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Introduction: Few studies have investigated the prognostic factors for non-adenocarcinoma of the lung. We retrospectively evaluated the prognostic factors on the basis of histological type of non-adenocarcinoma of the lung treated by pulmonary resection. Methods: We enrolled 266 patients with non-adenocarcinoma of the lung in this retrospective study: 196 with squamous cell carcinoma (SCC) and 70 with non-SCC. Results: Relapse-free survival (RFS) did not differ significantly between SCC and non-SCC patients (p = 0.33). For SCC patients, RFS differed significantly between patients who underwent wedge resection and non-wedge resection (p < 0.01) and between patients with Clavien-Dindo grade ≥3a and 0–2 postoperative complications (p < 0.01). For non-SCC patients, RFS rates were significantly different in the groups divided at neutrophil-to-lymphocyte ratio = 2.40 (p = 0.02), maximum standardized uptake value (SUVmax) = 8.39 (p < 0.01), between patients with pathological stage (pStage) 0–I and with pStage more than II (p < 0.01). For SCC patients, male sex (p = 0.04), wedge resection (p = 0.01), and Clavien-Dindo grade ≥3a (p = 0.02) were significant factors for RFS in multivariate analysis. For non-SCC patients, neutrophil-to-lymphocyte ratio >2.40 (p < 0.01), SUVmax >8.39 (p = 0.01), and pStage ≥II (p = 0.03) were significant factors for RFS in multivariate analysis. Conclusion: RFS did not differ significantly differently between SCC and non-SCC patients. It is necessary to perform more than segmentectomy and to avoid severe postoperative complications for SCC patients. SUVmax might be an adaptation criterion of adjuvant chemotherapy for patients with non-adenocarcinoma and non-SCC of the lung. [ABSTRACT FROM AUTHOR]

Background: Recent advancements in advanced non‐small‐cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first‐line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first‐line treatment for KRAS‐mutant NSCLC. Methods: We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression‐free survival (PFS) and overall survival (OS). A random‐effects network meta‐analysis was conducted to perform direct and indirect comparisons among treatment groups. Results: Six RCTs were eligible for inclusion. In the network meta‐analysis for KRAS‐mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22–0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47–0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49–0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34–0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48–0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56–0.92). Regarding OS in wild‐type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50–1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63–0.99). Conclusion: The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS‐mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first‐line treatment. [ABSTRACT FROM AUTHOR]

A 73-year-old man with lung squamous cell carcinoma was administered carboplatin + nab-paclitaxel + pembrolizumab for four cycles. Subsequently, he presented with multiple purpuras on his extremities, joint swelling on his fingers, abdominal pain, and diarrhea, accompanied by acute kidney injury (AKI), increased proteinuria, hematuria, and elevated C-reactive protein levels. Skin biopsy showed leukocytoclastic vasculitis as well as IgA and C3 deposition in the vessel walls. Based on these findings, the patient was diagnosed with IgA vasculitis as an immune-related adverse event (irAE) induced by carboplatin + nab-paclitaxel + pembrolizumab. After discontinuation of pembrolizumab and glucocorticoids, the symptoms immediately resolved. Regular monitoring of skin, blood tests, and urinalysis are necessary, and the possibility of irAE IgA vasculitis should be considered in cases of purpura and AKI during treatment with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: The use of stereotactic ablative radiotherapy (SABR) over conventional fractionated radiotherapy (CFRT) for early‐stage non‐small‐cell lung cancer (NSCLC) has been advocated, but is also debated in the literature. Methods: In this retrospective cohort study, we adopted a target trial emulation framework to identify eligible patients diagnosed between 2011 and 2021 using the Taiwan Cancer Registry. In the primary analysis, the overall survival (OS) was the primary endpoint, whereas incidences of lung cancer mortality and radiation pulmonary toxicity were the secondary endpoints. Extensive supplementary analyses were also conducted. Results: We included 351 patients in the primary analysis and found that the OS was not significantly different between the SABR (n = 290) and CFRT (n = 61) groups. The propensity score weighting adjusted hazard ratio of death was 0.75 (95% confidence interval 0.53–1.07, p = 0.118). The secondary endpoints and supplementary analyses showed no significant differences. Conclusions: The OS of patients with early‐stage NSCLC treated with SABR was not significantly different from that of patients treated with CFRT alone. The results of the relevant ongoing clinical trials are eagerly awaited. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) is characterized by high invasiveness, poor prognosis, and a high mortality rate. Single radiotherapy (RT) is ineffective in the treatment of NSCLC due to radio-resistance. Therefore, photothermal therapy (PTT) in combination with RT has been proposed, and PTT–RT synergistic therapy has been extensively explored for feasible cancer treatment. In this study, targeted Au nanoclusters embedded in polydopamine (AuNC/PDA–RGD) was constructed for PTT–RT combined therapy of NSCLC. The AuNC/PDA was prepared based on a one-pot seedless coassembly strategy. In the reaction, HAuCl4 was directly reduced by dopamine to form the gold (Au) core, and dopamine was oxidized and spontaneously self-polymerized to form a PDA shell encapsulating the Au core. After modification with an active targeted Arg-Gly-Asp (RGD) peptide, AuNC/PDA–RGD was obtained, which showed good colloidal stability and low cytotoxicity. This nanosystem could be actively taken up by NSCLC (i.e., A549) cells via the RGD peptide-mediated internalization. Based on the high photothermal conversion capability of AuNC/PDA and the strong radiosensitivity of Au, the AuNC/PDA–RGD could be used for hyperthermia-synergized RT. The in vitro and in vivo experiments showed that the constructed nanosystem had an enhanced curative effect for the treatment of NSCLC by integrating PTT and RT compared with monotherapy. Our studies demonstrated that this AuNC/PDA–RGD nanoplatform has promising medical applications in cancer therapy. [ABSTRACT FROM AUTHOR]

