alterations, integrated molecular and clinical data should be used to guide treatment decisions, always considering rebiopsy at the moment of disease progression. [ABSTRACT FROM AUTHOR]

Treatment guidelines for non-small cell lung cancer (NSCLC) vary by several factors including pathological stage, patient candidacy, and goal of treatment. With many therapeutics and even more combinations available in the NSCLC clinician's toolkit, a multitude of questions remain unanswered vis-a-vis treatment optimization. While some studies have begun exploring the interplay among the many pillars of NSCLC treatment—surgical resection, radiotherapy, chemotherapy, and immunotherapy—the vast number of combinations and permutations of different therapy modalities in addition to the modulation of each constituent therapy leaves much to be desired in a field that is otherwise rapidly evolving. Given NSCLC's high incidence and lethality, the experimentation of synergistic benefits that combinatorial treatment may confer presents a ripe target for advancement and increased understanding without the cost and burden of novel drug development. This review introduces, synthesizes, and compares prominent NSCLC therapies, placing emphasis on the interplay among types of therapies and the synergistic benefits some combinatorial therapies have demonstrated over the past several years. [ABSTRACT FROM AUTHOR]

In this study we demonstrated for the first time synthetic procedures for composites of salinomycin (SalH) and two-line ferrihydrite. The products were characterized by various methods such as elemental analysis, attenuated total reflectance–Fourier-transform spectroscopy (ATR-FTIR), electron paramagnetic resonance spectroscopy (EPR), powder X-ray diffraction analysis (XRD), electrospray-ionization mass spectrometry (ESI-MS), thermogravimetric analysis with differential thermal analysis (DTA) and mass spectrometry (TG-DTA/MS). The EPR spectra of the isolated compounds consisted of signals associated with both isolated Fe3+ ions and magnetically coupled Fe3+ ions. Powder XRD analyses of the isolated products showed two intense and broad peaks at 9° and 15° 2Θ, corresponding to salinomycinic acid. Broad peaks with very low intensity around 35°, assigned to two-line ferrihydrite, were also registered. Based on the experimental results, we concluded that salinomycin sodium reacted with Fe(III) chloride to form composites consisting of two-line ferrihydrite and salinomycinic acid. One of the composites exerted pronounced antitumor activity in the sub-micromolar concentration range against human cervical cancer (HeLa), non-small-cell lung cancer (A549), colon cancer (SW480), and ovarian teratocarcinoma (CH1/PA1) cells. [ABSTRACT FROM AUTHOR]

RNA-based next-generation sequencing (RNA-seq) represents the gold standard for detecting gene fusion in non-small cell lung cancer (NSCLC). Despite this, RNA instability makes the management of tissue samples extremely complex, resulting in a significant number of test failures with missing data or the need to switch to other techniques. In the present study, we analyzed pre-analytical variables in 140 tumor tissue samples from patients affected by NSCLC to detect features that increase the chances of successful RNA-seq. We found that the success rate of the analysis positively correlates with the RNA concentration and fragmentation index. Interestingly, small biopsies were more suitable samples than surgical specimens and cell blocks. Among surgical specimens, wedge resections demonstrated better results than lobectomy. Moreover, samples stored for less than 30 days (1 month) had a better chance of success than older samples. Defining the role of pre-analytical variables in RNA-seq allows the detection of more suitable samples for analysis and more effective planning of molecular-based diagnostic approaches in NSCLC. [ABSTRACT FROM AUTHOR]

A pediatric dosage form for crizotinib (Xalkori) was commercialized using quality-by-design principles in a material-sparing fashion. The dosage form consists of spherical multiparticulates (microspheres or pellets) that are coated and encapsulated in capsules for opening. The crizotinib (Xalkori)-coated pellet product is approved in the US for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) and unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. The product is also approved in the US for adult patients with non-small cell lung cancer (NSCLC) who are unable to swallow intact capsules. The lipid multiparticulate is composed of a lipid matrix, a dissolution enhancer, and an active pharmaceutical ingredient (API). The API, which remains crystalline, is embedded within the microsphere at a 60% drug loading in the uncoated lipid multiparticulate to enable dose flexibility. The melt spray congealing technique using a rotary atomizer is used to manufacture the lipid multiparticulate. Following melt spray congealing, a barrier coating is applied via fluid bed coating. Due to their particle size and content uniformity, this dosage form provides the dosing flexibility and swallowability needed for the pediatric population. The required pediatric dose is achieved by opening the capsules and combining doses of different encapsulated dose strengths, followed by administration of the multiparticulates directly to the mouth. The encapsulation process was optimized through equipment modifications and by using a design of experiments approach to understand the operating space. A limited number of development batches produced using commercial-scale equipment were leveraged to design, understand, and verify the manufacturing process space. The quality by design and material-sparing approach taken to design the melt spray congeal and encapsulation manufacturing processes resulted in a pediatric product with exceptional content uniformity (a 95% confidence and 99% probability of passing USP <905> content uniformity testing for future batches). [ABSTRACT FROM AUTHOR]

