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Objectives: With wide application of computed tomography (CT) in early lung cancer screening, solitary pulmonary nodules (SPNs) are frequently detected. Due to their high etiological diversity and potential for malignancy, rapid and accurate identification and malignant SPNs are crucial in the clinical management. In the present study, plasma exosomal microRNAs were identified and evaluated as sensitive and specific indicators for malignant SPNs., Materials and Methods: Exosomal miRNAs isolated from the plasmas of pathologically confirmed patients with SPN (four malignant and four benign, designated as the screening set) were subjected for high throughput sequencing and eight candidate miRNAs were selected. The pre-operation plasma levels of the candidate miRNAs in 77 patients with SPN (48 malignant and 29 benign, designated as the identification set) were detected by quantitative PCR, five miRNAs were identified as potential biomarkers for malignant SPNs, and the diagnostic values of the five miRNAs each alone or combined were then analyzed by AUROC analysis. The prediction values of the identified miRNAs were further evaluated in 95 patients with SPN (double blind, 74 malignant and 21 benign, designated as the validation set)., Results: High-throughput sequencing identified 45 miRNAs with statistical differences between benign and malignant SPNs. Among the eight candidate miRNAs in the identification set, miR-1-3p alone had the best diagnostic value, with the sensitivities and specificities of 89.6% and 100% for malignant SPNs. Unexpectedly, when miR-1-3p was combined with miR-99a-5p, both the sensitivity and specificity reached 100% for malignant SPNs. miR-1-3p+miR-125b-5p and miR-1-3p+miR-218-5p were also good indicators of malignant SPNs with sensitivities of 95.8% and 97.9%, specificities of 100% and 96.6%. Further analysis of these microRNA combinations in the validation set indicated that the PPV were 91.4%, 97.4%, and 93.5% and the NPV were 100%, 100%, and 88.9% for miR-1-3p+miR-99a-5p, miR-1-3p+miR-218-5p, and miR-1-3p+miR-125b-5p, with the sensitivities were 100%, 100%, and 97.3% and the specificities were 66.7%, 90.5%, and 76.2% for miR-1-3p+miR-99a-5p, miR-1-3p+miR-218-5p, and miR-1-3p+miR-125b-5p, respectively., Conclusions: Through high throughput sequencing, qPCR determination of plasma microRNAs and AUROC analysis, miR-1-3p combined with miR-99a-5p, miR-125b-5p, or miR-218-5p have been found to be sensitive and specific indicators of malignant SPNs in both the identification and validation sets. Our results indicate that the panels of plasma miRNAs can be used as diagnostic biomarkers for malignant SPNs., (© 2024 The Author(s). Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Objective: To analyze the clinical characteristics and prognostic factors of non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations who developed small cell lung cancer (SCLC) transformation after treatment with EGFR tyrosine kinase inhibitors (TKI). Methods: We conducted a retrospective collection of clinical data for 21 patients with advanced EGFR mutant NSCLC who developed SCLC transformation after EGFR-TKI treatment at Beijing Chest Hospital, Capital Medical University from January 2015 to December 2021. The clinical characteristics were summarized and the prognosis analysis was conducted. Patients were followed up until February 2024. The efficacy was evaluated using Solid Tumor Response Evaluation Criteria, and survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the differences in survival time (OS) between limited stage and extensive stage in transformed SCLC patients. Cox proportional hazards model was used to analyze the influencing factors of survival after SCLC transformation. Results: Among the 21 patients, there were 5 males and 16 females, with an age range of 33-74 years old [(58.9±2.6) years old]. All 21 patients were adenocarcinoma with sensitive EGFR mutations. There were 18 cases (85.7%) with EGFR gene 19del mutation, including 1 case of 19del+anaplastic lymphoma kinase (ALK) mutation, and 3 cases of L858R mutation. Among the transformed SCLC, there were 11 cases of pure SCLC and 10 cases of mixed SCLC (coexisting of adenocarcinoma and small cell carcinoma components). The median time from diagnosis of NSCLC to SCLC transformation was 12.0 months (95% CI : 7.6-16.3 months). Among the 21 cases of SCLC transformation, there were 13 cases with the extensive stage and 8 cases with the limited stage. Among them, 16 patients received systemic chemotherapy based on etoposide, of which 13 cases could be evaluated for efficacy, 11 cases could be calculated for PFS. Five cases had partial remission, 5 cases were stable, 3 cases had disease progression, and 3 cases cloud not be evaluated. The median progression free survival time (PFS) was 4.8 months (95% CI : 2.8-6.8 months). The median survival time (OS) after SCLC transformation in 21 patients was 10.6 months (95% CI : 7.0-14.2 months), with a median OS of 8.8 months (95% CI : 6.3-11.4 months) for patients with the extensive stage and 27.5 months (95% CI : 9.6-34.4 months) for patients with the limited stage, with statistically significant differences ( P =0.002). Cox proportional hazards model analysis showed that the limited stage after SCLC transformation was a protective factor for OS ( HR =0.32, 95% CI : 0.12-0.73, P =0.010). The median OS of 21 patients from the diagnosis of lung cancer was 24.9 months (95% CI : 13.0-36.7 months). Conclusions: NSCLC patients with SCLC transformation are all adenocarcinomas, and the proportion of EGFR19del mutations is relatively high. After SCLC transformation, the standard chemotherapy regimen for SCLC is generally used for treatment. The OS after SCLC transformation is related to the stage, and the prognosis is better in the limited stage.

