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Background: Pulmonary rehabilitation (PR) has been shown to effectively support postsurgical recovery in patients with lung cancer (LC) at various stages. While digital PR programs offer a potential solution to traditional challenges, such as time and space constraints, their efficacy and feasibility for patients undergoing LC surgery remain unclear., Objective: This systematic review aims to assess the feasibility and effectiveness of digital PR programs for individuals undergoing LC surgery., Methods: A systematic review was conducted, retrieving data from 6 English and 4 Chinese databases from their inception to January 1, 2024. References in related studies were also manually reviewed. The primary outcomes assessed were physical capacity, lung function, and the incidence of postoperative pulmonary complications (PPCs). The secondary outcomes were compliance, hospital stay, chest tube duration, anxiety, depression, and quality of life. Where applicable, recruitment and withdrawal rates were also evaluated. Meta-analysis and descriptive analysis were used to assess the outcomes., Results: A total of 5 randomized controlled trials and 6 quasi-experimental studies (n=1063) were included, with 4 studies being included in the meta-analyses. Our meta-analyses revealed that digital PR reduced the decline in 6-minute walk distance (6-MWD) by an average of 15 m compared with routine PR programs from admission to discharge, demonstrating a clinically significant improvement in physical capacity (mean difference -15.00, 95% CI -25.65 to -4.34, P=.006). Additionally, digital PR was associated with a reduction (26/58, 45%) in the likelihood of PPCs (risk ratio 0.45, 95% CI 0.30-0.66, P<.001) and a reduction of 1.53 days in chest tube duration (mean difference -1.53, 95% CI -2.95 to -0.12, P=.03), without a statistically significant effect on postoperative hospital stay (mean difference -1.42, 95% CI -3.45 to 0.62, P=.17). Descriptive analyses suggested that digital PR has the potential to improve knowledge, lung function, quality of life, and self-efficacy, while reducing depression and anxiety. Notably, digital PR was found to be a safe, feasible, and acceptable supplementary intervention. Despite challenges with low recruitment, digital PR enhanced exercise compliance, increased patient satisfaction, and lowered dropout rates., Conclusions: This systematic review is the first comprehensive analysis to suggest that digital PR is a safe, feasible, acceptable, and effective intervention for promoting recovery in patients with LC after surgery. Digital PR has the potential to be a valuable supplement, expanding access to traditional PR programs. Future research should prioritize the development of interactive and inclusive digital solutions tailored to diverse age groups and educational backgrounds. Rigorous studies, including large-scale, high-quality randomized controlled trials with detailed protocols and robust methodologies, are needed to assess the short-, medium-, and long-term efficacy of digital PR, ensuring reproducibility in future research., Trial Registration: PROSPERO CRD42023430271; https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=430271., (©Taiping Lu, Ting Deng, Yangyang Long, Jin Li, Anmei Hu, Yufan Hu, Li Ouyang, Huiping Wang, Junliang Ma, Shaolin Chen, Jiale Hu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.11.2024.)

Purpose: The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition ( MET ), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring c-Met alterations., Methods: This multicenter, multicohort, open-label, single-arm, phase II trial enrolled patients with c-Met dysregulated, locally advanced or metastatic NSCLC from January 2020 to August 2022 across 17 centers. Cohort 1 included patients with MET exon 14 skipping ( MET ex14)-mutant NSCLC who had not previously received MET inhibitors. Participants were administered vebreltinib at a dosage of 200 mg twice a day in 28-day cycles. The primary end point was the objective response rate (ORR), and the key secondary end point was the duration of response (DoR), both evaluated by a blinded independent review committee according to the RECIST version 1.1., Results: As of August 9, 2022, 52 patients had been enrolled in cohort 1, of whom 35 (67.3%) were treatment-naïve. The ORR reached 75% (95% CI, 61.1 to 86). Among treatment-naïve patients, the ORR was 77.1% (95% CI, 59.9 to 89.6), and in previously treated patients, it was 70.6% (95% CI, 44.0 to 89.7). The disease control rate was 96.2%, with a median DoR of 15.9 months, a median progression-free survival of 14.1 months, and a median overall survival of 20.7 months. The most common treatment-related adverse events were peripheral edema (82.7%), QT prolongation (30.8%), and elevated serum creatinine (28.8%)., Conclusion: Vebreltinib has shown promising efficacy and a favorable safety profile in patients with MET ex14-mutant NSCLC.

Tumor-derived extracellular vesicles (EVs) are potential biomarkers for tumors, but their reliable molecular targets have not been identified. The previous study confirms that ubiquitin-specific protease 22 (USP22) promotes lung adenocarcinoma (LUAD) metastasis in vivo and in vitro. Moreover, USP22 regulates endocytosis of tumor cells and localizes to late endosomes. However, the role of USP22 in the secretion of tumor cell-derived EVs remains unknown. In this study, it demonstrates that USP22 increases the secretion of tumor cell-derived EVs and accelerates their migration and invasion, invadopodia formation, and angiogenesis via EV transfer. USP22 enhances EV secretion by upregulating myosin IB (MYO1B). This study further discovers that USP22 activated the SRC signaling pathway by upregulating the molecule KDEL endoplasmic reticulum protein retention receptor 1 (KDELR1), thereby contributing to LUAD cell progression. The study provides novel insights into the role of USP22 in EV secretion and cell motility regulation in LUAD., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Neoadjuvant immunotherapy has ushered in a new era of perioperative treatment for resectable non-small cell lung cancer (NSCLC). However, large-scale data for verifying the efficacy and optimizing the therapeutic strategies of neoadjuvant immunochemotherapy in routine clinical practice are scarce., Methods: NeoR-World (NCT05974007) was a multicenter, retrospective cohort study involving patients who received neoadjuvant immunotherapy plus chemotherapy or chemotherapy alone in routine clinical practice from 11 medical centers in China between January 2010 and March 2022. Propensity score matching was performed to address indication bias., Results: A total of 408 patients receiving neoadjuvant immunochemotherapy and 684 patients receiving neoadjuvant chemotherapy were included. The pathologic complete response (pCR) and major pathologic response (MPR) rates of the real-world neoadjuvant immunochemotherapy cohort were 32.8% and 58.1%, respectively. Notably, patients with squamous cell carcinoma exhibited significantly higher pCR and MPR rates than those with adenocarcinoma (pCR, 39.2% vs 16.5% [P < .001]; MPR, 66.6% vs 36.5% [P < .001]), whereas pCR and MPR rates were comparable among patients receiving different neoadjuvant cycles. In addition, the 2-year rates of disease-free survival (DFS) and overall survival (OS) rate were 82.0% and 93.1%, respectively. Multivariate analyses identified adjuvant therapy as an independent prognostic factor for DFS (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.89; P = .018) and OS (HR, 0.28; 95% CI, 0.13-0.58; P < .001). A significantly longer DFS with adjuvant therapy was observed in patients with non-pCR or 2 neoadjuvant cycles. We observed significant benefits in pCR rate (32.4% vs 6.4%; P < .001), DFS (HR, 0.50; 95% CI, 0.38-0.68; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.94; P = .024) with immunotherapy plus chemotherapy compared to chemotherapy alone both in the primary propensity-matched cohort and across most key subgroups., Conclusions: The study validates the superior efficacy of neoadjuvant immunochemotherapy over chemotherapy alone for NSCLC. Adjuvant therapy could prolong DFS in patients receiving neoadjuvant immunochemotherapy, and patients with non-pCR or those who underwent 2 neoadjuvant cycles were identified as potential beneficiaries of adjuvant therapy., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer., Methods: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors., Results: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, β-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis., Conclusion: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP., 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.)

