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Background: Tyrosine kinase inhibitors (TKIs) have significantly improved treatment-related outcomes of patients with oncogene-driven non-small-cell lung cancer (NSCLC). TKIs are usually well tolerated and used for a prolonged time, although experienced toxicity varies between patients. It is unclear whether patients report all (low grade) toxicities and how these impact their daily lives. The use of therapeutic drug monitoring (TDM) to, for example, manage toxicities is increasingly applied, but there is limited insight into the patient perspective regarding TDM. This qualitative study aims to explore patient perspectives on TKI toxicity and TDM. Methods: Five semi-structured focus group interviews were held, each with three to four patients with NSCLC using a TKI and their (care) partners. Two researchers independently performed a directive content analysis. Results: In total, 16 patients and 12 (care) partners participated. Experienced treatment-related toxicities were encountered limitedly and patients felt no boundaries discussing these with their treatment team. However, symptoms were sometimes not reported as they were doubted as treatment related. The concept of TDM-guided dosing to, for example, reduce TKI exposure to account for dosing outside the therapeutic window resulted in feelings of uncertainty regarding treatment efficacy. Patients emphasized the need for thorough research and frequent check-ups to ensure treatment efficacy. Conclusion: Perceived TKI-related toxicities seem limited, although the treatment team should pay attention to symptoms not directly described by patients as treatment related. In general, patients are open to implement TDM-guided dosing, but only if thorough scientific evidence demonstrates retained or enhanced safety and efficacy. Plain language summary: Patient perspectives on side effects and therapeutic drug monitoring with tyrosine kinase inhibitors for the treatment of non-small cell lung cancer Background: Tyrosine kinase inhibitors (TKIs) have greatly improved the outcomes for patients with non-small cell lung cancer (NSCLC). These drugs are generally well tolerated and used for long periods, although the experienced side effects can vary between patients. It is not clear if patients always report mild side effects and how these affect their daily lives. Therapeutic drug monitoring (TDM), which is used to adjust drug doses to manage side effects, is becoming more common, but the patient's perspective on this is largely unknown. This study explores patient perspectives on potential side effects of TKIs and the use of TDM. Methods: Five group interviews with 3 to 4 patients each, who were taking TKIs, and their caregivers or partners were held. Two researchers analyzed the data independently. Results: A total of 16 patients and 12 caregivers participated. Most patients experienced few side effects and felt comfortable discussing these with their healthcare team. However, some symptoms were not reported because patients were unsure if they were related to the treatment. The idea of using TDM to adjust doses caused some patients to feel uncertain about whether their treatment would still work effectively. They stressed the importance of thorough research and regular check-ups to ensure the treatment remains effective. Conclusion: While patients generally experience few side effects from TKIs, healthcare teams should be attentive to symptoms patients may not directly associate with the treatment. Overall, patients are open to using TDM to adjust their doses, but only if there is strong scientific evidence proving it is safe and effective. [ABSTRACT FROM AUTHOR]

For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy is a preferred first-line treatment. These patients have comparatively worse outcomes than those with higher PD-L1 expression, underscoring the need for new combination strategies. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has demonstrated encouraging antitumor activity and safety in this patient population. We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival. Clinical Trial Registration:NCT05555732 (ClinicalTrials.gov) Plain Language Summary Most patients discover they have non-small-cell lung cancer (NSCLC) after it has already spread beyond the lungs (metastasized) making it more challenging to treat. If patients with NSCLC also lack specific genetic changes, called "actionable genomic alterations", or have low levels of a protein called PD-L1 (which cancer cells use to avoid attack from the immune system and continue to grow), current treatments may not fully help, or only help for a while. However, newer approaches are being investigated that may benefit these patients with fewer side effects than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is an investigational drug which combines an antibody with a chemotherapy agent to specifically target and kill cancer cells. The antibody in Dato-DXd attaches to a protein called TROP2, which is widely expressed in NSCLC tumors, and delivers chemotherapy directly into cancer cells to kill them. The TROPION-Lung07 study will assess the potential benefits and side effects of adding Dato-DXd to other drugs, including pembrolizumab (an immunotherapy which attaches to PD-1 on immune cells and triggers the death of cancer cells) and chemotherapy. Three treatment groups will be compared: pembrolizumab with chemotherapy; Dato-DXd with pembrolizumab; and Dato-DXd with pembrolizumab and chemotherapy. The study will help us to understand if adding Dato-DXd to other anticancer drugs allow patients to live longer without their disease getting worse. Article highlights Background NSCLC accounts for 80–85% of all new lung cancer diagnoses, with most patients diagnosed at an advanced or metastatic stage and thus having a poor prognosis. For patients with advanced/metastatic NSCLC without actionable genomic alterations and with low PD L1 expression (<50%), pembrolizumab combined with pemetrexed and cisplatin or carboplatin is a preferred first-line treatment option. Data suggest that outcomes with immunotherapy in patients with lower PD-L1 expression are comparatively worse than in those with higher PD-L1 expression, resulting in lower quality of life for these patients. Thus, new combination strategies, which have the potential to replace standard-of-care treatments without compromising safety or efficacy, are needed to improve outcomes. Datopotamab deruxtecan Dato-DXd is a novel TROP2-directed ADC that consists of a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody covalently linked to a highly potent topo I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. In the ongoing TROPION-PanTumor01 study, Dato-DXd as monotherapy demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated patients with NSCLC. In the Phase Ib TROPION-Lung02 combination study, Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy also showed favorable tolerability and encouraging efficacy, regardless of PD-L1 expression, in patients with advanced/metastatic NSCLC. The TROPION-Lung04 Phase Ib study is evaluating the safety, tolerability and antitumor activity of Dato-DXd plus immunotherapy with or without carboplatin in patients with advanced/metastatic NSCLC. TROPION-Lung07 study TROPION-Lung07 is a global, multicenter, randomized, open-label Phase III study assessing the safety and efficacy of Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pemetrexed in combination with platinum-based chemotherapy in patients with no prior therapy for advanced/metastatic non-squamous NSCLC, without actionable genomic alterations and with low PD-L1 expression (TPS <50%). Patients will be randomized in a 1:1:1 ratio into the following treatment arms: Dato-DXd 6.0 mg/kg plus pembrolizumab 200 mg IV plus platinum-based chemotherapy, Dato-DXd 6.0 mg/kg plus pembrolizumab 200 mg IV, and pembrolizumab 200 mg IV plus pemetrexed 500 mg/m2 plus platinum-based chemotherapy. Objectives The primary objectives of this study are to compare the efficacy of Dato-DXd in combination with pembrolizumab with or without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy, as measured by PFS and OS. The key secondary objective is to evaluate the efficacy of treatment in each arm as measured by ORR by BICR. Other secondary objectives include PFS, duration of response, time to response, disease control rate and PFS2. PROs, including time to deterioration in cough, dyspnea, or chest pain and treatment-emergent adverse events will be evaluated, and other safety parameters and Dato-DXd immunogenicity will be assessed. Exploratory objectives include evaluation of biomarkers and pharmacogenetics and pharmacokinetic exposures for potential association with efficacy and safety, and exploring how changes in biomarkers may relate to exposure, AEs and clinical outcomes. Biomarkers of interest include the proportion of tumor cells expressing TROP2. Conclusion The TROPION-Lung07 study will assess the safety and efficacy of Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pemetrexed in combination with platinum-based chemotherapy as a first-line treatment option in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and with low PD-L1 expression (TPS <50%). The outcomes of this study will help establish whether the Dato-DXd doublet and/or triplet regimens may replace the platinum doublet and/or the platinum partner in combination with pembrolizumab therapy as first-line treatment for patients with advanced/metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Aim: We investigated association between skin adverse events (AEs) and efficacy with dacomitinib in patients with EGFR-positive non-small-cell lung cancer (NSCLC). Methods:Post hoc analyses from ARCHER 1050 evaluated efficacy in patients who did and did not experience grade ≥2 skin AEs with dacomitinib. Landmark analyses were performed at 3 and 6 months. Results: In patients who had skin AEs (72.2%) vs. those who did not (27.7%), median progression-free survival was 16.0 vs. 9.2 months, median overall survival (OS) was 37.7 vs. 21.6 months, and objective response rate was 80.2 vs. 61.5%; OS was improved at 3 and 6 months landmark analyses. Conclusion: Presence of grade ≥2 skin AEs was associated with numerically improved efficacy and represents a valuable biomarker of treatment outcome with dacomitinib in patients with advanced NSCLC. Clinical Trial Registration:NCT01774721 (ClinicalTrials.gov) Plain Language Summary The ARCHER 1050 study assessed how the drugs called dacomitinib and gefitinib affected people with non-small-cell lung cancer (NSCLC) who had mutations in the EGFR gene. In this study, people who were treated with dacomitinib lived longer without their cancer getting worse than people who were treated with gefitinib. Skin adverse reactions were higher in people who were treated with dacomitinib than gefitinib. In this follow-up analysis, researchers wanted to see if the treatment effect of dacomitinib was different between people who had skin adverse reactions and people who did not have skin adverse reactions after treatment with dacomitinib. The results from this analysis showed that after treatment with dacomitinib, half of the people who had skin adverse reactions lived for 16.0 months, and half of the people who did not have skin adverse reactions lived for 9.2 months without their cancer getting worse. This study also showed that half of the people who had skin adverse reactions lived for 37.7 months, and half of the people who did not have skin adverse reactions lived for 21.6 months. In summary, the results from this study showed that the treatment effect of dacomitinib was better in people who had skin adverse reactions after treatment with dacomitinib. Therefore, skin adverse reactions can be a marker of better treatment effect in people with NSCLC who had mutations in the EGFR gene when treated with dacomitinib. Article highlights. Introduction In the Phase III ARCHER 1050 study, dacomitinib showed improved progression-free survival vs. gefitinib in patients with EGFR-positive non-small-cell lung cancer (NSCLC). Methods The association between the presence of skin-related adverse events (AEs) and improved efficacy of EGFR tyrosine kinase inhibitors was assessed. Results The presence of grade ≥2 skin AEs was associated with numerically improved efficacy in patients treated with dacomitinib. Conclusions Skin AEs may represent a clinically valuable biomarker of treatment outcome in patients with advanced NSCLC treated with dacomitinib. [ABSTRACT FROM AUTHOR]

