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Background: Presented here is a straightforward detection system designed to track non-small cell lung cancer (specifically A549 cells) using a combination of liquid crystals (LCs) and aptamer sequences, marking a pioneering approach in this field. A change in the alignment of LCs from perpendicular to random status by the aptamer-cell complex altered the murky polarized background of the aptasensor to multicolored., Results: The LC-designed aptasensor could determine A549 cancerous cells in the range of 2.0E+01-7.0E+07 cell mL -1 with a limit of detection (LOD) as low as 10 cell mL -1 . Through precise quantification of A549 cells in human serum samples diluted 20 times, with recovery rates ranging from 97.59 % to 101.31 %, the suggested aptasensor proves to be a dependable method for cancer screening. Furthermore, the LC aptasensor was identified as a fast sensing array due to a 10-min incubation period for the aptamer-cell complexation., Significance: The LC aptasensor is label-free, operator-independent, low-cost, sensitive, and user-friendly, making it potent as a miniaturized portable sensing chip for efficient healthcare monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The domestic combustion of locally sourced smoky (bituminous) coal in Xuanwei and Fuyuan counties, China, is responsible for some of the highest lung cancer rates in the world. Recent research has pointed to methylated PAHs (mPAHs), particularly 5-methylchrysene (5MC), within coal combustion products as a driving factor. Here we describe measurements of mPAHs in Xuanwei and Fuyuan derived from controlled burnings (i.e., water boiling tests, WBT, n = 27) representing exposures during stove use, and an exposure assessment (EA) study (n = 116) representing 24 h weighted exposures. Using smoky coal has led to significantly higher concentrations of known and likely human carcinogens than using smokeless coal, including 5MC (3.7 ng/m 3 vs. 1.0 ng/m 3 for EA samples and 100.8 ng/m 3 vs. 2.2 ng/m 3 for WBT samples), benzo[a]pyrene (38.0 ng/m 3 vs. 7.9 ng/m 3 for EA samples and 455.3 ng/m 3 vs. 12.0 ng/m 3 for WBT samples) and 7,12-dimethylbenz[a]anthracene (1.9 ng/m 3 vs. 0.2 ng/m 3 for EA samples and 47.7 ng/m 3 vs. 0.6 ng/m 3 for WBT samples). Mixed effect models for both EA samples and WBT samples revealed clear variation in mPAHs concentrations depending on smoky coal source while stove ventilation was consistently found to reduce measured concentrations (by up to nine fold and 65 fold for EA and WBT samples respectively when using smoky coal). Fuel type had a larger influence on mPAHs concentrations than stove type. These findings indicate that users of smoky coal experience exposure to many PAHs, including known and suspected human carcinogens (especially during cooking activities), many of which are not routinely tested for. Collectively, this provides insights into the potential etiologies of lung cancer in the region and further highlights the importance of targeting clean fuel transitions and stove refinements as the final goal for reducing household air pollution and its associated health risks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Soy isoflavones have been reported to exhibit anti-tumor effects. We hypothesize that genetic variants in soy isoflavone metabolism-related genes are associated with the risk of lung cancer., Methods: A two-stage case-control study design was conducted in this study. The discovery stage included 300 lung cancer cases and 600 healthy controls to evaluate the association of candidate genetic variants with lung cancer risk. The validation stage involved 1200 cases and 1200 controls to validate the associations found. Furthermore, qPCR was performed to assess the mRNA expression levels of different genotypes of the SNP. ELISA was used to explore the association between genotype and soy isoflavone levels, as well as the association between soy isoflavone levels and lung cancer risk., Results: A nonlinear association was observed between plasma soy isoflavone levels and lung cancer risk, with higher soy isoflavone levels associated with lower lung cancer risk (P < 0.001). The two-stage case-control study identified that UGT1A1 rs3755319 A > C was associated with decreased lung cancer risk (Recessive model: adjusted OR = 0.69, 95 %CI = 0.57-0.84, P < 0.001). Moreover, eQTL analysis showed that the expression level of UGT1A1 in the rs3755319 CC genotype was lower than in the AA + AC genotype (P < 0.05). The plasma concentration of soy isoflavones in the rs3755319 CC genotype was higher than in the AA + AC genotype (P = 0.008)., Conclusions: We identified a potentially functional SNP, UGT1A1 rs3755319 A > C, as being associated with decreased lung cancer risk. Further experiments will be needed to explore the mechanisms underlying the observed associations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769&#95;D770insASV (insASV) and D770&#95;N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower K m, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants., Competing Interests: Competing interests statement:M.J.E. receives or has received sponsored research support from Novartis, Sanofi, Takeda, and Springworks Therapeutics and consulting income or honoraria from Novartis, H3 Biomedicine and Ikena Oncology. P.A.J. has received consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Takeda Oncology, ACEA Biosciences, Eli Lilly and Company, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, LOXO Oncology, Daiichi Sankyo, Sanofi Oncology, Voronoi, SFJ Pharmaceuticals, Biocartis, Novartis Oncology, Nuvalent, Esai, Bayer, Transcenta, Silicon Therapeutics, Allorion Therapeutics, Accutar Biotech and AbbVie; receives post-marketing royalties from DFCI-owned intellectual property on EGFR mutations licensed to Lab Corp; receives or has received sponsored research funding from AstraZeneca, Astellas, Daichi-Sankyo, PUMA, Boehringer Ingelheim, Eli Lilly and Company, Revolution Medicines and Takeda and has stock ownership in Gatekeeper Pharmaceuticals. H.Z. was a consultant at Boston Consulting Group and is currently a consultant at Bain & Company. All other authors declare no competing interests.

Glutaminase inhibitors are currently being explored as potential treatments for cancer. This study aimed to elucidate the molecular mechanisms underlying the effects of CB-839 on lung tumor cell lines compared to non-tumor cell lines. Viability assays based on NADPH-dependent dehydrogenases activity, ATP energy production, or mitochondrial reductase activity were used to determine that CB-839 caused significant tumor cell specific inhibition of cellular functions. Clonogenic survival assay revealed a dose dependent reduction in clonogenic survival of various lung tumor cells presenting estimated IC 50 values between 10 and 90 nM, while no effect on non-tumor cells was observed. CB-839 led to a 20% reduction in glutaminase (GLS1, a mitochondrial enzyme that catalyzes the conversion of glutamine to glutamate) activity, and a dose-dependent reduced glutamine consumption in tumor cells and had no effect on non-tumor cells. Cell cycle analysis showed the CB-839 did not lead to cell cycle arrest. Apoptosis and necrosis assays revealed an only slight increase in apoptosis in tumor cells. Furthermore, a trypan blue exclusion assay revealed about 40% growth reduction in tumor cells at 0.1-1 μM CB-839 treatment. Surprisingly, treated cells resumed normal growth when re-plated in a drug-free medium, demonstrating reversibility. In hypoxic conditions, CB-839's effect on clonogenic survival was amplified in a dose dependent manner consistent with increased role of GLS1 for energy production under hypoxic conditions. In conclusion, these results suggest CB-839 efficacy is linked to temporary and reversible reduction in glutamine utilization suggesting induction of dormancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: In the era of precision medicine, liquid biopsy rapidly emerges as an integrative diagnostic tool to successfully stratify solid tumor patients in accordance with molecular fingerprinting. As the matter of fact, a plethora of analytes may be isolated from liquid biosources supporting the potential application of liquid biopsy in several clinical scenarios. Despite this promising role, liquid biopsy is drastically affected by low abundance of analytes in biological matrix requiring highly sensitive technologies, trained personnel, and optimized diagnostic procedures to successfully administrate this revolutionary diagnostic tool in clinical practice., Areas Covered: This review aims to investigate the recent advancements in technical approaches available to manage liquid biopsy samples, particularly focusing on their application in LC diagnosis and treatment., Expert Opinion: The rapidly evolving scenario of liquid biopsy-based approaches is revolutionizing clinical administration of lung cancer patients. Of note, the integration of genomic, epigenomic, and transcriptomic markers lays the basis for 'comprehensive' molecular fingerprinting of lung cancer patients. Here, the next-generation technologies are fundamental in molecular profiling in diagnostic routine biofluids.

