Lung adenocarcinoma is prone to brain metastasis, and the prognosis of patients is extremely poor. The inhibitor of apoptosis-stimulating protein of p53 (iASPP) protein, encoded by the protein phosphatase 1 regulatory subunit 13-like (PPP1R13L) gene, is a key inhibitor of the p53 pathway and promotes carcinogenesis in various tumors, but its role in brain metastasis of lung adenocarcinoma is unknown. This study aims to analyze the tumor microenvironment characteristics of patients with brain metastasis of lung adenocarcinoma and explore the expression of PPP1R13L in brain metastasis tissues and its clinical significance by single-cell sequencing and clinical sample analysis. Brain tissues from 4 patients with lung adenocarcinoma brain metastasis and 2 patients with oligodendroglioma (ODG) were collected from the Affiliated Tumor Hospital of Xinjiang Medical University from January 2014 to December 2024 for single-cell sequencing. The tumor microenvironment was analyzed by combining single-cell sequencing data from 4 lung adenocarcinoma samples and 4 normal lung tissue samples from public databases. Additionally, clinical data and paraffin sections of 50 patients with lung adenocarcinoma brain metastasis in this hospital were collected, and immunohistochemistry was used to assess iASPP expression and its association with clinicopathologic features and patient outcome. Compared with the ODG and lung adenocarcinoma groups, the specific epithelial cells in the lung adenocarcinoma brain metastasis group were mainly enriched in oxidative phosphorylation, apoptosis, hypoxia, and p53 pathways. PPP1R13L, as an upregulated differential gene, was highly expressed in the specific epithelial cell subpopulation of the brain metastasis group; the interaction between PPP1R13L-positive cells and fibroblasts was significant, activating cell-matrix adhesion related pathways, with the key ligand-receptor pair being collagen type I alpha 1 chain-cluster of differentiation 44 (COL1A1-CD44). Statistical evaluation revealed that smoking (HR=2.543, 95%CI: 1.159-5.583, P=0.020) and high expression of iASPP (HR=3.351, 95%CI: 1.310-8.575, P=0.012) were independent predictors of poor prognosis in lung adenocarcinoma patients with brain metastases. This study revealed the interaction between epithelial cells and fibroblasts in the microenvironment of lung adenocarcinoma brain metastasis and implicate PPP1R13L as a potential prognostic indicator and actionable target, offering rationale for precision therapy against lung adenocarcinoma brain metastases. 【中文题目：PPP1R13L在肺腺癌脑转移瘤中
的表达特征及预后研究】 【中文摘要：背景与目的 肺腺癌易发生脑转移，患者预后极差。蛋白磷酸酶1调节亚基13样（protein phosphatase 1 regulatory subunit 13-like, PPP1R13L）基因编码的p53凋亡刺激蛋白家族抑制成员（inhibitor of apoptosis-stimulating protein of p53, iASPP）蛋白是p53通路的关键抑制因子，在多种肿瘤中促癌，但其在肺腺癌脑转移中的作用未知。本研究通过单细胞测序数据整合与临床样本分析，旨在分析肺腺癌脑转移患者的肿瘤微环境特征，并探讨PPP1R13L在脑转移组织中的表达情况及其临床意义。方法 收集2014年1月至2024年12月新疆医科大学附属肿瘤医院就诊的4例肺腺癌脑转移和2例少突胶质细胞瘤患者的脑组织进行单细胞测序，并结合公共数据库中4例肺腺癌样本和4例正常肺组织样本的单细胞测序数据解析肿瘤微环境；另收集此医院50例肺腺癌脑转移患者的临床资料及石蜡切片，采用免疫组化技术检测iASPP蛋白表达，分析其与临床特征及预后的关系。结果 相较于胶质瘤和肺腺癌组，肺腺癌脑转移组特异的上皮细胞主要富集于氧化磷酸化、细胞凋亡、缺氧和p53通路；PPP1R13L作为上调差异基因，在脑转移组特异上皮细胞亚群高表达；PPP1R13L阳性细胞与成纤维细胞交互作用显著，激活细胞-基质黏附相关通路，关键配体-受体对为I型胶原蛋白α1链-白细胞分化抗原44（collagen type I alpha 1 chain-cluster of differentiation 44, COL1A1-CD44）。临床数据分析显示，吸烟史（HR=2.543, 95%CI: 1.159-5.583, P=0.020）和iASPP高表达（HR=3.351, 95%CI: 1.310-8.575, P=0.012）为肺腺癌脑转移患者预后的独立危险因素。结论 本研究阐明了肺腺癌脑转移微环境中上皮细胞与成纤维细胞的相互作用，提示PPP1R13L可作为潜在预后标志物及治疗靶点，为肺腺癌脑转移的精准治疗提供依据。
】 【中文关键词：肺肿瘤；脑转移；单细胞测序；上皮细胞；PPP1R13L】.