Background: Despite the demonstrated efficacy of pembrolizumab in KEYNOTE-024, effectiveness and safety in routine practice remain unclear. Methods: The authors identified first-line pembrolizumab or chemotherapy patients from April 2013 to March 2021. The primary outcome was overall survival; the secondary safety outcomes included rates of hospitalization, emergency department visits, specialist visits, and adverse events. Baseline differences were adjusted using propensity score matching (1:1). Results: The matched cohort included 2284 pairs. Median overall survival for pembrolizumab (13.0 months) was significantly longer than for chemotherapy (9.2 months), with a hazard ratio of 0.81 (95% CI: 0.71–0.92). Pembrolizumab patients reported significantly more adverse events and specialist visits, as well as a higher 1-year cumulative incidence of direct hospitalizations. Conclusion: The survival benefit of first-line pembrolizumab persists in the real world, although with increased toxicity and diminished benefit. Previous literature examining the real-world effectiveness of first-line pembrolizumab for metastatic non-small-cell lung cancer has produced conflicting results regarding the potential for differences between clinical trial efficacy and real-world effectiveness. In this population-based study of 2284 propensity score-matched patients, pembrolizumab was associated with a median overall survival improvement of 3.8 months compared with chemotherapy but resulted in higher rates of hospitalization, emergency department visits, treatment-related adverse events, and specialist visits. This study demonstrates an efficacy–effectiveness gap for pembrolizumab. When compared with the initial KEYNOTE-024 trial, pembrolizumab resulted in lower magnitudes of absolute and relative survival benefit. The real-world safety profile of pembrolizumab was also worse than anticipated from the trial. The findings of this study can be used by clinicians to counsel patients on the magnitude of risks and benefits of treatment with pembrolizumab in routine practice. Additionally, the safety results support a need for more proactive and multidisciplinary approaches to the management of toxicities. This study demonstrates the importance of reassessing safety and effectiveness using real-world data to provide patients and decision-makers with evidence that reflects actual practice. [ABSTRACT FROM AUTHOR]

Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions. Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action. Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority. Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials. • Lung cancer research and treatment require strong global collaborations. • Tobacco cessation and screening programs need better implementation, focusing on the at-risk population for screening. • Dedicated funding for treatment and research is needed to guarantee access for underserved communities. • Improved trial design requires early collaboration with academia, industry, organizations, and regulatory authorities. • New technologies and novel biomarkers could help personalize treatment to improve efficacy and lower toxicity. [ABSTRACT FROM AUTHOR]

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP -deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP- deleted solid tumors. In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A -deleted and/or MTAP -deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP -deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP -deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance. [ABSTRACT FROM AUTHOR]

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFR m) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFR m NSCLC and as adjuvant treatment for resected EGFR m NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFR m NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFR m NSCLC. • CNS metastases are a poor prognostic factor in NSCLC that can negatively impact clinical outcomes and quality of life. • In LAURA, PFS efficacy was similar regardless of pre-CRT positron emission tomography staging. • Osimertinib protected against CNS progression and distant progression versus placebo. • These findings support osimertinib post-CRT as the new standard of care for unresectable stage III EGFR m NSCLC. [ABSTRACT FROM AUTHOR]

20-Hydroxyecdysone (ecdysterone, 20E) is a natural compound that has a number of beneficial pharmacological activities in human, including antioxidant, anti-inflammatory, cardio-, neuro-, hepatoprotective, etc. We recently demonstrated 20E-dependent suppression of glycolysis and respiration in cell models of non-small-cell lung cancer (NSCLC). In this study, using the same cell models, we assessed the effect of 20E on the expression of genes encoding enzymes of fatty-acid metabolism. Gene-expression profiling using a commercial panel revealed a negative effect of 20E on the expression of genes involved in β‑oxidation of fatty acids. We also showed that 20E reduces the amount of carnitine palmitoyltransferase CPT1A, a key component of the carnitine-dependent transport system that limits the intensity of the β-oxidation process, at the protein level. Bioinformatics analysis revealed a negative association between high levels of expression of CPT1A in NSCLC tumors and patient survival. The data obtained confirm the antitumor activity of 20E in NSCLC cells and indicate its inhibitory effect on β-oxidation of fatty acids. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) accounts for the vast majority of all diagnosed lung cancers. According to their histology, most NSCLCs are considered non-squamous cell carcinoma (NSCC), and up to 85% of the latter may lack either one of the two main actionable oncogenic drivers (i.e., EGFR mutations and ALK rearrangements). Objective: Our analysis aimed to describe the clinical and epidemiological characteristics of Spanish patients suffering from NSCC with no actionable oncogenic driver in daily clinical practice. Design: A retrospective, cross-sectional, descriptive analysis. Methods: We analyzed the records of all Spanish patients with advanced NSCC diagnosed between January 2011 and January 2020 and included in the Spanish Thoracic Tumor Registry database. We evaluated the presence of metastasis and molecular profiling at the time of diagnosis and treatments received. We also assessed overall survival (OS) and progression-free survival (PFS) according to first-line treatment. Results: One thousand seven hundred ninety-seven Spanish patients with NSCC were included. They were mainly men (73.2%), smokers (current [44.4%] and former [44.4%]) and presented adenocarcinoma histology (97.6%). Most patients had at least one comorbidity (80.4%) and one metastatic site (96.8%), and a non-negligible number of those tested were PD-L1 positive (35.2%). Notably, the presence of liver metastasis indicated a shorter median OS and PFS than metastasis in other locations (p < 0.001). Chemotherapy was more often prescribed than immunotherapy as first-, second-, and third-line treatment in that period. In first-line, the OS rates were similar in patients receiving either regimen, but PFS rates significantly better in patients treated with immunotherapy (p = 0.026). Also, a high number of patients did not reach second- and third-line treatment, suggesting the failure of current early diagnostic measures and therapies. Conclusions: This analysis of the most lethal tumor in Spain could highlight the strengths and the weaknesses of its clinical management and set the ground for further advances and research. [ABSTRACT FROM AUTHOR]