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

Objective To observe the effects of miR-888-5p on the proliferation and invasion abilities of non-smallcell lung cancer (NSCLC) cells, and to explore the possible mechanism. Methods Real-time fluorescence quantitative PCR was used to detect the relative expression levels of miR-888-5p in NSCLC cell lines (A549, NCI-H1299, PC-9, LLC, and NCI-H1650) and human normal lung epithelial cell line (BEAS-2B), . A549 cells with the most significant changes in the miR-888-5p relative expression were selected for subsequent experiments. A549 cells were divided into the miR-888-5p mimics group, miR-888-5p inhibitor group, and scramble group, which were transfected with miR-888-5p mimics, miR-888-5p inhibitor, and scramble sequences, respectively. Real-time fluorescence quantitative PCR was used to detect the relative expression level of miR-888-5p in cells. MTT assay was used to detect the cell proliferation abilities at 0, 24, 48, and 72 h of culture. Transwell chamber invasion assay was used to detect the cell invasion ability (expressed as the number of invading cells), . StarBase online prediction website predicted that the target gene of miR-888-5p was Tob1, which was verified through luciferase assay. Western blotting was used to detect the relative expression levels of Tob1, E-cadherin, vimentin proteins, p-JAK2/JAK2, and p-STAT3/STAT3 in cells. Results The relative expression levels of miR-888-5p in the miR-888-5p mimics group, miR-888-5p inhibitor group, and scramble group were 48. 9 ± 1. 78, 1. 06 ± 0. 24, and 8. 23 ± 0. 90, respectively, with statistically significant difference between groups (all P<0. 05), . Over the time of culture, the proliferation abilities of the three groups showed an increasing trend. At the same time point, the cell proliferation abilities and the invasive cells decreased in the miR-888-5p mimics group, scramble group, and miR888-5p inhibitor group in turn, with statistically significant difference between groups (all P<0. 05), . The relative expression levels of Tob1 and E-cadherin proteins in the miR-888-5p mimics group, scramble group, and miR-888-5p inhibitor group increased sequentially, while the relative expression levels of vimentin protein and p-JAK2/JAK2, p-STAT3/STAT3 decreased sequentially (all P<0. 05), . Conclusion MiR-888-5p can enhance the proliferation and invasion abilities of NSCLC cells, and their mechanism may be related to the activation of JAK2/STAT signaling pathway and targeted downregulation of Tob1 expression, thereby promoting the epithelial-mesenchymal transition. [ABSTRACT FROM AUTHOR]