Distinguishing lung cancer from pulmonary infection and interstitial lung disease (ILD) remains challenging. This study aimed to evaluate the diagnostic value of T lymphocyte subsets and neutrophil CD64 (nCD64) index in bronchoalveolar lavage fluid (BALF), alone and in combination, to address this challenge. BALF was collected between October 2021 and October 2022 from 70 patients admitted to West China Hospital, Sichuan University. Based on final diagnosis, the patients were divided into the lung cancer group (21 cases, including 14 with pure lung cancer and 7 with lung cancer and infection) and the non‑lung cancer group (49 cases, including 39 with pulmonary infection and 10 with ILD). Flow cytometry was used to detect T lymphocyte subsets and CD64 expression in BALF, and the CD4+/CD8+ ratio and nCD64 index were calculated. Receiver operating characteristic (ROC) curves were used to evaluate the performance of both indicators in differentiating lung cancer from pulmonary infection and from ILD, and the area under the curve (AUC) and 95% confidence interval (CI) were calculated. The diagnostic efficacy of combining the CD4+/CD8+ ratio and nCD64 index for differentiating lung cancer from pulmonary infection was further analyzed. Firth's logistic regression was performed to adjust for age and to assess the independent differential diagnosis value of the two indicators between lung cancer and pulmonary infection. Compared with the non-lung cancer group, the lung cancer group showed significantly lower CD4+ T cell proportion, CD4+/CD8+ ratio, and nCD64 index (all P<0.05). Further analysis revealed that the lung cancer group also had significantly lower values of the above indicators compared with the pulmonary infection group (P<0.05), but no significant differences were observed compared with the ILD group (P>0.05). ROC curve analysis showed that the CD4+/CD8+ ratio had an AUC of 0.712 (95%CI: 0.575‑0.849, P=0.008) for differentiating lung cancer from pulmonary infection, with a sensitivity of 56.76% and a specificity of 85.00%; the nCD64 index had an AUC of 0.677 (95%CI: 0.539‑0.814, P=0.026), with a sensitivity of 44.74% and a specificity of 95.24%. When the two indicators were combined, the parallel test increased the sensitivity to 78.38%, while the serial test achieved 100.00% specificity and positive predictive value. After adjusting for age, Firth's logistic regression demonstrated that both the CD4+/CD8+ ratio and nCD64 index retained independent differential diagnosis value for differentiating lung cancer from pulmonary infection (both P<0.05). The combined detection of the CD4+/CD8+ ratio and nCD64 index in BALF improves the diagnostic efficacy for differentiating lung cancer from pulmonary infection. 【中文题目：支气管肺泡灌洗液CD4+/CD8+联合
