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Abstract Background The association between sarcopenia and cardiovascular disease (CVD) is well known. However, the clinical diagnosis of sarcopenia is complex and not suitable for early clinical identification and prevention of CVD. Relative muscle strength (RMS) is a relatively quantitative and straightforward indicator, but its association with CVD remains unclear. Hence, the objective of this research was to investigate the correlation between RMS and CVD incidence. Methods This was a cross-sectional study, using data from the China Health and Retirement Longitudinal Study (CHARLS) in 2011. CVD events were assessed through self-reported physician diagnoses. The RMS was determined by dividing the maximum grip strength by the appendicular skeletal muscle mass (ASM). This study used multivariate logistic regression and restricted cubic spline (RCS) curves to explore the correlation between RMS and CVD incidence. Additionally, we conducted subgroup analyses to provide additional evidence supporting the association between the two variables. Results A total of 8,733 people were included in our study, with 1,152 (13.19%) CVD patients and 7,581 (86.81%) non-CVD patients. When the data were grouped according to quartiles (Q) of RMS, the inverse association between CVD and RMS remained statistically significant even after controlling for all potential confounding factors. Compared with participants in Q1 of RMS, the ORs (95% CIs) of CVD among those in Q2-Q4 were 0.99 (0.83, 1.17), 0.81 (0.67, 0.98), and 0.70 (0.57, 0.85), respectively. Moreover, the RCS results showed a negative linear correlation between the RMS and CVD incidence (P for nonlinearity = 0.555). Subgroup analysis revealed no significant interaction in any of the groups except for the sex group (P for interaction = 0.046). Conclusion Our study indicated a stable negative correlation between RMS and CVD incidence. RMS is helpful for the early identification and prevention of CVD.

Abstract Disulfidptosis, a newly identified programmed cell death pathway in prostate cancer (PCa), is closely associated with intracellular disulfide stress and glycolysis. This study aims to elucidate the roles of disulfidptosis-related genes (DRGs) in the pathogenesis and progression of PCa, with the goal of improving diagnostic and therapeutic approaches. We analyzed PCa datasets and normal tissue transcriptome data from TCGA, GEO, and MSKCC. Using consensus clustering analysis and LASSO regression, we developed a risk scoring model, which was validated in an independent cohort. The model's predictive accuracy was confirmed through Kaplan–Meier curves, receiver operating characteristic (ROC) curves, and nomograms. Additionally, we explored the relationship between the risk score and immune cell infiltration, and examined the tumor microenvironment and somatic mutations across different risk groups. We also investigated responses to immunotherapy and drug sensitivity. Our analysis identified two disulfidosis subtypes with significant differences in survival, immune environments, and treatment responses. According to our risk score, the high-risk group exhibited poorer progression-free survival (PFS) and higher tumor mutational burden (TMB), associated with increased immune suppression. Functional enrichment analysis linked high-risk features to key cancer pathways, including the IL-17 signaling pathway. Moreover, drug sensitivity analysis revealed varied responses to chemotherapy, suggesting the potential for disulfidosis-based personalized treatment strategies. Notably, we identified PROK1 as a crucial prognostic marker in PCa, with its reduced expression correlating with disease progression. In summary, our study comprehensively assessed the clinical implications of DRGs in PCa progression and prognosis, offering vital insights for tailored precision medicine approaches.

Abstract Background The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. Methods We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. Results The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients’ fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. Conclusions The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Key Clinical Message One Kirsten Ras (KRAS) G12C mutated non‐small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first‐line KRAS‐targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8‐month median progress‐free survival (PFS) and 12.5‐month overall survival (OS) in previously treated KRAS G12C‐mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next‐generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG‐PS) with metastatic KRAS G12C‐mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first‐line treatment. Although 5‐month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG‐PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first‐line treatment with sotorasib for the advance untreated KRAS G12C‐mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C‐mutated patient may favor the immunotherapy.