Lung cancer, a leading cause of cancer mortality, often involves epidermal growth factor receptor (EGFR) mutations, common in 17% of Caucasian and 40% of Asian non-small-cell lung cancer (NSCLC) patients. While the exon 19 deletion and L858R mutation are prevalent, rare variants like L833V/H835L are less understood. This case reports a 75-year-old female with NSCLC harboring L833V/H835L mutations. Initial imaging showed a right upper lobe mass and nodularity in the left upper lobe. Biopsy confirmed adenocarcinoma, and genomic analysis identified EGFR L833V/H835L mutations. Based on these findings, the patient was treated with osimertinib 160 mg daily, reduced to 80 mg due to side effects. After 3 months, positron emission tomography (PET) scans revealed significant tumor reduction, and brain metastasis remained stable. This case demonstrates the efficacy of osimertinib for rare EGFR mutations, aligning with literature suggesting its potential for managing such variants. Although large-scale trials are impractical due to the rarity of these mutations, this report adds valuable evidence supporting osimertinib's use, highlighting the need for comprehensive genomic profiling in NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: Luteolin, a naturally occurring flavonoid compound, demonstrates promising anti-cancer properties. However, its mechanism against non-small-cell lung cancer (NSCLC) remains unknown. This study employed network pharmacology, molecular docking, molecular dynamics simulation (MDS), and in vitro experiments to investigate the potential mechanisms by which luteolin against NSCLC. Methods: Initially, the potential targets of luteolin and NSCLC-related targets were identified from public databases such as TCMSP, GeneCards, OMIM, DrugBank, and TTD. Subsequently, the protein-protein interaction (PPI) network screening and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. The binding affinity and stability of luteolin with the core targets were assessed using molecular docking and MDS. Finally, the results were validated by in vitro experiments. Results: A total of 56 luteolin targets and 2145 NSCLC-related targets were identified. Six core targets, TP53, EGFR, AKT1, TNF, JUN, and CASP3, were screened via the PPI network. The GO and KEGG analyses indicated that luteolin's activity against NSCLC potentially involves PI3K-Akt, NF-kappa B, and other signaling pathways. Molecular docking revealed that luteolin had high binding affinity with the core targets. MDS confirmed the stable interaction between luteolin and key proteins TP53 and AKT1. in vitro , luteolin significantly inhibited the proliferation and migration of A549 cells, while also inducing apoptosis. In addition, luteolin downregulated the expression of p-Akt (Ser473), MDM2, and Bcl-2 but upregulated the expression of p53 and Bax, which was consistent with the effect of LY294002. Conclusion: Luteolin had a good anti-NSCLC effect, and the apoptosis-inducing effect might be related to the Akt/MDM2/p53 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease (COVID)-19 can lead to chronic lung damage and respiratory issues, potentially increasing surgical difficulty and risk for patients with non-small-cell lung cancer (NSCLC). However, the impacts of a COVID-19 history on early outcomes in NSCLC patients remain controversial. Objectives: To evaluate the effect of COVID-19 history on early outcomes in NSCLC patients and identify high-risk groups undergoing radical resection based on the largest Chinese multi-center real-world data to date. Design: Multi-center retrospective cohort study. Methods: NSCLC patients with (POCVD group) or without (NCVD group) a history of COVID-19 who underwent radical surgery at six institutions from January 2022 to January 2024 were retrospectively reviewed from a prospectively maintained database. Propensity-score matching (PSM) was utilized to minimize patient selection bias. Results: Out of 7932 cases included, PSM resulted in 3021 cases per group. The two groups were comparable regarding the proportion of male patients (52.0% vs 51.6%) and those aged ⩾70 years (13.3% vs 13.8%). Although the two groups had comparable incidences of complications with Clavien-Dindo grades ⩾II (13.0% vs 14.4%, p = 0.117), the POCVD group had longer surgical durations (120.87 ± 40.23 min vs 110.74 ± 38.76 min, mean difference (95% confidence interval (CI) = 10.13 (8.138–12.122)) and higher rates of respiratory complications than the NCVD group. Subgroup logistic regression analysis indicated that patients aged ⩾70 years (odds ratio (OR) (95% CI) = 1.322 (1.022–1.876)) and those with a smoking history (OR (95% CI) = 1.235 (1.008–1.543)) had an increased risk of developing complications with Clavien-Dindo grades ⩾II. Further analysis confirmed that these high-risk patients experienced extended surgical durations, longer chest tube drainage, and prolonged postoperative hospital stay, along with increased postoperative respiratory complications following COVID-19. Conclusion: Generally, radical resection is safe for NSCLC patients with a COVID-19 history. However, these patients experienced prolonged surgical durations and a higher incidence of postoperative respiratory complications compared to those without a COVID-19 history. In addition, individuals aged ⩾70 years or with a smoking history faced elevated surgical risks following COVID-19. Plain language summary: Analyzing the impact of COVID-19 history on early outcomes and identifying high-risk groups among non-small cell lung cancer patients undergoing radical resection Aim and Purpose Research Question: Does a COVID-19 history affect the early outcomes of radical surgery (lobectomy/bi-lobectomy/pneumectomy) in patients with non-small cell lung cancer (NSCLC)? Hypothesis: Patients with a COVID-19 history face elevated surgical risks compared to those without. Objective: To understand how past COVID-19 infection impacts early outcomes in NSCLC patients undergoing surgery and to identify high-risk groups. Background Why This Study: COVID-19 can cause long-term lung damage, making surgery riskier for NSCLC. However, it's unclear how past COVID-19 infection affects NSCLC patients receiving surgery. Importance: The research helps to understand the additional risks for NSCLC patients with a COVID-19 history based on the largest cohort to date, aiming to improve their surgical outcomes. Method and Design Research Design: Multi-center retrospective cohort study. Methods and Participants: 7932 NSCLC patients undergoing radical surgery between January 2022 and January 2024 were included and divided into two groups: those with a COVID-19 history (POCVD group) and those without (NCVD group). Result and Importance Findings: 1. The POCVD group had longer surgical durations and higher rates of respiratory complications compared to the NCVD group. 2. The POCVD and NCVD groups were associated with a comparable incidence of postoperative complications with Clavien-Dindo grades ⩾II. 3. The elderly (aged ⩾70 years) and smokers were at higher risk for complications post-COVID-19. Implications: While surgery is generally safe for NSCLC patients with a COVID-19 history, they do face increased risks and complications. This highlights the need for special care and monitoring for older patients and those with smoking histories. Key Message: NSCLC patients with a COVID-19 history can safely undergo radical surgery, but they may experience longer surgical durations and more postoperative respiratory complications, especially the elderly and smokers. [ABSTRACT FROM AUTHOR]

Objective To observe the occurrence of thyroid dysfunction in patients with advanced non-small-cell lung cancer (NSCLC) treated with programmed cell death protein-1 (PD-1) inhibitor and to analyze its influencing factors. Methods Totally 350 patients with advanced NSCLC who received PD-1 inhibitor treatment were divided into the thyroid dysfunction group and control group based on changes in thyroid function indicators after treatment. General information and laboratory test results were collected from both groups, and univariate analysis and multivariate Logistic regression were used to analyze the influencing factors of thyroid dysfunction. Results Among 350 patients, 77 (22. 0%) had thyroid dysfunction. The onset time of thyroid dysfunction was between weeks 3-31 of treatment, with a median time of week 9. Fifty-two patients initially presented with clinical hypothyroidism or subclinical hypothyroidism, while 25 patients initially presented with clinical hyperthyroidism or subclinical hyperthyroidism. There was no statistically significant difference in the median time of onset of hyperthyroidism and hypothyroidism (P>0. 05). Compared with the control group, the thyroid dysfunction group showed decreased lymphocyte count, increased C-reactive protein, thyroid stimulating hormone levels, and baseline thyroid antibody positivity rate, and longer immunotherapy cycle (all P<0. 05). The results of multiple Logistic regression analysis showed that baseline thyroid antibody positivity (OR=7. 750, 95% CI: 3. 878-15. 487) and immunotherapy cycle ≥ 6 weeks (OR=1. 225, 95% CI: 1. 158-1. 296) were independent risk factors for thyroid dysfunction (all P<0. 05). Conclusions The incidence of thyroid dysfunction in patients with advanced NSCLC treated with PD-1 inhibitor is relatively high, and hypothyroidism is more common. Basal thyroid antibody positivity and long immunotherapy cycle (≥6 weeks) are risk factors for thyroid dysfunction. [ABSTRACT FROM AUTHOR]

Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) on the abscopal effect of radiotherapy in mice with lung cancer via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and the underlying mechanism. Methods Lung cancer LLC1 cells in the logarithmic growth phase were randomly divided into the control group and irradiation group. Cells in the control group were cultured normally without intervention, while cells in the irradiation group were irradiated with 4 Gy (2 Gy/min for 2 min). Twenty-four hours later, the mRNA levels of MB21D1, TMEM173, TBK1, IRF3, IRF5, IRF7, IFNAR1, IFNAR2, MX1, MX2, IFIT1, and IFIT related genes in the cells were determined by real-time PCR (rtPCR). In addition, 100 µL of LLC1 cell suspension in the logarithmic growth phase was injected subcutaneously into the groin of mice to prepare bilateral subcutaneous tumor-bearing models. The tumor-bearing mice were randomly divided into the control group, 8 Gy group, EGFRTKI group, and 8 Gy + EGFR-TKI group, with 3 mice in each group. The tumor-bearing mice in the control group were not intervened. The tumor-bearing mice in the 8 Gy group were radiated at 8 Gy for 3 times, the tumor-bearing mice in the EGFR-TKI group were intragastrically administered 1 mg/g EGFR-TKI for 3 times, and the tumor-bearing mice in the 8 Gy + EGFR-TKI group received both radiation and EGFR-TKI as above. The tumor on the right side of the mice was taken out after 17 days of intervention. The levels of cGAS, STING, p-STING, and type I interferon (IFN-1) proteins in the tumor tissues were determined by Western blotting. Tumor cell proliferation antigen (ki67) and tumor microenvironment-related proteins CD4, CD8, epidermal growth factor receptor (EGFR), forkhead transcription factor p3 (Foxp3), calreticulin (CRT), and major histocompatibility complex (MHC) were detected by immunohistochemistry. Results Compared with the control group, LLC1 cells in the radiation group showed significantly higher mRNA expression levels of MB21D1, TMEM173, TBK1, IRF3, IRF5, IFNAR1, IFNAR2, MX1, MX2, IFIT1, and IFIT (all P<0. 05), and lower IRF7 mRNA expression (P<0. 05). After 17 days of intervention, compared with the control group, tumor volume, tumor weight and relative expression of ki67 protein decreased in all three intervention groups (all P<0. 05), with the largest decrease in the 8 Gy + EGFR-TKI group. Compared with the control group, the EGFR-TKI group showed no significant difference in expression levels of cGAS, STING, p-STING or IFN-1 (all P>0. 05); the 8 Gy group showed no significant difference in expression levels of STING or IFN-1 proteins (both P>0. 05), but significantly elevated cGAS and p-STING protein expression (both P<0. 05); the 8 Gy + EGFR-TKI group showed significantly elevated expression of all cGAS, STING, p-STING and IFN-1 proteins (all P<0. 05). Compared with the 8 Gy + EGFR-TKI group, the expression levels of cGAS, IFN-1, and STING proteins were significantly lower in both the 8 Gy group and EGRF-TKI group (all P<0. 05). The expression levels of CD4, CD8, and MHC proteins in all three intervention groups significantly increased (all P<0. 05), and the expression levels of EGFR, Foxp3, and CRT proteins significantly decreased in comparison with those of the control group (all P< 0. 05). Compared with the radiation group, the 8 Gy+EGFR-TKI group had higher CD4, CD8, and MHC proteins, and lower EGFR and CRT protein levels (all P<0. 05). Similarly, CD4, CD8, and MHC were significantly higher, and EGFR, Foxp3, and CRT were significantly lower in the 8 Gy+ EGFR-TKI group than in the EGFR-TKI group (all P<0. 05). Conclusion EGFR-TKI improves the immune function of the tumor microenvironment by activating the cGAS-STING pathway, thereby enhancing the abscopal effect of radiotherapy in mice with lung cancer. [ABSTRACT FROM AUTHOR]