nCD64指数对肺癌与非肺癌疾病的鉴别诊断价值】 【中文摘要：背景与目的 肺癌与肺感染性疾病、间质性肺疾病（interstitial lung disease, ILD）的临床鉴别尚存在困难，本研究旨在探讨支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）中T淋巴细胞亚群及中性粒细胞CD64（neutrophil CD64, nCD64）指数单独及联合检测在上述疾病中的鉴别诊断价值。方法 收集2021年10月至2022年10月于四川大学华西医院就诊的70例患者BALF标本，根据诊断分为肺癌组（21例，含单纯肺癌14例、肺癌合并感染7例）和非肺癌组（49例，含肺感染性疾病39例、ILD 10例）。采用流式细胞术检测BALF中T淋巴细胞亚群及CD64表达，计算CD4+/CD8+比值及nCD64指数。采用受试者工作特征（receiver operating characteristic, ROC）曲线评估各指标鉴别肺癌与肺感染性疾病、肺癌与ILD的价值，计算曲线下面积（area under the curve, AUC）及其95%置信区间（confidence interval, CI），并分析CD4+/CD8+比值及nCD64指数联合对肺癌与肺感染性疾病的鉴别诊断效能。采用Firth's logistic回归进行多因素分析，探讨两指标对肺癌与肺感染的独立鉴别价值。结果 与非肺癌组相比，肺癌组CD4+ T细胞比例、CD4+/CD8+比值及nCD64指数均显著降低（均P<0.05）。进一步分析发现，与肺感染性疾病组相比，肺癌组上述指标亦显著下降（P<0.05），但与ILD组相比无显著差异（P>0.05）。ROC曲线显示，CD4+/CD8+比值鉴别肺癌和肺感染性疾病的AUC为0.712（95%CI: 0.575-0.849, P=0.008），灵敏度为56.76%，特异度为85.00%；nCD64指数鉴别肺癌与肺感染性疾病的AUC为0.677（95%CI: 0.539-0.814, P=0.026），灵敏度为44.74%，特异度为95.24%。联合应用CD4+/CD8+比值及nCD64指数时，并联试验的灵敏度提升至78.38%，串联试验的特异度及阳性预测值均达100.00%。校正年龄后，Firth's logistic回归显示CD4+/CD8+比值和nCD64指数仍对肺癌与肺感染性疾病的鉴别具有独立价值（均P<0.05）。结论 BALF中CD4+/CD8+比值与nCD64指数联合检测可提高肺癌与肺感染性疾病的鉴别诊断效能。
】 【中文关键词：支气管肺泡灌洗液；T淋巴细胞亚群；CD4+/CD8+比值；nCD64指数；肺肿瘤；肺感染性疾病；鉴别诊断】.
Serous effusion is a common complication in patients with advanced lung cancer, which often indicates that the tumor has metastasized to the pleura or other serosal membranes. It is essential to achieve an accurate diagnosis and pathological classification of tumor cells in effusion to guide clinical treatment. However, there are limitations to relying solely on morphological diagnosis, especially in atypical cases where diagnostic uncertainty is common. The International System for Serous Fluid Cytopathology (TIS) proposes a standardized hierarchical diagnostic framework that integrates morphology and auxiliary techniques. Nevertheless, its clinical application value in the Chinese lung cancer population remains insufficiently validated. This study aimed to systematically evaluate the diagnostic performance of the TIS system in the assessment and classification of serous effusions based on a large sample of lung cancer cases. A retrospective analysis was conducted on 1274 serous effusion specimens from the Cancer Hospital Chinese Academy of Medical Sciences between January 2018 and December 2023, all of which were derived from patients with lung cancer confirmed by histopathology and/or clinical history. The diagnostic procedure strictly followed the TIS protocol, which commenced with the morphological evaluation and assignment to categories I-V. For some cases with ambiguous morphology (categories III and IV) and category V, immunocytochemistry (ICC) was performed using cell blocks to comprehensively determine the final diagnostic category, tumor subtyping, and tumor origin. Statistical analyses were applied to assess the diagnostic concordance between initial morphology and combined ICC. Additionally, the trend in category changes and the clinical value of ICC in pathological subtyping and origin determination were analyzed. Based on morphology alone, 83.1% (1059/1274) of cases were classified as malignant (category V), while 12.3% (157/1274) were categorized as indeterminate (categories III or IV). Further analysis of the 69 cases that underwent ICC detection revealed that the rate of upgraded diagnosis was 85.5% (59/69), and the upgrading proportion in category IV cases (89.6%, 43/48) was significantly higher than that in category III cases (76.2%, 