Objectives: Pretreatment biomarkers are needed to identify patients with non‐small‐cell lung cancer (NSCLC) likely to have worse survival. This ensures that only patients with a real chance of benefit receive immune checkpoint inhibitor (ICI) treatment. In this study, we examined the associations of baseline nutritional and inflammatory biomarkers with overall survival in a real‐world cohort of NSCLC patients who received ICIs. Materials and Methods: We used prospectively collected data from the OncoLifeS data biobank. The cohort included 500 advanced‐stage NSCLC patients treated with ICIs from May 2015 to June 2021. Biomarkers were evaluated within 2 weeks before ICI treatment: neutrophil‐to‐lymphocyte ratio, C‐reactive protein (CRP), Glasgow prognostic score, CRP/albumin ratio (CAR), prognostic nutritional index (PNI), and advanced lung cancer inflammation index. For each biomarker, low‐ and high‐risk groups were defined using literature‐based cut‐offs. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were estimated using adjusted survival analysis. Results: Most patients were male (60.8%), the mean baseline age was 65 ± 9 years, and 88% had stage IV disease. For each biomarker, low‐risk patients had better overall survival (all, p < 0.001), with CAR and PNI showing the strongest associations. In multivariable analyses a combined CAR/PNI risk score had a stronger association with overall survival (aHR 3.09, 95% CI 2.36–4.06) than CAR alone (aHR 2.22, 95% CI 1.79–2.76) or PNI alone (aHR 2.09, 95% CI 1.66–2.61). Conclusion: These results highlight the potential value of nutritional and inflammatory biomarkers, in particular CAR and PNI, in identifying NSCLC patients with highest mortality risk before starting ICI treatment. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) mutations are key drivers in a significant portion of non‐small‐cell lung cancer (NSCLC) patients. While third‐generation EGFR‐tyrosine kinase inhibitors (TKIs) such as osimertinib have demonstrated efficacy, the management of patients who continue to experience disease progression during treatment remains challenging. The emergence of drug resistance, including the development of secondary mutations, necessitates exploration of alternative treatment strategies. This study aims to evaluate and observe the efficacy and safety of almonertinib combined with anlotinib in patients after cancer progression during third‐generation EGFR‐TKI therapy. Methods: In this retrospective analysis, we included EGFR‐mutated NSCLC patients who were resistant to third‐generation EGFR‐TKIs. All patients were treated with almonertinib combined with anlotinib. The clinical characteristics, treatment history, clinical benefits, and adverse events of these patients were retrospectively collected. Results: A total of 16 eligible patients were included in the analysis. The results revealed that combination therapy with almonertinib and anlotinib was effective in this patient cohort. The overall response rate was 25% and the disease control rate was 93.75%. The 6 and 12 months of PFS rates were 92.9% (95% confidence interval [CI] 80.3%, 100.0%) and 84.4% (95% CI 66.6%, 100.0%), respectively. Moreover, this combination therapy was generally well‐tolerated, with manageable adverse events. Conclusion: Our retrospective analysis suggests that almonertinib and anlotinib combination therapy may represent a viable option for EGFR‐mutated NSCLC patients who have progressed on third‐generation EGFR‐TKIs, especially for those with posterior lines and no standard treatment options. Further investigation and larger clinical trials are warranted to validate these observations and refine treatment guidelines. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions To evaluate the value of computed tomography (CT)‐based radiomics combined with clinical‐genetic features in predicting brain metastasis in patients with stage III/IV epidermal growth factor receptor (EGFR)‐mutant non‐small‐cell lung cancer (NSCLC).The study included 147 eligible patients treated at our institution between January 2018 and May 2021. Patients were randomly divided into two cohorts for model training (n = 102) and validation (n = 45). Radiomics features were extracted from the chest CT images before treatment, and a radiomics signature was constructed using the Least Absolute Shrinkage and Selection Operator regression. Kaplan–Meier survival analysis was used to describe the differences in brain metastasis‐free survival (BM‐FS) risk. A clinical‐genetic model was developed using Cox regression analysis. Radiomics, genetic, and combined prediction models were constructed, and their predictive performances were evaluated by the concordance index (C‐index).Patients with a low radiomics score had significantly longer BM‐FS than those with a high radiomics score in both the training (p < 0.0001) and the validation (p = 0.0016) cohorts. The C‐indices of the nomogram, which combined the radiomics signature and N stage, overall stage, third‐generation tyrosine kinase inhibitor treatment, and EGFR mutation status, were 0.886 (95% confidence interval [CI] 0.823–0.949) and 0.811 (95% CI 0.719–0.903) in the training and validation cohorts, respectively. The combined model achieved a higher discrimination and clinical utility than the single prediction models.The combined radiomics‐genetic model could be used to predict BM‐FS in stage III/IV NSCLC patients with EGFR mutations. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression of microRNA-363-3p （miR-363-3p） and sex-determining region Y-box protein 4（SOX4） mRNA in the non-small-cell lung cancer （NSCLC） tissues and their effects on the epithelmesenchymal transformation （EMT). Methods Cancer tissues and adjacent tissues of 84 patients with NSCLC who underwent surgical resection were collected. Real-time fluorescence quantitative PCR was used to detect miR-363-3p and SOX4 mRNA in the cancer tissues and adjacent tissues, and immunohistochemistry was used to detect the E-cadherin and Vimentin expression in the cancer tissues and adjacent tissues. The mRNA expression levels of miR-363-3p and SOX4 in the cancer tissues of patients with different pathological characteristics were compared. Spearman's rank correlation test was used to analyze the correlation between miR-363-3p, SOX4 mRNA expression and E-cadherin and Vimentin in the cancer tissues. The interaction of miR-363-3p and SOX4 in EMT process was analyzed using relative excess risk due to interaction （RERI), attributable proportion due to interaction （AP） and interaction index （SI）. Results The expression of miR-363-3p in the cancer tissues was lower than that in the adjacent tissues, and the expression of SOX4 mRNA was higher than that in the adjacent tissues （both P<0. 05）. The mRNA expression levels of miR-363-3p and SOX4 in the cancer tissues were not related to gender, age, smoking history or tumor diameter （all P>0. 05), but was related to differentiation degree and TNM stage (all P<0. 05). The positive expression rate of E-cadherin in the cancer tissues was lower than that in the adjacent tissues, and the positive expression rate of Vimentin was higher than that in the adjacent tissues （both P<0. 05）. The miR-363-3p was positively correlated with the expression of E-cadherin (r=0. 491，P<0. 05), and was negatively correlated with the expression of Vimentin （r=–0. 506，P<0. 05). SOX4 mRNA was negatively correlated with E-cadherin expression (r=–0. 527, P<0. 05), and was positively correlated with Vimentin expression （r=0. 463，P<0. 05). The miR-363-3p and SOX4 in the cancer tissues had negative interactions with EMT process （RERI=29. 639， AP=70. 91, SI=3. 656). Conclusion The abnormal expression of miR-363-3p and SOX4 mRNA in NSCLC tissues is related to EMT, and the two have negative interaction with EMT process. [ABSTRACT FROM AUTHOR]