Following a previous article that focused on integrating epidemiological data from prospective cohort studies into toxicological risk assessment, this paper shifts the focus to case-control studies. Specifically, it utilizes the odds ratio (OR) as the main epidemiological measure, aligning it with the benchmark dose (BMD) methodology as the standard dose-response modeling approach to determine chemical toxicity values for regulatory risk assessment. A standardized BMD analysis framework has been established for toxicological data, including input data requirements, dose-response models, definitions of benchmark response, and consideration of model uncertainty. This framework has been enhanced by recent methods capable of handling both cohort and case-control studies using summary data that have been adjusted for confounders. The present study aims to investigate and compare the "effective count" based BMD modeling approach, merged with an algorithm used for converting odds ratio to relative risk in cohort studies with partial data information (i.e., the Wang algorithm), with the adjusted OR-based BMD analysis approach. The goal is to develop an adequate BMD modeling framework that can be generalized for analyzing published case-control study data. As in the previous study, these methods were applied to a database examining the association between bladder and lung cancer and inorganic arsenic exposure. The results indicate that estimated BMDs and BMDLs are relatively consistent across both methods. However, modeling adjusted OR values as continuous data for BMD estimation aligns better with established practices in toxicological BMD analysis, making it a more generalizable approach., (© 2024 The Author(s). Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes., (© 2024. The Author(s).)

Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation that affects mRNA stability, localization and translation efficiency. Previous pan-cancer studies have revealed that APA is frequently disrupted in cancer and is associated with patient outcomes. Yet, little is known about cancer type-specific APA alterations. Here, we integrated RNA-sequencing data from a Korean cohort (GEO: GSE40419) and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA alterations in lung adenocarcinomas (LUADs). Comparing expression levels of core genes involved in polyadenylation, we find that overall, the set of 28 of 31 genes are upregulated, with CSTF2 particularly upregulated. We observed broad and recurrent APA changes in LUAD growth-promoting genes. In addition, we find enrichment of APA events in genes associated with known LUAD pathways and an increased heterogeneity in polyadenylation (polyA) site usage of proliferation-associated genes. Upon further investigation, we report smoking-specific APA changes are also highly relevant to LUAD development. Overall, our in-depth analysis reveals APA as an important driver for the molecular and clinical features of lung adenocarcinoma., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Novel 1,10-phenanthroline-2,9-bistriazoles derivatives have been synthesized by copper-catalyzed azide/alkyne cycloaddition reactions and assessed for their ability to bind and stabilize G-quadruplex (G4) structures. Ten novel compounds were evaluated using Förster resonance energy transfer (FRET) melting, circular dichroism (CD), and fluorescence spectroscopy on several G4 sequences. Biophysical characterization led to the identification of compounds 4a, 4b, and 5b as good G4 ligands of KRAS G4 sequences. The cell viability of all derivatives was also assessed, revealing weak effects. However, compound 2a exhibited cytotoxicity activity on A549 and H1299 cancer cells and low cytotoxicity towards non-malignant cells MRC-5 not connected with its G4-binding ability. Flow cytometry showed that 2a induced a cell viability decrease in S and G2/M phases for A549 and H1299; thus, more studies should be performed to explore the proteins involved in cell cycle regulation., (© 2024 Wiley‐VCH GmbH.)

Objectives: The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated., Methods: In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4-6 weeks after treatment initiation., Results: Median cGAS and STING H-scores were 220 (range, 5-300) and 190 (range, 0-300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels., Conclusion: cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414)., (© 2024. The Author(s).)

Background: There is a general rise in incidentally found pulmonary nodules (PNs) requiring follow-up due to increased CT use. Biopsy and repeated CT scan are the most useful methods for distinguishing between benign PNs and lung cancer, while they are either invasive or involves radiation exposure. Therefore, there has been increasing interest in the analysis of exhaled volatile organic compounds (VOCs) to distinguish between benign PNs and lung cancer because it's cheap, noninvasive, efficient, and easy-to-use. However, the exact value of breath analysis in this regard remains unclear., Methods: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-oriented systematic search was performed to include studies that established exhaled VOC-based predictive models to distinguish between benign PNs and lung cancer and reported the exact VOCs used. Data regarding study characteristics, performance of the models, which predictors were incorporated, and methodologies for breath collection and analysis were independently extracted by two researchers. The exhaled VOCs incorporated into the predictive models were narratively synthesized, and those compounds that were reported in > 2 studies and reportedly exhibited consistent associations with lung cancer were considered key breath biomarkers. A quality assessment was independently performed by two researchers using both the Newcastle-Ottawa Scale (NOS) and the Prediction Model Risk of Bias Assessment Tool (PROBAST)., Results: A total of 11 articles reporting on 46 VOC-based predictive models were included. The majority relied solely on exhaled VOCs (n = 44), while two incorporated VOCs, demographical factors, and radiological signs. The variation in the sensitivity, specificity, and AUC indicators of the models that incorporated multiple factors was lower compared with those of the models that relied solely on exhaled VOCs. A total of 84 VOCs were incorporated. Of these, 2-butanone, 3-hydroxy-2-butanone, and 2-hydroxyacetaldehyde were identified as key predictors that had significantly higher concentrations in the exhaled breath samples of patients with lung cancer. Substantial heterogeneity was observed in terms of the modeling and validation methods used, as well as the approaches to breath collection and analysis. Many of the reports were missing certain key pieces of clinical and methodological information., Conclusions: Although exhaled VOC-based models for predicting cancer risk might be a conceivable role as monitoring tools for PNs risk, there has been little overall change in the accuracy of these tests over time, and their role in routine clinical practice has not yet been established., Clinical Trial Number: PROSPERO registration number CRD42023381458., (© 2024. The Author(s).)

Invasive mucinous adenocarcinoma (IMA) of lung is a unique subset of adenocarcinomas characterized by an intrapulmonary aerogenous spread resulting in multicentric, multilobar, and bilateral lesions with a low frequency of distant metastasis. The treatment options for IMA are limited, and advanced IMA has a poor prognosis, with a median survival of less than a year. Lung transplantation performed in a handful of selected patients showed improved survival outcomes and clinical improvement. However, high postoperative recurrence rates have been observed and recurrence appeared to originate from the primary tumor in many cases. Techniques, such as non-sequential double lung transplantation utilizing cardiopulmonary bypass, have been performed to reduce recurrence. Here, we present the first case of bilateral lung transplantation employing cardiopulmonary bypass in a patient with stage ⅣA lung-limited IMA without lymph node or distant metastasis. At 15 months post-transplantation, the patient remains stable with no evidence of disease recurrence or organ rejection. Additionally, we describe the classification, clinical outcomes, protein expression, and genetic characteristics of IMA. IMA was previously classified as a subset of bronchioalveolar carcinoma (BAC), which is invasive and mucinous with goblet or columnar cells secreting mucin. We reviewed and summarized the lung transplantation cases reported to date for BAC. The 5-year overall survival and disease-free survival have been reported approximately 50% (range, 39-100) and 50% (range, 35-100), respectively. The literature shows these outcomes are comparable to bilateral lung transplantation performed for non-cancerous pulmonary disease., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03)., Methods: Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1 > 2 cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status., Results: Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P = 0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status., Conclusion: In pathologic stage I (>2 cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed., (© The Author(s) 2024. Published by Oxford University Press.)