16/21). Furthermore, 7.2% (5/69) of category III cases were downgraded to benign (category II), while another 7.2% (5/69) remained unchanged due to insufficient cellularity or poor differentiation. These findings indicate that ICC can markedly improve the diagnostic accuracy for indeterminate serous effusions in lung cancer. Among definitively malignant cases, ICC was employed to enable subtyping and origin assessment in 542 cases, achieving precise pathological classification in 533 cases (98.3%): including adenocarcinoma (86.7%), small cell carcinoma (4.4%), and squamous cell carcinoma (3.9%), and confirming pulmonary origin in 510 cases (94.0%). Analysis of key ICC marker expression profiles revealed that lung adenocarcinoma in serous effusions showed high expressions of thyroid transcription factor-1 (TTF-1) and Napsin A (positivity rates: 93.0% and 76.2%, respectively); lung squamous cell carcinoma characteristically expressed P40 and P63 (positivity rates: 60.0% and 73.7%, respectively); and small cell carcinoma strongly expressed Syn and CD56 (positivity rates: 87.0% and 81.8%, respectively). Integrated interpretation using a complementary antibody panel effectively validated and supplemented morphological findings, providing a reliable basis for subtype differentiation. The TIS-based stratified diagnostic pathway of "initial morphological diagnosis followed by ancillary techniques confirmation" significantly improves diagnostic accuracy for lung cancer-associated serous effusions, optimizes the management of indeterminate cases, and achieves high-precision pathological subtyping and determination of tumor origin. It is recommended to widely implement the TIS system in clinical practice to enhance standardization and diagnostic precision in serous fluid cytopathology. 【中文题目：浆膜腔积液细胞病理学国际报告系统在肺癌相关浆膜腔积液分层诊断中的临床应用研究】 【中文摘要：背景与目的 浆膜腔积液是中晚期肺癌患者常见并发症，其出现往往提示肿瘤已发生胸膜或其他浆膜转移。准确诊断积液中的肿瘤细胞并进行病理分型，对指导临床治疗至关重要。然而，单纯依赖细胞形态学诊断存在局限性，尤其在不典型病例中易出现不确定性诊断。《浆膜腔积液细胞病理学国际报告系统》（The International System for Serous Fluid Cytopathology, TIS）提出了形态学与辅助技术相结合的标准化分层诊断框架，但其在国内肺癌人群中的临床应用价值尚缺乏大规模验证。本研究旨在基于大样本肺癌病例，系统性评估TIS系统在肺癌浆膜腔积液诊断与分型中的效能。方法 回顾性纳入2018年1月至2023年12月中国医学科学院肿瘤医院的1274例浆膜腔积液样本，其均来源于组织病理学和/或临床病史确诊的肺癌患者。严格遵循TIS系统诊断流程，先进行形态学评估并分级（I-V级），对部分形态学不确定（III、IV级）及V级病例，利用细胞蜡块进行免疫细胞化学（immunocytochemistry, ICC）检测，综合确定最终诊断级别并进行肿瘤分型与起源判断。统计分析形态学初诊与联合ICC诊断一致性、分级变化趋势及ICC检测在病理分型与溯源中的临床价值。结果 形态学初诊中，83.1%（1059/1274）的病例直接诊断为恶性（V级），12.3%（157/1274）的病例为不确定性诊断（III或IV级）。对69例接受ICC检测的病例进一步分析显示，升级诊断率为85.5%（59/69），其中IV级病例的升级比例（89.6%, 43/48）高于III级（76.2%, 16/21）；7.2%（5/69）的III级病例降级为良性（II级），另7.2%（5/69）因细胞量不足或分化差而维持原级，表明ICC可显著提升肺癌浆膜腔积液不确定性诊断的明确性。在最终诊断恶性的病例中，ICC对542例进行分型与溯源，533例（98.3%）实现精准病理分型（腺癌86.7%、小细胞癌4.4%、鳞癌3.9%），510例（94.0%）明确为肺来源。关键ICC标志物表达谱分析显示，浆膜腔积液中肺腺癌甲状腺转录因子-1（thyroid transcription factor-1, TTF-1）与Napsin A呈高表达，阳性率分别为93.0%和76.2%；肺鳞癌特征性表达P40和P63，阳性率分别为60.0%和73.7%；小细胞癌强表达Syn与CD56，阳性率分别达87.0%和81.8%。通过采用一组互补抗体进行综合判读，可以对形态学初诊报告进行验证与补充，为亚型鉴别提供可靠依据。结论 TIS系统构建的“形态学初诊、辅助技术确证”分层诊断路径，能显著提高肺癌浆膜腔积液诊断的准确性，有效优化不确定性病例分流，实现高精度的病理分型与组织起源判断。建议在临床实践中推广应用TIS系统，以促进浆膜腔积液细胞病理学诊断的规范化与精准化。
】 【中文关键词：肺肿瘤；浆膜腔积液；浆膜腔积液细胞病理学国际报告系统；免疫细胞化学；分层诊断】.