Currently, the treatment of patients with advanced non-small cell lung cancer (NSCLC) mainly relies on traditional chemotherapeutic drugs; however, most of them have limited therapeutic effects and high toxicity. Some natural products with good therapeutic efficacy and low toxicity and side effects are limited in clinical application due to their low solubility and bioavailability. In this study, a nanoliposome drug-carrying system (Lip-Cur/Ba) was developed for the co-delivery of curcumin (Cur) and baicalin (Ba) using the thin-film hydration method. In vitro experiments demonstrated that Lip-Cur/Ba had a strong killing effect on A549 cells, and the inhibitory effect of Lip-Cur/Ba on A549 cells was enhanced by 67.8% and 51.9% relative to that of the single-carrier system, which could reduce the use of a single-drug dose (Lip-Cur and Lip-Ba), delay the release rate of the drug and improve the bioavailability. In vivo experiments demonstrated the antitumor activity of Lip-Cur/Ba by intravitreal injection in BALB/c mice, and there were no obvious toxic side effects. This study provides a new idea for curcumin and baicalin to be used in the co-treatment of NSCLC by constructing a new vector. [ABSTRACT FROM AUTHOR]

Gefitinib is a selective inhibitor of the epidermal growth factor receptor that is used to treat advanced and metastatic non-small cell lung cancer (NSCLC). Dermatological adverse reactions are most commonly associated with gefitinib treatment. The cause of adverse reactions in individuals is multifactorial. Pharmacogenetics is an effective tool to detect such adverse reactions. This case report describes a female patient with NSCLC who was administered gefitinib at a dose of 250 mg/day. However, due to severe adverse dermatological reactions, the treatment was interrupted for 15 d and antibiotic therapy was administered to manage the skin rashes, maculopapular rashes, and hyperpigmentation. Treatment adherence was adequate, and no drug interactions were detected. A pharmacogenetic analysis revealed homozygosity in the ATP-binding cassette (ABC)-B1 rs1128503 (c.1236A>G), heterozygosity in ABCG2 rs2231142 (c.421G>T) and rs2622604 (c.-20+614T>C), and a non-functional variant of the cytochrome P450 family 3, subfamily A, member 5 (CYP3A5). The relationship between altered genetic variants and the presence of adverse reactions induced by gefitinib is still controversial. Overall, this case report highlights the importance of continuing to study pharmacogenetics as predictors of adverse drug reactions. [ABSTRACT FROM AUTHOR]

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids show wide structural diversity and mediate a great number of biological responses relevant for human health, including cancer prevention and cytotoxicity. Resveratrol is known to modulate several pathways directly linked to cancer progression, as well as its analogue pterostilbene, characterized by an increased metabolic stability and significant pharmacological activities. To study the potential anticancer activity of other stilbenoids, a home-made collection of resveratrol dimers and simplified analogues was tested on melanoma A375, non-small cell lung cancer H460 and PC3 prostate cancer cell lines. The structural determinants responsible for the antiproliferative activity have been highlighted. Moreover, to investigate the DNA damage ability of the selected molecules, the expression of the γ-H2AX after compound exposure was evaluated. [ABSTRACT FROM AUTHOR]

There is limited information on the treatment trajectory and outcomes of patients with advanced cEGFRm NSCLC treated with osimertinib in routine clinical practice in Canada. By using and analyzing population-based administrative data and detailed chart abstraction in the province of Alberta, our objective was to capture Canadian-specific real-world treatment patterns, health outcomes, and healthcare resource utilization (HCRU) in advanced cEGFRm NSCLC patients who were (a) treated with osimertinib and (b) those receiving treatment after osimertinib. In our study cohort, we found that the overall survival rates for real-world patients receiving osimertinib were less favorable than those observed in clinical trials (24.0 versus 38.6 months). The attrition rate after osimertinib was substantial and high HCRU persisted across many years after diagnosis and treatment. This study provides important real-world evidence on contemporary survival, treatment patterns, and healthcare use among cEGFRm NSCLC patients treated with osimertinib and suggests that further research efforts are needed to improve therapeutic options in both the first and subsequent line settings. [ABSTRACT FROM AUTHOR]