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2 K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: We aimed to validate the prognostic implication of uncertain resection, R(un), proposed by International Association for the Study of Lung Cancer (IASLC) and evaluate the prognostic value of spread through air spaces (STAS) in reclassifying the R classification among patients with lung adenocarcinoma after segmentectomy., Methods: We enrolled 1007 patients who underwent segmentectomy for c-stage IA lung adenocarcinoma between 2014 and 2017. Recurrence-free survival (RFS) and overall survival (OS) were compared to evaluate the prognostic value of IASLC-R(un) and STAS. Whether STAS would skip into complementary lobectomy was evaluated in a prospective cohort., Results: The current IASLC-R(un) failed to significantly stratify the RFS (P = .078) in segmentectomy, and STAS was a stronger risk factor of poor prognosis for both RFS and OS (P < .001). Moreover, the presence of STAS was associated with increased locoregional recurrence in patients undergoing segmentectomy (P < .001) but not in those treated with lobectomy (P = .187), indicating that only STAS-positive segmentectomy was consistent with the concept of R(un) in relapse pattern. After reclassifying STAS-positive segmentectomy into the R(un) category, the proposed R(un) showed an improvement in prognosis stratification. In addition, 2 of 30 patients (6.2%) in the prospective cohort who underwent initial segmentectomy and complementary lobectomy had STAS clusters in the complementary lobectomy specimens., Conclusions: Unfavorable prognosis, relapse patterns consistent with R(un), and pathologic verification that saltatory spread of STAS observed in complementary lobectomy specimens supported reclassifying STAS-positive segmentectomy as R(un). STAS is a critical concern for the surgical completeness evaluation after segmentectomy., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Despite excellent 5-year survival, there are limited data on the long-term prognostic characteristics of clinical stage IA part-solid lung adenocarcinoma. The objective was to elucidate the dynamics of prognostic characteristics through conditional survival analysis., Methods: Consecutive patients who underwent complete resection for clinical stage IA part-solid lung adenocarcinoma between 2011 and 2015 were retrospectively reviewed. Conditional survival is defined as the probability of surviving further y years, conditional on the patient has already survived x years. The conditional recurrence-free survival (CRFS) and conditional overall survival (COS) were analysed to evaluate prognosis over time, with conditional Cox regression analysis performed to identify time-dependent prognostic factors., Results: A total of 1539 patients were included with a median follow-up duration of 98.4 months, and 80 (5.2%) patients experienced recurrence. Among them, 20 (1.3%) recurrence cases occurred after 5 years of follow-up with 100% intrathoracic recurrence. The 5-year CRFS increased from 95.8% to 97.4%, while the 5-year COS maintained stable. Multivariable Cox analysis revealed that histologic subtype was always an independent prognostic factor for CRFS even after 5 years of follow-up, while the independent prognostic value of consolidation-to-tumour ratio, visceral pleural invasion and lymph node metastasis was observed only within 5 years. Besides, age, pathologic size and lymph node metastasis maintained independent predictive value for COS during long-term follow-up, while consolidation-to-tumour ratio was predictive for COS only within 5 years of follow-up., Conclusions: The independent prognostic factors for clinical stage IA part-solid lung adenocarcinoma changed over time, along with gradually increasing 5-year CRFS and stable 5-year COS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Rationale and Objectives: To explore and externally validate habitat-based radiomics for preoperative prediction of epidermal growth factor receptor (EGFR) mutations in exon 19 and 21 from MRI imaging of non-small cell lung cancer (NSCLC)-originated brain metastasis (BM)., Methods: A total of 170, 62 and 61 patients from center 1, center 2 and center 3, respectively were included. All patients underwent contrast-enhanced T1-weighted (T1CE) and T2-weighted (T2W) MRI scans. Radiomics features were extracted from the tumor active (TA) and peritumoral edema (PE) regions in each MRI slice. The most important features were selected by the least absolute shrinkage and selection operator regression to develop radiomics signatures based on TA (RS-TA), PE (RS-PE) and their combination (RS-Com). Receiver operating characteristic (ROC) curve analysis was performed to access performance of radiomics models for both internal and external validation cohorts., Results: 10, four and six most predictive features were identified to be strongly associated with the EGFR mutation status, exon 19 and exon 21, respectively. The RSs derived from the PE region outperformed those from the TA region for predicting the EGFR mutation, exon 19 and exon 21. The RS-Coms generated the highest performance in the primary training (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.955 vs. 0.946 vs. 0.928), internal validation (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.879 vs. 0.819 vs. 0.882), external validation 1 (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.830 vs. 0.825 vs. 0.822), and external validation 2 (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.812 vs. 0.818 vs. 0.800) cohort., Conclusion: The developed habitat-based radiomics model can be used to accurately predict the EGFR mutation subtypes, which may potentially guide personalized treatments for NSCLC patients with BM., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Based on the FLAURA and AURA III trials, compared to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), osimertinib provides a longer overall survival benefit for patients with untreated EGFR mutated non-small cell lung cancer. Similar to other EGFR-TKIs, drug resistance is, however, inevitable. The most common mechanism of acquired resistance to first-line osimertinib therapy is the C797S mutation, which accounts for 6% of cases. In view of the current challenges of the development of the next generation of EGFR inhibitors, the mechanism of third-generation targeted drug resistances and targeted strategies are key for further exploration. Our case report discusses a female patient with advanced lung adenocarcinoma carrying the EGFR exon19 E746&#95;A750delinsIP mutation who received osimertinib as first-line therapy and acquired C797S resistance during treatment. The patient was then treated with icotinib for 8 months until the disease progressed. Icotinib may be effective in patients with the EGFR 19del-C797S resistant mutation acquired after osimertinib treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

ABSTRCTDysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N -(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide ( LAH-1 ), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.

This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II-III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2-4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3-48.1) in arm A and were 55.6% (95% CI 21.2-86.3) and 11.1% (95% CI 0.3-48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8-61.6) and 55.6% (95% CI 21.2-86.3). With a median follow-up of 22.4 months (95% CI 19.0-26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II-III NSCLC., (© 2024. The Author(s).)

Background: The aim of the study was to evaluate the prognostic value of postoperative folate receptor-positive circulating tumor cell (FR + CTC) detection in patients with stage I-III invasive adenocarcinoma (IAC) treated with surgery., Methods: Patients with lung adenocarcinoma (LUAD) who underwent surgical resection in Peking University Cancer Hospital and received postoperative FR + CTC analysis from July 2016 to January 2021 were retrospectively collected. Comparisons between or among groups were made using the Kruskal-Wallis or Mann-Whitney U tests. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression analyses were performed to explore the factors predicting recurrence and survival., Results: There were significant differences between the high and low groups in terms of age (p = 0.002), postoperative CA199 (p = 0.038), and postoperative SCC (p = 0.024). There were no significant differences in the other indicators (all p>0.05). N stage 1, N stage 2, and neoadjuvant therapy (NAT) were independent risk factors for disease recurrence and death; pleural invasion (PI), and nerve invasion were independent risk factors for death. The Kaplan-Meier curve showed a notable trend for a worse disease-free survival (DFS) or overall survival (OS) for patients with high levels of FR + CTCs in our study, but none of these were statistically significant., Conclusion: The detection of FR + CTCs postoperatively was an independent predictor of recurrence in patients treated for stage I-III IAC. Standardized detection methods and optimal time points for assessment should be established in future studies., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Objectives: Invasive mucinous adenocarcinoma (IMA) has a rare incidence with better prognosis than nonmucinous adenocarcinoma. We aimed to investigate the prognosis between limited resection and lobectomy for patients with clinical stage IA IMA ≤ 2 cm., Methods: Data were taken from two cohorts: In Shanghai Pulmonary Hospital (SPH) corhort, we identified 403 patients with clinical stage IA IMA who underwent surgery. In the SEER corhort, 480 patients with stage T1 IMA who after surgery were included. Recurrence-free survival (RFS) for SPH corhort, lung cancer-specific survival (LCSS) for the SEER corhort and overall survival (OS) for both corhort were compared between patients undergoing lobectomy and limited resection by Log-rank and Cox proportional hazard regression model., Results: In SPH corhort, patients who underwent limited resection had equivalent prognosis than those underwent lobectomy (5-year RFS: 79.3% versus. 82.6%, p = 0.116; 5-year OS: 86.2% versus. 88.3%, p = 0.235). However, patients with IMA > 2 to 3 cm had worse prognosis than those with IMA ≤ 2 cm (5-year RFS: 73.7% versus. 86.1%, p = 0.007). In the analysis of IMA > 2 to 3 cm subgroup, multivariate analysis showed that limited resection was an independent risk factor of RFS (hazard ratio, 2.417; 95% confidence interval, 1.157-5.049; p = 0.019), while OS (p = 0.122) was not significantly different between two groups. For IMA ≤ 2 cm, limited resection was not a risk factor of RFS (p = 0. 953) and OS (p = 0.552). In the SEER corhort, IMA ≤ 2 cm subgroup, limited resection was equivalent prognosis in LCSS (p = 0.703) and OS (p = 0.830)., Conclusions: Limited resection could be a potential surgical option which comparable to lobectomy in patients with clinical stage IA IMA ≤ 2 cm., (© 2024. The Author(s).)

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors., Significance: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188., (©2024 American Association for Cancer Research.)