The discrimination between benign and malignant pulmonary space-occupying lesions and the classification of pathological subtypes of lung cancer are critical for clinical decision-making. However, conventional methods often suffer from insufficient utilization of multi-source clinical data and poor interpretability of deep learning models. This study investigates the performance of interpretable deep learning algorithms in diagnosing benign versus malignant pulmonary space-occupying lesions and classifying pathological subtypes of lung cancer, using a hybrid architecture based on Tab-Transformer-designed for tabular data and Residual Multi-Layer Perceptron (ResMLP), referred to as TT-ResMLP. Data including radiological characteristics, medical history, and laboratory findings from 345 patients with pathologically confirmed pulmonary space-occupying lesions were collected. The dataset was randomly split into a development set and a test set at an 8:2 ratio. Stable features were selected using the Spearman correlation test and the Least Absolute Shrinkage and Selection Operator (LASSO). The Synthetic Minority Over-sampling Technique (SMOTE) was employed to balance the samples, and 10-fold cross-validation was used to enhance model generalizability. Models were constructed using the Tab-Transformer algorithm, the ResMLP algorithm, and the TT-ResMLP hybrid. Model performance was evaluated using receiver operating characteristic (ROC) curves, the area under the curve (AUC), accuracy, specificity, sensitivity, and micro-averaged ROC (micro-ROC). SHapley Additive exPlanations (SHAP) analysis was performed based on the optimal model. In the benign vs malignant diagnosis task, all three models performed well. The Tab-Transformer model demonstrated the best performance on the test set, followed by TT-ResMLP and ResMLP. SHAP analysis of the top-performing Tab-Transformer model revealed that the feature importance ranking was: age, pleural indentation, thrombin time, mean density, and ground-glass opacity. Pleural indentation contributed substantially to malignant diagnosis, and its contribution was further enhanced with increasing age and decreasing thrombin time. In the lung cancer subtype classification task, all three models exhibited excellent performance, with the TT-ResMLP hybrid showing the best overall performance. SHAP analysis further revealed that the Lung Imaging Reporting and Data System (Lung-RADS) category held high importance across all three pathological subtypes. Male gender was positively associated with the prediction