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases. [ABSTRACT FROM AUTHOR]

Background: The value of pretreatment baseline 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/computed tomography (CT) as a prognostic factor for survival of patients with non-small-cell lung cancer (NSCLC) receiving immunotherapy remained uncertain. Objectives: To investigate the prognostic ability of baseline 18F-FDG PET/CT in patients with NSCLC receiving immunotherapy. Design: A systematic review and meta-analysis. Data sources and methods: We searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases until May 7, 2024, and extracted data related to patient characteristics, semiquantitative parameters of 18F-FDG PET/CT, and survival. We pooled hazard ratios (HRs) to evaluate the prognostic value of the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for overall survival (OS) and progression-free survival (PFS). Results: A total of 22 studies (1363 patients, average age range 30–88 years) were included. Baseline 18F-FDG PET/CT-derived MTV was significantly associated with both OS (HR: 1.124, 95% confidence interval (CI) 1.058–1.195, I 2 = 81.70%) and PFS (HR: 1.069, 95% CI: 1.016–1.124, I 2 = 71.80%). Other baseline 18F-FDG PET/CT-derived parameters, including SUVmax (OS: HR: 0.930, 95% CI: 0.718–1.230; PFS: HR: 0.979, 95% CI: 0.759–1.262), SUVmean (OS: HR: 0.801, 95% CI: 0.549–1.170; PFS: HR: 0.688, 95% CI: 0.464–1.020), and TLG (OS: HR: 0.999, 95% CI: 0.980–1.018; PFS: HR: 0.995, 95% CI: 0.980–1.010), were not associated with survival. Sensitivity analyses by removing one study at a time did not significantly alter the association between MTV and PFS or between MTV and OS. There was no evidence of publication bias. Conclusion: Pretreatment baseline 18F-FDG PET/CT-derived MTV might be a prognostic biomarker in NSCLC patients receiving immunotherapy. Further studies are needed to support routine use. Plain language summary: Using PET/CT scans to predict survival in lung cancer patients receiving immunotherapy: a study review Aims and Purpose of the Research We wanted to know if a type of scan called 18F-FDG PET/CT can help predict how long people with a type of lung cancer (NSCLC) will live after treatment with immunotherapy. Background of the Research This research matters because NSCLC is a common and serious type of lung cancer. Knowing how long patients might live after treatment can help doctors plan better care. Many people are affected by this disease, so finding good ways to predict survival can help a lot of patients. Methods and Research Design They reviewed and analyzed data from 22 different studies involving 1363 patients, with ages ranging from 30 to 88 years.We focused on certain measurements from the scans, like SUVmax, SUVmean, MTV, and TLG. We checked if these measurements were linked to how long patients lived and how long they lived without their cancer getting worse. Results and Importance We found that one of these measurements, the Metabolic Tumor Volume (MTV), was linked to how long the patients lived and how long they stayed free of disease after treatment. Specifically, higher MTV was associated with poorer overall survival and progression-free survival. The other measurements (SUVmax, SUVmean, and TLG) did not show a significant connection to patient survival. In conclusion, the MTV from PET/CT scans might help doctors predict the outcomes for lung cancer patients undergoing immunotherapy. However, more studies are needed to confirm these findings and to consider using this measurement regularly in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiation therapy (SBRT) in treating non-small-cell lung cancer (NSCLC) exhibits a remarkable therapeutic efficacy. However, its effectiveness in overcoming resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced EGFR mutations (EGFRm) NSCLC remains uncertain. Objective: We aimed to analyze the effect of SBRT on patients with first-line EGFR-TKIs. Design and methods: Eligible patients with advanced NSCLC initially diagnosed with EGFRm were enrolled. Patients in the EGFR-TKIs group received only the first-generation EGFR-TKIs until disease progression or death, while the others in the EGFR-TKIs + SBRT group received EGFR-TKIs and early SBRT (dose of 40–60 Gy/5–8 F) targeting the primary lung tumor at 1 month after EGFR-TKIs. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were treatment-related adverse effects, overall survival (OS), and sites of initial failure. Results: A total of 184 advanced NSCLC patients with EGFRm were enrolled, including 39 patients in the EGFR-TKIs + SBRT group and 145 patients in the EGFR-TKIs group. The median PFS was 15.50 months in the EGFR-TKIs + SBRT group compared to 9.33 months in the EGFR-TKIs group (p = 0.0020). However, the median OS was 29.10 months in the EGFR-TKIs + SBRT group and 26.33 months in the EGFR-TKIs group, with no significant difference observed (p = 0.22). SBRT is an independent positive prognostic factor for PFS in advanced EGFRm NSCLC. EGFR exon 19 deletion mutation (16.33 vs 11.55 months, p = 0.0087) and fewer metastases (0–5) (31.94 vs 9.59 months, p = 0.0059) were associated with improved PFS in EGFR-TKIs + SBRT versus EGFR-TKIs. Combination therapy increased radiation pneumonitis mainly in Grades 1–2 (89.74% vs 0.0%). The EGFR-TKIs + SBRT group mainly had new site failure (57.10% vs 32.10%) rather than the original site failure. Conclusion: Early SBRT for primary lung tumors may overcome targeted resistance in advanced EGFRm NSCLC patients combined with EGFR-TKIs without serious toxicities, especially for EGFR exon 19-del. Trial registration: ChiCTR-OIN-17013920. [ABSTRACT FROM AUTHOR]

Cremastrae Pseudobulbus Pleiones Pseudobulbus (CPPP) is derived from the dried pseudobulb of the orchid family plants Cremastra appendiculata (D.Don) Makino, Pleione bulbocodioides (Franch.) Rolfe, or Pleione yunnanensis Rolfe, and has the properties of clearing heat, detoxification, resolving phlegm, and dispersing nodules. It is frequently used for the treatment of various malignant tumors in clinical practice, especially lung cancer. CPPP is divided into two commercial specifications in the market, Maocigu (MCG) and Bingqiuzi (BQZ). However, owing to a lack of appropriate research strategies, the active ingredients and molecular mechanisms involved have not yet been clarified. This study intended to discover the combination of effective anti-lung-cancer ingredients in CPPP and explore their potential mechanisms of action. In this study, UHPLC-MS fingerprints of MCG and BQZ were established separately. Inhibitory effects on the proliferative viability and migratory ability of A459 and H1299 cells were evaluated as pharmacodynamic indicators. GRA and BCA were used to determine spectrum–effect relationships. Next, the identification and analysis of components of drug-containing serum were performed using UHPLC-Q-Exactive Orbitrap MS. Then, the results of the two analyses were combined to jointly screen out the anti-lung-cancer candidate active monomers of CPPP, and their in vitro activities were verified. Afterward, all effective ingredient combinations of MCG (MCGC) and BQZ (BQZC) were prepared according to their contents in the original medicinal materials. Their anti-lung-cancer activities in vitro and in vivo were compared and verified. Finally, we used the human lung cancer cell line A549 and the Lewis tumor xenograft model to investigate how BQZC would influence autophagy and apoptosis processes and the mechanisms involved. Overall, 11 predominant anti-lung-cancer active ingredients from CPPP were screened. Next, MCGC and BQZC were prepared according to their contents in the original medicinal materials, respectively, and their anti-tumor effects were equivalent to those of the original materials in vitro and in vivo. We found that BQZC could inhibit lung cancer cell growth and induce protective autophagy and apoptosis in lung cancer cells by activating the AMPK–mTOR–ULK1/BMF signaling pathway. These results provide important evidence for the clinical application and deep development of CPPP against tumors. [ABSTRACT FROM AUTHOR]

We aimed to evaluate whether progression-directed radiation therapy (PDRT) can prolong the initiation of a subsequent systemic therapy regimen in a cohort of patients with oligoprogressive NSCLC. A retrospective analysis was conducted on NSCLC patients who underwent PDRT for extracranial oligoprogressive NSCLC, defined as limited (up to five) progressing lesions following initial complete, partial, or stable response to systemic therapy according to REC1ST 1.1 and/or PERCIST 1.0 criteria. Cox proportional hazard regressions were performed to identify factors influencing time to next treatment (TTNT), which was considered the primary endpoint. Forty patients were analyzed. First, second, and ≥3 lines of systemic therapy were administered in 22 (58.2%), 14 (27.2%), and 4 (14.6%) cases, respectively. The median total dose was 36 Gy (range: 12–60) in five fractions (1–10), with a median biological effective dose for tumor control (BED10) of 52 Gy (26.4–151.2). After a median follow-up of 11 months (2–50), PDRT delayed further systemic therapy in 32 (80.0%) treatments. Median TTNT was not reached at 8 months (1–47) with a one-year Kaplan–Meier estimate of 81.4% (95% CI: 75.0% to 87.8%). No >grade 3 adverse event was observed. On multivariate analysis, patients with ≥3 lines of systemic therapy and/or with larger CTV volumes did not benefit from PDRT. Despite the use of sub-ablative doses, our findings show that PDRT represents an effective, safe, and viable option for oligoprogressive NSCLC. Patients irradiated early during their systemic treatment course, with a low volume of disease and nonmetastatic oligoprogression, could derive substantial benefits from PDRT. [ABSTRACT FROM AUTHOR]