Background: This study aimed to investigate whether placebo control is differently disclosed in drug and non-drug randomised clinical trial (RCT) participant information leaflets (PILs) and how this might affect participant blinding and direction of study outcomes. Methods: PILs were obtained from trials registered in the International Standard Randomised Controlled Trial Number database via email. Placebo descriptions in PILs were categorised as Full Disclosure (FD), Partial Disclosure (PD), or Missing Information (MI). Associations between intervention type (drug or non-drug)/placebo disclosure (FD or PD/MI) and participant blinding success/trial outcome direction (positive or non-positive) were examined using a two-sided Fisher's exact test. Results: Of 116 collected PILs, 56 % were for drug trials and 44 % were for non-drug trials. Among them, 88 PILs had the corresponding publications available and 68 reports specified primary outcomes. Drug trials were more likely to fully disclose placebo information than non-drug trials (92.3 % vs. 74.5 %, p < 0.05). However, the success rate of blinding was only reported in 3 out of 88 trial publications (3.4 %), precluding further analysis. Furthermore, there was no significant association between the direction of trial results and the type of intervention or placebo disclosure. Conclusion: Our study findings suggest that drug and non-drug RCTs might differ in the way they reveal placebo control information. Further research is warranted to understand what leads to more common PD of placebo information in non-drug trials than drug trials and to determine the optimal placebo control disclosure in specific trial context.

Abstract This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab–chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA–IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9–81.0%). For patients with ctDNA– vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Background: Some studies of dual-targeted therapy (DTT) targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Consequently, patient management following DTT resistance has gained significance. However, the underlying resistance mechanisms and clinical outcomes in these patients remain unclear. Objectives: This study aimed to delineate the molecular characteristics and survival outcomes of patients with NSCLC harboring EGFR mutations and acquired MET amplification after developing resistance to DTT. Design: We conducted a retrospective analysis of patients with NSCLC with EGFR mutations and acquired MET amplification who exhibited resistance to EGFR/MET DTT. Methods: Next-generation sequencing (NGS) was performed on patients with available tissue samples before and/or after the development of resistance to DTT. Stratified analyses were carried out based on data sources and subsequent salvage treatments. Univariate/multivariate Cox regression models and survival analyses were employed to explore potential independent prognostic factors. Results: The study included 77 NSCLC patients, with NGS conducted on 19 patients. We observed many resistance mechanisms, including EGFR-dependent pathways (4/19, 21.1%), MET-dependent pathways (2/19, 10.5%), EGFR/MET co-dependent pathways (2/19, 10.5%), and EGFR/MET-independent resistance mechanisms (11/19, 57.9%). Post-progression progression-free survival (pPFS) and post-progression overall survival (pOS) significantly varied among patients who received the best supportive care (BSC), targeted therapy, or chemotherapy (CT), with median pPFS of 1.5, 3.9, and 4.9 months, respectively ( p = 0.003). Median pOS were 2.3, 7.7, and 9.2 months, respectively ( p

Abstract Background Malignant melanoma is a highly heterogeneous skin cancer with the highest mortality rate among dermatological cancers. Catenins form functional networks in the nucleus to regulate gene expression and determine cell fate. Dysregulation of catenin expression correlates with the malignant characteristics of the tumor. We aimed to investigate the regulatory mechanisms of catenins in melanoma and to further define the function of catenin-related molecular signaling in the tumor microenvironment. Methods In this study, a bioinformatics approach combined with experimental validation was used to explore the potential tumor biology mechanisms of catenin-related signaling. Results Melanoma patients can be divided into two catenin clusters. Patients defined by high Junction Plakoglobin (JUP), Plakophilin 1 (PKP1), Plakophilin 3 (PKP3) levels (C2) had shorter survival time than other patients (C1). We demonstrated that JUP regulates Anterior Gradient 2 (AGR2)/LY6/PLAUR Domain Containing 3 (LYPD3) to maintain melanoma stemness and promotes glycolysis. We also found that LYPD3 was co-expressed with S100A9 and associated with immunosuppressive tumor microenvironment (TME). Conclusion The JUP/AGR2/LYPD3 signaling axis plays an important role in the malignant features of melanoma. Targeting the JUP/AGR2/LYPD3 signaling axis can help develop promising drugs.