Background: Radiomics provided opportunities to quantify the tumor phenotype non-invasively. This study extracted contrast-enhanced computed tomography (CECT) radiomic signatures and evaluated clinical features of bone metastasis in non-small-cell lung cancer (NSCLC). With the combination of the revealed radiomics and clinical features, the predictive modeling on bone metastasis in NSCLC was established. Methods: A total of 318 patients with NSCLC at the Tianjin Medical University Cancer Institute & Hospital was enrolled between January 2009 and December 2019, which included a feature-learning cohort (n = 223) and a validation cohort (n = 95). We trained a radiomics model in 318 CECT images from feature-learning cohort to extract the radiomics features of bone metastasis in NSCLC. The Kruskal-Wallis and the least absolute shrinkage and selection operator regression (LASSO) were used to select bone metastasis-related features and construct the CT radiomics score (Rad-score). Multivariate logistic regression was performed with the combination of the Rad-score and clinical data. A predictive nomogram was subsequently developed. Results: Radiomics models using CECT scans were significant on bone metastasis prediction in NSCLC. Model performance was enhanced with each information into the model. The radiomics nomogram achieved an AUC of 0.745 (95% confidence interval [CI]: 0.68,0.80) on predicting bone metastasis in the training set and an AUC of 0.808(95% confidence interval [CI]: 0.71,0.88) in the validation set. Conclusion: The revealed invisible image features were of significance on guiding bone metastasis prediction in NSCLC. Based on the combination of the image features and clinical characteristics, the predictive nomogram was established. Such nomogram can be used for the auxiliary screening of bone metastasis in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. Methods: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Results: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. Conclusions: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC. [ABSTRACT FROM AUTHOR]

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

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

Background: Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death in men in Algeria. Little is known about the characteristics of lung cancer in Algeria. This study aimed to determine the clinicopathological characteristics and prognosis of non–small cell lung cancer (NSCLC) patients in Algeria. Methods: This retrospective study was performed on 269 pathologically confirmed cases of NSCLC at the Benbadis University Hospital of Constantine (2015–2023). Of these, 95 patients were included in the survival analysis. The clinicopathological and outcome data were investigated based on the patients' medical records. Results: This study showed male predominance with sex ratio of 5.7, with a mean age of 61.8 years. Histologically, 67.3% of cases had adenocarcinoma (ADC) and 22.7% squamous cell carcinoma (SCC). ADC and SCC occurred more frequently in female (p = 0.02) and male (p = 0.003) patients, respectively. Smoking was estimated at 82.2% in men. Over 28% were non-smokers, of which 50.7% were women, and presented at younger age (p = 0.04). Most of our patients (75.5%) have an advanced stage at diagnosis. Around 70% of patients underwent chemotherapy (CT) as first-line treatment, with medians diagnostic and treatment delays of 4 and 1 months, respectively. The median overall survival (mOS) was estimated at 10.3 and 6.7 months in I-III and IV stages, respectively. Other factors that negatively impact OS were age > 65 years (p = 0.01), and the presence of symptoms (p = 0.005) and comorbidity (p = 0.004) in stage IV, and delayed treatment (p = 0.03) and receiving CT alone (p = 0.03) in stages I-III cases. Medians progression free survival (mPFS) in stage IV, III, and II patients were 4.1, 5.2, and 8.3 months, respectively, and negatively affected by the comorbidity (stage IV, p = 0.03) and receiving CT alone (stages II-III, p = 0.03). Conclusions: NSCLC presents at an early age and advanced stage in Algerian patients. ADC is the most frequent histological subtype and smoking remains the most important risk factor in men. Furthermore, the prognostic factors affecting survival are stage, age, comorbidity, symptoms, and treatment. Thus, tobacco control, early detection program, and access to novel therapies may be the best strategies to reduce NSCLC morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Non‐small‐cell lung cancer (NSCLC) often presents at later stages, typically associated with poor prognosis. Autophagy genes play a role in the progression of tumors. This study investigated the clinical relevance, prognostic value, and biological significance of RBBP4 in NSCLC. Methods: We assessed RBBP4 expression using the GSE30219 and TCGA NSCLC datasets and NSCLC cells, exploring its links with clinical outcomes, tumor immunity, and autophagy genes through bioinformatics analysis after transcriptome sequencing of RBBP4‐knockdown and control PC9 cells. We identified differentially expressed genes (DEGs) and conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein–protein interaction network analyses. The significance of autophagy‐related DEGs was evaluated for diagnosis and prognosis using the GSE30219 dataset. Experiments both in vivo and in vitro explored the biological mechanisms behind RBBP4‐mediated autophagic cell death in NSCLC. Results: RBBP4 overexpression in NSCLC correlates with a poorer prognosis. Eighteen types of immune cell were significantly enriched in cultures that had low RBBP4 expression compared high expression. DEGs associated with RBBP4 are enriched in autophagy pathways. Transcriptomic profiling of the PC9 cell line identified autophagy‐related DEGs associated with RBBP4 that exhibited differential expression in NSCLC, suggesting prognostic applications. In vitro experiments demonstrated that RBBP4 knockdown induced autophagy and apoptosis in PC9 cells, promoting cell death, which was inhibited by 3‐MA. In vivo, targeted siRNA against RBBP4 significantly reduced tumor development in PC9 cell‐injected nude mice, elevating autophagy‐related protein levels and inducing apoptosis and necrosis in tumor tissues. Conclusion: In NSCLC, RBBP4 upregulation correlates with poor prognosis and altered immunity. Its knockdown induces autophagic cell death in NSCLC cells. These results indicate RBBP4 as a potential NSCLC diagnostic marker and its autophagy modulation as a prospective therapeutic target. [ABSTRACT FROM AUTHOR]