The relationship between lung cancer surgery and venous thromboembolism (VTE) in Japan has not been elucidated. This was a post hoc analysis of the Cancer-VTE Registry. The 1057 patients who underwent surgery for lung cancer were divided into the surgery alone (SA) group (n = 598) and the surgery plus chemotherapy (SC) group (n = 459), and the 1-year incidences of VTE and cerebral ischemia were analyzed. In the SA and SC groups, composite VTE was observed in one (0.2%) and 15 (3.3%) patients, respectively, and cerebral ischemia was observed in eight (1.3%) and four (0.9%) patients, respectively. Lymph node metastasis was more common in patients with D-dimer >1.2 μg/ml (odds ratio: 1.781, P = .004). SA had a low risk of VTE but a high risk of cerebral ischemia. Chemotherapy increases the risk of VTE. The D-dimer level was related to VTE and advanced cancer., (© The Author(s) 2024. Published by Oxford University Press.)

The global obesity epidemic, attributed to sedentary lifestyles, unhealthy diets, genetics and environmental factors, has led to over 1.9 billion adults being classified as overweight and 650 million living with obesity. Despite advancements in early detection and treatment, lung cancer prognosis remains poor due to late diagnoses and limited therapies. The obesity paradox challenges conventional thinking by suggesting that individuals with obesity and certain diseases, including cancer, may have an improved prognosis compared with their counterparts of a normal weight. This observation has prompted investigations to understand protective mechanisms, including potentially favorable adipokine secretion and metabolic reserves that contribute to tolerating cancer treatments. However, understanding the association between obesity and lung cancer is complex. While smoking is the primary risk factor of lung cancer, obesity may independently impact lung cancer risk, particularly in non‑smokers. Adipose tissue dysfunction, including low‑grade chronic inflammation, and hormonal changes contribute to lung cancer development and progression. Obesity‑related factors may also influence treatment responses and survival outcomes in patients with lung cancer. The impact of obesity on treatment modalities such as chemotherapy, radiotherapy and surgery is still under investigation. Challenges in managing patients with obesity and cancer include increased surgical complexity, higher rates of postoperative complications and limited treatment options due to comorbidities. Targeted interventions aimed at reducing obesity prevalence and promoting healthy lifestyles are crucial for lung cancer prevention. The impact of obesity on lung cancer is multifaceted and requires further research to elucidate the underlying mechanisms and develop personalized interventions for prevention and treatment.

Background: The incidence of lung cancer is unequally distributed in France. Although several studies have shown a link between the socioeconomic environment of populations and the incidence of cancer, the contribution has not been quantified. We aimed to analyse the geographical variability of lung cancer incidence in Normandy and calculate the proportion explained by the socioeconomic environment., Methods: We included 7665 lung cancer cases recorded in the General Tumor Registry of Calvados and the Cancer Registry of Manche. A Bayesian model was used to map the spatial variation in the incidence of lung cancer in the territory, and an innovative approach was used to evaluate the influence of geographical variability in the socioeconomic environment on the spatial heterogeneity of lung cancer incidence., Results: The maps of the spatial components showed high contrasts for both genders, and the socioeconomic environment integration in the model made the maps less contrasting. The socioeconomic environment of the population explained one-third of the spatial variation in the incidence of lung cancer in women and one-fifth in men., Conclusion: The results showed that a non-negligible part of the spatial variation in the incidence of lung cancer could be explained by the geographical distribution of the socioeconomic environment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Analysis of [18F]-Fluorodeoxyglucose (FDG) kinetics in cancer has been most often limited to the evaluation of the average uptake over relatively large volumes. Nevertheless, tumor lesions also contain inflammatory infiltrates whose cells are characterized by a significant radioactivity washout due to the hydrolysis of FDG-6P catalyzed by glucose-6P phosphatase. The present study aimed to verify whether voxel-wise compartmental analysis of dynamic imaging can identify tumor regions characterized by tracer washout. The study included 11 patients with lung cancer submitted to PET/CT imaging for staging purposes. Tumour was defined by drawing a volume of interest loosely surrounding the lesion and considering all inside voxels with a standardized uptake value (SUV) > 40% of the maximum. Eight whole-body scans were repeated after 20 min of dynamic imaging centered on the heart. Six parametric maps were generated progressively by computing a Patlak regression line for each voxel. Each analysis considered a different set of frames: starting with all eight frames, then the last seven frames, and so on, down to the last three frames., Results: Delaying the starting point of the compartmental analysis revealed a progressive increase in the prevalence of voxels with a negative slope. In the most delayed parametric map, these voxels represented 0.5-4.5% (median 2%) of the tumor volume. This effect was independent of tumor size and was predominantly located at the lesion borders., Conclusions: The voxel-wise parametric maps provided by compartmental analysis identify a measurable volume characterized by radioactivity washout. The spatial localization of this pattern is compatible with the recognized preferential site of inflammatory infiltrates populating the tumor stroma and might improve the power of FDG imaging in monitoring the effectiveness of treatments aimed at empowering the host immune response against cancer., Trial Registration: ClinicalTrials. The study was approved by the local ethical committee and it represented a single Institution ancillary trial within the expanded-access program for Nivolumab. NCT02475382. Registered 2015-06-16. URL: https://clinicaltrials.gov/study/NCT02475382?id=NCT02475382.&rank=1., (© 2024. The Author(s).)