Simple Summary: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. In this study, a high serum cytokeratin fraction 21–1 (CYFRA 21-1) level was found to be a poor prognostic marker in patients with NSCLC receiving anti-PD-1/L1 antibodies even stratifying by histology or treatment regimen. Thus, serum CYFRA 21-1 may be useful for precision medicine with anti-PD-1/PD-L1 antibody treatment. Background: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. This study explored serum cytokeratin fraction 21–1 (CYFRA 21-1), which represents a squamous cell histology, as a prognostic factor in anti-PD-1/PD-L1 antibody treatment, stratifying by histology and treatment regimen. Methods: This study retrospectively evaluated patients with advanced NSCLC without driver mutations receiving anti-PD-1/PD-L1 antibodies between November 2015 and March 2023. Cutoff values for CYFRA 21-1 and carcinoembryonic antigen (CEA) were 3.5 and 5.0 ng/mL, respectively. The Kaplan–Meier method and a log-rank test were conducted. The Cox proportional hazards model was utilized for univariate and multivariate analyses. Results: This study included 258 patients. The squamous NSCLC group demonstrated a shorter overall survival (OS) than the non-squamous NSCLC group (median, 17.8 vs. 23.7 months, p = 0.141). Patients with high serum CYFRA 21-1 and CEA levels exhibited a significantly shorter OS than those with normal levels (median, 11.7 vs. 32.7 months, p < 0.005; 15.8 vs. 29.7 months, p < 0.005). The multivariate analysis identified a performance status (PS) of ≥2, a PD-L1 expression of ≥50%, and a serum CYFRA 21-1 of >3.5 ng/mL as independent prognostic factors. Patients with high serum CYFRA 21-1 levels exhibited a significantly shorter OS even focusing on non-squamous NSCLC, anti-PD-1/PD-L1 antibody and chemotherapy combination therapy, or anti-CTLA-4 antibody combination therapy. Conclusion: Serum CYFRA 21-1 is a poor prognostic marker for patients with NSCLC receiving anti-PD-1/PD-L1 antibody treatment even when stratifying by histology or treatment regimen. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examined the real-world effectiveness of osimertinib, a third-generation tyrosine kinase inhibitor, on EGFR-mutated non-small-cell lung cancer. Osimertinib has shown promising results in clinical trials, but this research study looked at how it performs in real-world settings, where patients may have different characteristics than those typically included in trials. This study reviewed data from over 600 patients treated with osimertinib, either as their first (L1) or second metastatic line (L2) of treatment. The results showed that patients who took osimertinib as L1 experienced a median progression-free survival of 12.4 months, compared to 7.4 months for those treated in L2. The presence of brain metastases was associated with a poorer prognosis. Overall survival rates were lower than those reported in clinical trials, likely due to differences in patient conditions, such as older age and worse overall health. This study highlights the challenges of applying trial results to everyday medical practice and emphasizes the need for tailored treatment approaches for patients with advanced lung cancer. Background: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), demonstrated superior efficacy over first-generation TKIs in the FLAURA trial, resulting in its approval as first-line therapy for metastatic non-small-cell lung cancer (NSCLC). However, the real-world application of these trial results requires an evaluation of sequential therapeutic strategies. Methods: This retrospective, non-interventional study utilized data from the Epidemiological Strategy and Medical Economics (ESME) platform, which includes information on patients treated for lung cancer since 2015. Out of 39,974 patients in the database, 624 patients with EGFR-mutant advanced NSCLC treated with osimertinib as first-line (L1, n = 198) or second-line (L2, n = 426) treatment after first- or second-generation TKIs (n = 1262) were identified. Patient demographics, disease characteristics, treatment strategies, and disease progression were examined. Survival analyses were performed using Kaplan–Meier estimates and Cox proportional-hazards models. Results: In the study population (n = 624), 73.4% were female, with a median age of 70 years (range 28–93). Brain metastases at the start of osimertinib treatment were observed in 282 patients. ECOG PS-2 was reported in 29.4% of patients. The T790M mutation in exon 20 was identified in 257/426 patients (60.3%) receiving osimertinib in L2. Median progression-free survival (PFS) was 12.4 months (95% CI [10.7–14.7]) for L1 and 7.4 months (95% CI [6.2–8.7]) for L2. Median overall survival (OS) from advanced diagnosis was 28.5 months (95% CI [26.3–38.7]) for osimertinib L1 and 29.9 months (95% CI [28.6–31.8]) for osimertinib L2 (HR = 0.93; 95% CI [0.75–1.16]; p = 0.50). For L1, median OS was 27.1 months (95% CI [22.0–30.2]) for patients with cerebral metastases and 38.7 months (95% CI [26.3–52.8]) for those without (HR = 0.73; 95% CI [0.48–1.11]; p = 0.15). Discussion: Patients in the real-world ESME database exhibited a poorer prognosis compared to those in the FLAURA trial. The presence of cerebral metastases at diagnosis worsens the prognosis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficiency and safety of afatinib in combination with bevacizumab in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) G719X, S768I, and L861Q mutations. Patients and Methods: We retrospective studied treatment naïve patients with local advanced or metastatic non-small cell lung cancer harboring EGFR G719X, S768I, and L861Q mutations from January 2017 to August 2021. EGFR tyrosine kinase inhibitors (TKIs) were the first-line treatment in all patients. The demographic, clinical data and treatment results were collected and analyzed. Results: A total of 12 Chinese patients were studied. There were seven EGFR G719X mutations, three of the seven patients with single mutation and the others with compound mutations. Four patients had EGFR S768I mutations and one of them with single mutation. Four patients had EGFR L861Q/P mutations and one of them with compound mutations. The overall response rate of the EGFR TKIs treatment was 58.33% (7/12). The median progression-free survival (PFS) was 11.0 months, and median overall survival (OS) was 35.40 months. Two of five (40%) patients had required EGFR T790M mutations after TKIs were resistant. The side effects were mild to moderate hand-foot-syndrome, hypertension, and proteinuria. Conclusion: Afatinib in combination with bevacizumab are effective and safe in the management of patients with NSCLC harboring EGFR G719X, S768I, L861Q/P single or compound mutations. [ABSTRACT FROM AUTHOR]

Background and Objectives: The burdened symptomatology accompanying advanced non-small-cell lung cancer (NSCLC) is associated with poor prognosis and lower quality of life (QoL). Although both chemotherapy and immunotherapy increase survival, they are still associated with reduced functionality due to their toxicity. This study aimed to estimate the QoL and symptom burden of NSCLC patients receiving second-line chemotherapy compared to patients receiving second-line immunotherapy. Materials and Methods: This comparative, prospective study, conducted from January 2020 to December 2021, included 111 NSCLC patients who were divided into two groups: 61 patients receiving second-line chemotherapy and 50 patients receiving second-line immunotherapy. Patients' QoL and symptom burden were estimated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C-30) (value range 0–100) from treatment cycle 1 to 6. Results: The QoL (mean score > 50) and functionality dimensions (mean score > 50) were moderate to good in both treatment groups, while the symptom burden did not appear to be a serious problem (mean score < 50). From cycle 3 to cycle 5, QoL was significantly better in the immunotherapy group. From cycle 3, the role and social functioning scores were higher in the immunotherapy group, while emotional and cognitive functioning were higher from cycle 2 (p <0.05). The chemotherapy group experienced higher levels of nausea/vomiting, constipation and financial difficulties in all the cycles (p < 0.05). Fatigue and appetite loss were significantly greater from cycle 2 and insomnia was significantly greater from cycle 3. On the contrary, the immunotherapy group experienced higher levels of diarrhea in cycles 5 and 6 (p < 0.05). Conclusions: Although both therapy groups did not report significantly impaired QoL and severe symptoms, it seems that QoL improved in the immunotherapy group, which reported a lower symptom burden compared to the chemotherapy group. [ABSTRACT FROM AUTHOR]

Background and objectives: Lung cancer is a common cancer, and its impact on public health is not only reflected in the 1 million deaths it causes annually but also in the significant implications it has on daily activities and quality of life, resulting in a considerable burden on healthcare systems. This review aims to determine the effects of pulmonary rehabilitation and pre- or post-surgical exercise in patients with lung cancer. Materials and methods: A systematic review with a meta-analysis of randomized controlled trials published between 2010 and 2024 was conducted; the search was carried out in PubMed, Cochrane Clinical Trial, SCOPUS, Science Direct, Web of Science, Scielo, and LILAC. Results: Pulmonary rehabilitation or exercise before surgery was associated with a greater 6 min walking distance (MD: 37.42, 95% CI: 9.68–65.1; p = 0.008); however, it had no implications on hospital stay (MD: −0.91, 95% CI: −1.88–0.055; p = 0.06). When the intervention was performed post-surgery, higher FEV1 (SMD: 0.62, 95% CI: 0.32–0.92; p = 0.0001) and improved 6 min walking distances (60.8, 95% CI: 20.96–100.6; p = 0.0033) were found compared to standard management. Conclusions: This review suggests that, depending on the timing of implementation, pulmonary rehabilitation or exercise could produce positive effects on certain clinical variables in lung cancer patients. [ABSTRACT FROM AUTHOR]