Objective: To investigate the effects of normal group without gavage of LBP and various doses of Lycium barbarum leaves polysaccharides (LBP) on mouse metabolism, antioxidant, immune function, and intestinal microorganisms, C57BL/6 female mice were continuously gavaged with 50, 100, and 150 mg/kg of LBP for 7 weeks. Methods: The ultrastructure of the intestinal mucosa of each group of mice was observed by scanning electron microscopy, and the levels of serum malondialdehyde (MDA), activities of glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) were detected to evaluate the antioxidant capacity of different doses of LBP, the number of T, B and dendritic cells (DC) in the spleen was detected by flow cytometry, fully automated biochemical analyzer for the detection of biochemical indicators in mouse serum, and the changes of intestinal flora in mouse fecal samples were detected by 16S RNA sequencing. Results: There were no variations in the intestinal mucosa's ultrastructure between the groups. The activity of T-SOD (45.27±2.73 U/g) and GSH-Px (1585.76±33.69 U/g) was increased by high-dose LBP, while MDA levels (6.15±1.03 nmol/g) were decreased. The high dose group of LBP could significantly boost the number of T and DC cells, lower serum levels of aspartate aminotransferase (161.48±14.98 U/L) and triglycerides (0.30±0.04 mmol/L) and can increase the relative abundance of probiotic genera like Dubosiella, Akkermansia, and Lactobacillus, and others in the gut. Conclusions: The findings of this study demonstrated that LBP given orally to mice had no effect on the structure of the intestinal mucosa, while also improving antioxidant capacity, enhancing immune system function, enhancing intestinal microflora, and promoting triglyceride and aspartate aminotransferase biological metabolism in mice. This will provide the theoretical basis for the development and utilization of LBP in food, medicine and health products.

Background: Mesenchymal–epithelial transition ( MET ) amplification is a crucial oncogenic driver and a resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) of non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection. However, it is inapplicable when tissue samples are unavailable. Objective: This study assessed the performance of plasma droplet digital polymerase chain reaction (ddPCR) in MET amplification detection in NSCLC patients. Design and methods: A total of 87 NSCLC patients were enrolled, and 94 paired tissue and plasma samples were analyzed for the concordance between FISH and plasma ddPCR/tissue next-generation sequencing (NGS) in detecting MET amplification. In addition, the efficacy of patients with MET amplification using different detection methods who were treated with MET-TKIs was evaluated. Results: Plasma ddPCR showed substantial concordance with FISH (74.1% sensitivity, 92.5% specificity, and 87.2% accuracy with a kappa value of 0.68) and outperformed tissue NGS (kappa value of 0.64) in MET amplification detection. Combined plasma ddPCR and tissue NGS showed substantial concordance with FISH (92.3% sensitivity, 89.2% specificity, and an accuracy of 90.1% with a kappa value of 0.77). The efficacy is comparable in these NSCLC patients with MET amplification detected by FISH and plasma ddPCR who were treated with MET-TKIs. Conclusion: Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection.

Abstract Objectives Primary pulmonary lymphoepithelioma‐like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB‐treated PLELC. Viral EBNA‐1 and BamHI‐W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results Progression‐free survival (PFS) was significantly longer in EBNA‐1 high or BamHI‐W high groups. A longer PFS was also observed in patients with both high plasma EBNA‐1 or BamHI‐W and PD‐L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA‐1 and BamHI‐W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions Plasma EBV DNA could be a useful and easy‐to‐use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.