Background: Based on the proposed lung-intestinal axis, there is a significant correlation between the microbiota and lung metastasis. Targeting the microbial composition is valuable in modulating the host response to cancer therapeutics. As a traditional Chinese medicine (TCM) formula, Shuangshen granules (SSG) are clinically useful in delaying lung metastasis, but its underlying mechanisms remain unknown., Methods: The C57BL/6N mice were chosen to establish the Lewis lung cancer models. The broad-spectrum antibiotics (ABX) group was set up to estimate the effect of microbiota composition on metastasis. The therapeutic effects of different doses of SSG in treating lung metastasis were investigated through histopathology, immunohistochemistry, and Western blot analysis methods. Additionally, the phenotype of tumor-associated macrophages (TAMs) in the lung and blood was evaluated by flow cytometry. The fecal microbiota transplantation (FMT) and negative control (ABX plus high dose SSG group) experiments were also designed to assess intestinal microbiota's role in SSG intervention's outcome in lung metastasis. The 16S rRNA amplicon sequencing and Untargeted metabolomic analysis were used to analyze intestinal microbiota and metabolite changes mediated by SSG in tumor-bearing mice with lung metastasis., Result: ABX could observably lead to intestinal microbiota dysbiosis and enhance metastasis. SSG showed a significant chemopreventive effect in lung metastasis, reduced metastatic nodules and the expression levels of pre-metastatic niche biomarkers, and enriched the ratio of CD86+F4/80+CD11b+ cells, while FMT delayed metastasis similarly. The analysis of microbiota and metabolites revealed that SSG significantly enriched probiotics in feces, including Akkermansia muciniphila, Lachnoclostridium sp YL32, Limosilactobacillus reuteri, and potential anti-cancer serum metabolites, including Ginsenoside Rb1, Isoquinoline, Betulin and so on. We also investigated the mechanism of SSG protection against lung metastasis and showed that SSG regulated microbiota, improved TAMs polarization, and inhibited the expression of the NF-κB pathway., Conclusion: The results presented in our article demonstrated that SSG improved TAMs polarization and inhibited the NF-κB pathway by alleviating intestinal microbiota imbalance and metabolic disorders in tumor-bearing mice, resulting in delayed lung metastasis., 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 GmbH.. All rights reserved.)

Objectives: Comprehensive cross-interaction of multiple programmed cell death (PCD) patterns in the patients with lung adenocarcinoma (LUAD) have not yet been thoroughly investigated., Methods: Here, we collected 19 different PCD patterns, including 1911 PCD-related genes, and developed an immune-derived multiple programmed cell death index (MPCDI) based on machine learning methods., Results: Using the median MPCDI scores, we categorized the LUAD patients into two groups: low-MPCDI and high-MPCDI. Our analysis of the TCGA-LUAD training cohort and three external GEO cohorts (GSE37745, GSE30219, and GSE68465) revealed that patients with high-MPCDI experienced a more unfavorable prognosis, whereas those with low-MPCDI had a better prognosis. Furthermore, the results of both univariate and multivariate Cox regression analyses further confirmed that MPCDI serves as a novel independent risk factor. By combining clinical characteristics with the MPCDI, we constructed a nomogram that provides an accurate and reliable quantitative tool for personalized clinical management of LUAD patients. The findings obtained from the analysis of C-index and the decision curve revealed that the nomogram outperformed various clinical variables in terms of net clinical benefit. Encouragingly, the low-MPCDI patients are more sensitive to commonly used chemotherapy drugs, which suggests that MPCDI scores have a guiding role in chemotherapy for LUAD patients., Conclusion: Therefore, MPCDI can be used as a novel clinical diagnostic classifier, providing valuable insights into the clinical management and clinical decision-making for LUAD patients., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Introduction: Frailty is a syndrome affecting primarily older adults that can impact disease course, treatment, and outcomes in patients with lung cancer (LC). We systematically reviewed current data on the correlation between frailty and overall survival (OS), recurrence-free survival (RFS), and the risk of complications in older patients with LC., Materials and Methods: PubMed, EMBASE, and Scopus databases were searched for observational cohort, cross-sectional, and case-control studies involving participants aged 18 years or older diagnosed with LC. Eligible studies were required to perform frailty assessments and have non-frail participants as a comparator group. Random-effects models were used for analysis, and the reported effect sizes were represented as hazards ratio (HR) or odds ratios (OR) with associated 95% confidence intervals (CI)., Results: Seventeen studies were included, most with a retrospective cohort design (n = 16) and patients with non-small cell lung carcinoma (NSCLC). Older patients with LC and frailty had lower OS (HR 1.70, 95% CI: 1.39, 2.07) and RFS (HR 2.50, 95% CI: 1.02, 6.12), compared to non-frail subjects. Frail subjects also had increased risk of complications (OR 1.89, 95% CI: 1.42, 2.53)., Discussion: The observed association between frailty and OS, RFS, and an increased susceptibility to complications emphasizes the potential significance of frailty status as a substantial prognostic indicator. Our results underscore the vital role of including frailty assessment as an integral element within the management plan for patients dealing with lung cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study., Methods: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS)., Results: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed., Conclusions: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases., Trial Registration: ClinicalTrials.gov number, NCT03849768., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME) and can induce functional polarization of tumor macrophages. This study aimed to explore the effect of CAFs-derived exosome LINC01833 on the malignant biological behavior of non-small cell lung cancer (NSCLC) cells and its mechanism. Tumor tissues (n = 3) and adjacent noncancerous tissues (n = 3) were collected from patients with NSCLC, and fibroblasts (CAF, NF) were isolated from the two tissues. Expression of LINC01833/miR-335-5p/VAPA in NSCLC clinical tissues and cell lines was detected by RT-qPCR. Exosomes of CAFs and NFs were isolated by ultracentrifugation. Cell proliferation, migration, invasion, and M2 macrophage polarization were detected by MTT, transwell, wound-healing assay, and flow cytometry assay, while western blot was used to verify the expression of M2 macrophage polarization-related proteins. Tumor volume weight and M2 macrophage polarization were detected by tumor xenografts in nude mice. LINC01833 was highly expressed in NSCLC tumor tissues and cells. Knockdown of LINC01833 exosomes could significantly inhibit proliferation, migration, invasion of NSCLC cells, and M2 macrophage polarization of THP-1 cells, while simultaneous knockdown of miR-335-5p on the above basis could reverse the effect of knockdown of LINC01833. In vivo experiments also indicated that knockdown of LINC01833 exosomes suppressed tumor growth and M2 macrophage polarization. CAF-derived LINC01833 exosomes can promote the proliferation, migration and invasion of NSCLC cells and M2 macrophage polarization by inhibiting miR-335-5p and regulating VAPA activity., (© 2024 Wiley Periodicals LLC.)