Aims: PD‐1 block was reported to impair opioid‐induced antinociception and affect cognitive function in rodents and non‐human primates. This prospective multicenter cohort study aims to investigate the possible impact of neoadjuvant immunotherapy with PD‐1 antibody on perioperative analgesic effect of opioids and postoperative delirium (POD) for non‐small‐cell lung cancer (NSCLC) patients. Methods: Eighty‐four NSCLC patients from three medical centers with neoadjuvant chemoimmunotherapy (nCIT) or chemotherapy (nCT) were enrolled. The primary outcome is the total perioperative opioid consumption defined as the sum of intraoperative and postoperative opioid use within 3 days after surgery. Secondary outcomes compromise of incidence of POD, pain intensity, and number of analgesic pump press. Tumor prognostic parameters and perioperative change of inflammatory cytokines and soluble PD‐L1 level were also recorded. Results: Eighty‐one patients were included in the final analysis. The total opioid consumption (sufentanil equivalent) perioperatively in the nCIT group was significantly higher than that in the nCT group, with mean difference of 60.39 μg, 95% CI (25.58–95.19), p < 0.001. Multiple linear regression analysis showed that nCIT was correlated with increased total opioid consumption (β = 0.305; 95% CI, 0.152–0.459; p < 0.001). The incidence of moderate‐to‐severe pain and cumulative analgesic pump press within 72 h was significantly higher in subjects with nCIT. There is no statistical difference in incidence of POD between groups within 72 h after surgery. The pathologic complete response rate and perioperative serum IL‐6 level were higher in the nCIT group than in the nCT group. Conclusion: Patients with NSCLC receiving nCIT warrant increased opioid consumption perioperatively and suffered from more postoperative pain. Clinical Trial Registration: NCT05273827. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to assess the impact of physical activity on both therapeutic efficacy and immune-related adverse events (irAEs) during immunotherapy for non-small cell lung cancer (NSCLC). Methods: Physical activity was divided into three groups: light physical activity (LPA), moderate physical activity (MPA), and vigorous physical activity (VPA) for laboratory indexes, efficacy, and irAEs. A multivariate logistic regression was employed to analyze the relationship between sedentary behavior with efficacy and irAEs. Results: The study included 121 patients. The three levels of physical activity were not significantly associated with efficacy or irAEs. However, noteworthy disparities were observed in base-hemoglobin levels (F = 3.4, P = 0.037) and base-lymphocyte levels (χ2 = 6.13, P = 0.047) among the three groups. After treatment, we identified statistically significant variations in albumin levels (P = 0.012) and lymphocyte counts (P = 0.035). Furthermore, a negative correlation emerged between pre-treatment sedentary behavior duration and immune-efficacy (β: −0.005, P = 0.027). Conclusions: In summary, within the cohort of NSCLC patients undergoing single immunotherapy or a combination of immunotherapy and chemotherapy, physical activity is closely related to immune and inflammatory indicators in patients, and prolonged sitting will reduce the therapeutic effect. [ABSTRACT FROM AUTHOR]

Osimertinib induces a marked response in non–small‐cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) gene mutations. However, acquired resistance to osimertinib remains an inevitable problem. In this study, we aimed to investigate osimertinib‐resistant mechanisms and evaluate the combination therapy of afatinib and chemotherapy. We established osimertinib‐resistant cell lines (PC‐9‐OR and H1975‐OR) from EGFR‐mutant lung adenocarcinoma cell lines PC‐9 and H1975 by high exposure and stepwise method. Combination therapy of afatinib plus carboplatin (CBDCA) and pemetrexed (PEM) was effective in both parental and osimertinib‐resistant cells. We found that expression of thrombospondin‐1 (TSP‐1) was upregulated in resistant cells using cDNA microarray analysis. We demonstrated that TSP‐1 increases the expression of matrix metalloproteinases through integrin signaling and promotes tumor invasion in both PC‐9‐OR and H1975‐OR, and that epithelial‐to‐mesenchymal transition (EMT) was involved in H1975‐OR. Afatinib plus CBDCA and PEM reversed TSP‐1‐induced invasion ability and EMT changes in resistant cells. In PC‐9‐OR xenograft mouse models (five female Balb/c‐Nude mice in each group), combination therapy strongly inhibited tumor growth compared with afatinib monotherapy (5 mg/kg, orally, five times per week) or CBDCA (75 mg/kg, intraperitoneally, one time per week) + PEM (100 mg/kg, intraperitoneally, one time per week) over a 28‐day period. These results suggest that the combination of afatinib plus CBDCA and PEM, which effectively suppresses TSP‐1 expression, may be a promising option in EGFR‐mutated NSCLC patients after the acquisition of osimertinib resistance. [ABSTRACT FROM AUTHOR]

Background and Objectives: Lung cancer is the leading cause of cancer-related deaths. Spread through air spaces (STAS) is an adverse prognostic factor that has become increasingly known in recent years. This study aims to investigate the impact of STAS presence on overall survival (OS) and disease-free survival (DFS) in patients with surgically resected stage IA-IIIA lung cancer and to identify clinicopathological features associated with STAS. Materials and Methods: This research involved 311 lung cancer surgery patients. The relationship between the presence of STAS in the patients' surgical pathology and OS and DFS values was examined. Clinicopathological features associated with the presence of STAS were determined. Results: There were 103 (33%) STAS-positive patients. Adenocarcinoma histological subtype, perineural invasion (PNI), and lymphovascular invasion (LVI) were significantly correlated with being STAS positive. STAS significantly predicted DFS and OS. One-year and five-year DFS rates were significantly lower in the STAS-positive group compared to the STAS-negative group (65% vs. 88%, 29% vs. 62%, respectively, p ≤ 0.001). Similarly, one-year and five-year OS rates were significantly lower in the STAS-positive group compared to the STAS-negative group (92% vs. 94%, 54% vs. 88%, respectively, p ≤ 0.001). In multivariate analysis, STAS was found to be an independent prognostic factor for both DFS and OS (HR: 3.2 (95%CI: 2.1–4.8) and 3.1 (95%CI: 1.7–5.5), p < 0.001 and <0.001, respectively). Conclusions: In our study, STAS was found to be an independent prognostic biomarker in operated stage IA-IIIA lung cancer patients. It may be a beneficial pathological biomarker in predicting the survival of patients and managing their treatments. [ABSTRACT FROM AUTHOR]