of squamous cell carcinoma. Neuron-specific enolase (NSE) played a significant role in predicting small cell carcinoma. For adenocarcinoma, the diagnostic probability was positively correlated with the Lung-RADS category, a relationship more pronounced at lower prothrombin time (PT) values. In contrast, a negative correlation was observed in the squamous cell carcinoma and small cell carcinoma subgroups, although gender and NSE levels could enhance their contributory risk prediction. Analysis of feature decision boundaries indicated that the Lung-RADS grade possessed high discriminative power for identifying adenocarcinoma, whereas NSE demonstrated stronger discriminative ability for identifying small cell carcinoma. The TT-ResMLP hybrid architecture is effective for diagnosing the benign or malignant nature of pulmonary space-occupying lesions and classifying pathological subtypes of lung cancer. The model possesses good interpretability, aiding in the identification of key predictive features and unravelling their interactive mechanisms, thereby providing an effective tool for a deeper understanding of lung cancer biology and clinical decision support. 【中文题目：可解释性深度学习算法在肺占位性病变
良恶性诊断及肺癌病理亚型分类中的运用】 【中文摘要：背景与目的 肺占位性病变的良恶性鉴别与肺癌病理亚型分类是临床决策的关键，但传统方法存在多源临床数据利用不足及深度学习模型可解释性差的问题。本研究基于针对表格化数据设计的Transformer（Tab-Transformer）与残差多层感知器（Residual Multi-Layer Perceptron, ResMLP）的混合架构（TT-ResMLP），探讨可解释性深度学习算法在肺占位性病变良恶性诊断及肺癌病理亚型分类中的性能。方法 收集345例经病理证实的肺占位性病变患者的影像学特征、病史资料及实验室检查等数据，按8:2随机分为训练集和测试集。采用Spearman检验与最小绝对收缩和选择算子（Least Absolute Shrinkage and Selection Operator, LASSO）筛选稳定特征，使用合成少数类过采样技术（Synthetic Minority Over-sampling Technique, SMOTE）平衡样本，采用10折交叉验证提高模型泛化能力，选用Tab-Transformer算法、ResMLP算法、TT-ResMLP构建模型，通过受试者工作特征（receiver operating characteristic, ROC）曲线、曲线下面积（area under the curve, AUC）、准确率、特异性、敏感性和微平均ROC（micro-averaged ROC, micro-ROC）曲线评估模型性能，并基于最优模型进行SHAP（SHapley Additive exPlanations）特征分析。结果 良恶性诊断模型中，3种模型均表现良好，其中Tab-Transformer在测试集表现最优，TT-ResMLP和ResMLP次之；SHAP分析显示，表现最优的Tab-Transformer模型特征重要性依次是年龄、胸膜凹陷征、凝血酶时间、平均密度、磨玻璃样改变等，其中胸膜凹陷征有较高的恶性诊断贡献，且随年龄增长、凝血酶时间缩短，其贡献度进一步增强。在肺癌亚型分类任务中，3种模型均表现出优异性能，其中TT-ResMLP综合表现最优。SHAP分析进一步揭示，肺部影像报告和数据系统评分（Lung Imaging Reporting and Data System, Lung-RADS）在3种病理亚型中均具较高重要性；男性与鳞癌预测呈正相关；神经元特异性烯醇化酶（neuron-specific enolase, NSE）在小细胞癌预测中起重要作用。在腺癌中，诊断概率与Lung-RADS分级呈正相关，且在低凝血酶原时间值时更显著；而在鳞癌与小细胞癌亚组中呈负相关，但性别和NSE水平可增强其风险预测的贡献。特征决策边界分析显示，Lung-RADS分级在腺癌识别中具有较高的区分能力，而NSE在小细胞癌识别中展现出更强的区分能力。结论 TT-ResMLP混合架构能达到肺占位性病变的良恶性诊断及肺癌病理亚型分类的目的，模型具备良好的可解释性，有助于识别关键预测特征并揭示其交互机制，为深入理解肺癌生物学行为及临床辅助决策提供了有效工具。
】 【中文关键词：肺肿瘤；肺占位性病变；机器学习；特征诠释；良恶性诊断；深度学习】.