Background/aim: Lung cancer remains a leading cause of cancer-related mortality worldwide, necessitating the development of effective early diagnostic strategies. Despite advancements in imaging and screening technologies, late-stage diagnoses remain common, limiting treatment options and reducing survival rates. Thus, there is a critical need for reliable, minimally invasive biomarkers to improve early detection and patient outcomes. Plasma protein biomarkers offer promising potential for early lung cancer detection and continuous disease monitoring. This study explored the potential of specific plasma protein markers as early indicators of lung cancer., Patients and Methods: Plasma samples were collected from normal healthy individuals and lung cancer patients, and protein purification and analysis were conducted using LC-MS/MS. A mixed-effect model was applied to select lung cancer-related protein markers based on label-free relative quantification values., Results: We identified 29 proteins with potential for early lung cancer diagnosis, including complement proteins (CFB, C3, C8G, C1QA, C1R, C6), orosomucoid proteins (ORM1, ORM2), ceruloplasmin (CP), alpha-1-B glycoprotein (A1BG), and others. These proteins play diverse roles in immune response, inflammation, and cell signaling, suggesting their relevance in lung cancer pathophysiology., Conclusion: Our findings suggest the potential of plasma proteins as early diagnostic biomarkers for lung cancer. Further validation in larger cohorts is needed to confirm their clinical utility. Integrating these biomarkers into existing diagnostic modalities could enhance early detection accuracy, leading to improved patient outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Natural compounds such as propolis have gained wide popularity in the last decades. While its antibacterial, antiviral, and antifungal properties are well known, the anticancer properties of propolis are just beginning to be appreciated. Herein, we comparatively investigate the cytotoxic and radiosensitizing potential of four different ethanolic propolis extracts originating from three different countries (Germany, Ireland, South Africa) in human lung cancer cell models., Materials and Methods: Liquid chromatography-mass spectrometry (LC-MS/MS) was applied to characterize the four different propolis extracts. Cytotoxicity and radiation survival were determined by 3D matrix-based clonogenic assays and autophagy was examined by western blotting., Results: We found cytotoxicity in a propolis type-, time- and cell model- dependent manner. In the four ethanolic propolis extracts, Coumaric acid, Caffeic acid phenethyl ester, Pinocembrin and Chrysin presented the major compounds identified. Examining the induction of autophagy using the marker LC3B and autophagy inhibition with chloroquine suggested autophagy to be part of the survival mechanisms upon propolis treatment in a cell model-dependent manner. Combining propolis with X-ray irradiation showed the radiosensitizing potential of propolis in human lung cancer cell models, which clearly presented in a manner dependent on the incubation time of propolis and the cell model treated., Conclusion: Propolis treatment showed cytotoxic and radiosensitizing effects of propolis on human lung cancer cells. Since these effects differ greatly between the four propolis extracts studied and originating from different regions, further studies are urgently needed to differentiate propolis species and their anticancer properties in more detail., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Small cell lung cancer (SCLC) is one of the most lethal malignancies worldwide. This study aimed to examine the clinical benefits of new systemic therapies derived from randomized controlled trials (RCTs) published from 2002 to 2023 based on the magnitude of clinical benefit scale developed by the European Society for Medical Oncology (ESMO-MCBS)., Methods: We searched PubMed for Phase 3 RCTs on systemic therapy for SCLC published between January 2002 and December 2023. Therapeutic benefit was graded from 5 to 1 according to the ESMO-MCBS framework, with a score of 4 or 5 representing a meaningful clinical benefit. The statistical power of the trial design was also assessed using ESMO-MCBS., Results: Sixty-four RCTs with 23 683 participants were eligible for inclusion. The number of RCTs related to molecular targeted therapy or immunotherapy has increased over the years. Among the 62 RCTs for which statistical power could be evaluated, 38 (61.3%) were designed to identify an effect size that would meet the ESMO-MCBS benefit threshold and were less likely to investigate second- or subsequent-line treatment (15.8% vs. 50.0%, p = 0.004), have noninferiority design (0% vs. 25.0%, p = 0.002) and set PFS (0% vs. 16.7%) or response rate (0% vs. 16.7%) as the only primary endpoint (p = 0.002). The ESMO-MCBS framework was applied in 29 RCTs reporting positive results, and only 8 (27.6%) met the threshold for a clinical benefit. The RCTs designed to detect differences that would meet the thresholds were more likely to demonstrate meaningful clinical benefit (87.5% vs. 50.0%, p = 0.099)., Conclusion: Most positive SCLC-RCTs did not meet the ESMO-MCBS threshold for meaningful clinical benefits. Strict power calculations should be adopted in the design of future RCTs., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background/aim: Transmembrane protein 158 (TMEM158) has emerged as a potential contributor to cancer progression. While TMEM158 has been studied in various cancer types, its role in lung cancer remains unclear., Materials and Methods: Kaplan-Meier curves were used to evaluate the association between TMEM158 expression and overall survival rates. Gene set enrichment analysis (GSEA) was performed to explore pathways related to TMEM158, and sequence analysis was conducted to identify putative hypoxia-responsive element (HRE) sites in the TMEM158 promoter region. Hypoxic conditions were induced, and TMEM158 expression levels were measured by qPCR. The effect of hypoxia-inducible factor-1α (HIF-1α) depletion on TMEM158 expression was also examined. Additionally, lung cancer cells with either over-expressed or reduced TMEM158 levels were analyzed for epithelial-mesenchymal transition (EMT) and cell migration., Results: Analysis of clinical datasets revealed elevated TMEM158 expression in tumors, particularly in patients with advanced stages. High TMEM158 expression was correlated with lower overall survival. TMEM158 was associated with EMT, hypoxia, and other tumor-promoting pathways. Under hypoxic conditions, TMEM158 expression was at least partially induced in a HIF-1α-dependent manner. Functional studies showed that over-expression of TMEM158 promoted EMT and increased lung cancer cell migration, while depletion of TMEM158 reduced these effects, indicating its role in aggressive tumor behavior., Conclusion: TMEM158 is highly expressed in lung cancer, is associated with hypoxia, and promotes EMT and cell migration. These findings suggest TMEM158 as a potential target for lung cancer therapies., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Standard treatment options include surgery, radiation therapy, chemotherapy, and targeted therapies. Despite advancements over the past 25 years, the prognosis of patients with lung cancer remains poor. This study evaluated the synergistic anticancer effects of fenbendazole (FZ) and diisopropylamine dichloroacetate (DADA) on A549 lung cancer cells., Materials and Methods: Fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a broad-spectrum benzimidazole anthelmintic commonly used in veterinary medicine. Diisopropylamine Dichloroacetate (DADA), an over-the-counter treatment for chronic liver disease, has demonstrated anti-tumor properties as an inhibitor of pyruvate dehydrogenase kinase., Results: The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells. After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression. The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells. The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins., Conclusion: The synergistic anticancer effects of the FZ-DADA combination were confirmed at both cellular and protein levels in A549 lung cancer cells. The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production, suggesting a promising approach for lung cancer treatment that warrants further investigation and development., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cisplatin-based chemotherapy is the mainstay of therapeutic agents for lung cancer. Hence, we investigated the role and mechanism of circ&#95;0006225 in tumorigenesis and cisplatin resistance in lung cancer. Levels of circ&#95;0006225, microRNA (miR)-1236-3p and ankyrin repeat domain 22 (ANKRD22) were detected. Cell cisplatin (DDP) sensitivity and growth were determined by Cell Counting Kit-8, cell colony formation, 5-ethynyl-2'-deoxyuridine, and murine xenograft assays, respectively. A high level of circ&#95;0006225 in lung cancer tissues and cells with cisplatin resistance was observed. Circ&#95;0006225 deletion elevated cisplatin sensitivity and constrained proliferation in DDP-resistant lung cancer cells in vitro. Mechanistically, Circ&#95;0006225 was confirmed to modulate ANKRD22 by sequestering miR-1236-3p. Furthermore, the suppressive effects of circ&#95;0006225 downregulation on cisplatin resistance and proliferation in DDP-resistant lung cancer cells were reversed by miR-1236-3p inhibition or ANKRD22 overexpression. Besides that, circ&#95;0006225 silencing also repressed cisplatin resistance and tumor growth in lung cancer in vivo. In conclusion, knockdown of circ&#95;0006225 restrained the growth and reduced cisplatin resistance in lung cancer by the miR-1236-3p/ANKRD22 axis, suggesting a better effective therapeutic target for overcoming cisplatin resistance in lung cancer patients., (© 2024 Wiley Periodicals LLC.)