Recent advancements in targeted therapies for non-small-cell lung cancer (NSCLC), specifically focusing on epidermal growth factor receptor (EGFR) mutations, have revolutionized treatment strategies. Osimertinib, an approved therapy for metastatic NSCLC with EGFR mutations, highlights remarkable efficacy but also harbors the potential for severe adverse events, whose rarity or lack of precedence may mask their criticality. This article delves into the exploration of adverse events linked to osimertinib, shedding light on a rare yet life-threatening occurrence: severe myelosuppression. A case study detailing a patient with EGFR-mutated NSCLC exhibiting a robust treatment response but experiencing severe myelosuppression following osimertinib initiation is presented. Immediate discontinuation of osimertinib alongside concurrent blood transfusions facilitated toxicity recovery, prompting a successful reduction in myelosuppression severity upon re-administration at a lowered dosage. [ABSTRACT FROM AUTHOR]

Introduction: This systematic review and network meta-analysis(NMA) was designed to compare the long-term outcomes of pembrolizumab monotherapy and pembrolizumab plus chemotherapy as first-line therapy for metastatic non-small-cell lung cancer(NSCLC). Materials and Methods: Four databases(Medline, Embase, Web of Science and CENTRAL were searched published from establishment of database to August 17, 2023, for articles studying pembrolizumab monotherapy or pembrolizumab plus chemotherapy for non-small cell lung cancer (NSCLC). Network meta-analyses of progression-free survival(PFS), overall survival(OS), objective response rate (ORR), treatment-related adverse events(trAEs) and immune-related adverse events(irAEs) were performed. Results: A total of five studies were considered for NMA. This NMA includes a cohort of 2878 patients diagnosed with advanced NSCLC. Among them, 791 patients received pembrolizumab monotherapy, 1337 patients received chemotherapy, and 748 patients received pembrolizumab plus chemotherapy. The IPDformKM software was utilized to reconstruct Kaplan-Meier curves for OS and PFS, offering a lucid and intuitive depiction of oncological outcomes. For patients who have high levels of programmed death-ligand 1(PD-L1) expression (≥50%), pembrolizumab plus chemotherapy was more effective than using pembrolizumab alone as first-line therapy in terms of PFS (median survival time: 10.41 months versus 7.41 months, HR: 0.81, 95%CI 0.67 to 0.97, P=0.02) and ORR (RR:1.74, 95% CI: 1.25-2.43). Nevertheless, there was no statistically significant difference observed between the two groups in terms of OS (median survival time: 22.54 months versus 22.62 months, HR: 0.89, 95%CI 0.73 to 1.08, P=0.24). Furthermore, pembrolizumab plus chemotherapy provided a more advantageous long-term survival advantage in terms of OS (median survival time: 20.88 months versus 13.60 months, HR: 0.77, 95%CI: 0.62 to 0.95, P=0.015) compared to pembrolizumab monotherapy in patients with low PD-L1 expression levels (1% to 49%). With regards to safety, there was no statistically significant disparity between the two groups in relation to any irAEs (RD=0.02, 95% CI: -0.12 to 0.16) or Grade≥ 3 irAEs (RD=0.01, 95% CI: -0.10 to 0.12). Nevertheless, pembrolizumab plus chemotherapy exhibited a greater likelihood of encountering any trAEs (RD=0.23, 95% CI: 0.17 to 0.30) and Grade≥ 3 trAEs (RD=0.28, 95% CI: 0.21 to 0.35) in comparison to pembrolizumab monotherapy. Conclusions: The present network meta-analysis reported comparative longterm outcomes of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy as first-line therapy for metastatic non-small-cell lung cancer. Pembrolizumab plus chemotherapy led to improved PFS and ORR in patients with advanced NSCLC who had a PD-L1 expression level of 50% or above. However, there was no noticeable benefit in terms of OS when pembrolizumab was paired with chemotherapy compared to utilizing pembrolizumab alone. In addition, pembrolizumab plus chemotherapy offered a greater long-term survival benefit in terms of OS when compared to utilizing pembrolizumab alone in patients with PD-L1 expression levels ranging from 1% to 49%. Furthermore, the increased effectiveness of pembrolizumab plus chemotherapy was accompanied by an increase in adverse side effects. [ABSTRACT FROM AUTHOR]

Background: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex—unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis. [ABSTRACT FROM AUTHOR]