Background: To identify independent factors of cognitive frailty (CF) and construct a nomogram to predict cognitive frailty risk in patients with lung cancer receiving drug therapy., Methods: In this cross-sectional study, patients with lung cancer undergoing drug therapy from October 2022 to July 2023 were enrolled. The data collected includes general demographic characteristics, clinical data characteristics and assessment of tools for cognitive frailty and other factors. Logistic regression was harnessed to determine the influencing factors, R software was used to establish a nomogram model to predict the risk of cognitive frailty. The enhanced bootstrap method was employed for internal verification of the model. The performance of the nomogram was evaluated by using calibration curves, the area under the receiver operating characteristic curve, and decision curve analysis., Results: A total of 372 patients were recruited, with a cognitive frailty prevalence of 56.2%. Age, education background, diabetes mellitus, insomnia, sarcopenia, and nutrition status were identified as independent factors. Then, a nomogram model was constructed and patients were classified into high- and low-risk groups with a cutoff value of 0.552. The internal validation results revealed good concordance, calibration and discrimination. The decision curve analysis presented prominent clinical utility., Conclusions: The prevalence of cognitive frailty was higher in lung cancer patients receiving drug therapy. The nomogram could identify the risk of cognitive frailty intuitively and simply in patients with lung cancer, so as to provide references for early screening and intervention for cognitive frailty at the early phases of drug treatment., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Objective: We developed a simple, rapid predictive model to evaluate the prognosis of older patients with lung adenocarcinoma., Methods: Demographic characteristics and clinical information of patients with lung adenocarcinoma aged ≥60 years were retrospectively analyzed using Surveillance, Epidemiology, and End Results (SEER) data. We built nomograms of overall survival and cancer-specific survival using Cox single-factor and multi-factor regression. We used the C-index, calibration curve, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to evaluate performance of the nomograms., Results: We included 14,117 patients, divided into a training set and validation set. We used the chi-square test to compare baseline data between groups and found no significant differences. We used Cox regression analysis to screen out independent prognostic factors affecting survival time and used these factors to construct the nomogram. The ROC curve, calibration curve, C-index, and DCA curve were used to verify the model. The final results showed that our predictive model had good predictive ability, and showed better predictive ability compared with tumor-node-metastasis (TNM) staging. We also achieved good results using data of our center for external verification., Conclusion: The present nomogram could accurately predict prognosis in older patients with lung adenocarcinoma., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Objectives: It has been demonstrated that neoadjuvant immune checkpoint inhibitor (ICI) plus chemotherapy was safe and feasible referred to neoadjuvant chemotherapy for patients with non-small cell lung cancer undergoing sleeve lobectomy. Nevertheless, no survival data were reported in the previous researches. Therefore, we conducted this study to compare neoadjuvant ICI plus chemotherapy versus neoadjuvant chemotherapy followed by sleeve lobectomy for long-term survival outcomes., Methods: Patients who underwent bronchial sleeve lobectomy following neoadjuvant ICI plus chemotherapy or neoadjuvant chemotherapy were retrospectively identified. Treatment response, perioperative outcomes, event-free survival and overall survival were compared between groups in the overall and the inverse probability of treatment weighting-adjusted cohort., Results: A total of 139 patients with 39 lung cancer recurrence and 21 death were included. Among them, 83 (59.7%) and 56 (40.3%) patients received neoadjuvant chemotherapy and neoadjuvant ICI plus chemotherapy, respectively. After inverse probability of treatment weighting, more patients achieved complete pathological response in the neoadjuvant ICI plus chemotherapy group (6.0% vs 26.3%, P < 0.001). There was no significant difference regarding overall postoperative complication (23.8% vs 20.2%, P = 0.624) and specific complications (all P > 0.05). Patients receiving neoadjuvant ICI plus chemotherapy had favourable event-free survival (hazard ratio 0.37, 95% confidence interval 0.16-0.85, P = 0.020) and overall survival (hazard ratio 0.23, 95% confidence interval 0.06-0.80, P = 0.021). Multivariable analysis revealed that neoadjuvant ICI plus chemotherapy was an independent predictor for favourable event-free survival (hazard ratio 0.37, 95% confidence interval 0.15-0.86, P = 0.020, adjusted for clinical TNM stage)., Conclusions: Neoadjuvant ICI plus chemotherapy was correlated with favourable long-term survival in patients with non-small cell lung cancer undergoing sleeve lobectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins., Methods: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing., Findings: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%])., Interpretation: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988)., Funding: Dizal Pharmaceutical., Competing Interests: Declaration of interests ZY reports employment by Dizal Pharmaceutical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate the prognostic impact of initial lung cancer (LC) on second primary breast cancer after LC (LC-BC) and further develop a nomogram for predicting the survival of patients., Methods: All patients diagnosed with LC-BC and first primary BC (BC-1) during 2000-2017 were collected from Surveillance, Epidemiology, and End Results database. Pathological features, treatment strategies and survival outcomes were compared between LC-BC and BC-1 before and after propensity score matching (PSM). Cox regression analysis was performed to identify the prognostic factors associated with LC in patients with LC-BC. Additionally, least absolute shrinkage and selection operator regression analysis was used to select clinical characteristics for nomogram construction, which were subsequently evaluated using the concordance index (C-index), calibration curve and decision curve analysis (DCA)., Results: 827 429 patients with BC-1 and 1445 patients with LC-BC were included in the analysis. Before and after PSM, patients with BC-1 had a better prognosis than individuals with LC-BC in terms of both overall survival (OS) and breast cancer-specific survival (BCSS). Furthermore, characteristics such as more regional lymph node dissection, earlier stage and the lack of chemotherapy and radiation for LC were found to have a stronger predictive influence on LC-BC. The C-index values (OS, 0.748; BCSS, 0.818), calibration curves and DCA consistently demonstrated excellent predictive accuracy of the nomogram., Conclusion: In conclusion, patients with LC-BC have a poorer prognosis than those with BC-1, and LC traits can assist clinicians estimate survival of patients with LC-BC more accurately., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36 -/- ) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36 -/- mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment., (© 2024. The Author(s).)

Background: As lung cancer becomes a primary source of death in China, investigation on incidence rate, death rate, and disability-adjusted life years (DALYs) is of great significance to optimize prevention measures and allocation of healthcare resources., Methods: We utilized data from the Global Burden of Disease (GBD) database to evaluate the incidence rate, death rate, and DALYs of lung cancer in China from 1990 to 2019. Analysis of lung cancer risk factor-related death rate and DALYs was performed. Age-standardized rates (ASR) and estimated annual percentage change (EAPC) were calculated. The incidence trend of lung cancer from 2020 to 2034 was predicted by the Nordpred age-period-cohort (APC) model., Results: Age-standardized incidence rate (ASIR) increased from 30.2/100000 (95 % UI 26.2-34.3) in 1990 to 41.7/100000 (95 % UI 35.2-48.8) in 2019, and EAPC was 1.33 (95 % CI 1.16-1.49). From 1990 to 2019, men were noted for the highest incidence rate, death rate, and DALYs rate across three age groups (15-49 years, 50-69 years, and over 70). During this period, the ASIR of lung cancer in females was always lower than that in males. The predominant risk factors of lung cancer were smoking, air pollution, and diet, among which smoking was the most significant one. The analysis results showed that new cases and deaths may increase in the following 15 years since 2020 in the context of lung cancer., Conclusion: Faced with the heavy burden of lung cancer, China must issue corresponding policies and roll out prevention avenues against smoking and air pollution., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Aim: Evaluate the clinical value of lung-cancer-related autoantibodies (CAGE, GAGE7, GBU4-5, MAGEA1, P53, PGP9.5, SOX2) in auxiliary diagnosis of non-small-cell lung cancer (NSCLC). Methods: We detected the concentrations of above 7 antibodies and lung cancer markers (CEA, NSE, CYFRE21-1) and drew area under the receiver characteristic curve of 316 patients. Results: The concentrations of CAGE, GBU4-5, MAGEA1, P53, PGP9.5 and SOX2 of significantly higher than other groups ( p  < 0.01). The sensitivity of different stages and pathological types of NSCLC consistent. Among them, the sensitivity of combined-detection in diagnosing adenocarcinoma and squamous cell carcinoma significantly better than CEA, NSE and CYFRA21-1. Conclusion: The combined detection has better efficacy in assisting the diagnosis of NSCLC and has certain clinical promotion and application value.