BackgroundKnee osteoarthritis (OA) is a chronic, degenerative bone and joint disease. It can lead to major pressure to the quality of life and mental health of patients, and also brings a serious economic burden to society. However, it is difficult for patients with knee OA to access rehabilitation when discharging from the hospital. Internet-based rehabilitation is one of the promising telemedicine strategies for the improvement of knee OA, but the effect of different telerehabilitation strategies on knee OA is not clear. ObjectiveThe aim of this systematic review and meta-analysis was to identify telerehabilitation strategies attributing to the improvement of pain and physical function outcomes in patients with knee OA. MethodsWe reviewed and analyzed telerehabilitation strategies from randomized controlled trials (RCTs) comparing telerehabilitation with conventional treatment or usual care. For each strategy, we examined whether RCTs that applied the telerehabilitation strategy resulted in a significant improvement in pain or physical function compared with conventional treatment or usual care. ResultsWe included 6 RCTs (n=734) incorporating 8 different telerehabilitation strategies. The duration of the interventions ranged from 1 to 48 weeks, and sample sizes ranged from 20 to 350 patients. The results showed that RCTs that provided telerehabilitation were found to be more effective than conventional treatments for improving pain (P=.003; standardized mean difference [SMD] –0.21, 95% CI –0.35 to –0.07), but not physical function (P=.24; SMD –0.09, 95% CI –0.25 to 0.06). Furthermore, this systematic review and meta-analysis indicated that there is no significant correlation between different telerehabilitation strategies and the pain and physical function of patients with knee OA. ConclusionsThis systematic review and meta-analysis showed that telerehabilitation programs could relieve pain but not improve physical function for patients with knee OA. These results indicated that telerehabilitation is beneficial for the implementation of home rehabilitation exercises for patients with knee OA, thereby reducing the economic burden of health. However, there were limitations in terms of the number of search results and the number of studies that were eligible for this review and meta-analysis. Therefore, the results need to be interpreted with caution, and more high-quality studies with large samples are needed to focus on the long-term outcomes of telerehabilitation for patients with knee OA to address this limitation.

The efficacy of immunotherapy in advanced HER2‐mutated non‐small‐cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%] to compare clinical/molecular features and immune checkpoint inhibitor (ICI)‐based therapy efficacy between patients with ex20ins and non‐ex20ins. Two external cohorts (TCGA, n = 21; META‐ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death‐ligand 1 (PD‐L1) expression

Abstract Background The introduction of multiparameter MRI and novel biomarkers has greatly improved the prediction of clinically significant prostate cancer (csPCa). However, decision-making regarding prostate biopsy and prebiopsy examinations is still difficult. We aimed to establish a quick and economic tool to improve the detection of csPCa based on routinely performed clinical examinations through an automated machine learning platform (AutoML). Methods This study included a multicenter retrospective cohort and two prospective cohorts with 4747 cases from 9 hospitals across China. The multimodal data, including demographics, clinical characteristics, laboratory tests, and ultrasound reports, of consecutive participants were retrieved using extract-transform-load tools. AutoML was applied to explore potential data processing patterns and the most suitable algorithm to build the Prostate Cancer Artificial Intelligence Diagnostic System (PCAIDS). The diagnostic performance was determined by the receiver operating characteristic curve (ROC) for discriminating csPCa from insignificant prostate cancer (PCa) and benign disease. The clinical utility was evaluated by decision curve analysis (DCA) and waterfall plots. Results The random forest algorithm was applied in the feature selection, and the AutoML algorithm was applied for model establishment. The area under the curve (AUC) value in identifying csPCa was 0.853 in the training cohort, 0.820 in the validation cohort, 0.807 in the Changhai prospective cohort, and 0.850 in the Zhongda prospective cohort. DCA showed that the PCAIDS was superior to PSA or fPSA/tPSA for diagnosing csPCa with a higher net benefit for all threshold probabilities in all cohorts. Setting a fixed sensitivity of 95%, a total of 32.2%, 17.6%, and 26.3% of unnecessary biopsies could be avoided with less than 5% of csPCa missed in the validation cohort, Changhai and Zhongda prospective cohorts, respectively. Conclusions The PCAIDS was an effective tool to inform decision-making regarding the need for prostate biopsy and prebiopsy examinations such as mpMRI. Further prospective and international studies are warranted to validate the findings of this study. Trial registration Chinese Clinical Trial Registry ChiCTR2100048428. Registered on 06 July 2021.