Hepatoid adenocarcinoma of the lung (HAL) is a rare and aggressive subtype of lung cancer. The prognosis for patients with HAL is generally poor and currently, there are only limited treatment options. Here, we present a case of a 47-year-old male diagnosed with locally advanced-stage HAL who achieved a remarkably long disease-free survival after receiving neoadjuvant and adjuvant camrelizumab plus chemotherapy and surgery. This case highlights the potential of immunochemotherapy plus surgery in improving outcomes for patients with HAL.

Abstract: This expert consensus reviews current literature and provides clinical practice guidelines for the diagnosis and treatment of multiple ground glass nodule-like lung cancer. The main contents of this review include the following: ① follow-up strategies, ② differential diagnosis, ③ diagnosis and staging, ④ treatment methods, and ⑤ post-treatment follow-up., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy., (© 2024 John Wiley & Sons Ltd.)

Multiple primary lung cancer (MPLC) refers to patients with two or more primary lesions of lung cancer. It can be divided into synchronous MPLC (sMPLC) and metachronous MPLC (mMPLC) based on the timing of occurrence. In recent years, the detection rate of MPLC has gradually increased. However, considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis (IM), especially when the histopathological types are identical. Given the significant differences in treatment strategies and prognosis in clinical practice currently, accurate diagnosis of MPLC is crucial for personalized precision therapy. Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors. There have been reports of coexisting mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusion genes in non-small cell lung cancer, but case of EGFR mutation following an ALK mutation has not been mentioned. This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery, and reviews the relevant literature. This paper aims to deepen the understanding of mMPLC and provide clinical references for the diagnosis and treatment of such patients.
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Objectives: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC)., Materials and Methods: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP)., Results: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001)., Conclusion: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD., (© 2024. The Author(s).)

Background: CDH3 is a glycoprotein with a single-span transmembrane domain that mediates cell-to-cell adhesion. Abnormal expression of CDH3 is associated with a poor prognosis in patients with breast, thyroid, colorectal carcinomas and glioblastoma. Soluble CDH3 in pleural effusions can be used as a marker for real-time monitoring of resistance to first- and second-generation EGFR-TKIs. The CDH3 mechanism underlying lung adenocarcinomas (LUADs) has not been established., Objective: This study analyzed the correlation between CDH3 expression and lung cancer prognosis and the effect of down-regulation CDH3 expression on the proliferation and migration of lung cancer cells., Methods: CDH3 expression was studied using the Oncomine, TIMER, PanglaoDB, and GEPIA databases. The effect of CDH3 on clinical prognosis was assessed with GEPIA, the PrognoScan database, and Kaplan-Meier plotter. The relationship between CDH3 to immune infiltrating cells was explored using TIMER and TISIDB. The function of CDH3 in lung cancer cell lines was determined by CCK-8 and wound healing assays in vitro. Furthermore, RNA sequencing was used to identify key signaling pathways and differentially-expressed genes., Results: LUAD tissues had higher CDH3 expression compared with normal tissues and were associated with worse overall survival in patients with LUAD. CDH3 expression had positive associations with infiltration of CD4 + T cells, Tregs and exhausted T cells, but negative associations with infiltration of B cells in patients with LUAD. CCK-8 and wound healing assays revealed that downregulation of CDH3 inhibited the proliferation and migration of cells. KEGG analysis revealed that the TGF-beta signaling pathways were demonstrated to be enriched pathways for genes negatively regulated by knockdown of CDH3., Conclusion: CDH3 expression affects proliferation and migration of lung cancer cells and might serve as a potential prognostic marker in LUAD patients., (© 2023. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Background: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level., Methods: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients., Results: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC., Conclusions: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies., (© 2024 John Wiley & Sons Ltd.)

Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors., (© 2024. The Author(s).)

Purpose: Primary lung cancer is extremely rare in children and adolescents. The aim of this study is to clarify clinical features and outcomes of primary lung cancer in children and adolescents., Methods: Young patients (aged ≤ 20 years) diagnosed as primary lung cancer between 2012 and 2023 were retrospective reviewed. According to radiological appearance of the nodules, they were divided into solid nodule (SN) group and ground glass opacity (GGO) group., Results: A total of 74 patients were identified, with a median age at diagnosis of 18 years old (range: 11-20), including 7 patients in SN group and 67 patients in GGO group. In the GGO group, none of the nodules enlarged or changed during an average surveillance period of 10.8 months before surgery, except one. Wedge resection was the most common procedure (82.1%), followed by segmentectomy (16.4%) and lobectomy (1.5%). Histopathological analysis revealed that 64.2% of GGO nodules were adenocarcinoma in situ and minimally invasive adenocarcinomas, while the remaining 35.8% were invasive adenocarcinomas. Mutational analysis was performed in nine patients, with mutations identified in all cases. After a mean follow-up period of 1.73 ± 1.62 years, two patients in the SN group died due to multiple distant metastases, while all patients in the GGO group survived without recurrence. The overall survival (100%) of the GGO group was significantly higher than SN group (66.7%)., Conclusions: Primary lung cancer in children and adolescents are rare and histopathological heterogeneous. Persistent GGO nodules may indicate early-stage lung adenocarcinoma in children and adolescents., (© 2024. The Author(s).)