Introduction and Importance: Partial anomalous pulmonary venous connection (PAPVC) is a relatively rare congenital vascular anomaly that complicates the surgical management of lung cancer and other lung lesions., Case Presentation: A 74-year-old woman underwent computed tomography (CT) during an episode of chest trauma. Chest CT showed a 24-mm ground glass opacity in the right lower lobe and a PAPVC in the right upper lobe. She was diagnosed with suspected stage IA1 lung cancer with clinical T1miN0M0 and was scheduled for surgery. Preoperative catheterization revealed a pulmonary to systemic flow ratio (Qp/Qs) of 0.98. Surgical repair of PAPVC is indicated when the patient is symptomatic and has a Qp/Qs of 1.5 to 2.0 or more. The patient was scheduled for right lower lobectomy. Although worsening of postoperative right heart strain was considered, the Qp/Qs results indicated that surgical repair of the PAPVC was unnecessary. The intraoperative circulatory dynamics remained stable, and a right lower lobectomy was performed. Her postoperative course was uneventful. There was no evidence of right heart failure or recurrence of lung cancer at the last follow-up examination 6 and 12 months after surgery., Clinical Discussion: If the PAPVC is in the non-resected lobe, preoperative assessment is really important, as major lung resection can increase shunt flow and cause right heart failure., Conclusion: We believe that careful interpretation of CT images of all pulmonary veins before major lung resection while considering PAPVC is important for safe perioperative management and adequate evaluation of cardiac dynamics when PAPVC is present., Competing Interests: Conflict of interest statement The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: Lung cancer growth rate influences screening strategies and treatment decisions. This review aims to provide an overview of primary lung cancer growth rate, quantified by volume doubling time (VDT) through computed tomography (CT) measurement., Methods: Using PRISMA-DTA guideline, PubMed, EMBASE, and Web of Science were searched until March 2024 for studies reporting CT-measured VDT of pathologically confirmed primary lung cancer before intervention. Summary data were extracted from published reports by two independent researchers. Primary outcomes were pooled mean VDT of lung cancer by nodule type and histology, distribution of indolent lung cancer (defined as VDT>400 days or negative), and correlated factors., Results: Thirty-three studies were eligible, comprising 3959 patients with primary lung cancer (mean age range:57.6-77.0 years; 60.0 % men). The pooled mean VDT for solid, part-solid, and nonsolid lung cancer were 207, 536, and 669 days, respectively (p < 0.001). When stratified by histology within solid lung cancer, the pooled mean VDT of adenocarcinoma, squamous cell carcinoma, small cell lung cancer, and others were 223, 140, 73, and 178 days, respectively (p < 0.001). Indolent lung cancer was observed in 34.9 % of lung cancer, predominantly in adenocarcinoma (68.9 %). Adenocarcinoma was associated with slower growth, whereas factors such as tumor size, solidity, TNM staging, and smoking history were positively associated with growth rates., Conclusions: Pooled mean VDT of solid lung cancer was approximately 207 days, demonstrating significant variability in histology yet remaining under the 400-day referral threshold. Key predictors of growth rate include histology, size, solidity, and smoking history, essential for tailoring early intervention strategies., Trial Registration Number: CRD42023408069., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Several phase III trials have altered the management of oncogenic driven non-small cell lung cancer (NSCLC) including those harboring EGFR and ALK mutations. However, several of these pivotal trials deviated from standard-of-care practices for either baseline imaging or surveillance imaging. This occurred despite sponsor acknowledgement in a clinical trial protocol that historical trials utilized imaging modalities that potentially under-staged patients. Inadequate baseline imaging for adjuvant trials instead of PET/CT may not identify individuals with metastatic disease, and thereby subject such individuals with metastatic disease to inferior treatment if randomized to the control arm. Similarly, more frequent surveillance imaging than what is considered standard-of-care may identify disease progression earlier than what is expected in real-world clinical practice and therefore embellish the magnitude of benefit between a targeted therapy and the control arm. While targeted therapies have provided clinical benefit for individuals with oncogenic driven NSCLC, physicians and patients must be cognizant that clinical trial deviations from standard-of-care imaging practices may have embellished the magnitude of benefit for several of these therapies., Competing Interests: Declaration of Competing Interest D.J.B. has the following disclosures: Consulting or Advisory Role: AIMED BIO, Astellas, Eisai, Seagen. Speakers’ Bureau: Merck. Travel and Accommodations: Merck, Seagen. V.P. receives research funding from Arnold Ventures through a grant made to UCSF, and royalties for books and writing from Johns Hopkins Press, MedPage, and the Free Press. He declares consultancy roles with UnitedHealthcare and OptumRX; He hosts the podcasts, Plenary Session, VPZD, Sensible Medicine, writes the newsletters, Sensible Medicine, the Drug Development Letter and VP's Observations and Thoughts, and runs a YouTube channel, which collectively earn revenue on the platforms: Patreon, YouTube and Substack., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: Lung cancer is the most common cause of cancer death in Portugal. The Dutch-Belgian lung cancer screening (LCS) study (NELSON), the biggest European LCS study, showed a lung cancer mortality reduction in a high-risk population when being screened. In this study, the cost-effectiveness of LCS, based on the NELSON study protocol and outcomes, was evaluated compared with no screening in Portugal. Methods: The present study modified an established decision tree by incorporating a state-transition Markov model to evaluate the health-related advantages and economic implications of low-dose computed tomography (LDCT) LCS from the healthcare standpoint in Portugal. The analysis compared screening versus no screening for a high-risk population aged 50-75 with a smoking history. Various metrics, including clinical outcomes, costs, quality-adjusted life years (QALYs), life-years (LYs) and the incremental cost-effectiveness ratio (ICER), were calculated to measure the impact of LDCT LCS. Furthermore, scenario and sensitivity analyses were executed to assess the robustness of the obtained results. Results: Annual LCS with volume-based LDCT resulted in €558 million additional costs and 86,678 additional QALYs resulting in an ICER of €6440 per QALY for one screening group and a lifetime horizon. In total, 13,217 premature lung cancer deaths could be averted, leading to 1.41 additional QALYs gained per individual diagnosed with lung cancer. Results are robust based on the sensitivity analyses. Conclusion: This study showed that annual LDCT LCS for a high-risk population could be cost-effective in Portugal based on a willingness to pay a threshold of one-time the GDP (€19,290 per QALY gained).