ROS1 rearrangements are considered rare in non-small-cell lung cancer (NSCLC). This retrospective real-world study aimed to evaluate first-line treatment with crizotinib, a tyrosine kinase inhibitor (TKI) standard of care vs. new generation ROS1 anti-cancer agents. Forty-nine ROS1-expressing NSCLC patients, diagnosed with advanced metastatic disease, were included. Molecular profiling using either FISH/CISH or NGS was performed on tissue samples. Twenty-eight patients were treated with crizotinib, while fourteen patients were administered newer drugs (entrectinib, repotrectinib) and seven patients received platinum-doublet chemotherapy in a first-line setting. Overall response rate and disease control rate for the crizotinib and entrectinb/repotrectinib cohort were 68% and 82% vs. 86% and 93%, respectively. Median progression free survival was 1.6 years (95% CI 1.15–2.215) for the crizotinib treatment vs. 2.35 years for the entrectinib/repotrectinib cohort (95% CI 1.19–3.52). Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents. [ABSTRACT FROM AUTHOR]

In advanced non-squamous non-small-cell lung cancer (NSCLC), routine testing with next-generation sequencing (NGS) is recommended to identify actionable genomic alterations (AGAs). The therapeutic implications of repeated NGS testing on synchronous and metachronous tumors are unclear. Between February 2017 and October 2020, NSCLC samples from a single institution were reflex-tested using a targeted 15-gene NGS panel (TruSight Tumor 15, Illumina). Thirty-eight patients were identified with multiple NGS results from 82 samples: 11% were from single unifocal, 51% were from synchronous, and 38% were from metachronous tumors. Changes in EGFR, KRAS, PI3KCA, and TP53 variants were found in 22 patients' samples (58%). No changes were seen with longitudinal testing of multiple samples from single unifocal tumors, while changes were observed in 60% of synchronous and 71% of metachronous tumors. Of these, 26% of patients had AGA differences between samples. Acknowledging the limited sample size, a significant difference in overall survival was observed between synchronous separate primaries and metastasis. Repeat NGS testing of synchronous and metachronous NSCLC tumors may identify differing variants in >50% of patients. These changes may reflect separate primary lung carcinomas, tumor heterogeneity among intrapulmonary metastases, and clonal evolution. NGS testing of multiple tumors may enhance the identification of therapeutic targets for treatment decisions. [ABSTRACT FROM AUTHOR]

ALK detection was performed on 2813 EGFR-unmutated NSCLC cases by simultaneous use of immunohistochemistry (VENTANA® anti-ALK D5F3, Roche Molecular Systems, Inc., Rotkreuz, Switzerland) and fluorescence in situ hybridization with the ALK break apart and the ALK/EML4 fusion probe (ZytoVision, Bremerhaven, Germany). A total of 33 cases were positive discordant (FISH-positive, IHC-negative) and 17 cases were negative discordant (FISH-negative, IHC-positive). This study's aim was to reevaluate the methods used and compare discordant samples to positive concordant samples in order to ellucidate the differences. FISH signal variants were examined and compared. Positive discordant cases featured one pattern of ALK rearrangement in 41.4%, two patterns in 48.3%, and three patterns in 10.3% of analysed samples, with a higher variability of detected patterns and a higher number of ALK copy gains. Positive concordant cases displayed one pattern of rearrangement in 82%, two patterns in 17.8%, and three patterns in 0.6% of analysed samples. The association between number of patterns and concordance/discordance was statistically significant (p < 0.05). Eleven positive discordant and two negative concordant cases underwent NGS analysis, which resulted in identification of ALK fusion in one positive discordant and two negative discordant cases. Positive protein expression regardless of FISH result correlated more with a positive NGS result compared to samples with a positive FISH result with negative protein expression. FISH analysis was able to detect atypical or heterogenous patterns of rearrangement in a proportion of cases with negative protein expression, which may be associated with more extensive genetic alterations rather than true ALK rearrangement. [ABSTRACT FROM AUTHOR]

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