Background/Aim: Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. Materials and Methods: A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. Results: The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). Conclusion: The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the combination of chemotherapy with staged Chinese herbal medicine (CHM) therapy could enhance health-related quality of life (QoL) in non-small-cell lung cancer (NSCLC) patients and prolong the time before deterioration of lung cancer symptoms, in comparison to chemotherapy alone. Methods: A prospective, double-blind, randomized, controlled trial was conducted from December 14, 2017 to August 28, 2020. A total of 180 patients with stage I B–IIIA NSCLC from 5 hospitals in Shanghai were randomly divided into chemotherapy combined with CHM (chemo+CHM) group (120 cases) or chemotherapy combined with placebo (chemo+placebo) group (60 cases) using stratified blocking randomization. The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life-Core 30 Scale (QLQ-C30) was used to evaluate the patient-reported outcomes (PROs) during postoperative adjuvant chemotherapy in patients with early-stage NSCLC. Adverse events (AEs) were assessed in the safety analysis. Results: Out of the total 180 patients, 173 patients (116 in the chemo+CHM group and 57 in the chemo+placebo group) were included in the PRO analyses. The initial mean QLQ-C30 Global Health Status (GHS)/QoL scores at baseline were 57.16 ± 1.64 and 57.67 ± 2.25 for the two respective groups (P>0.05). Compared with baseline, the chemo+CHM group had an improvement in EORTC QLQ-C30 GHS/QoL score at week 18 [least squares mean (LSM) change 17.83, 95% confidence interval (CI) 14.29 to 21.38]. Conversely, the chemo+placebo group had a decrease in the score (LSM change −13.67, 95% CI −22.70 to −4.63). A significant between-group difference in the LSM GHS/QoL score was observed, amounting to 31.63 points (95% CI 25.61 to 37.64, P<0.001). The similar trends were observed in physical functioning, fatigue and appetite loss. At week 18, patients in the chemo+CHM group had a higher proportion of improvement or stabilization in GHS/QoL functional and symptom scores compared to chemo+placebo group (P<0.001). The median time to deterioration was longer in the chemo+CHM group for GHS/QoL score [hazard ratio (HR)=0.33, 95% CI 0.23 to 0.48, P<0.0010], physical functioning (HR=0.43, 95% CI 0.25 to 0.75, P=0.0005), fatigue (HR=0.47, 95% CI 0.30 to 0.72, P<0.0001) and appetite loss (HR=0.65, 95% CI 0.42 to 1.00, P=0.0215). The incidence of AEs was lower in the chemo+CHM group than in the chemo+placebo group (9.83% vs. 15.79%, P=0.52). Conclusion: The staged CHM therapy could help improve the PROs of postoperative patients with early-stage NSCLC during adjuvant chemotherapy, which is worthy of further clinical research. (Registry No. NCT03372694) [ABSTRACT FROM AUTHOR]

Locoregional recurrence of non–small‐cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT‐D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT‐D group. After IPTW adjustment, the CRT‐D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW‐adjusted median progression‐free survival was 25.4 and 11.5 months for the CRT‐D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30–0.64); the median overall survival was not reached in either group favoring CRT‐D (hazard ratio, 0.49; 95% confidence interval, 0.24–0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT‐D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection. [ABSTRACT FROM AUTHOR]

This study investigated the effectiveness of acoustic separation for platelet analysis in patients with non–small‐cell lung cancer (NSCLC), comparing it with traditional centrifugation methods. In total, 10 patients with NSCLC and 10 healthy volunteers provided peripheral blood samples, which were processed using either acoustic separation or centrifugation to isolate platelets. The study included whole transcriptome analysis of platelets, peripheral blood mononuclear cells, and tumor tissue samples, employing hierarchical clustering and Gene Ontology analysis to explore gene expression differences. Acoustic separation proved more efficient than centrifugation in terms of platelet yield, recovery rate, and RNA yield. Gene expression profiles of platelets from patients with NSCLC showed distinct patterns compared with healthy volunteers, indicating tumor‐influenced alterations. Gene Ontology analysis revealed enrichment in pathways associated with platelet activation and the tumor microenvironment. This finding indicates the potential of acoustic isolation in platelet separation and its relevance in understanding the unique gene expression profile of platelets in patients with NSCLC. The findings of this study suggested that platelets from cancer patients separated by acoustic techniques exhibited tumor‐specific alterations and provided new insights into the diagnosis of cancer in platelet analysis systems in clinical practice. [ABSTRACT FROM AUTHOR]

Echinoderm microtubule-associated protein 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene detection is of great significance in personalized tumor treatment. With the development of EML4-ALK fusion variants detection, it is necessary to establish traceability to ensure the consistency and comparability of its detection results in clinical practice. The establishment of traceability relies on SI traceable reference materials (RMs) and potential reference measurement procedures (RMPs). In this study, a potential RMP for the quantitative detection of V1 and V3 fusion mutations and the reference type (ALK-ref, including wild type, V1 and V3 mutant type) based on reverse transcription dPCR (RT-dPCR) and EML4-ALK fusion gene RMs were established. The proposed potential RMP has high specificity, good inter-laboratory reproducibility (CV < 7.3%) and good linear relationship (0.92 < slope < 1.06, R2 ≧ 0.99). The limit of detection (LoD) of V1, V3, and ALK-ref are 2 copies/reaction, 2 copies/reaction, and 1 copy/reaction, respectively. Interlaboratory studies using the EML4-ALK RMs and potential RMP showed that participating laboratories can produce consistent copy concentrations of fusion variant and ALK-ref as well as the ratio of EML4-ALK/ALK-ref. The established potential RMP with high specificity and accuracy can be used to characterize the EML4-ALK RMs, and the potential RMP and RM are useful to establish the traceability of EML4-ALK fusion measurement to improve the comparability and consistency in clinical tests. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectiveMethodsResultsConclusionsThe significance of local radiotherapy (RT) in advanced non-small-cell lung cancer (NSCLC) is well documented. However, the advent of immunotherapy has raised questions regarding the synergistic survival benefits or potential adverse effects.This study aimed to explore whether a combination of RT and systematic immune checkpoint inhibitors (ICIs) can improve the survival outcomes for NSCLC patients.Based on collected data patients who received RT were defined as the RT group, and those who had not for any site were defined as the non-RT group. Propensity score matching (PSM) was employed to mitigate bias. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and treatment-related adverse events (AEs).Out of 709 patients (235 in RT group and 474 in non-RT group) were included, with 213 patients per group. The median PFS of the RT group was better than that of the non-RT group (13.8 months versus 9.5 months; p < 0.0001), although no superiority in median overall survival (OS) of the RT group was observed (p = 0.715). However, among the cohort of patients with ≤3 metastases, the median OS of the RT group improved significantly (HR = 0.60, [95% CI 0.44–0.83]; p = 0.004). Treatment-related AEs occurred in 94.5% of RT group patients and in 94.9% of non-RT group patients (p = 0.792), which indicated no observable increase in AEs from RT.These results demonstrate the tolerability of RT when administered along with immunotherapy, suggesting its potential to positively impact the survival outcomes of NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: There has been significant improvement in treating metastatic non–small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. Methods: This is a descriptive retrospective cohort study. All non–small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Results: A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). Conclusions: The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications. [ABSTRACT FROM AUTHOR]

Aim: To describe patient and treatment characteristics associated with bevacizumab BS-Pfizer, rituximab BS-Pfizer and trastuzumab BS-Pfizer and their reference products in Japan. Methods: This retrospective observational study used an administrative claims database to identify patients with ≥1 biosimilar or reference product prescription from 2019 to 2022 for approved indications. Descriptive statistics were calculated. Results: Overall, 14–39% of biosimilar-prescribed patients initiated therapy with reference products. Biosimilar utilization significantly increased from 2019 to 2022. The most-commonly prescribed concomitant class of therapy with biosimilars was antineoplastic therapy. Conclusion: Reference products were most frequently prescribed among the Japanese cohorts, but substantial and increasing proportions received biosimilars over time. Future studies should extend our initial insights to assess biosimilar clinical outcomes in Japanese settings. Plain Language Summary This study examines the adoption of cancer biosimilar therapies in Japan from 2019 to 2022. Cancer biosimilars are complex treatments that closely resemble established cancer therapies already available in Japan. We looked into the characteristics of patients receiving three specific biosimilars – bevacizumab BS-Pfizer, rituximab BS-Pfizer and trastuzumab BS-Pfizer. We also investigated where patients received biosimilar treatment, other therapies they received alongside biosimilars and the proportion of patients using these therapies each year during the study. Our analysis utilized data from the 'Medical Data Vision' database, which records care provided in hospitals across Japan. We analyzed patient demographics and treatment patterns, and compared different groups using statistics to identify significant differences. Notably, we observed that between 14 and 39% of patients initially started treatment with the original version of the drug on the market, known as the 'reference product,' before switching to the biosimilar. Furthermore, our findings revealed a significant increase in the use of biosimilars each year during the study period. Biosimilars were most-commonly used alongside chemotherapy drugs. These initial findings shed light on the patient population using cancer biosimilars in Japan and the treatment contexts in which they are utilized. Future research should delve deeper into aspects such as cost of care, patient survival, side effects and other pertinent factors related to the use of biosimilars in cancer care in Japan. Article highlights The use of oncology biosimilars in clinical practice in Japan is limited, at least partly, by the lack of evidence demonstrating real-world outcomes in Japanese patients. This retrospective observational study provides descriptive insights into the real-world use of bevacizumab, rituximab and trastuzumab biosimilars in Japan for colorectal cancer and non-small-cell lung cancer, B-cell non-Hodgkin's lymphoma and HER2-positive breast and gastric cancers, respectively. We observed significant increases in biosimilar utilization over time from 2019 to 2022. Across indications, from 14 to 39% of biosimilar-prescribed patients switched to the biosimilar after initiating therapy with the corresponding refence product. The most commonly prescribed concomitant class of therapy with biosimilars was antineoplastic therapy across each setting. This study has several limitations that should be noted, including that the Medical Data Vision hospital-based claims database has missing data for some variables, lacks detailed diagnosis and prognosis data (histology, Eastern Cooperative Oncology Group performance status, disease severity, etc.) and does not record deaths that occur outside the hospital. Initial real-world insights in Japan demonstrate comparable patient characteristics, treatment patterns and treatment duration between bevacizumab, rituximab and trastuzumab biosimilar and originator-treated patients. [ABSTRACT FROM AUTHOR]