Immune checkpoint inhibitors (ICIs) have profoundly reshaped the treatment paradigm for non-small cell lung cancer (NSCLC). Despite these advancements, primary and secondary resistance to ICIs remain prevalent challenges in managing advanced NSCLC. Recent studies have highlighted the significant role of the tumor microenvironment (TME) in modulating treatment responses. This review aims to comprehensively examine the interactive roles of immune/stromal cells-such as T cells, B cells, neutrophils, macrophages, and CAFs within the TME, elucidating how these diverse cellular interactions contribute to immunotherapy resistance. It focuses on the dynamic interactions among diverse cell types such as the varying states of T cells under the influence of TME constituents like immune cells and cancer-associated fibroblasts (CAFs). By exploring the mechanisms involved in the complex cellular interactions, we highlight novel therapeutic targets and strategies aimed at overcoming resistance, thereby enhancing the efficacy of ICIs in NSCLC. Our synthesis of recent research provides critical insights into the multifaceted mechanisms of resistance and paves the way for the development of more effective, personalized treatment approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breast and lung cancers are the leading causes of cancer-related deaths in the world. Although considerable progress has been made in the field of cancer therapy, quest to discover potent, safe and cost-effective alternatives especially from natural sources is being pursued. Snake venom, which is a treasure trove of various peptides and proteins including natural toxins that specifically target tissues and receptors in the envenomated victims. Many such proteins are being explored for their therapeutic potential against various diseases including cancers. Here, we report the mechanism of cytotoxic activity of crude venom and a purified protein, Cytotoxin from the monocled cobra (Naja kaouthia), an elapid snake with neurotoxic venom prominently found in the North-East India. The crude venom showed significant cytotoxicity against breast (MCF-7and MDA-MB-231) and lung (A549, NCI-H522) cancer cell lines. Bioassay-guided fractionation using RP-HPLC showed highest cytotoxic activity in peak P9. Liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS) analysis was employed and the fraction is identified as Cytotoxin 10 which showed comparable cytotoxicity against the experimental cell lines. Cytotoxin 10 also exhibited apoptosis in MCF-7 and A549 cell lines using AO/EtBr and flow cytometry analysis. Expressions of apoptosis related proteins e.g. Bax, Bcl-2, Caspase-7 and PARP were also studied following Cytotoxin 10 treatment in both cell lines. Molecular docking experiments performed to investigate the interactions between Cytotoxin 10 and the apoptotic proteins revealed favourable binding scores compared to their corresponding inhibitors. Interestingly, Cytotoxin 10 inhibited migration and adhesion in a time and dose-dependent manner in both MCF-7 and A549 cells. This is the first report elucidating the mechanism of cytotoxic activity of Cytotoxin 10 purified from Naja kaouthia venom of North-East India origin and could pave the way for development of potential therapeutic strategies against breast and lung cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robin Doley reports financial support was provided by Tezpur University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Macrophages have crucial roles in immune responses and tumor progression, exhibiting diverse phenotypes based on environmental cues. In the present study, the impact of cinobufagin (CB) on macrophage polarization and the consequences on tumor‑associated behaviors were investigated. Morphological transformations of THP‑1 cells into M0, M1 and M2 macrophages were observed, including distinct changes in the size, shape and adherence properties of these cells. CB treatment inhibited the viability of A549 and LLC cells in a concentration‑dependent manner, with an IC 50 of 28.8 and 30.12 ng/ml, respectively. CB at concentrations of <30 ng/ml had no impact on the viability of M0 macrophages and lung epithelial (BEAS‑2B) cells. CB influenced the expression of macrophage surface markers, reducing CD206 positivity in M2 macrophages without affecting CD86 expression in M1 macrophages. CB also altered certain expression profiles at the mRNA level, notably downregulating macrophage receptor with collagenous structure (MARCO) expression in M2 macrophages and upregulating tumor necrosis factor‑α and interleukin‑1β in both M0 and M1 macrophages. Furthermore, ELISA analyses revealed that CB increased the levels of pro‑inflammatory cytokines in M1 macrophages and reduced the levels of anti‑inflammatory factors in M2 macrophages. CB treatment also attenuated the migration and invasion capacities of A549 and LLC cells stimulated by M2 macrophage‑conditioned medium. Additionally, CB modulated peroxisome proliferator‑activated receptor γ (PPARγ) and MARCO expression in M2 macrophages and epithelial‑mesenchymal transition in A549 cells, which was partially reversed by rosiglitazone, a PPARγ agonist. Finally, CB and cisplatin treatments hindered tumor growth in vivo , with distinct impacts on animal body weight and macrophage marker expression in tumor tissues. In conclusion, the results of the present study demonstrated that CB exerted complex regulatory effects on macrophage polarization and tumor progression, suggesting its potential as a modulator of the tumor microenvironment and a therapeutic for cancer treatment.

Background: Venous thromboembolism (VTE) is a leading cause of death among cancer patients. Despite this, studies show that patients with cancer feel inadequately informed about the VTE risk and symptoms, which may impede their ability to recognise symptoms and react promptly. Patients with lung cancer are especially vulnerable due to a high relative risk of developing VTE combined with a high prevalence of low health literacy. This study aimed to explore the VTE information needs of lung cancer patients and how patients and healthcare professionals (HCPs) communicate about VTE., Material and Methods: Data was collected via semi-structured interviews with patients with lung cancer and HCPs. All participants (n = 20) were recruited from an oncological department. The analysis was performed in an inductive manner using a Ricoeur inspired strategy., Findings: Patients had varying information needs regarding VTE, but HCPs did not routinely communicate about VTE, as the topic tended to be lowly prioritised. HCPs communicated about VTE when patients expressed a need or presented symptoms of VTE. HCPs expressed concerns about adding to patient's emotional burden by informing about VTE, while some patients emphasised the importance of being mentally prepared for potential complications., Conclusion: The study demonstrates the challenging balance HCPs must maintain between adequately communicating about VTE and not causing undue psychological distress. However, given patient's often limited awareness of VTE, the responsibility to initiate communication about VTE must fall on the HCPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti-cancer and anti-metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase-type plasminogen activator and matrix metalloproteinase-2. Gossypol reversed TGF-β-induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p-FAK, p-Src and p-paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice., (© 2024 Wiley Periodicals LLC.)