Background: The safety and efficacy of video-assisted thoracic surgical (VATS) versus open lobectomy for non-small-cell lung cancer (NSCLC) following neoadjuvant therapy remained controversial. The aim of this study was to compare the outcomes of VATS with those of open lobectomy for NSCLC after neoadjuvant therapy., Methods: Patients who had undergone VATS or open lobectomy for NSCLC following neoadjuvant therapy in nine hospitals in China from July 2014 to July 2020 were retrospectively reviewed. The clinical characteristics and overall survival (OS) of patients were analyzed using Cox regression models and propensity score matching., Results: We identified 685 patients, 436 (63.6%) who had undergone VATS lobectomy and 249 (36.4%) who had undergone open lobectomy. Patients who had undergone VATS lobectomy tended to have had fewer nodes removed than those who had undergone open lobectomy. However, compared with open group, the VATS group had a better perioperative outcome, such as smaller blood loss volumes and shorter postoperative stays. The groups had a similar operation durations and postoperative complications, and there was a nonsignificant difference between their 30-day mortality rates. After propensity score matching, there was no significant different between the OS of the groups, and only postoperative adjuvant therapy was associated with worse OS., Conclusion: This multi-center analysis of patients with NSCLC who had undergone surgery subsequent to neoadjuvant therapy reveals that VATS lobectomy tended to have a better perioperative outcome, and have a similar OS compared to open lobectomy. These findings suggest that VATS lobectomy is appropriate for NSCLC following neoadjuvant therapy., Competing Interests: Disclosure The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM., Implications: SB9 as a therapeutic target for LCBM., (©2024 American Association for Cancer Research.)

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11β1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFβ and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11β1 axis inhibited fibroblast TGFβ production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11β1 axis is a potential strategy to inhibit osteosarcoma lung metastasis., Significance: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11β1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis., (©2024 American Association for Cancer Research.)

Since its first discovery, long noncoding RNA Linc00673 has been linked to carcinogenesis and metastasis of various human cancers. Linc00673 had five transcriptional isoforms and their biological functions remained to be explored. Here we have reported that Linc00673-V3, one of the isoforms of Linc00673, promoted non-small cell lung cancer chemoresistance, and increased Linc00673-V3 expression level was associated with enhanced autophagy. Mechanistically, we discerned the existence of a stem-loop configuration engendered by the 1-100-nt and 2200-2275-nt fragments within Linc00673-V3. This structure inherently interacted with Smad3, thereby impeding its ubiquitination and subsequent degradation orchestrated by E3 ligase STUB1. The accumulation of Smad3 contributed to autophagy via up-regulation of LC3B transcription and ultimately conferred chemoresistance in NSCLC. Our results revealed a novel transcriptional regulation network between Linc00673-V3, Smad3, and LC3B , which provided an important insight into the interplay between autophagy regulation and non-canonical function of Smad3. Furthermore, the results from in vivo experiments suggested Linc00673-V3 targeted antisense oligonucleotide as a promising therapeutic strategy to overcome chemotherapy resistance in NSCLC., (© 2024 Ni et al.)

Until now, there are still few comparisons between neoadjuvant immunochemotherapy and chemotherapy as first-line treatment for patients with stage IB-IIIB lung squamous cell carcinoma (LUSC). In addition, the ability of pathologic response to predict long-term survival has still not been established. In this retrospective, controlled clinical trial, we ultimately enrolled 231 patients with stage IB to IIIB LUSC who received 2-4 cycles perioperative immunochemotherapy or chemotherapy alone, followed by resection. The primary endpoint of this study was pathological response. Secondary endpoints were disease-free survival (DFS), overall survival (OS), objective response rate (ORR), surgical resection rate and adverse events (AEs). The rates of major pathologic response (MPR) and pathologic complete response (pCR) in the immunochemotherapy group were 66.7% and 41.9%, respectively, which were both higher than that in the other group (MPR: 25.0%, pCR: 20.8%) (P < 0.001). The median DFS in the chemotherapy group was 33.1 months (95% CI 8.4 to 57.8) and not reached in the immunochemotherapy group (hazard ratio [HR] for disease progression, disease recurrence, or death, 0.543; 95% CI 0.303 to 0.974; P = 0.038). The median OS of the immunochemotherapy group was not achieved (HR for death, 0.747; 95% CI 0.373 to 1.495; P = 0.41), with the chemotherapy group 64.8 months (95% CI not reached to not reached). The objective response rate (ORR) of immunochemotherapy regimen was higher than that of the chemotherapy regimen (immunochemotherapy: 74.5%, chemotherapy: 42.3%, P < 0.001). About 60.8% in the immunochemotherapy group and 61.5% in the chemotherapy group eventually underwent surgery. The incidence of grade3 and 4 adverse events was 18.3% in the immunochemotherapy group and 2.6% in the chemotherapy group. MPR was significantly associated with DFS and OS (HR, 0.325; 95% CI 0.127 to 0.833; P = 0.019; and HR, 0. 906; 95% CI 0.092 to 1.008; P = 0.051, respectively). The C-index of MPR (0.730 for DFS, 0.722 for OS) was higher than the C-index of cPR (0.672 for DFS, 0.659 for OS) and clinical response (0.426 for DFS, 0.542 for OS). Therapeutic regimen (P < 0.001; OR = 7.406; 95% CI 3.054 to 17.960) was significantly correlated with MPR. In patients with stage IB to IIIB LUSC, neoadjuvant treatment with immunochemotherapy can produce a higher percentage of patients with a MPR and longer survival than chemotherapy alone. MPR may serve as a surrogate endpoint of survival to evaluate neoadjuvant therapy., (© 2024. The Author(s).)

Background: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated., Methods: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype., Results: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation., Conclusions: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients., (© 2024. The Author(s).)

Aim: To develop a clinical-radiological model to predict the malignancy of solitary pulmonary nodules (SPNs) and to evaluate the accuracy of chest computed tomography imaging characteristics of SPN in diagnosing pathological type., Materials and Methods: The predictive model was developed using a retrospective cohort of 601 SPN patients (Group A) between July 2015 and July 2020. The established model was tested using a second retrospective cohort of 124 patients between August 2020 and August 2021 (Group B). The radiological characteristics of all adenocarcinomas in two groups were analysed to determine the correlation between radiological and pathological characteristics., Results: Malignant nodules were found in 78.87% of cases and benign in 21.13%. Two clinical characteristics (age and gender) and four radiological characteristics (calcification, vascular convergence, pleural retraction sign, and density) were identified as independent predictors of malignancy in patients with SPN using logistic regression analysis. The area under the receiver operating characteristic curve (0.748) of the present model was greater than the other two reported models. Diameter, spiculation, lobulation, vascular convergence, and pleural retraction signs differed significantly among pre-invasive lesions, minimally invasive adenocarcinoma, and invasive adenocarcinoma. Only diameter and density were significantly different among invasive adenocarcinoma subtypes., Conclusions: Older age, male gender, no calcification, vascular convergence, pleural contraction sign, and lower density were independent malignancy predictors of SPNs. Furthermore, the pathological classification can be clarified based on the radiological characteristics of SPN, providing a new option for the prevention and treatment of early lung cancer., (Copyright © 2023. Published by Elsevier Ltd.)