Accumulating studies suggest that Huaier exerts anti-tumor effects through intricate mechanisms. Despite extensive research on its efficacy in lung cancer, further investigation is required to elucidate the molecular mechanism of Huaier. The involvement of long noncoding RNAs (lncRNAs) in the anti-lung cancer effects of Huaier remains unknown. In this study, we found Huaier suppressed cell viability, migration and invasion in non-small cell lung cancer (NSCLC) cells. LncRNA sequencing analysis revealed Deleted in lymphocytic leukemia 2 (DLEU2) to be significantly downregulated in Huaier-treated NSCLC cells. Furthermore, DLEU2 silencing was observed to suppress NSCLC progression, while DLEU2 overexpression attenuated the anti-tumor effects of Huaier in NSCLC, thereby promoting cell viability, migration and invasion of NSCLC. The ceRNA role of DLEU2 had been demonstrated in NSCLC, which directly interacted with miR-212-5p to rescue the repression of E74 Like ETS Transcription Factor 3 (ELF3) by this microRNA. Additionally, Huaier was found to regulate the expression of miR-212-5p and ELF3. Functionally, miR-212-5p inhibitor or ELF3 overexpression reversed the effects of DLEU2 silencing or Huaier treatment, resulting in increased colony formation, migration and invasion in NSCLC. Taken together, these results illuminate the mechanism underlying Huaier's anti-tumor effects via the DLEU2/miR-212-5p/ELF3 signaling pathway, which offers novel insights into the anti-tumor effects of Huaier and constitutes a promising therapeutic target for the treatment in NSCLC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: Lung cancer is classified into central and peripheral types based on the anatomic location. The present study aimed to explore the distinct patterns of genomic alterations between central- and peripheral-type non-small cell lung cancers (NSCLCs) with negative driver genes and identify potential driver genes and biomarkers to improve therapy strategies for NSCLC., Methods: Whole-exome sequencing (WES) was performed with 182 tumor/control pairs of samples from 145 Chinese NSCLC patients without EGFR, ALK, or ROS1 alterations. Significantly mutated genes (SMGs) and somatic copy number alterations (SCNAs) were identified. Subsequently, tumor mutation burden (TMB), weighted genome integrity index (wGII), copy number alteration (CNA) burden, Shannon diversity index (SDI), intratumor heterogeneity (ITH), neoantigen load (NAL), and clonal variations were evaluated in central- and peripheral-type NSCLCs. Furthermore, mutational signature analysis and survival analysis were performed., Results: TP53 was the most frequently mutated gene in NSCLC and more frequently mutated in central-type NSCLC. Higher wGII, ITH, and SDI were found in central-type lung adenocarcinoma (LUAD) than in peripheral-type LUAD. The NAL of central-type lung squamous cell carcinoma (LUSC) with stage III/IV was significantly higher than that of peripheral-type LUSC. Mutational signature analysis revealed that SBS10b, SBS24, and ID7 were significantly different in central- and peripheral-type NSCLCs. Furthermore, central-type NSCLC was found to evolve at a higher level with fewer clones and more subclones, particularly in central-type LUSC. Survival analysis revealed that TMB, CNA burden, NAL, subclonal driver mutations, and subclonal mutations were negatively related to the overall survival (OS) and the progression-free survival (PFS) of central-type LUAD., Conclusions: Central-type NSCLC tended to evolve at a higher level and might suggest a favorable response to immunotherapy. Our study also identified several potential driver genes and promising biomarkers for the prognosis and prediction of chemotherapy responses in NSCLC., 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 Elsevier B.V. All rights reserved.)

Background: The clinical management of lung cancer (LC) patients with bone metastasis (BM) is still a significant challenge. This study aimed to explore the role of primary tumor resection (PTR) on survival outcome of LC patients with BM and to develop two web-based nomograms for predicting the overall survival (OS) of LC patients with BM who received PTR and those who did not., Methods: We enrolled LC patients with BM from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Propensity score matching (PSM) was then conducted to balance the baseline characteristics of covariates between patients in surgery and non-surgery groups. Next, Kaplan-Meier analysis with log-rank test was performed to evaluate the survival benefit of PTR before and after PSM methods and to explore the impact of surgical resection extent on the prognosis of LC patients with BM and clinical outcomes in patients with different metastatic patterns. Cox proportional hazard regression analysis was then applied to determine the independent prognostic factors for OS of patients receiving PTR and did not receiving PTR, respectively. Subsequently, we constructed two individualized nomograms for predicting the 12-, 18- and 24-months OS. Finally, receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) were generated to evaluate discrimination, accuracy and clinical utility of the nomograms., Results: A total of 7747 eligible patients were included in this analysis. The survival analysis revealed that PTR was closely associated with better survival outcome among LC patients with BM(P < 0.05), while the survival benefit of PTR was suboptimal in patients presented with multiple metastases(P > 0.05). Besides, lobectomy shows best survival benefit. Two nomograms were then constructed based on independent prognostic factors of patients in the surgery group and the non-surgery group. The ROC curves showed good discrimination of the two nomograms, with the area under curve (AUC) of each time point being higher than 0.7 in both the training set and testing set. The calibration curves also demonstrated satisfactory consistency between actual survival and nomogram-predicted OS of both nomograms. The DCA showed high benefit of nomogram in a clinical context. Moreover, the study population was stratified into three groups based on the scores of the nomogram, and the survival analysis showed that this prognostic stratification was statistically significant (p < 0.05)., Conclusions: This study showed that surgical resection of the primary site strategy can prolong survival of LC patients with BM to some extent, depending on different sites of metastasis and highly selected patients. Furthermore, the web-based nomograms showed significant accuracy in predicting OS for patients with or without surgery, which may provide valuable insights for patients' counseling and individualized decision-making for clinicians., Competing Interests: Declaration of competing interest Conflicts of interest All authors have completed the ICMJE uniform disclosure form. The authors declared no any conflict of interest to declare., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Background: The eighth edition of nodal classification is defined only by the anatomical location of metastatic lymph nodes and has limited prognostic discrimination power. The authors aimed to evaluate the prognostic significance and discriminatory capability of the number of metastatic lymph nodes (nN) in resected nonsmall cell lung cancer., Materials and Methods: Patients with stage IA to IIIB resected nonsmall cell lung cancer between 1 January 2009 and 31 December 2013 were analyzed as a Chinese cohort. The optimal thresholds for the nN classification were determined by the X-tile. The receiver operating characteristic curve, net reclassification improvement and standardized net benefit calculated by decision curve analysis was estimated to quantify the nN classification's performance in prognostic stratification. External validation in the surveillance, epidemiology, and end results database was performed to test the robustness of the nN classification., Results: Both cohorts showed a stepwise prognosis deterioration with increasing nN. One to three, four to six, and more than six were selected as optimal thresholds of nN classification in the Chinese cohort, which included 4432 patients, then validated in the SEER cohort ( n =28 022 patients). Multivariate Cox analysis showed the nN classification was an independent predictive factor for overall survival in both cohorts (Chinese cohort and SEER cohort: N 0 vs. N 1-3 , P <0.001; N 0 vs. N 3-6 , P <0.001; N 0 vs. N >6 , P <0.001). And prognostic discriminatory capability was improved in the nN classification compared with location-based N classification [5-year NRI score, 0.106 (95% CI: 0.049-0.132) and 5-year time-independent AUC, 0.593 (95% CI: 0.560-0.625) vs. 0.554 (95% CI: 0.520-0.588), P <0.001]., Conclusions: The nN classification tended to be a superior prognostic indicator than the location-based N classification. The number of metastatic lymph nodes should be considered in the future revision of the TNM system., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The performance of positron emission tomography/computed tomography (PET/CT) for the prediction of ypN2 disease in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy has not been reported. This multicenter study investigated the utility of PET/CT to assess ypN2 disease in these patients., Methods: A total of 181 consecutive patients (chemoimmunotherapy = 86, chemotherapy = 95) at four institutions were enrolled in this study. Every patient received a PET/CT scan prior to surgery and complete resection with systematic nodal dissection. The diagnostic performance was evaluated through area under the curve (AUC). Kaplan-Meier method and Cox analysis were performed to identify the risk factors affecting recurrences., Results: The sensitivity, specificity, and accuracy of PET/CT for ypN2 diseases were 0.667, 0.835, and 0.779, respectively. Therefore, the AUC was 0.751. Compared with the false positive cases, the mean value of max standardized uptake value (SUV max ) (6.024 vs. 2.672, p < 0.001) of N2 nodes was significantly higher in true positive patients. Moreover, the SUV max of true positive (7.671 vs. 5.976, p = 0.365) and false (2.433 vs. 2.339, p = 0.990) positive cases were similar between chemoimmunotherapy and chemotherapy, respectively. Survival analysis proved that pathologic N (ypN) 2 patients could be stratified by PET/CT-N2(+ vs. -) for both chemoimmunotherapy (p = 0.023) and chemotherapy (p = 0.010)., Conclusions: PET/CT is an accurate and non-invasive test for mediastinal restaging of NSCLC patients who receive neoadjuvant chemoimmunotherapy. The ypN2 patients with PET/CT-N2( +) are identified as an independent prognostic factor compared with PET/CT-N2(-)., Clinical Relevance Statement: Imaging with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) plays an integral role during disease diagnosis, staging, and therapeutic response assessments in patients with NSCLC. PET/CT could be an effective non-invasive tool for predicting ypN2 diseases after neoadjuvant chemoimmunotherapy., Key Points: • PET/CT could serve as an effective non-invasive tool for predicting ypN2 diseases. • The ypN2 patients with PET/CT-N2( +) were a strong and independent prognostic factor. • The application of PET/CT for restaging should be encouraged in clinical practice., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Anlotinib is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor for the treatment of lung cancer. Pneumothorax is a rare complication of anlotinib treatment. Here, the case of a male patient in his early seventies, with lung cancer combined with emphysema, who developed a pneumothorax during treatment with anlotinib, is described. The patient was admitted to hospital mainly for dyspnoea and was diagnosed with pneumothorax after digital radiography of the chest. The patient's symptoms improved significantly after closed chest drainage, and a repeat chest digital radiography showed a more resolved pneumothorax. The patient had no previous history of pneumothorax. After discontinuation of anlotinib, the latest follow-up chest computed tomography assessment in August 2023 showed no recurrence of pneumothorax, thus, the pneumothorax is presumed to have been associated with anlotinib in this patient. In addition, the authors speculate that emphysema may be a cause of pneumothorax in patients with lung cancer receiving anlotinib treatment. Therefore, clinicians should be alert to the risk of pneumothorax occurrence in patients with emphysema combined with lung cancer who are treated with anlotinib., Competing Interests: Declaration of conflicting interestsThe authors declare that there is no conflict of interest.