Abstract Background Radical prostatectomy remains the fundamental treatment for prostate cancer, and improving patients’ compliance with postoperative follow-ups is essential for improving patients’ quality of life. This study investigates the effect of education levels on patients’ recovery and follow-up after radical prostatectomy. Methods Data from 1,112 patients undergoing radical prostatectomy between 2011 and 2020 were collected using medical records, and “pc-follow” systems were used to collect patients’ baseline information, education level, pathological information, number of outpatient visits, the time interval between each visit, and PSA test data. Results Regarding postoperative outpatient data, there was no difference in the number of outpatient visits among the different education level groups in Shanghai (P = 0.063). A significant difference was found in the interval between outpatient visits among the groups (P

Abstract Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with poor prognosis. Our integrative analyses of transcriptome and proteome reveal distinctive molecular features of ccRCC with VTT, and yield the development of a prognostic classifier to facilitate ccRCC molecular subtyping and treatment. The RNA sequencing and mass spectrometry were performed in normal-tumor-thrombus tissue triples of five ccRCC patients. Statistical analysis, GO and KEGG enrichment analysis, and protein–protein interaction network construction were used to interpret the transcriptomic and proteomic data. A six-gene-based classifier was developed to predict patients’ survival using Cox regression, which was validated in an independent cohort. Transcriptomic analysis identified 1131 tumorigenesis-associated differentially expressed genes (DEGs) and 856 invasion-associated DEGs. Overexpression of transcription factor EGR2 in VTT indicated its important role in tumor invasion. Furthermore, proteomic analysis showed 597 tumorigenesis-associated differentially expressed proteins (DEPs) and 452 invasion-associated DEPs. The invasion-associated DEPs showed unique enrichment in DNA replication, lysine degradation, and PPAR signaling pathway. Integration of transcriptome and proteome reveals 142 tumorigenesis-associated proteins and 84 invasion-associated proteins displaying changes consistent with corresponding genes in transcriptomic profiling. Based on their different expression patterns among normal-tumor-thrombus triples, RAB25 and GGT5 were supposed to play a consistent role in both tumorigenesis and invasion processes, while SHMT2 and CADM4 might play the opposite roles in tumorigenesis and thrombus invasion. A prognostic classifier consisting of six DEGs (DEPTOR, DPEP1, NAT8, PLOD2, SLC7A5, SUSD2) performed satisfactorily in predicting survival of ccRCC patients (HR = 4.41, P

Summary: Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon’s minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).

Abstract EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously; 2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase). Objective response rate (ORR), complete pathologic response (pCR), PFS, and overall survival (OS) were assessed along with safety. Post hoc analysis was performed for subsequent treatments after disease recurrence. Among investigated 72 patients (erlotinib, n = 37; GC, n = 35), the median follow-up was 62.5 months. The median OS was 42.2 months (erlotinib) and 36.9 months (GC) (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.47–1.47; p = 0.513). The 3- and 5-year OS rates were 58.6% and 40.8% with erlotinib and 55.9% and 27.6% with GC (p 3-y = 0.819, p 5-y = 0.252). Subsequent treatment was administered in 71.9% and 81.8% of patients receiving erlotinib and GC, respectively; targeted therapy contributed mostly to OS (HR, 0.35; 95% CI, 0.18–0.70). After disease progression, the ORR was 53.3%, and the median PFS was 10.9 months during the EGFR-TKI rechallenge. During postoperative therapy, grade 3 or 4 adverse events (AEs) were 13.5% in the erlotinib group and 29.4% in the GC group. No serious adverse events were observed. Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

ABSTRACTMetabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.