Chemotherapy is still a prevalent strategy for clinical lung cancer treatment. However, the inevitable emerged drug resistance has become a great hurdle to therapeutic effect. Studies have demonstrated that the primary cause of drug resistance is a decrease in the chemotherapeutic medicine concentration. Several lectins have been confirmed to be effective as chemotherapy adjuvants, enhancing the anti-tumor effects of chemotherapy drugs. Here, we combined phytohemagglutinin (PHA), which has been reported possess anti-tumor effects, with chemotherapy drugs Cisplatin (DDP) and Adriamycin (ADM) on lung cancer cells to detect the sensitivities of PHA as a chemotherapy adjuvant. Our results demonstrated that the PHA significantly enhanced the sensitivity of lung cancer cells to DDP and ADM, and Western blot showed that PHA combined with DDP or ADM enhance cytotoxic effects by inhibiting autophagy and promoting apoptosis. More importantly, we found PHA enhanced the chemotherapeutic drugs cytotoxicity by changing the cell membrane to increase the intracellular chemotherapeutic drugs concentration. Besides, the combination of PHA and ADM increased the ADM concentration in the multidrug-resistant strain A549-R cells and achieved the drug sensitization effect. Our results suggest that PHA combined with chemotherapy can be applied in the treatment of lung cancer cells and lung cancer multidrug-resistant strains, and provide a novel strategy for clinical tumor chemotherapy and a new idea to solve the problem of drug resistance in clinical lung cancer., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies 1 . Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8 + alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8 + cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention., (© 2024. The Author(s).)

Continuous stimulation of tumor neoantigens and various cytokines in the tumor microenvironment leads to T cell dysfunction, but the specific mechanisms by which these key factors are distributed among different cell subpopulations and how they affect patient outcomes and treatment response are incompletely characterized. By integrating single-cell and bulk sequencing data of non-small cell lung cancer patients, we constructed a clinical outcome-associated T cell exhaustion signature. We discovered a significant association between the T cell exhaustion state and tumor cell hypoxia. Hypoxic malignant cells were significantly correlated with the proportion of exhausted T cells, and they co-occurred in patients at advanced stage. By analyzing the ligand-receptor interactions between these two cell states, we observed that T cells were recruited towards tumor cells through production of chemokines such as CXCL16-CXCR6 axis and CCL3/CCL4/CCL5-CCR5 axis. Based on 15 immune checkpoint blockade (ICB)-treatment cohorts, we constructed an interaction signature that can be used to predict the response to immune checkpoint blockade therapy. Among genes composed of the signature, CXCR6 alone has similarly high prediction efficacy (Area Under Curve (AUC) = 1, 0.89 and 0.73 for GSE126044, GSE135222 and GSE93157, respectively) with the signature and thus could serve as a potential biomarker for predicting immunotherapy response. Together, we have discovered and validated a significant association between exhausted T cells and hypoxic malignant cells, elucidating key interaction factors that significantly associated with response to immunotherapy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The existence of cancer stem cells is widely acknowledged as the underlying cause for the challenging curability and high relapse rates observed in various tumor types, including non-small cell lung cancer (NSCLC). Despite extensive research on numerous therapeutic targets for NSCLC treatment, the strategies to effectively combat NSCLC stemness and achieve a definitive cure are still not well defined. The primary objective of this study was to examine the underlying mechanism through which Fructose-1,6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme, functions as a tumor suppressor to regulate the stemness of NSCLC. Herein, we showed that overexpression of FBP1 led to a decrease in the proportion of CD133-positive cells, weakened tumorigenicity, and decreased expression of stemness factors. FBP1 inhibited the activation of Notch signaling, while it had no impact on the transcription level of Notch 1 intracellular domain (NICD1). Instead, FBP1 interacted with NICD1 and the E3 ubiquitin ligase FBXW7 to facilitate the degradation of NICD1 through the ubiquitin-proteasome pathway, which is independent of the metabolic enzymatic activity of FBP1. The aforementioned studies suggest that targeting the FBP1-FBXW7-NICD1 axis holds promise as a therapeutic approach for addressing the challenges of NSCLC recurrence and drug resistance., (© 2024. The Author(s).)

Objective: Photodynamic therapy (PDT) primarily treats skin diseases or cancer by generating reactive oxygen species (ROS) to damage cellular DNA, yet drug resistance limits its application. To tackle this problem, the present study was carried out to improve the efficacy of chlorin e6 (Ce6)-PDT using Cepharanthine (CEP) as well as to reveal the potential molecular mechanism., Materials and Methods: Lewis lung cancer cell line (LLC) was utilized as the cancer cell model. chlorin e6 (Ce6) acted as the photosensitizer to induce PDT. The in vitro anti-cancer efficacy was measured by CCK-8, Annexin-V/PI staining, and migration assay. The Ce6 uptake was observed using flow cytometry and confocal microscopy. The ROS generation was detected by the DCFH-DA probe. The analysis of MutT Homolog 1 (MTH1) expression, correlation, and prognosis in databases was conducted by bioinformatic. The MTH1 expression was detected through western blots (WB). DNA damage was assayed by WB, immunofluorescent staining, and comet assay., Results: Ce6-PDT showed robust resistance in lung cancer cells under certain conditions, as evidenced by the unchanged cell viability and apoptosis. The subsequent findings confirmed that the uptake of Ce6 and MTH1 expression was enhanced, but ROS generation with laser irradiation was not increased in LLC, which indicated that the ROS scavenge may be the critical reason for resistance. Surprisingly, bioinformatic and in vitro experiments identified that MTH1, which could prevent the DNA from damage of ROS, was highly expressed in lung cancer and thereby led to the poor prognosis and could be further up-regulated by Ce6 PDT. CEP exhibited a dose-dependent suppressive effect on the lung cancer cells. Further investigations presented that CEP treatment boosted ROS production, thereby resulting in DNA double-strand breakage (DDSB) with activation of MTH1, indicating that CEP facilitated Ce6-PDT-mediated DNA damage. Finally, the combination of CEP and Ce6-PDT exhibited prominent ROS accumulation, MTH1 inhibition, and anti-lung cancer efficacy, which had synergistic pro-DNA damage properties., Conclusion: Collectively, highly expressed MTH1 and the failure of ROS generation lead to PDT resistance in lung cancer cells. CEP facilitates ROS generation of PDT, thereby promoting vigorous DNA damage, inactivating MTH1, alleviating PDT resistance, and ameliorating the anti-cancer efficacy of Ce6-PDT, provides a novel approach for augmented PDT., 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 © 2023. Published by Elsevier B.V.)