Background: Sarcandra glabra (S. glabra), a traditional Chinese medicine (TCM), has demonstrated significant anticancer activity; however, the underlying mechanisms have not yet been fully elucidated., Purpose: This study aimed to investigate the effects of S. glabra on lung cancer and to explore its underlying mechanisms., Methods: The chemical profile of S. glabra was analyzed via ultrahigh-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). The effects of S. glabra on the viability, proliferation, apoptosis, migration, and invasion of lung cancer cells were assessed via CCK8, colony formation, flow cytometry, scratch, and Transwell assays. In vivo anticancer activity was evaluated in an LLC mouse model. Proteomic analysis was performed to identify key molecules and pathways in S. glabra-treated LLC cells. The expression of ferroptotic proteins and associated cellular events were examined via western blotting, ROS production, iron accumulation, and lipid peroxidation assays. Immune modulation in tumor-bearing mice was evaluated by detecting immune cells and cytokines in the peripheral blood and tumor tissue., Results: Our analysis quantified 1997 chemical markers in S. glabra aqueous extracts. S. glabra inhibited the viability and proliferation of lung cancer cells and induced cell cycle arrest and apoptosis. Scratch and Transwell assays demonstrated that S. glabra suppressed the migration and invasion of lung cancer cells. Oral administration of S. glabra significantly inhibited tumor growth in LLC tumor-bearing mice. Proteomic analysis revealed that S. glabra upregulated the expression of the HMOX1 protein and activated the ferroptosis pathway. Consistent with these findings, we found that S. glabra triggered ferroptosis in lung cancer cells, as evidenced by the upregulation of HMOX1, downregulation of GPX4 and ferritin light chain proteins, iron accumulation, increased ROS production, and lipid peroxidation. Furthermore, S. glabra demonstrated immunostimulatory properties in LLC tumor-bearing mice, leading to increased populations of immune cells (NK cells) and elevated cytokine levels (IL-2)., Conclusion: This study is the first to demonstrate that S. glabra induces ferroptosis in lung cancer cells by regulating HMOX1, GPX4, and FTL. These findings provide a robust scientific basis for the clinical application of S. glabra in lung cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Recently approved RET tyrosine kinase inhibitors (TKIs) have shown promising therapeutic effects against RET-rearranged non-small cell lung cancer (NSCLC) or RET-mutated thyroid cancer. However, resistance develops, limiting long-term efficacy. Although many RET-TKI resistance mechanisms, such as secondary mutations in RET or activation of bypass pathways, are known, some primary or acquired resistance mechanisms are unclear. Here, human genome-wide CRISPR/Cas9 screening was performed to identify genes related to drug-tolerant persister cells. Patient-derived cells with RET-fusion were introduced genome-wide sgRNA library and treated with RET-TKI for 9 days, resulting in the discovery of several candidate genes. Knockout of MED12 or MIG6 significantly increased residual drug-tolerant persister cells under RET-TKI treatment. MIG6 loss induced significant EGFR activation even with low concentrations of EGFR ligands and led to resistance to RET-TKIs. EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. By contrast, a KIF5B-RET positive cells established from a RET-rearranged NSCLC patient, showed significant resistance to RET-TKIs and high dependence on EGFR bypass signaling. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.R. Katayama received research grants from Chugai, and TOPPAN. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cell-free DNA (cfDNA) analysis has shown potential in detecting early-stage lung cancer based on non-genetic features. To distinguish patients with lung cancer from healthy individuals, peripheral blood were collected from 926 lung cancer patients and 611 healthy individuals followed by cfDNA extraction. Low-pass whole genome sequencing and targeted methylation sequencing were conducted and various features of cfDNA were evaluated. With our customized algorithm using the most optimal features, the ensemble stacked model was constructed, called ESim-seq (Early Screening tech with Integrated Model). In the independent validation cohort, the ESim-seq model achieved an area under the curve (AUC) of 0.948 (95 % CI: 0.915-0.981), with a sensitivity of 79.3 % (95 % CI: 71.5-87.0 %) across all stages at a specificity of 96.0 % (95 % CI: 90.6-100.0 %). Specifically, the sensitivity of the ESim-seq model was 76.5 % (95 % CI: 67.3-85.8 %) in stage I patients, 100 % (95 % CI: 100.0-100.0 %) in stage II patients, 100 % (95 % CI: 100.0-100.0 %) in stage III patients and 87.5 % (95 % CI: 64.6%-100.0 %) in stage IV patients in the independent validation cohort. Besides, we constructed LCSC model (Lung Cancer Subtype multiple Classification), which was able to accurately distinguish patients with small cell lung cancer from those with non-small cell lung cancer, achieving an AUC of 0.961 (95 % CI: 0.949-0.957). The present study has established a framework for assessing cfDNA features and demonstrated the benefits of integrating multiple features for early detection of lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Survival analysis based on cancer registry data is of paramount importance for monitoring the effectiveness of health care. As new methods arise, the compendium of statistical tools applicable to cancer registry data grows. In recent years, machine learning approaches for survival analysis were developed. The aim of this study is to compare the model performance of the well established Cox regression and novel machine learning approaches on a previously unused dataset., Material and Methods: The study is based on lung cancer data from the Schleswig-Holstein Cancer Registry. Four survival analysis models are compared: Cox Proportional Hazard Regression (CoxPH) as the most commonly used statistical model, as well as Random Survival Forests (RSF) and two neural network architectures based on the DeepSurv and TabNet approaches. The models are evaluated using the concordance index (C-I), the Brier score and the AUC-ROC score. In addition, to gain more insight in the decision process of the models, we identified the features that have an higher impact on patient survival using permutation feature importance scores and SHAP values., Results: Using a dataset including the cancer stage established by the Union for International Cancer Control (UICC), the best performing model is the CoxPH (C-I: 0.698±0.005), while using a dataset which includes the tumor size, lymph node and metastasis status (TNM) leads to the RSF as best performing model (C-I: 0.703±0.004). The explainability metrics show that the models rely on the combined UICC stage and the metastasis status in the first place, which corresponds to other studies., Discussion: The studied methods are highly relevant for epidemiological researchers to create more accurate survival models, which can help physicians make informed decisions about appropriate therapies and management of patients with lung cancer, ultimately improving survival and quality of life., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Dose-escalation in lung cancer comes with a high risk of severe toxicity. This study aimed to calculate the delivered dose in a Scandinavian phase-III dose-escalation trial., Methods: The delivered dose was evaluated for 21 locally-advanced non-small cell lung cancer (LA-NSCLC) patients treated as part of the NARLAL2 dose-escalation trial. The patients were randomized between standard and escalated heterogeneous dose-delivery. Both treatment plans were created and approved before randomization. Daily cone-beam CT (CBCT) for patient positioning, and adaptive radiotherapy were mandatory. Standard and escalated plans, including adaptive re-plans, were recalculated on each daily CBCT and accumulated on the planning CT for each patient. Dose to the clinical target volume (CTV), organs at risk (OAR), and the effects of plan adaptions were evaluated for the accumulated dose and on each treated fraction scaled to full treatment., Results: For the standard treatment, plan adaptations reduced the number of patients with CTV-T underdosage from six to one, and the total number of fractions with CTV-T underdosage from 161 to 56; while for the escalated treatment, the number of patients was reduced from five to zero and number of fractions from 81 to 11. For dose-escalation, three patients had fractions exceeding trial constraints for heart, bronchi, or esophagus, and one had an accumulated heart dose above the constraints., Conclusion: Dose-escalation for LA-NSCLC patients, using daily image guidance and adaptive radiotherapy, is dosimetrically safe for the majority of patients. Dose calculation on daily CBCTs is an efficient tool to monitor target coverage and OAR doses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Radiomics, analysing quantitative features from medical imaging, has rapidly become an emerging field in translational oncology. Radiomics has been investigated in several neoplastic malignancies as it might allow for a non-invasive tumour characterization and for the identification of predictive and prognostic biomarkers. Over the last few years, evidence has been accumulating regarding potential clinical applications of machine learning in many crucial moments of cancer patients' history. However, the incorporation of radiomics in clinical decision-making process is still limited by low data reproducibility and study variability. Moreover, the need for prospective validations and standardizations is emerging. In this narrative review, we summarize current evidence regarding radiomic applications in high-incidence cancers (breast and lung) for screening, diagnosis, staging, treatment choice, response, and clinical outcome evaluation. We also discuss pro and cons of the radiomic approach, suggesting possible solutions to critical issues which might invalidate radiomics studies and propose future perspectives., Competing Interests: Declaration of Competing Interest AF reports advisory boards/honoraria/speakers’ fee/consultant from BMS, MSD, Roche; MVD reports personal fees for consultancy/advisory role from Eli Lilly, Pfizer, Novartis, Seagen, Gilead, MSD, Exact Sciences, AstraZeneca, Roche, Daiichi Sankyo, Roche; FM reports fees from Roche, Novartis, Seagen, Pfizer, Lilly, Gilead and MSD; LB reports speaker fee/advisory board: Astra-Zeneca, MSD, BMS, Roche, Novartis, Lilly; steering committee and coordinating PI: Astra-Zeneca; local PI: Astra-Zeneca, Roche, MSD, BMS, Janssen, Pharmamar, OSEimmunotherapeutics; unconditioned research support: Astra-Zeneca; VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Novartis, Roche and Zentiva; personal fees for expert testimony for Eli Lilly; GG reports personal fees as invited speaker from Eli Lilly, Novartis and MSD, advisory boards for Gilead, Seagen and Menarini; GP reports advisory boards/honoraria/speakers’ fee/consultant from Amgen, AstraZeneca, BMS, Eli Lilly, Jansenn, MSD, Novartis, Roche and unconditioned research support From AstraZeneca, Roche, MSD. The remaining authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To identify potential predictors of prolonged length of hospital stay in patients submitted to lung resection surgery., Materials and Methods: This is a cohort study, carried out in 105 patients with lung cancer, submitted to posterolateral thoracotomy pulmonary resection. Data collection included preoperative assessment of demographic, clinical, pulmonary function, respiratory muscle function, physical fitness, and behavioral habits. After surgery, length of hospital stay was documented, and the sample was divided into two groups according to the length of hospital stay (LOS): the normal hospital stay group (NLOS) until 8 days, and the prolonged hospital stay group (PLOS) with more than 8 days of hospital stay. Multiple linear regressions were performed between length of hospital stay and the studied variables, for the total sample and, specifically, for the PLOS group., Results: The multiple linear regression for the total sample, the most explanatory power variables were TLC, MIP, PEF, and BMI. When considering only the PLOS, the variables that mostly explained were the MIP%, MEP and TLC%., Conclusion: Besides the classic outcomes used to calculate surgical risk, the body mass index, respiratory muscle strength, peak expiratory flow, and total lung capacity are predictors of the variation on length of hospital stay in patients submitted to lung resection.