The efficacy of pembrolizumab in the treatment-naïve non-small-cell lung cancer (NSCLC) patients was proved in the KEYNOTE-024 randomized trial. The aim of this systematic literature review was to identify and summarize the real world evidence (RWE) of overall survival (OS) in previously untreated patients with NSCLC receiving pembrolizumab monotherapy. A systematic search was conducted in PubMed (MEDLINE®) and EMBASE databases. Analyses were focused on survival data (median OS and survival rates at specific time points). To explore the population comparable with the KEYNOTE-024 study, we focused on studies enrolling at least 50% of patients at stage IV of cancer and ECOG performance status 0–2. A total of 41 RWE studies covering over 7600 advanced NSCLC patients naïve to systemic treatment were identified. Overall, survival outcomes reported in those studies vary considerably (median OS range: 3.0–34.6 months). Most RWE studies reported median OS shorter to that reported in KEYNOTE-024 (26.3 months), but about half of reported OS medians were in range of 95% confidence interval for OS as reported in KEYNOTE-024 trial (18.3–40.4 months). Patients with similar characteristics of stage and performance status to those of KEYNOTE-024 trial benefited the same with pembrolizumab monotherapy as their survival outcomes (18.9–22.8 months) were consistent with those reported in the clinical trial. RWE data showed substantially worse outcomes in patients with ECOG-PS 2+ compared to ECOG-PS 0–1 patients. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification. [ABSTRACT FROM AUTHOR]

Simple Summary: The 18F-FDG PET parameters reflecting the intensity and distribution of glucose uptake by the tumor are associated with prognosis in non-small-cell lung cancer (NSCLC) patients. We developed and evaluated an imaging-based model utilizing these 18F-FDG PET-derived features for predicting the five-year survival in NSCLC patients after curative surgery. The PET-based risk score constructed using the LASSO logistic method outperformed the predictive performances of individual 18F-FDG PET parameters. The PET-based risk score was an independent prognostic factor for clinical variables. Additionally, it demonstrated better predictive performance when combined with clinical variables. The FDG PET-based imaging model could aid in risk stratification for personalized adjuvant treatment and follow-up management of NSCLC patients after surgery. The aim of our retrospective study is to develop and assess an imaging-based model utilizing 18F-FDG PET parameters for predicting the five-year survival in non-small-cell lung cancer (NSCLC) patients after curative surgery. A total of 361 NSCLC patients who underwent curative surgery were assigned to the training set (n = 253) and the test set (n = 108). The LASSO regression model was used to construct a PET-based risk score for predicting five-year survival. A hybrid model that combined the PET-based risk score and clinical variables was developed using multivariate logistic regression analysis. The predictive performance was determined by the area under the curve (AUC). The individual features with the best predictive performances were co-occurrence_contrast (AUC = 0.675) and SUL peak (AUC = 0.671). The PET-based risk score was identified as an independent predictor after adjusting for clinical variables (OR 5.231, 95% CI 1.987–6.932; p = 0.009). The hybrid model, which integrated clinical variables, significantly outperformed the PET-based risk score alone in predictive accuracy (AUC = 0.771 vs. 0.696, p = 0.022), a finding that was consistent in the test set. The PET-based risk score, especially when integrated with clinical variables, demonstrates good predictive ability for five-year survival in NSCLC patients following curative surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the leading cause of cancer-related death in the U.S. and the majority of these cases are non-small-cell lung cancer (NSCLC). While immune checkpoint inhibitors (ICIs) are initially effective, patients often develop resistance to the treatment. Tumor-associated neutrophils (TANs) play a key role in the tumor environment and immune response. The main challenge is to understand how TANs influence the effectiveness of ICI treatment. This review discusses current research on how neutrophils interact with cancer cells and other components in the tumor environment. Ongoing clinical trials are exploring treatments that target these neutrophils to improve ICI therapy in NSCLC. Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, we summarize the current studies of neutrophil interaction with malignant cells, T-cells, and other components in the TME. Ongoing clinical trials are aimed at utilizing reagents that have putative effects on tumor-associated neutrophils, in combination with ICI. Elevated neutrophil populations and neutrophil-associated factors could be potential therapeutic targets to enhance anti-PD1 treatment in NSCLC. [ABSTRACT FROM AUTHOR]

The emergence of targeted therapies in non-small-cell lung cancer (NSCLC), including inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase, has increased the need for robust companion diagnostic tests. Nowadays, detection of actionable variants in exons 18–21 of the EGFR gene by qPCR and direct DNA sequencing is often replaced by next-generation sequencing (NGS). In this study, we evaluated the diagnostic usefulness of targeted NGS for druggable EGFR variants testing in clinical NSCLC material previously analyzed by the IVD-certified qPCR test with respect to DNA reference material. We tested 59 NSCLC tissue and cytology specimens for EGFR variants using the NGS 'TruSight Tumor 15' assay (Illumina) and the qPCR 'cobas EGFR mutation test v2' (Roche Diagnostics). The sensitivity and specificity of targeted NGS assay were evaluated using the biosynthetic and biological DNA reference material with known allelic frequencies (VAF) of EGFR variants. NGS demonstrated a sufficient lower detection limit for diagnostic applications (VAF < 5%) in DNA reference material; all EGFR variants were correctly identified. NGS showed high repeatability of VAF assessment between runs (CV% from 0.02 to 3.98). In clinical material, the overall concordance between NGS and qPCR was 76.14% (Cohen's Kappa = 0.5933). The majority of discordant results concerned false-positive detection of EGFR exon 20 insertions by qPCR. A total of 9 out of 59 (15%) clinical samples showed discordant results for one or more EGFR variants in both assays. Additionally, we observed TP53 to be a frequently co-mutated gene in EGFR-positive NSCLC patients. In conclusion, targeted NGS showed a number of superior features over qPCR in EGFR variant detection (exact identification of variants, calculation of allelic frequency, high analytical sensitivity), which might enhance the basic diagnostic report. [ABSTRACT FROM AUTHOR]