BRAF-V600E mutation is regarded as the source of lung cancer resistance to trametinib (Tr), and no solution available for completely addressing this intractable resistance has emerged yet. Herein, the combination of ultrasonic (US) propelled folic acid (FA)-modified liposomes strategy and BRAF-driven gene silencing program is proposed to effectively reverse Tr's resistance to lung cancer. Meanwhile, the prepared cationic nanoliposomes can assist Tr drug and BRAF siRNA to escape lysosome disposal, thereby avoiding Tr drug pumping out or siRNA degradation. More significantly, loaded BRAF siRNA is designed to silence BRAF-V600E mutation genes via modulating BRAF-ERK-pathway and remarkably reverse the PC9R resistance to Tr. Systematic experiments validate that these cooperatively sensitize PC9R cells to Tr and shrink resistant NSCLC in vivo, especially after combining with FA-mediated targeting and US-enhanced permeability that permits more intratumoral accumulations of Tr. Such a biocompatible targeting drug-resistance liberation agent and its underlying design strategy lay a foundation avenue to completely reverse tumor resistance, which is preferable to treat BRAF mutation-arised resistance of various tumors, holding high clinical translation potentials., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Patients who possess various histological subtypes of early-stage lung adenocarcinoma (LUAD) have considerably diverse prognoses. The simultaneous existence of several histological subtypes reduces the clinical accuracy of the diagnosis and prognosis of early-stage LUAD due to intratumour intricacy., Methods: We included 11 postoperative LUAD patients pathologically confirmed to be stage IA. Single-cell RNA sequencing (scRNA-seq) was carried out on matched tumour and normal tissue. Three formalin-fixed and paraffin-embedded cases were randomly selected for 10× Genomics Visium analysis, one of which was analysed by digital spatial profiler (DSP)., Results: Using DSP and 10× Genomics Visium analysis, signature gene profiles for lepidic and acinar histological subtypes were acquired. The percentage of histological subtypes predicted for the patients from samples of 11 LUAD fresh tissues by scRNA-seq showed a degree of concordance with the clinicopathologic findings assessed by visual examination. DSP proteomics and 10× Genomics Visium transcriptomics analyses revealed that a negative correlation (Spearman correlation analysis: r = -.886; p = .033) between the expression levels of CD8 and the expression trend of programmed cell death 1(PD-L1) on tumour endothelial cells. The percentage of CD8+ T cells in the acinar region was lower than in the lepidic region., Conclusions: These findings illustrate that assessing patient histological subtypes at the single-cell level is feasible. Additionally, tumour endothelial cells that express PD-L1 in stage IA LUAD suppress immune-responsive CD8+ T cells., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown., Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone., Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022., Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles., Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events., Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups., Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile., Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Lung cancer is a major public health problem worldwide, with high rates of morbidity and mortality. It often coexists with chronic obstructive pulmonary disease (COPD), the diagnosis and management of which often receives insufficient attention. In particular, the presence of COPD has significant implications for the clinical management of lung cancer patients. This review systematically assesses the influence of COPD on the efficacy of immunotherapy and the occurrence of immune-related adverse events in patients with lung cancer, identifies existing challenges and proposes avenues for future research in this field.

Objective: Spindle pole body component 25 (SPC25) is an important cyclin involved in chromosome segregation and spindle dynamics regulation during mitosis. However, the role of SPC25 in lung adenocarcinoma (LAUD) is unclear., Materials and Methods: The differential expression of SPC25 in tumor samples and normal samples was analyzed using TIMER, TCGA, GEO databases, and the correlation between its expression and clinicopathological features and prognosis in LUAD patients. Biological pathways that may be enriched by SPC25 were analyzed using GSEA. In vitro cell experiments were used to evaluate the effect of knocking down SPC25 expression on LUAD cells. Correlation analysis and differential analysis were used to assess the association of SPC25 expression with genes related to cell cycle, glycolysis, and ferroptosis. A ceRNA network involving SPC25 was constructed using multiple database analyses., Results: SPC25 was highly expressed in LUAD, and its expression level could guide staging and predict prognosis. GSEA found that high expression of SPC25 involved multiple cell cycles and glycolytic pathways. Knocking down SPC25 expression significantly affected the proliferation, migration and apoptosis of LUAD cells. Abnormal SPC25 expression levels can affect cell cycle progression, glycolytic ability and ferroptosis regulation. A ceRNA network containing SPC25, SNHG15/hsa-miR-451a/SPC25, was successfully predicted and constructed., Conclusions: Our findings reveal the association of up-regulation of SPC25 in LUAD and its expression with clinical features, prognosis prediction, proliferation migration, cell cycle, glycolysis, ferroptosis, and ceRNA networks. Our results indicate that SPC25 can be used as a biomarker in LUAD therapy and a target for therapeutic intervention.

Liquid biopsy as well as genotyping plays important roles in guiding the use of tumor-targeted drugs and monitoring the generation of drug resistance. However, current methods, such as next-generation sequencing (NGS) and pyrosequencing, require long analysis time and complicated steps. To achieve ultrafast and highly specific detection of cell-free DNA (cfDNA) from blood, we improved our recently developed FEN1-aided RPA (FARPA), which combined flap endonuclease 1 (FEN1)-catalyzed invasive reactions with recombinase polymerase amplification (RPA) by inactivating the RPA enzymes before invasive reactions, designing short RPA primers, and changing invasive reaction conditions. Using the L858R and T790M mutations as examples, FARPA was sensitive to detect 5 copies of targeted mutants, specific to sense the mutants with an abundance as low as 0.01% from blood, and ultrafast to get results within 40 min. The method was readily expended to genotyping, and 15 min was enough to report the allele species directly from oral swab samples by coupling quick DNA extraction reagents. Validation was carried out by detecting clinical samples, including 20 cfDNA from patients with non-small cell lung cancer (NSCLC) for liquid biopsy and 43 human genomic DNA (gDNA) purified from blood (33) or lysed from oral swabs (10) for genotyping, giving 100% agreement with NGS and pyrosequencing, respectively. Furthermore, a portable battery-driven device with dual-channel fluorescence detection was successfully constructed to facilitate point-of-care testing (POCT) of liquid biopsy and genotyping, providing doctors with a potential tool to achieve genotyping- or mutant-guided personalized medicine at emergency or source-limited regions.