Background: The aim of this study was to construct two web-based nomograms to predict the probability of bone metastasis (BM) in esophageal cancer (EC) patients and the prognostic of EC patients with BM (ECBM)., Methods: We collected the data of EC and ECBM patients in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2015. Independent risk variables for the development of BM in EC patients were identified using univariate and multivariate logistic regression analyses. Univariate and multivariate Cox regression analyses were used to assess independent prognostic variables in ECBM patients. And then, constructed two nomograms to predict the risk of bone metastases and overall survival (OS) of ECBM patients. Survival differences were studied by Kaplan-Meier (K-M) survival analysis. The predictive efficacy and clinical applicability of these two nomograms were assessed by using receiver operating characteristic (ROC) curve, the area under curve (AUC), calibration curve and decision curve analysis (DCA)., Results: We selected a total of 6839 patients with EC, of which 326 (4.77%) had BM at the time of initial diagnosis. The results of K-M survival and Cox regression analysis showed significant effects of BM on the OS in EC patients. Age, N stage, tumor size and brain/liver/lung organ metastasis were identified as BM-related risk variables. Chemotherapy and brain/liver organ metastasis were identified as ECBM-related prognostic variables. The ROC, AUC, calibration curves and DCA of two nomograms all showed excellent predictive efficacy and clinical applicability., Conclusions: These two nomograms were constructed and validated, which could objectively predict the risk of BM in EC patients and the prognostic in ECBM patients. These tools are expected to make valuable contributions in clinical work, informing surgeons in making decisions about patient care., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: As a subclass of endogenous stable noncoding RNAs, circular RNAs are beginning to be appreciated for their potential as tumor therapeutics. However, the functions and mechanisms by which circRNAs exert protective functions in non-small cell lung cancer (NSCLC) remain largely elusive., Methods: The prognostic role of circGUCY1A2 was explored in lung adenocarcinoma specimens. The overexpressed and knockdown plasmids were used to evaluate the effect of circGUCY1A2 on NSCLC cell proliferation and apoptosis efficacy. Luciferase reporter system is used to prove that circGUCY1A2 could bind to miRNA. Chip-PCR was used to prove that circGUCY1A2 could be initiated by transcription factors ARNTL. Subcutaneous tumorigenicity grafts models were established to validate findings in vivo., Results: The expression of circGUCY1A2 were significantly reduced (P < 0.001) and negatively correlated with tumor size (P < 0.05) in non-small cell lung cancer (NSCLC). CircGUCY1A2 upregulation promoted apoptosis and inhibits cell proliferation and growth of subcutaneous tumorigenicity grafts in nude mice (P < 0.01). In addition, intra-tumor injection of pLCDH-circGUCY1A2 inhibited tumor growth in patient-derived NSCLC xenograft models (PDX). Mechanism studies showed that circGUCY1A2 could act as a sponge to competitively bind miR-200c-3p, promote PTEN expression, and thereby inhibit PI3K/AKT pathway. In addition, we found that the circadian gene ARNTL, which was reduced in NSCLC and prolonged the overall survival of patients, could bind to the promoter of circGUCY1A2, thereby increasing its expression., Conclusions: This study is an original demonstration that ARNTL can inhibit the development of lung adenocarcinoma through the circGUCY1A2/miR-200c-3p/PTEN axis, and this finding provides potential targets and therapeutic approaches for the treatment of lung adenocarcinoma., (© 2023. Italian National Cancer Institute ‘Regina Elena’.)

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment., (© 2023. The Author(s).)

Objectives: The application of artificial intelligence (AI) to the field of pathology has facilitated the development of digital pathology, hence, making AI-assisted diagnosis possible. Due to the variety of lung cancers and the subjectivity of manual evaluation, invasive non-mucinous lung adenocarcinoma (ADC) is difficult to diagnose. We aim to offer a deep learning solution that automatically classifies invasive non-mucinous lung ADC histological subtypes., Design: For this investigation, 523 whole-slide images (WSIs) were obtained. We divided 376 of the WSIs at random for model training. According to WHO diagnostic criteria, six histological components of invasive non-mucinous lung ADC, comprising lepidic, papillary, acinar, solid, micropapillary and cribriform arrangements, were annotated at the pixel level and employed as the predicting target. We constructed the deep learning model using DeepLab v3, and used 27 WSIs for model validation and the remaining 120 WSIs for testing. The predictions were analysed by senior pathologists., Results: The model could accurately predict the predominant subtype and the majority of minor subtypes and has achieved good performance. Except for acinar, the area under the curve of the model was larger than 0.8 for all the subtypes. Meanwhile, the model was able to generate pathological reports. The NDCG scores were greater than 75%. Through the analysis of feature maps and incidents of model misdiagnosis, we discovered that the deep learning model was consistent with the thought process of pathologists and revealed better performance in recognising minor lesions., Conclusions: The findings of the deep learning model for predicting the major and minor subtypes of invasive non-mucinous lung ADC are favourable. Its appearance and sensitivity to tiny lesions can be of great assistance to pathologists., Competing Interests: Competing interests: SW is the cofounder and chief technology officer (CTO) of Thorough Future. LW is the algorithm researcher of Thorough Future. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The detection of epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer is critical for tyrosine kinase inhibitor therapy. EGFR detection requires tissue samples, which are difficult to obtain in some patients, costing them the opportunity for further treatment. To realize EGFR mutation prediction without molecular detection, we aimed to build a high-accuracy deep learning model with only haematoxylin and eosin (H&E)-stained slides., Methods: We collected 326 H&E-stained non-small cell lung cancer slides from Beijing Chest Hospital, China, and used 226 slides (88 with EGFR mutations) for model training. The remaining 100 images (50 with EGFR mutations) were used for testing. We trained a convolutional neural network based on ResNet-50 to classify EGFR mutation status on the slide level., Results: The sensitivity and specificity of the model were 76% and 74%, respectively, with an area under the curve of 0.82. When applying the double-threshold approach, 33% of the patients could be predicted by the deep learning model as EGFR positive or negative with a sensitivity and specificity of 100.0% and 87.5%. The remaining 67% of the patients got an uncertain result and will be recommenced to perform further examination. By incorporating adenocarcinoma subtype information, we achieved 100% sensitivity in predicting EGFR mutations in 37.3% of adenocarcinoma patients., Conclusions: Our study demonstrates the potential of a deep learning-based EGFR mutation prediction model for rapid and cost-effective pre-screening. It could serve as a high-accuracy complement to current molecular detection methods and provide treatment opportunities for non-small cell lung cancer patients from whom limited samples are available., (© 2023. The Author(s).)