Third-generation tyrosine kinase inhibitors are the first-line gold standard in treating advanced non-small-cell lung cancer bearing common EGFR mutations, but data documenting clinical efficacy in uncommon mutations are currently limited. In this paper, we describe the case of a patient bearing uncommon compound EGFR mutations in exon 20, who experienced a near-complete response to third-line Osimertinib, with metabolic complete response of pulmonary, nodal and ostheolytic lesions. This radiological assessment corresponded to an ECOG PS improvement (from three to one) and a substantial clinical benefit for the patients. Out of two mutations, S768I was associated with poor response to third-generation TKI and V774M had unknown clinical significance, highlighting the complexity of the correct management of these kinds of mutations. We reviewed the literature to document the up-to-date preclinical and clinical data concerning third-generation tyrosine kinase inhibitors for the treatment of patients bearing uncommon EGFR mutations. [ABSTRACT FROM AUTHOR]

Objective: To compare the uniportal and multiportal video-assisted thoracoscopic surgery (VATS) in patients with nonsmall- cell lung cancer (NSCLC). Methods: Medical records of 128 patients with NSCLC who underwent surgical treatment in the First School of Clinical Medicine, Southern Medical University from August 2020 to February 2022 were retrospectively analyzed. There were 60 patients who underwent uniportal VATS (UVATS group) and 68 patients underwent multiportal VATS (MVATS group). The relevant indexes, complications, postoperative pain levels and quality of life, recurrence, metastases and survival between the two groups were compared. Results: UVATS was associated with longer operation time and higher intraoperative blood loss compared to MVATS (P<0.05). The postoperative drainage volume, and the visual analogue scale (VAS) scores at 24 and 72 hours were lower in the UVATS group compared to the MVATS group, while the chest tube retention time and hospitalization time were shorter than those in the MVATS group (P<0.05). The quality of life at six months after surgery in the UVATS group was significantly higher than that in the MVATS group (P<0.05). Conclusions: UVATS and MVATS have similar outcomes in patients with NSCLC. Although UVATS surgery takes longer and is associated with more interoperative bleeding, it can reduce postoperative pain, shorten postoperative recovery time, and help further improve the quality of life of patients after surgery. [ABSTRACT FROM AUTHOR]

We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2–13.4 months) and PFS was 3.2 months (95% CI 2.5–3.9 months). ORR was 15% (95% CI 10–21%) and DCR was 61% (95% CI 53–67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the repurposing of a class of non-cancer drugs, phosphodiesterase inhibitors, to increase the potency of an anti-folate chemotherapy drug against non-small-cell lung cancer. We showed that this approach represents a double-edged strategy. While the use of phosphodiesterase inhibitors potentiated the killing of lung cancer cells by combination low-dose anti-folate chemotherapy, in half of the tumors evaluated, the benefit was lost when using higher doses of chemotherapy. Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses. [ABSTRACT FROM AUTHOR]

Simple Summary: The present research investigates the counterintuitive effects of sublethal chemotherapy doses in non-small-cell lung cancer (NSCLC), focusing on their role in enhancing cancer cell malignancy and the role of Aldo-keto reductase family 1 member B10 (AKR1B10) in this process. This study is designed to understand how sublethal doses of chemotherapy drugs like taxol and doxorubicin lead to increased cancer cell migration, invasion, metastasis, and the consequent upregulation of AKR1B10. Our findings uncover the fact that AKR1B10 plays a crucial role in NSCLC progression and chemoresistance, with its increased expression being linked to enhanced malignancy. The results are significant for the research community as they provide insight into the currently paradoxical molecular mechanisms of chemotherapy-induced resistance in lung cancer. This could lead to the potential development of more effective treatment strategies that consider the impact of chemotherapy dosing on cancer cell behavior, potentially improving patient outcomes by preventing the unintentional enhancement of cancer aggressiveness. Chemotherapy remains a cornerstone in lung cancer treatment, yet emerging evidence suggests that sublethal low doses may inadvertently enhance the malignancy. This study investigates the paradoxical effects of sublethal low-dose chemotherapy on non-small-cell lung cancer (NSCLC) cells, emphasizing the role of Aldo-keto reductase family 1 member B10 (AKR1B10). We found that sublethal doses of chemotherapy unexpectedly increased cancer cell migration approximately 2-fold and invasion approximately threefold, potentially promoting metastasis. Our analysis revealed a significant upregulation of AKR1B10 in response to taxol and doxorubicin treatment, correlating with poor survival rates in lung cancer patients. Furthermore, silencing AKR1B10 resulted in a 1–2-fold reduction in cell proliferation and a 2–3-fold reduction in colony formation and migration while increasing chemotherapy sensitivity. In contrast, the overexpression of AKR1B10 stimulated growth rate by approximately 2-fold via ERK pathway activation, underscoring its potential as a target for therapeutic intervention. The reversal of these effects upon the application of an ERK-specific inhibitor further validates the significance of the ERK pathway in AKR1B10-mediated chemoresistance. In conclusion, our findings significantly contribute to the understanding of chemotherapy-induced adaptations in lung cancer cells. The elevated AKR1B10 expression following sublethal chemotherapy presents a novel molecular mechanism contributing to the development of chemoresistance. It highlights the need for strategic approaches in chemotherapy administration to circumvent the inadvertent enhancement of cancer aggressiveness. This study positions AKR1B10 as a potential therapeutic target, offering a new avenue to improve lung cancer treatment outcomes by mitigating the adverse effects of sublethal chemotherapy. [ABSTRACT FROM AUTHOR]