Background: Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy., Methods: A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed., Results: A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n = 173) had a significantly lower risk of progression or death from immunotherapy than the other group (n = 311) (PFS: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.62-0.96]; p = .018; OS: HR, 0.77 [95% CI, 0.1-0.98]; p = .032). In a propensity score-matched population, the winter group (n = 162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p = .009) than the other group (n = 162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p = .012). The trend toward longer survival in the winter group continued in subgroup analyses., Conclusions: Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons., (© 2024 American Cancer Society.)

Introduction: Rib fracture is a known complication after stereotactic body radiotherapy (SBRT). Patient-related parameters are essential to provide patient-tailored risk estimation, however, their impact on rib fracture is less documented compared to dosimetric parameters. This study aimed to predict the risk of rib fractures in patients with localized non-small cell lung cancer (NSCLC) post-SBRT based on both patient-related and dosimetric parameters with death as a competing risk., Materials and Methods: In total, 602 patients with localized NSCLC treated with SBRT between 2010-2020 at Odense University Hospital, Denmark were included. All patients received SBRT with 45-66 Gray (Gy)/3 fractions. Rib fractures were identified in CT-scans using a word embedding model. The cumulative incidence function was based on cause-specific Cox hazard models with variable selection based on cross-validation model likelihood performed using 50 bootstraps., Results: In total, 19 % of patients experienced a rib fracture. The cumulative risk of rib fracture increased rapidly from 6-54 months post-SBRT. Female gender, bone density, near max dose to the rib, V30 and V40 to the rib, gross tumor volume, and mean lung dose were significantly associated with rib fracture risk in univariable analysis. The final multi-variable model consisted of V20 and V30 to the rib and mean lung dose., Conclusion: Female gender and low bone density in male patients are significant predictors of rib fracture risk. The final model predicting cumulative rib fracture risk of 19 % in patients with localized NSCLC treated with SBRT contained no patient-related parameters, suggesting that dosimetric parameters are the primary drivers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Lung cancer remains one of the most common malignant cancers worldwide, and its survival rate is extremely low. Chemotherapy, the mainstay of lung cancer treatment, is not as effective as it could be due to the development of cellular resistance. The molecular mechanisms of drug resistance in lung cancer remain to be elucidated. Accumulating evidence suggests that ceRNAs are involved in various carcinogenesis and development. CeRNA is a transcript that regulates each other through competition with miRNA. However, the relationship between ceRNAs and chemoresistance in lung cancer remains unclear. In this narrative review, we provided a summary of treatment approaches that focus on ceRNA networks to overcome drug resistance.

This study aimed to estimate workers' occupational lifetime exposure to chrysotile and examine the respiratory symptoms and lung cancer risk. A total of 112 workers were interviewed about their occupational histories. Exposure modeling using information on the determinants of exposure was used to estimate chrysotile emissions. The cumulative lifetime exposure was then assessed for each worker. Respiratory symptoms were obtained using a validated questionnaire. Lung cancer mortality rate was also predicted using a model. Almost all the workers were male and young (mean age = 30 years, SD = 7). The estimated lifetime occupational chrysotile inhalation exposure ranged from 0.0001 to 0.0486 f/mL.years (median = 0.0018 f/mL.years, IQR = 0.486). A high prevalence of cough symptom (11.7%), and low estimated cancer risk (<1%) were reported. In conclusion, the lung cancer risk among our cohort of workers was at a low level because of lower cumulative lifetime occupational chrysotile exposure., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Surgical manipulation of the lungs increases the number of circulating tumor cells and the subsequent risk of metastasis in patients with lung cancer. This study investigated whether or not ligating the tumor-draining pulmonary vein first during lobectomy could improve the prognosis of these patients., Methods: We retrospectively evaluated patients who underwent curative lobectomy for solitary nonsmall-cell lung carcinoma between January 2012 and December 2016. We divided the patients into the vein-first group, in which all associated pulmonary veins were dissected and severed before cutting the pulmonary artery, bronchus, or pulmonary fissure, and the other procedure group., Results: Overall, we included 177 and 413 patients in the vein-first and other procedure groups, respectively. Propensity score matching yielded 67 pairs of patients. The 5-year overall survival (85.6% [95% confidence interval, 77.3-94.8%] vs. 69.4% [58.7-81.9%], P = 0.03%) and recurrence-free survival (73.4% [63.3-85.1%] vs. 53.5% [42.5-67.3%], P = 0.02) were significantly better in the vein-first group than in the other procedure group. The cumulative recurrence rate at 5 years post-surgery was significantly lower in the vein-first group than in the other procedure group (21.7% vs. 38.3%, P = 0.04)., Conclusion: Our study suggests that ligating the pulmonary vein first during lobectomy for lung cancer can improve the overall survival, recurrence-free survival, and cumulative recurrence rate., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Olanzapine is prescribed as prophylaxis for chemotherapy-induced nausea and vomiting at a dose of 2.5 or 5 mg in Asian countries. We compared the effectiveness of olanzapine 2.5 mg and 5 mg in preventing chemotherapy-induced nausea and vomiting among patients receiving high-emetogenic chemotherapy for lung cancer., Methods: Using a Japanese national inpatient database, we identified patients who received olanzapine doses of 2.5 or 5 mg during high-emetogenic chemotherapy for lung cancer between January 2016 and March 2021. We conducted a 1:1 propensity score-matched analysis with adjustment for various factors, including those affecting olanzapine metabolism. The outcomes were additional antiemetic drug administration (within 2-5 days after chemotherapy initiation), length of hospital stay, and total hospitalization costs., Results: Olanzapine 2.5 and 5.0 mg were used in 2905 and 4287 patients, respectively. The propensity score-matched analysis showed that olanzapine 2.5 mg administration was significantly associated with a higher proportion of additional antiemetic drug administration (36% vs. 31%, p < 0.001) than olanzapine 5 mg. The median length of hospital stay was 8 days in both groups. Total hospitalization cost did not differ significantly between the two doses of olanzapine (5061 vs. 5160 USD, p = 0.07). The instrumental variable analysis demonstrated compatible results., Conclusion: Prophylactic use of olanzapine 2.5 mg during chemotherapy for lung cancer was associated with a higher rate of additional antiemetic drugs than olanzapine 5 mg., (© 2024. The Author(s).)