Background: Ginsenoside Rh2 (G-Rh2) exerts anti-tumor activity in non-small cell lung cancer (NSCLC). microRNAs (miRNAs, miRs) play pivotal roles in NSCLC. We aimed to investigate whether G-Rh2 inhibited NSCLC progression by targeting miRNA., Methods: Cell viability, apoptosis and cycle were determined by Cell Counting Kit-8, 6-diamidino-2-phenylindole (DAPI) staining and flow cytometry. The potential target miRNAs of G-Rh2 were screened by real-time quantitative polymerase chain reaction (RT-qPCR). The difference in miR-28-5p expression between lung adenocarcinoma (LUAD) tissues and normal tissues or lung squamous cell carcinoma (LUSC) tissues and normal tissues was retrieved from TCGA-LUAD and TCGA-LUSC, respectively. Kaplan-Meier Plotter was conducted to analyze the survival rate for different serine/threonine-protein kinase 4 (STK4) expressions with different prognostic risks. immunohistochemistry of STK4 expression in non-tumor and tumor tissues was analyzed from the HPA database. RT-qPCR and Western blot were adopted for detecting mRNA and protein expression. TargetScan V7.2, miRanda and PITA were adopted for predicting targets of miR-28-5p, overlapped genes were subjected to GO analysis. The interactions of miR-28-5p-Wnt and miR-28-5p-STK4 were detected by TOP/FOP luciferase reporter assay and dual luciferase reporter assay, respectively., Results: Current study observed that G-Rh2 reduced miR-28-5p expression in NSCLC cells dose-dependently. miR-28-5p was upregulated in NSCLC tissues and cells. The target genes of miR-28-5p were enriched in negative regulation of Wnt signaling. miR-28-5p inhibitor inactivated Wnt signaling, inhibited cell viability and cell cycle, while enhanced cell apoptosis of NSCLC cells by targeting STK4. G-Rh2 exerted the similar effects with miR-28-5p inhibitor by reducing miR-28-5p. G-Rh2 and miR-28-5p inhibitor exerted a synergistic effect on inhibiting NSCLC tumor growth., Conclusion: In conclusion, G-Rh2 attenuates NSCLC development by affecting miR-28-5p/STK4 axis and inactivating Wnt signaling. Taken together, we project out a novel therapeutic target for NSCLC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Micropapillary (MIP) component was a major concern in determining surgical strategy in lung adenocarcinoma (LUAD). We sought to develop a novel method for detecting MIP component during surgery., Methods: Differentially expressed proteins between MIP-positive and MIP-negative LUAD were identified through proteomics analysis. The semi-dry dot-blot (SDB) method which visualises the targeted protein was developed to detect MIP component., Results: Cellular retinoic acid-binding protein 2 (CRABP2) was significantly upregulated in MIP-positive LUAD (P < 0.001), and the high CRABP2 expression zone showed spatial consistency with MIP component. CRABP2 expression was also associated with decreased recurrence-free survival (P < 0.001). In the prospective cohort, the accuracy and sensitivity of detecting MIP component using SDB method by visualising CRABP2 were 82.2% and 72.7%, which were comparable to these of pathologist. Pathologist with the aid of SDB method would improve greatly in diagnostic accuracy (86.4%) and sensitivity (78.2%). In patients with minor MIP component (≤5%), the sensitivity of SDB method (63.6%) was significantly higher than pathologist (45.4%)., Conclusions: Intraoperative examination of CRABP2 using SDB method to detect MIP component reached comparable performance to pathologist, and SDB method had notable superiority than pathologist in detecting minor MIP component., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: SH-1028 is a new third-generation EGFR tyrosine kinase inhibitors (TKI) to benefit patients with EGFR T790M-mutated NSCLC. Here, the authors report its clinical safety, preliminary efficacy, and pharmacokinetic (PK) profile for the first time., Methods: Patients with EGFR T790M mutation, locally advanced non-small cell lung cancer (NSCLC), or metastatic NSCLC who had progressed after previous EGFR TKI therapy were eligible. Patients received SH-1028 at five oral dose levels (60 mg, 100 mg, 200 mg, 300 mg, and 400 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were the safety, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and PK profile. Secondary end points included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), etc. RESULTS: Data cut off on December 31, 2020, a total of 20 patients were enrolled during the trial, two of three patients in 300 mg cohort experienced a DLT, and no DLT was observed in 240 mg cohort, 240 mg was determined to be the MTD of SH-1028. A total of 95.0% (19 of 20) of patients reported treatment-related adverse events (TRAEs), and the incidence of serious adverse events was 20.0% (4 of 20). The ORR and DCR of the 200 mg cohort were 75% (95% confidence interval [CI], 19.41-99.37) and 75.0% (95% CI, 19.41-99.37), respectively. The overall ORR was 40% (95% CI, 19.12-63.95), and DCR was 70.0% (95% CI, 45.72-88.11). According to the PK profile, the dosage regimen for future studies was determined as 200 mg once daily., Conclusions: SH-1028 showed a manageable safety and promising antitumor activity in patients with EGFR T790M mutation at the dose of 200 mg once daily., Plain Language Summary: Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non-small cell lung cancer accounts for approximately 85% of lung cancer. First- or second-generation EGFR TKIs' weak selectivity often led to the occurrence of treatment-related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year. A dose of 200 mg of SH-1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non-small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential., Significance: Analysis of sQTL reveals the role of genetically driven mRNA splicing alterations in NSCLC risk and elucidates that rs156697 variant impacts risk by altering GSTO2 splicing., (©2023 American Association for Cancer Research.)

Aims: For non-small-cell lung cancer (NSCLC) patients receiving neoadjuvant therapy, the major pathological response (MPR) is defined as the percentage of residual viable tumour cells (%RVT) in the tumour bed of no more than 10%. It has been proposed as a predictor of survival in neoadjuvant therapy-treated cohorts. Nonetheless, the significance of %RVT in the pathological assessment of lung adenocarcinoma cohorts remains undetermined., Methods and Results: Overall, 152 lung adenocarcinoma patients were included in this retrospective study, among whom 67 received neoadjuvant targeted therapy and 85 received neoadjuvant chemotherapy. Clinicopathological characteristics, neoadjuvant treatment response and survival status were investigated. The routinely adopted standard for MPR (%RVT ≤ 10%) failed to differentiate prognosis in the lung adenocarcinoma population. For the neoadjuvant chemotherapy cohort, the optimal %RVT cut-off value of RFS was 60%. However, this cut-off value was clinically insignificant in the neoadjuvant targeted-therapy cohort. Hence, for these patients, we built a nomogram model including high-grade patterns and ypN stage to predict disease recurrence, demonstrating high efficacy (a bootstrap-corrected C-index of 0.731)., Conclusions: %RVT served as a strong indicator of the prognosis of lung adenocarcinoma in patients receiving neoadjuvant chemotherapy but not neoadjuvant targeted therapy. Residual high-grade pathological patterns might substitute MPR in prognostic evaluation of lung adenocarcinoma post-targeted therapy., (© 2022 John Wiley & Sons Ltd.)