In this study, the core carcinogenic elements in Xuanwei Formation coal were identified. Thirty-one samples were collected based on the age-standardized mortality rate (ASMR) of lung cancer; Si, V, Cr, Co, Ni, As, Mo, Cd, Sb, Pb, and rare earth elements and yttrium (REYs) were analyzed and compared; multivariate statistical analyses (CA, PCA, and FDA) were performed; and comprehensive identification was carried out by combining multivariate statistical analyses with toxicology and mineralogy. The final results indicated that (1) the high-concentration Si, Ni, V, Cr, Co, and Cd in coal may have some potential carcinogenic risk. (2) The concentrations of Cr, Ni, As, Mo, Cd, and Pb meet the zoning characteristics of the ASMR, while the Si concentration is not completely consistent. (3) The REY distribution pattern in Longtan Formation coal is lower than that in Xuanwei Formation coal, indicating that the materials of these elements in coal are different. (5) The heatmap divides the sampling sites into two clusters and subtypes in accordance with carcinogenic zoning based on the ASMR. (6) PC1, PC2, and PC3 explain 62.629% of the total variance, identifying Co, Ni, As, Cd, Mo, Cr, and V. (7) Fisher discriminant analysis identifies Ni, Si, Cd, As, and Co based on the discriminant function. (8) Comprehensive identification reveals that Ni is the primary carcinogenic element, followed by Co, Cd, and Si in combination with toxicology. (9) The paragenesis of Si (nanoquartz), Ni, Co, and Cd is an interesting finding. In other words, carcinogenic elements Ni, Co, Cd, and Si and their paragenetic properties should receive more attention., (© 2024. The Author(s).)

Backgrounds: It was highlighted by recent studies on the biological significance of vasculogenic mimicry (VM) in tumorigenicity and progression. However, it is unclear whether VM also plays a potential role in immune regulation and tumor microenvironment (TME) formation., Methods: To identify patterns of VM alterations and VM-associated genetic features in non-small cell lung adenocarcinoma, we have screened 309 VM regulators and performed consensus molecular typing by the NMF algorithm. The ssGSEA and CIBORSORT algorithms were employed to measure the relative infiltration of distinct immune cell subpopulations. Individual tumors with immune responses were evaluated for alteration patterns of VM with typing-based differential genes., Results: In 490 LUAD samples, two distinctive VM alteration patterns connected to different clinical outcomes and biochemical pathways were established. TME characterization showed that the observed VM patterns were primarily saturated with cell proliferation and metabolic pathways and higher in immune cell infiltration of the C1 type. Vasculogenic mimicry-related genes (VMRG) risk scores were constructed to divide patients with lung adenocarcinoma into subgroups with high and low scores. Patients with lower scores had better immunological scores and longer survival times. Upon further investigation, higher scores were positively correlated with higher tumor mutation burden (TMB), M1-type macrophages and immune checkpoint molecules. Nevertheless, in two other immunotherapy cohorts, individuals with lower scores had enhanced immune responses and long-lasting therapeutic benefits. Finally, we monitored the ANLN gene from the VMRG model, which was highly expressed in lung adenocarcinoma tissues and negatively correlated with prognosis; it was also highly expressed in lung adenocarcinoma cell lines, and knockdown of ANLN elicited low expression of VEGFA, MMP2 and MMP9., Conclusion: This study highlights that VM modifications are significantly associated with the diversity and complexity of TME, revealing new features of the immune microenvironment in lung adenocarcinoma and providing a new strategy for immunotherapy. Screening ANLN as a critical target for vasculogenic mimicry in lung adenocarcinoma provides a novel perspective for the targeted treatment of lung adenocarcinoma., Competing Interests: Declaration of Competing Interest The authors declare no competing interests. LZ and JTW contributed equally to this work. The study was designed by WWY and SWW. Bioinformatics analysis was conducted by LZ and ZWX. JTW and JJM provided useful advice to the analyses of the data. The manuscript was drafted by LZ and SWW, and was revised by all authors before the final version was approved to be published., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Bone metastasis pain (BMP) is a severe chronic pain condition. Our previous studies on BMP revealed functional brain abnormalities. However, the potential effect of BMP on brain structure and function, especially gray matter volume (GMV) and related functional networks, have not yet been clearly illustrated. Voxel-based morphometry and functional connectivity (FC) analysis methods were used to investigate GMV and intrinsic FC differences in 45 right-handed lung cancer patients with BMP(+), 37 lung cancer patients without BMP(-), and 45 healthy controls (HCs). Correlation analysis was performed thereafter with all clinical variables by Pearson correlation. Compared to HCs, BMP(+) group exhibited decreased GMV in medial frontal gyrus (MFG) and right middle temporal gyrus (MTG). Compared with BMP(-) group, BMP(+) group exhibited reduced GMV in cerebelum&#95;6&#95;L and left lingual gyrus. However, no regions with significant GMV differences were found between BMP(-) and HCs groups. Receiver operating characteristic analysis indicated the potential classification power of these aberrant regions. Correlation analysis revealed that GMV in the right MTG was positively associated with anxiety in BMP(+) group. Further FC analysis demonstrated enhanced interactions between MFG/right MTG and cerebellum in BMP(+) patients compared with HCs. These results showed that BMP was closely associated with cerebral alterations, which may induce the impairment of pain moderation circuit, deficits in cognitive function, dysfunction of emotional control, and sensorimotor processing. These findings may provide a fresh perspective and further neuroimaging evidence for the possible mechanisms of BMP. Furthermore, the role of the cerebellum in pain processing needs to be further investigated., (© 2023 Wiley Periodicals LLC.)

Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multifunctional and tunable physiochemical properties in alignment with tumor genetic profiles can achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, this work reviews the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy, and outlines novel strategies for the development of nanomedicine against drug resistance. This work focuses on engineering design, customized delivery, current challenges, and clinical translation of nanomedicine in the application of resistant lung cancer., (© 2023 Wiley-VCH GmbH.)

Benzo[a]pyrene (BaP) is commonly found in the environment as a result of incomplete combustion of organic materials and cigarette smoke. Epidemiological studies have consistently suggested that elderly smokers are at higher risk for small cell lung cancer (SCLC), with risks and clinical stages increasing with the intensity and duration of smoking. However, the underlying mechanism remains insufficiently investigated. Here, we established a positive correlation between smoking and BaP metabolite 3-hydroxybenzo[a]pyrene (3OH-BaP) in urine. The pooled standardized mean difference of urinary 3OH-BaP concentration for smokers versus nonsmokers was 5.18 (95 % CI 2.86-7.50). Clinical data suggested that smoking led to more lymph node metastasis, higher pathological N-stage, and worse overall survival in SCLC patients. We identified 75 genes that participate in BaP-associated cancer stemness of SCLC from Comparative Toxicogenomics Database and validated the expression of these candidate genes in SCLC patient samples. Protein kinase cAMP-activated catalytic subunit alpha (PRKACA) was found to be most upregulated in SCLC patients and in vitro experiments indicated that long-term exposure of SCLC cells to BaP, at the concentration equivalent to those detected in blood, increased PKA protein level. Further investigation revealed that PKA could directly interact with SOX2 and protect SOX2 from COP1-mediated ubiquitination and degradation. Upregulated SOX2 then contributed to the stemness and metastasis of SCLC cells while inhibition of aryl hydrocarbon receptor (AhR) signaling pathway abolished BaP induced PKA expression and downstream PKA/SOX2 axis. Our findings firstly pinpoint BaP exposure as a high-risk factor for SCLC and worse outcomes in patients, with the underlying mechanism being the activation of cancer stemness of SCLC via the AhR/PKA/SOX2 axis., 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 © 2023. Published by Elsevier B.V.)

