Runxiang Yang

Comprehensive genomic analysis and optimal treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) G719X + S768I co-mutations remain limited. This study aimed to elucidate the genetic landscape and the clinical effectiveness of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in this subset. A total of 645 EGFR-mutant NSCLC patients were retrospectively screened, with 142 patients harbored EGFR G719X + S768I co-mutations. Among these patients, next-generation sequencing was performed in 126 patients, and the efficacy of first-line EGFR-TKIs was evaluated in 96 patients with stage IV disease. Impacts of variant allele frequency (VAF) and concurrent TP53 mutations were also analyzed. Among G719X variants, G719C was most prevalent (69.8%), followed by G719A (19.0%) and G719S (8.7%). The most common co-existing mutation was TP53 (38.0%), followed by ALK and PIK3CA (6.3% each). For first-line EGFR-TKIs, the overall objective response rate (ORR) reached 68.8%, with a median progression-free survival (mPFS) of 21.4 months (95% CI: 18.2–24.6). Afatinib showed a significantly better response compared to both first- and third-generation EGFR-TKIs (1st vs. 2nd vs. 3rd generations, ORR: 35.7% vs. 76.8% vs. 61.5%, P = 0.01; mPFS: 17.2 vs. 23.4 vs. 17.4 months, P = 0.008). VAF and TP53 mutation status did not affect outcomes (P > 0.05), but patients with metastases in the brain and liver experienced notably shorter mPFS. Brain metastases patients had an ORR of 70.5% without additional benefit from third-generation TKIs. This study delineates the genomic profile of EGFR G719X + S768I co-mutated NSCLC and highlights the superior effectiveness of second-generation EGFR-TKIs, particularly afatinib. These findings provided valuable insights to guide clinical decision-making and facilitate the development of tailored therapeutic strategies for this subset. The online version contains supplementary material available at 10.1186/s12885-026-15887-6.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC (‘EC alone’; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607.

Introduction: Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched.Methods: In this study, we performed transcriptome screening of peripheral blood plasma obtainedfrom 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance.Results: Our analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed PRICKLE3, TNFSFI0, ACSLl and EP300 as potential contributors to primary resistance, with SNWl, SENP2 and SMNDCl emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC.Discussion: These findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies.

Immune checkpoint inhibitors (ICIs) are approved as the first-line drug for treating many cancers and has shown significant survival benefits; however, it also causes immune-related adverse events (irAEs) while activating the immune system, involving multiple organs. Among them, cardiovascular immune-related adverse events (CV-irAE) are rare, but common causes of death in ICIs treated cancer patients, which manifest as myocardial, pericardial, vascular and other cardiovascular toxicities. Therefore, it is important that irAEs, especially CV-irAE should be carefully recognized and monitored during the whole ICIs treatment because early detection and treatment of CV-irAE can significantly reduce the mortality of such patients. Consequently, it is urgent to fully understand the mechanism and management strategies of CV-irAE. The effects of ICIs are multifaceted and the exact mechanism of CV-irAE is still elusive. Generally, T cells identify tumor cell antigens as well as antigen in cardiomyocytes that are the same as or homologous to those on tumor cells, thus causing myocardial damage. In addition, ICIs promote formation of cardiac troponin I (cTnI) that induces cardiac dysfunction and myocardial dilatation; moreover, ICIs also increase the production of cytokines, which promote infiltration of inflammation-linked molecules into off-target tissues. Currently, the management and treatment of cardiovascular toxicity are largely dependent on glucocorticoids, more strategies for prevention and treatment of CV-irAE, such as predictive markers are being explored. This review discusses risk factors, potential pathophysiological mechanisms, clinical manifestations, and management and treatment of CV-irAE, guiding the development of more effective prevention, treatment and management strategies in the future.

Weight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

Lung cancer is the leading cause of cancer death worldwide. The Xuanwei-Fuyuan (XF) region of Yunnan, China has a high incidence of lung cancer from coal-related pollution. Effort to raise public awareness screening for lung cancer has been ongoing. We retrospectively analyzed overall survival (OS) of lung cancer patients of a tertiary cancer center in Yunnan to investigate screening and regional residential status as predictive factors. Consecutive cases of newly diagnosed lung cancer were reviewed. The lung cancer cases diagnosed by screening were more likely to be early-staged and treated by surgery than those diagnosed not by screening. In patients diagnosed not by screening, XF residential status was a significant predictor of improved OS. Frailty model detected significant heterogeneity associated with region of residence in unscreened patients. Potential biases associated with screening were examined by Monte Carlo simulations and sensitivity analyses. Focused effort in cancer screening and increased public awareness of pollution-related lung cancer in XF might have led to early diagnosis and improved OS, and increased investment in health care resources in high risk areas may have produced additional unobserved factors that underlay the association of XF residential status with improved OS in patients diagnosed not by screening.