Introduction: The International Association for the Study of Lung Cancer (IASLC) newly proposed grading system for lung adenocarcinomas (ADC) has been shown to be of prognostic significance. Hence, intraoperative consultation for the grading system was important regarding the surgical decision-making. Here, we evaluated the accuracy and interobserver agreement for IASLC grading system on frozen section (FS), and further investigated the prognostic performance., Methods: FS and final pathology (FP) slides were reviewed by three pathologists for tumor grading in 373 stage I lung ADC following surgical resection from January to June 2013 (retrospective cohort). A prospective multicenter cohort (January to June 2021, n = 212) were included to confirm the results., Results: The overall concordance rates between FS and FP were 79.1% (κ = 0.650) and 89.6% (κ = 0.729) with substantial agreement in retrospective and prospective cohorts, respectively. Presence of complex gland was the only independent predictor of discrepancy between FS and FP (presence versus. absence: odds ratio, 2.193; P = 0.015). The interobserver agreement for IASLC grading system on FS among three pathologists were satisfactory (κ = 0.672 for retrospective cohort; κ = 0.752 for prospective cohort). Moreover, the IASLC grading system by FS diagnosis could well predict recurrence-free survival and overall survival for patients with stage I invasive lung ADC., Conclusions: Our results suggest that FS had high diagnostic accuracy and satisfactory interobserver agreement for IASLC grading system. Future prospective studies are merited to validate the feasibility of using FS to match patients into appropriate surgical type., 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 Elsevier B.V. All rights reserved.)

Introduction: Reliable predictive markers are lacking for resectable non-small cell lung cancer (NSCLC) patients treated with neoadjuvant chemoimmunotherapy. The present study investigated the utility of SUV max values acquired from PET/CT to predict the response to neoadjuvant chemoimmunotherapy for resectable NSCLC., Materal and Methods: SUV max , clinical and pathological outcomes, were collected from patients in 5 hospitals. Patients who received dynamic PET/CT surveillance were divided into cohorts A (chemoimmunotherapy) and B (chemotherapy), respectively, while cohort C (chemoimmunotherapy) comprised patients undergoing post-therapy PET/CT. Associations between SUV max and major pathologic response (MPR) were evaluated through receiver operating characteristic (ROC) curves., Results: A total of 129 cases with an MPR rate of 46.5 % was identified. In neoadjuvant chemoimmunotherapy, ΔSUV max % (AUC: 0.890, 95 % CI: 0.761-0.949) and post-therapy SUV max (AUC: 0.933, 95 % CI: 0.802-0.959) could accurately predict MPR. On the contrary, the baseline SUV max was not associated with MPR (p = 0.184). Furthermore, an independent cohort C proved that post-therapy SUV max could serve as an independent predictor (AUC: 0.928, 95 % CI: 0.823-0.958). In addition, robust predictive performance could be observed when we use the optimal cut-off point of both ΔSUV max % (54.4 %, AUC: 0.912, 95 % CI: 0.824-0.994) and post-therapy SUV max (3.565, AUC: 0.912, 95 % CI: 0.824-0.994) in neoadjuvant chemoimmunotherapy. The RNA data revealed that the expression of PFKFB4, a key enzyme in glycolysis, was positively correlated with SUV max value and tumor cell proliferation after neoadjuvant chemoimmunotherapy., Conclusion: These findings highlighted that the ΔSUV max % and remained SUV max were accurate and non-invasive tests for the prediction of MPR after neoadjuvant chemoimmunotherapy., 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 Elsevier B.V. All rights reserved.)

Background: Approximately 1-2% of non-small cell lung cancer (NSCLC) patients harbor RET (rearranged during transfection) fusions. The oncogenic RET fusions could lead to constitutive kinase activation and oncogenesis., Methods: 1746 Chinese NSCLC patients were analyzed in this study. Tumor tissues were collected, and were formalin fixed, paraffin-embedded (FFPE) and archived. Peripheral blood (PB) samples were also collected from each patient as control. In addition, we selected 17 of them for cfDNA NGS testing and 14 tumor samples for immunohistochemistry testing using PD-L1 rabbit monoclonal antibody, clones 28-8 (Abcam, Cambridge, UK)., Results: Of the 1746 NSCLC cases, RET rearrangements were identified in 25 cases (1.43%) with locally advanced or metastatic NSCLC, of which 20 (80%) were female. We found that 14 out of 25 patients had an KIF5B-RET fusion, with KIF5B exon15-RET exon12, KIF5B exon23-RET exon12, and KIF5B exon24-RET exon11 detected in 14, 3, and 1 patients, respectively. We also identified one novel RET fusion partner PLCE1 and 4 intergenic-breakpoint fusions., Conclusion: In this study, using the hybrid capture based next generation sequencing (NGS) techniques, we revealed the genomic profiling for the patients with RET fusion-positive NSCLC. To the best of our knowledge, this is the first study that exhibited the detailed breakpoints of Chinese NSCLC patients with RET rearrangement, and we found a novel new partner PLCE1. The results provided genomic information for patients with RET fusion which is significant for personalized clinical management in the era of precision medicine., (© 2022. The Author(s).)

Background: Respiratory diseases mainly include asthma, influenza, pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, lung fibrosis, and lung cancer. Given their high prevalence and poor prognosis, the prevention and treatment of respiratory diseases are increasingly essential. In particular, the development for the novel strategies of drug treatment has been a hot topic in the research field. Ginsenosides are the major component of Panax ginseng C. A. Meyer (ginseng), a food homology and well-known medicinal herb. In this review, we summarize the current therapeutic effects and molecular mechanisms of ginsenosides in respiratory diseases., Methods: The reviewed studies were retrieved via a thorough analysis of numerous articles using electronic search tools including Sci-Finder, ScienceDirect, PubMed, and Web of Science. The following keywords were used for the online search: ginsenosides, asthma, influenza, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung fibrosis, lung cancer, and clinical trials. We summarized the findings and the conclusions from 176 manuscripts on ginsenosides, including research articles and reviews., Results: Ginsenosides Rb1, Rg1, Rg3, Rh2, and CK, which are the most commonly reported ginsenosides for treating of respiratory diseases, and other ginsenosides such as Rh1, Rk1, Rg5, Rd and Re, all primarily reduce pneumonia, fibrosis, and inhibit tumor progression by targeting NF-κB, TGF-β/Smad, PI3K/AKT/mTOR, and JNK pathways, thereby ameliorating respiratory diseases., Conclusion: This review provides novel ideas and important aspects for the future research of ginsenosides for treating respiratory diseases., Competing Interests: Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Primary pulmonary sarcoma (PPS) is very rare in terms of incidence, henceforth, the clinical evidence pertinent to the prognosis of PPS is limited. The aim of this study was to construct a nomogram for evaluating the overall survival (OS) of patients diagnosed with PPS based on the stage, lymph node dissection, tumor size and degree of differentiation, and therapies. Methods: A total of 515 patients diagnosed with PPS during the period of 1998 to 2015 were obtained from the surveillance, epidemiology, and end results database and randomly segregated into 'training group' and 'validation group' with a ratio of 7:3. Regression analysis was executed for the training group to obtain the independent factors influencing prognosis of PPS patients. A nomogram was constructed as per the results obtained through multivariate Cox regression analysis subsequently validated using C index, receiver operating characteristic (ROC) curve, and calibration curves. Results: Age, tumor size, histology type, lymph node surgery, summary stage and differentiation grade were independent factors affecting the prognosis. C index was 0.775 and 0.737 for both training group, and validation group, respectively. Areas under the ROC curve of 1-year, 3-year, and 5-year OS were 87.6 (95% CI: 83.8-91.3), 90.1 (95% CI: 86.2-94.0) and 90.6 (95% CI: 85.8-95.4), respectively, in training group. Area under the curve values of 1-year, 3-year, and 5-year OS in the validation group were 83.1 (95% CI: 75.8-90.5), 82.9 (95% CI: 73.2-92.7) and 87.0 (95% CI: 75.9-98.1), respectively. Based on the nomogram, patients were segregated into low-risk group and high-risk group (degree of risk: cutoff score 193). OS of low-risk group was significantly higher when compared to high-risk group ( P < .001) in the training group and validation group. Radiotherapy was a risk factor for the low-risk group and adjuvant chemotherapy has not exhibited influence on OS pertinent to low-risk group. However, adjuvant radiotherapy or chemotherapy both significantly improved the prognosis of PPS patients ( P < .001) in the high-risk group. Conclusion: Constructed nomogram could have a strong predictive ability with higher accuracy for the prognosis of patients with PPS. Patients at low risk could not benefit from adjuvant radiotherapy or chemotherapy, while the prognosis clearly improved in the high-risk populations treated with either radiotherapy or chemotherapy.