Objective To study the effect of integrin subunit α3 (ITGA3) on paclitaxel resistance in non-small-cell lung cancer (NSCLC) and its mechanism. Methods Tumor tissues from 50 NSCLC patients treated with paclitaxel combined with cisplatin chemotherapy, A549/Tax (paclitaxel-resistant human lung adenocarcinoma) cells, human A549 cell line and human embryonic lung fibroblasts (MRC-5) were selected. RT-qPCR was used to detect the expression levels of ITGA3 mRNA in tissues and cells. A549/Tax cells were used as the research objects and were transfected with pcDNA3. 1- ITGA3 plasmid (oe-ITGA3) and pcDNA3. 1 empty vector (oe-NC), silencing ITGA3 small RNA (sh-ITGA3) and negative control (sh-NC), respectively, which were recorded as the oe-ITGA3 group, oe-NC group, sh-ITGA3 group and shNC group, respectively. Untreated A549/Tax cells were used as the control group. CCK-8 was used to detect the OD450 values at 24 and 48 h. Western blotting was used to detect the expression of EMT-related proteins [vimentin, E-cadherin, snail] and TGF-β, and immune escape protein [programmed death ligand-1 (PD-L1)]; RT-qPCR was used to detect the expression of ITGA3 mRNA in A549/Tax cells; Transwell assay was used to detect the migration and invasion abilities of A549/Tax cells. Results After treatment, the expression of ITGA3 mRNA in the tumor tissues was higher than that before treatment (P<0. 05). The expression levels of ITGA3 mRNA in the A549 cells and A549/Tax cells were higher than that in the MRC-5 cells (all P<0. 05). After treatment, Vimentin, snail, TGF-β and PD-L1 in the tumor tissues of NSCLC patients increased in comparison with those before treatment, while E-cadherin decreased (all P<0. 05) . Compared with the control group and the oe-NC group, the OD450 values at 24 and 48 h, the number of cell migration and invasion, the ITGA3 mRNA expression, the expression levels of Vimentin, snail, TGF-β and PD-L1 increased, and the expression of Ecadherin decreased in the oe-ITGA3 group (all P<0. 05). Compared with the control group and the sh-NC group, the OD450 values at 24 and 48 h, the number of cell migration and invasion, the ITGA3 mRNA expression, and the expression levels of Vimentin, snail, TGF-β and PD-L1 decreased, and the expression of E-cadherin increased in the sh-ITGA3 group (all P<0. 05). Conclusion Down-regulating ITGA3 expression can inhibit the drug resistance of NSCLC cells to paclitaxel, and its mechanism may be related to the inhibition of TGF-β expression. [ABSTRACT FROM AUTHOR]

AIM: This study aimed to explore the induction of ferroptosis in non-small-cell lung cancer （NSCLC） cells by tubeimoside II （TBMS II） and to elucidate the underlying molecular mechanisms. METHODS: H460 NSCLC cells were cultured in vitro. Cell survival rates were assessed by using MTT assays, and doses of TBMS II resulting in below 50% survival were selected for further experimentation. Cell migration was evaluated using Transwell assays and the effects of TBMS II on H460 cell proliferation were assessed by colony formation assays. Flow cytometry and fluorescence microscopy were used to assess changes in lipid peroxidation （lipid ROS）, and the levels of GSH, T-AOC, MDA, and Fe2+ were measured using commercial kits. Protein levels of GPX4, SLC7A11, FTH1, NCOA4, P62, and LC3 were examined using Western blot. Changes in mitochondrial structure were detected by transmission electron microscopy, and immunofluorescence was used to assess LC3 co-localization of FTH1 and NCOA4, as well as co-localization of LC3 and NCOA4 with lysosomes. RESULTS: Compared with the control group, TBMS II dose-dependently reduced H460 cell viability, migration, and clone formation, accompanied by the appearance of vacuoles within the cells. TBMS II treatment also led to decreased GSH and T-AOC levels, while increasing the cellular contents of MDA, indicating oxidative stress. Additionally, there was a decrease in the expression of the antioxidant proteins SLC7A11 and GPX4 in the cells, while lipid ROS and Fe2+ levels were increased in proportion to the TBMS II concentration. The ferroptosis inhibitor ferrostatin-1 reversed cell death caused by TBMS II, suggesting ferroptosis induction. Furthermore, increasing the TBMS II concentration resulted in an upregulation of the autophagy marker proteins LC3 II/LC3 I and P62, indicative of increased autophagy. TBMS II also affected mitochondrial morphology in the cells, as seen in reduced mitochondrial fluorescence intensity. Protein expression of NCOA4 increased with higher TBMS II concentrations, while that of FTH1 decreased. Co-localization of LC3 II with FTH1 and NCOA4, as well as the lysosomal association of LC3 II and FTH1, also increased in a dosedependent manner. CONCLUSION: TBMS II induces ferritinophagy in H460 cells, leading to decreased cell viability and increased ferroptosis. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) represent an emerging class of targeted anticancer agents that have demonstrated impressive efficacy in numerous cancer types. In non-small cell lung cancer (NSCLC), ADCs have become a component of the treatment armamentarium for a subset of patients with metastatic disease. Emerging data suggest that some ADCs exhibit impressive activity even in central nervous system (CNS) metastases, a disease site that is difficult to treat and associated with poor prognosis. Herein, we describe and summarize the existing evidence surrounding ADCs in NSCLC with a focus on CNS activity. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the impact of radiation doses to the heart and lungs on overall survival (OS) in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) treated with radiotherapy. An analysis of 120 patients, each with exactly three years of follow-up, revealed that higher radiation doses to the heart and lungs were significantly associated with worse OS. Importantly, the combination of heart and lung radiation doses provided enhanced and more detailed risk stratification, making it a more powerful predictor of poor survival than individual doses alone. These findings suggest that minimizing combined radiation exposure to both organs may improve survival outcomes in LA-NSCLC patients. Background/Objectives: Despite advancements in treatment for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC), overall survival (OS) remains poor. The specific effects of varying heart and lung doses on OS in LA-NSCLC patients have not been thoroughly investigated, especially their combined impact on survival. This study aimed to examine the impact on OS of both individual and combined heart and lung doses in patients with LA-NSCLC treated with radiotherapy over a three-year follow-up period. Methods: A total of 120 patients who received definitive radiotherapy for LA-NSCLC (stage III, 92.5%) from January 2015 to January 2020 were retrospectively reviewed. The endpoint in this study was OS. Each patient was followed for a fixed period of three years. Results: Univariate Cox regression analysis showed that OS was significantly related to mean heart dose (MHD, hazard ratio [HR], 3.4 [1.8–6.3]; p < 0.001), pericardium V40 (HR, 3.2 [1.7–6.0]; p < 0.001), and total lung V20 (HR, 2.6 [1.4–5.0]; p = 0.003), and these were independent predictors for worse OS in multivariate analysis. Kaplan–Meier curve analysis with log-rank tests revealed that survival was significantly worse in patients with higher MHD (p < 0.001), pericardium V40 (p < 0.001), and total lung V20 (p = 0.002). Combining MHD and total lung V20, and pericardium V40 and total lung V20 provided enhanced risk stratification for OS (p < 0.001 for both combinations). Conclusions: The combination of heart and lung doses provided enhanced and more detailed risk stratification in prediction of OS for a fixed period of three years in LA-NSCLC patients treated with radiotherapy. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) stands as a prevalent subtype of lung cancer, with circular RNAs emerging as key players in cancer development. This study elucidates the role of circRNA-CPA4 in NSCLC. Elevated circRNA-CPA4 expression in NSCLC lines was confirmed through qRT-PCR. Silencing circRNA-CPA4 with shRNA revealed, through CCK-8, colony formation, and flow cytometry assays, a notable constraint on proliferation and promotion of apoptosis in NSCLC cells. Subcellular localization analysis, RNA immunoprecipitation, and expression level assessments were employed to decipher the intricate interplay among miR-1183, circRNA-CPA4, and PDPK1. Results demonstrated heightened circRNA-CPA4 levels in NSCLC, and its knockdown curtailed NSCLC growth in vivo. Acting as a molecular sponge for miR-1183, circRNA-CPA4 regulated PDPK1 expression. Conversely, inhibiting miR-1183 counteracted the impact of circRNA-CPA4 silencing, reinstating NSCLC cell proliferation, and impeding apoptosis. Overall, this study unveils a novel mechanism: circRNA-CPA4 promotes PDPK1 expression by sequestering miR-1183, fostering NSCLC cell proliferation, and hindering apoptosis. [ABSTRACT FROM AUTHOR]

Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ −50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274 , PDCD1LG2 , and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible. • Intrapatient paired PD-L1 TPS and TMB assessments have good concordance. • Variations in PD-L1 TPS and TMB with clinical implications may occur. • Intervening ICI therapy is associated with decrease in PD-L1 TPS. • Copy number loss in CD274 , PDCD1LG2 , and JAK2 genes are strongly associated with major decrease in PD-L1 TPS (−50% to −100%). • Variations in PD-L1 TPS and TMB have significant impact on outcomes to a subsequent ICI-based therapy. [ABSTRACT FROM AUTHOR]

Purpose: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. Methods: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. Results: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). Conclusion: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to identify risk factors associated with symptomatic radiation pneumonitis (RP, Grade ≥ 2) following immunotherapy preceding thoracic radiotherapy (ICI-TRT) and establish safe dose constraints. Patients and Methods: This retrospective study enrolled patients diagnosed with non-small-cell lung cancer (NSCLC) who underwent thoracic radiotherapy (TRT) following immune checkpoint inhibitors (ICIs) treatment. The primary endpoint was the occurrence of symptomatic RP (Grade ≥ 2), as defined by the Common Terminology Criteria for Adverse Events version 5.0. Clinical and lung dosimetric parameters were analyzed to determine their associations with symptomatic RP. Dosimetric parameters included mean lung dose (MLD) and the percentage of lung volume receiving ≥ 10 Gy (V10), ≥ 20 Gy (V20), ≥ 30 Gy (V30), and ≥ 40 Gy (V40). Receiver operating characteristic curves were used to predict the risk of developing symptomatic RP to establish optimal threshold values for each dosimetric predictor. Results: Among the 118 patients included, the incidence of symptomatic RP was 25.4%. Tumor locations, intervals between immunotherapy and radiotherapy, and MLD, V10, V20, V30, and V40 were identified as independent risk factors for symptomatic RP. The area under the curve (AUC) values for MLD, V10, V20, V30, and V40 were 0.788 (95% confidence interval [CI] 0.704– 0.873), 0.789 (95% CI 0.705– 0.874), 0.791 (95% CI 0.706– 0.876), 0.784 (95% CI 0.697– 0.871), and 0.749 (95% CI 0.656– 0.842), respectively. The optimal threshold values for MLD, V10, V20, V30, and V40 were 9.7 Gy, 26.3%, 15.9%, 13.3%, and 8.6%, respectively. These thresholds are lower than current guideline recommendations, and maintaining dosimetric parameters below these values resulted in a cumulative symptomatic RP incidence of < 12%. Conclusion: The recommended dose thresholds for MLD, V10, V20, V30, and V40 are lower than the current guidelines, underscoring the importance of radiotherapy planning to minimize symptomatic RP occurrence in patients receiving ICI-TRT. [ABSTRACT FROM AUTHOR]

Objective Non-small-cell lung cancer (NSCLC) is a leading attributor to cancer deaths. High HDAC10 and low microRNA (miR)-223-5p levels have been observed in NSCLC. But their roles remain elusive. This study illustrated their roles in NSCLC cell ferroptosis and the mechanism. Methods HDAC10, miR-223-5p, and solute carrier family 7 member 11 (SLC7A11) levels in cells were determined by RT-qPCR. Iron ion content, reactive oxygen species (ROS), and glutathione (GSH) levels were tested using reagent kits, and levels of SLC7A11 and Acyl-CoA synthesis long chain family (ACSL4) were examined using Western blot. Chromatin immunoprecision was performed to analyze the enrichment of HDAC10 and acetylated lysine 9 of histone H3 (H3K9ac) on the miR-223-5p promoter. The targeted binding of miR-223-5p and SLC7A11 was analyzed by dual-luciferase assay. Joint experiments were designed to identify the role of miR-223-5p/SLC7A11 axis in HDAC10-regulated ferroptosis in NSCLC cells. Results HDAC10 was highly expressed in NSCLC cells. Silencing HDAC10 significantly reduced GSH and SLC7A11 levels, upregulated iron ion content, ROS levels, and ACSL4 expression, promoting cell ferroptosis. Mechanically, HDAC10 inhibited miR-223-5p expression through H3K9ac deacetylation of the miR-223-5p promoter, thereby targeting SLC7A11. The joint experimental results showed that overexpression of SLC7A11 or downregulation of miR-223-5p alleviated the promoting effect of silencing HDAC10 on ferroptosis in NSCLC cells. Conclusion HDAC10 inhibits miR-223-5p expression through H3K9ac deacetylation of the miR-223-5p promoter, thereby promoting SLC7A11 expression and inhibiting ferroptosis in NSCLC cells. [ABSTRACT FROM AUTHOR]

Rationale: Immune checkpoint inhibitor (ICI)–related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non–small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ IFN-γ–positive SP-B–specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B–specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is among the deadliest cancers worldwide. Despite the recent introduction of several new therapeutic approaches for the disease, improvements in overall survival and progression-free survival have been minimal. Conventional treatments for NSCLC include surgery, chemotherapy and radiotherapy. Except for surgery, these treatments can impair a patient's immune system, leaving them susceptible to bacterial infections. As such, Staphylococcus aureus infections are commonly seen in NSCLC patients receiving chemotherapy, and a major constituent of the S. aureus cell surface, lipoteichoic acid (LTA), is thought to stimulate NSCLC cancer cell proliferation. Thus, inhibition of LTA-mediated cell proliferation might be a useful strategy for treating NSCLC. Epinecidin-1 (EPI), a marine antimicrobial peptide, exhibits broad-spectrum antibacterial activity, and it also displays anti-cancer activity in glioblastoma and synovial sarcoma cells. Furthermore, EPI has been shown to inhibit LTA-induced inflammatory responses in murine macrophages. Nevertheless, the anti-cancer and anti-LTA activities of EPI and the underlying mechanisms of these effects have not been fully tested in the context of NSCLC. In the present study, we demonstrate that EPI suppresses LTA-enhanced proliferation of NSCLC cells by neutralizing LTA and blocking its effects on toll-like receptor 2 and interleukin-8. Moreover, we show that EPI induces necrotic cell death via mitochondrial damage, elevated reactive oxygen species levels, and disrupted redox balance. Collectively, our results reveal dual anti-cancer activities of EPI in NSCLC, as the peptide not only directly kills cancer cells but it also blocks LTA-mediated enhancement of cell proliferation. [ABSTRACT FROM AUTHOR]

Lung cancer is a type of cancer that can metastasize to the lungs, brain, bones, liver, adrenal glands, and other organs; however, the occurrence of brain metastases is the most common event. Symptoms of brain metastasis include motor dysfunction, mental dysfunction, seizures, headaches, nausea, and vomiting, and significantly reduce the quality of life of cancer patients. Brain metastases are a poor prognostic factor, and controlling them is extremely important for prolonging prognosis and improving the quality of life. Currently, local surgery and radiotherapy are recommended for their treatment. However, recently, cancer treatments using molecular-targeted drugs and immune checkpoint inhibitors have been introduced, which may also be effective against brain metastases. Therefore, it is necessary to determine whether local or systemic therapy is optimal for each case. In this review, we focus on recent findings regarding drug therapy in treating brain metastases from advanced non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

We aimed to evaluate whether progression-directed radiation therapy (PDRT) can prolong the initiation of a subsequent systemic therapy regimen in a cohort of patients with oligoprogressive NSCLC. A retrospective analysis was conducted on NSCLC patients who underwent PDRT for extracranial oligoprogressive NSCLC, defined as limited (up to five) progressing lesions following initial complete, partial, or stable response to systemic therapy according to REC1ST 1.1 and/or PERCIST 1.0 criteria. Cox proportional hazard regressions were performed to identify factors influencing time to next treatment (TTNT), which was considered the primary endpoint. Forty patients were analyzed. First, second, and ≥3 lines of systemic therapy were administered in 22 (58.2%), 14 (27.2%), and 4 (14.6%) cases, respectively. The median total dose was 36 Gy (range: 12–60) in five fractions (1–10), with a median biological effective dose for tumor control (BED10) of 52 Gy (26.4–151.2). After a median follow-up of 11 months (2–50), PDRT delayed further systemic therapy in 32 (80.0%) treatments. Median TTNT was not reached at 8 months (1–47) with a one-year Kaplan–Meier estimate of 81.4% (95% CI: 75.0% to 87.8%). No >grade 3 adverse event was observed. On multivariate analysis, patients with ≥3 lines of systemic therapy and/or with larger CTV volumes did not benefit from PDRT. Despite the use of sub-ablative doses, our findings show that PDRT represents an effective, safe, and viable option for oligoprogressive NSCLC. Patients irradiated early during their systemic treatment course, with a low volume of disease and nonmetastatic oligoprogression, could derive substantial benefits from PDRT.

Abstract Background Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens. Methods Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB. Results We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.

Abstract Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

Abstract Background No standard has been established for the clinical target volume (CTV) margins of lymph nodes (LNs) in patients with non-small-cell lung cancer (NSCLC) receiving chemotherapy or chemotherapy combined with immunotherapy followed by radiotherapy. This study aimed to discuss the CTV range of NSCLC after chemotherapy or chemotherapy combined with immunotherapy by observing the microscopic extent of tumor spread beyond the LN capsule. Methods We retrospectively analyzed the data of 240 patients with stage II and III NSCLC who underwent surgery without neoadjuvant therapy, with neoadjuvant chemotherapy (NAC), or with NAC combined with immunotherapy (NACI). We measured the maximal distance of extracapsular extension (ECE) using a digital microscope, analyzed the correlation between clinicopathological features and ECE distance, and determined the CTV margins of metastatic LN under different treatment methods. Results The ECE distance differed significantly among the three groups (p