Objective: The purpose of this study is to explore the biological mechanism of Schizandrin A (SchA) inducing non-small cell lung cancer (NSCLC) apoptosis., Methods: The reverse molecular docking tool "Swiss Target Prediction" was used to predict the targets of SchA. Protein-protein interaction analysis was performed on potential targets using the String database. Functional enrichment analyses of potential targets were performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The conformation of SchA binding to target was simulated by chemical-protein interactomics and molecular docking. The effect of SchA on the expression and phosphorylation level of EGFR was detected by Western blot. Lipofectamine 3000 and EGFR plasmids were used to overexpress EGFR. Apoptosis was tested with Annexin V-FITC and propidium iodide staining, and cell cycle was detected by propidium iodide staining., Results: The "Swiss Target Prediction" database predicted 112 and 111 targets based on the 2D and 3D structures of SchA, respectively, of which kinases accounted for the most, accounting for 24%. Protein interaction network analyses showed that molecular targets such as ERBB family and SRC were at the center of the network. Functional enrichment analyses indicated that ERBB-related signaling pathways were enriched. Compound-protein interactomics and molecular docking revealed that SchA could bind to the ATP-active pocket of the EGFR tyrosine kinase domain. Laboratory results showed that SchA inhibited the phosphorylation of EGFR. Insulin could counteract the cytotoxic effect of SchA. EGFR overexpression and excess EGF or IGF-1 had limited impacts on the cytotoxicity of SchA., Conclusions: Network pharmacology analyses suggested that ERBB family members may be the targets of SchA. SchA can inhibit NSCLC at least in part by inhibiting EGFR phosphorylation, and activating the EGFR bypass can neutralize the cytotoxicity of SchA., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Globally, lung adenocarcinoma (LUAD) is the most common type of lung cancer. The secreted protein angiopoietin-like 4 (ANGPTL4) has been implicated in a number of physiological and pathological processes, including angiogenesis and lipid metabolism. But the role of ANGPTL4 in LUAD remains unknown., Methods: The expression of ANGPTL4 and miR-133a-3p was confirmed by public database analysis. Xenograft model, MTT, Clone formation and EdU analysis were used to confirm the effects of miR-133a-3p/ANGPTL4 on LUAD cell proliferation and growth. Wound healing and Transwell analysis were used to elucidate the role of miR-133a-3p/ANGPTL4 in LUAD cell migration and invasion. Oil red O staining was used to confirm ANGPTL4 in LUAD lipids production. Dual-luciferase reporter gene analysis was used to demonstrate miR-133a-3p could directly bind ANGPTL4 3'-UTR. WB and PCR were used to confirm the protein expression of ANGPTL4., Results: ANGPTL4 was significantly increased in LUAD samples, which could promote LUAD cell proliferation, migration, invasion, growth and lipid production. miR-133a-3p could directly bind to ANGPTL4 mRNA, and repress the expression ANGPTL4, resulting in suppressing LUAD proliferation and metastasis., Conclusion: In conclusion, miR-133a-3p/ANGPTL4 axis might be a potential biomarker and therapeutic target for LUAD patients.

Introduction: This paper presents a case of a Chinese patient with advanced colon cancer who developed drug-induced interstitial lung disease while undergoing treatment with cetuximab combined with XELOX., Patient Concerns: A 75-year-old man with a history of colon cancer, had metastases in the liver, peritoneum, and lungs, which were initially treated with XELOX and cetuximab (0.4 g) in 2019. However, the lung metastases progressed, and the cetuximab dosage was adjusted to 0.9 g and then readjusted to 0.4 g., Diagnosis: In January 2021, computed tomography revealed developed interstitial lung disease, leading to the discontinuation of chemotherapy and cetuximab., Interventions: Receiving methylprednisolone pulse therapy., Outcomes: The patient experienced respiratory failure and passed away. The Naranjo Algorithm Assessment score indicated a probable relationship between cetuximab and the adverse event., Conclusion: This case highlights the need for regular pulmonary imaging examinations during cetuximab therapy, as drug-induced interstitial lung disease may be associated with the dose and duration of treatment., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Micropapillary and solid patterns indicate worse survival in lung adenocarcinoma patients, even in pathological stage IB patients. However, whether the presence of micropapillary or solid components is related to worse prognosis in pathological IA stage lung adenocarcinoma remains unclear., Methods: Several databases were searched up to December 31, 2022 for relevant studies investigating the association between micropapillary and solid components and the survival of IA stage lung adenocarcinoma patients. Primary and secondary outcomes are disease-free survival (DFS) and overall survival (OS), respectively. Hazard ratios (HRs) and 95% confident intervals (CIs) were combined, and subgroup analysis stratified by the pathological subtype and proportion of components was further performed., Results: A total of 19 studies with 12,562 cases were included. Pooled results indicated that micropapillary or solid components obviously predicted worse DFS (HR = 2.40, 95% CI: 1.96-2.94, P < .001) and OS (HR = 2.30, 95% CI: 1.68-3.15, P < .001). Subgroup analysis based on pathological subtype showed that both micropapillary and solid components were significantly associated with worse DFS (micropapillary: HR = 2.70, 95% CI: 1.70-4.28, P < .001; solid: HR = 3.98, 95% CI: 2.10-7.54, P < .001) and OS (micropapillary: HR = 2.29, 95% CI: 1.17-4.48, P = .015; solid: HR = 4.18, 95% CI: 1.72-10.17, P = .002). In addition, further subgroup analysis stratified by the proportion of micropapillary and solid components (>5%/1% or predominant) showed similar results., Conclusion: Micropapillary and solid patterns predicted a significantly worse prognosis in pathological IA stage lung adenocarcinoma patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC., Methods: We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1)., Results: Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3-8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5-7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83-1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62-1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group., Conclusions: Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion., (© 2023. The Author(s).)