The International Association for the Study of Lung Cancer (IASLC) recently proposed a new grading system for lung adenocarcinoma (LUAD). We aimed to validate the prognostic performance of the grading system and explore its role in guiding the strategy of lymph node (LN) dissection. We retrospectively reviewed 1029 patients with clinical stage I LUAD who underwent surgery between 2011 and 2013. The association between mediastinal nodal metastasis and grading system was evaluated. To investigate the value of the grading system in guiding LN dissection strategies, 3 pathologists evaluated the feasibility of identifying the grading system using frozen section (FS). The differences in prognosis between all neighboring grades were highly significant based on the grading system ( P <0.001). Notably, almost no grade 1 LUAD (1.4%) had pN2 disease, whereas higher rates were found in grade 2 LUAD (9.6%) and grade 3 LUAD (18.3%) ( P <0.001). Multivariate logistic regression analysis revealed that higher tumor grade was an independent predictor of mediastinal nodal metastasis ( P =0.002). Moreover, limited mediastinal LN dissection had equivalent prognosis in grade 1 LUAD, but significantly worse prognosis in grade 2 and grade 3 LUAD than systematic mediastinal LN dissection. The overall accuracy of using intraoperative FS to identify the IASLC grading system was 85.4% (κ=0.765) with substantial agreement. The IASLC grading system could accurately stratify prognosis and predict mediastinal nodal metastasis in patients with clinical stage I LUAD. FS was feasible for identifying the IASLC grading system., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: This study evaluated the clinicopathologic characteristics and prognostic impact of atypical epidermal growth factor receptor (EGFR) mutations in patients with completely resected lung adenocarcinoma (LUAD) and investigate whether adjuvant chemotherapy could benefit the survival outcomes for these subjects., Material and Methods: We retrospectively reviewed resected LUAD samples from 8437 patients and identified 5358 EGFR-mutated (EGFRm) cases. Of these, 4847 had classical mutations, while 511 had atypical mutations. For further survival analysis, propensity score matching, Kaplan-Meier curve, and Cox regression analyses were conducted., Results: Of the 511 patients with atypical EGFRm LUAD, 131 patients had compound mutations. The frequency of exon 20 insertion (20-ins), G719X, L861Q, S768I, and de novo T790M were 30.3%, 32.7%, 21.9%, 9.2%, and 11.4%, respectively. These patients included a higher proportion of males than those with classical EGFRm LUAD. Between the 483 matched pairs of the classical and atypical EGFRm patients, no significant difference emerged in disease-free survival (DFS) (p = 0.476). Patients with the L861Q mutation had the poorest DFS among those with atypical EGFRm LUAD (p = 0.005). Cox regression analyses revealed that the L861Q mutation was an independent prognostic factor for DFS in 487 patients with solely atypical EGFRm LUAD. In addition, adjuvant chemotherapy did not improve the DFS for those patients, whether in stage IB (p = 0.638) or II-III (p = 0.505) of the disease., Conclusion: The L861Q mutation is an independent prognostic factor for DFS in patients with atypical EGFRm LUAD after complete resection who would not benefit from adjuvant chemotherapy regardless of disease stage., Competing Interests: Conflict of interest statement 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 © 2022 Elsevier Ltd. All rights reserved.)

Lung Squamous Cell Carcinoma (LUSC) is an aggressive malignancy with limited therapeutic options. The response to immune therapy is a determining factor for the prognosis of LUSC patients. This study aimed to develop a reliable immune-related prognostic signature in LUSC. We extracted gene expression and clinical data of LUSC from The Cancer Genome Atlas (TCGA). A total of 502 patients enrolled and were divided into respond and non-responder groups by the TIDE algorithm. The CIBERSORT algorithm and the LM22 gene signature were used to analyze the distribution of immune cells in LUSC. Efficacy and response strength of immunotherapy are calculated by the tumor mutation burden (TMB) and ESTIMATE Score. Differentially expressed genes (DEGs) between the two groups were analyzed. The differential expression genes related to overall survival were pointed as hub DEGs, and a prognostic signature was constructed with lasso regression analysis. LUSC patients were divided into responder and non-responder groups based on the response to immunotherapy. The distribution of immune cells was significantly different between the two groups. Forty-four DGEs were considered as overall survival-related genes. A prognostic signature was constructed, consisting of 11 hub-DGEs, including MMP20, C18orf26, CASP14, FAM71E2, OPN4, CGB5, DIRC1, C9orf11, SPATA8, C9orf144B, and ZCCHC5. The signature can accurately distinguish LUSC patients into high and low-risk groups. Moreover, the high-risk group had a shorter survival time than the low-risk group. The area under the ROC curve was 0.67. The multivariate Cox regression showed that the risk score calculated by the constructed signature was an independent prognostic predictor for LUSC patients. In short, we established a novel immune-related prognostic signature in LUCS, which has significant sensitivity and accuracy in predicting the prognosis of patients. Our research can guide the evaluation of the prognosis of LUSC patients in clinical, and the discovered immune-related genes can provide a theoretical basis for the discovery of new therapeutic targets., (© 2022. The Author(s).)

ALK is an attractive therapeutic target for the treatment of non-small cell lung cancer. As an emerging element in medicinal chemistry, boron has achieved great success in the discovery of antitumor drugs and antibacterial agents. Through construction of a BCC (boron-containing compound) compound library and broad kinase screening, we found the ALK inhibitor hit compound 10a. Structural optimization by CADD and isosterism revealed that lead compound 10k has improved activity (ALK L1196M IC 50  = 8.4 nM, NCI-H2228 cells IC 50  = 520 nM) and better in vitro metabolic stability (human liver microsomes, T 1/2  = 238 min). Compound 10k showed good in vivo efficacy in a nude mouse NCI-H2228 lung cancer xenograft model with a TGI of 52 %. Molecular simulation analysis results show that the hydroxyl group on the oxaborole forms a key hydrogen bond with Asn1254 or Asp1270, and this binding site provides a new idea for drug design. This is the first publicly reported lead compound for a boron-containing ALK inhibitor., 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 © 2022 Elsevier Ltd. All rights reserved.)

Background: Evidence of neoadjuvant chemoimmunotherapy for locally advanced non-small cell lung cancer remains investigational and requires prospective validation. This phase II trial (https://www.chictr.org.cn/historyversionpub.aspx?regno=ChiCTR1900023758) aimed to investigate the safety and effectiveness of neoadjuvant PD-1 inhibitor sintilimab in addition to chemotherapy in the management of resectable stage IIIA non-small cell lung cancer., Methods: Eligible patients received two to four 21-day cycles of neoadjuvant therapy: sintilimab (200 mg) and carboplatin (area under the curve 5) on day 1, gemcitabine (1000 mg/m 2 ) on day 1 and day 8 for squamous cell carcinoma, or pemetrexed (500 mg/m 2 ) on day 1 for adenocarcinoma and non-small cell lung cancer not otherwise specified. The primary endpoints were adverse events and major pathological response. The secondary endpoint was disease-free survival at 1 year., Results: Fifty patients were enrolled, and 23 (46%) achieved partial response after neoadjuvant chemoimmunotherapy. Four (8%) patients experienced grade 3 to 5 adverse events. Thirty patients received surgery, none of whom experienced treatment-related surgery delays, and 13 (43.3%) of 30 patients achieved major pathological response (viable tumor ≤10%). With a median follow-up of 13.6 months, 85.3% of patients were disease-free at 1 year (N = 50)., Conclusions: Neoadjuvant sintilimab with platinum-containing dual-agent chemotherapy was feasible and safe for patients with resectable stage IIIA non-small cell lung cancer., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)