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide, and its occurrence and development are closely related to complex molecular mechanisms. Alternative splicing of precursor mRNA is a key step in gene expression regulation, and its dysregulation is common in tumors. The serine/arginine-rich splicing factor (SRSF) family, a core protein family in splicing regulation, has been confirmed to play oncogenic roles in various cancers. However, systematic research on the SRSF family in NSCLC remains insufficient. This study aims to systematically analyze the specific expression patterns, clinical prognostic value, collaborative mechanisms and potential biological functions of SRSF individual members in NSCLC by the combination of bioinformatics analysis and experimental verification. This study integrated NSCLC transcriptome data and clinical information from public databases such as The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and systematically analyzed the differential expressions of SRSF family members. Kaplan-Meier survival analysis was performed to assess the correlation between the expression levels of each SRSF member and patients' overall survival (OS). Furthermore, co-expression network analysis and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were employed to explore the biological processes and signaling pathways potentially involved by the SRSF family. Moreover, the expression and function of key members were verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR), cell counting kit-8 (CCK-8) and cell proliferation experiments in clinical samples and cell lines. Multiple members of the SRSF family (e.g., SRSF1, SRSF2, SRSF3, SRSF6, SRSF7, SRSF9, SRSF10) were found to be significantly upregulated in NSCLC tissues and cell lines. Survival analysis indicated that high expression of SRSF9 was associated with poor prognosis, while low expressions of SRSF11 and SRSF12 also indicated unfavorable outcomes. Functional enrichment analysis revealed that the SRSF family is not only involved in RNA splicing but also significantly enriched in pathways related to protein homeostasis, cellular stress response, and neurodegenerative diseases. In vitro experiments confirmed that knockdown of SRSF1, SRSF2, SRSF6, SRSF9 and SRSF10 significantly inhibited the proliferation of NSCLC cells. This study systematically delineates the expression and functional landscape of the SRSF family in NSCLC, confirming their potential as prognostic biomarkers and therapeutic targets. The findings suggest that the SRSF family may drive NSCLC progression by disrupting cellular homeostasis, a crucial aspect of tumorigenesis, such as protein homeostasis and stress responses. This research provides a theoretical foundation for a deeper understanding of the role of splicing dysregulation in lung cancer and for the development of novel therapeutic strategies. 【中文题目：非小细胞肺癌中SRSF家族蛋白
的表达和预后及功能分析】 【中文摘要：背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）是全球癌症相关死亡的主要原因之一，其发生发展与复杂的分子机制密切关联。前体mRNA选择性剪接的异常在肿瘤中普遍存在，丝氨酸/精氨酸富集剪接因子（serine and arginine rich splicing factor, SRSF）家族是该过程的核心调控者。然而，目前对于SRSF家族在NSCLC中的系统性研究仍不充分。本研究旨在通过生物信息学分析与实验验证相结合的方式，系统分析SRSF家族在NSCLC中的表达谱、预后价值及其潜在生物学功能。方法 本研究整合癌症基因组图谱（The Cancer Genome Atlas, TCGA）和癌细胞系百科全书（Cancer Cell Line Encyclopedia, CCLE）等公共数据库中的转录组与临床数据，分析SRSF家族在NSCLC中的差异表达。通过Kaplan-Meier生存分析评估其表达水平与患者总生存期的关系。利用基因本体（Gene Ontology, GO）及京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析探讨其功能。进一步收集临床样本和细胞系，通过逆转录定量聚合酶链反应（reverse transcription quantitative polymerase chain reaction, RT-qPCR）、细胞计数试剂盒-8（cell counting kit-8, CCK-8）及细胞增殖实验验证关键成员的表达与功能。结果 SRSF家族多个成员（如SRSF1、SRSF2、SRSF3、SRSF6、SRSF7、SRSF9、SRSF10等）在NSCLC组织及细胞系中显著高表达。生存分析表明，SRSF9的高表达与患者不良预后有关，而SRSF11和SRSF12的低表达提示预后较差。功能富集分析揭示，SRSF家族不仅参与RNA剪接，还显著富集于蛋白质稳态、细胞应激反应及神经退行性疾病相关通路。体外实验证实，敲低SRSF1、SRSF2、SRSF6、SRSF9、SRSF10可显著抑制NSCLC细胞的增殖能力。结论 本研究系统描绘了SRSF家族在NSCLC中的表达与功能图谱，证实了其作为预后生物标志物和治疗靶点的潜力。本研究提示，SRSF家族可能通过破坏细胞稳态（如蛋白质稳态与应激反应）这一在肿瘤发生中至关重要的环节来驱动NSCLC的进展，为深入理解剪接失调在肺癌中的作用及开发新型治疗策略提供了理论依据。
】 【中文关键词：肺肿瘤；SRSF家族；生存预后；选择性剪接；生物信息学分析；细胞增殖与活力】.
Lung cancer, one of the leading causes of cancer-related deaths worldwide, severely influences patients' quality of life and prognosis due to its complication of brain metastasis (primarily involving the brain parenchyma). While traditional treatments such as surgery, radiotherapy, and chemotherapy have demonstrated efficacy in clinical practice, their application remains limited due to toxicity and patient tolerance issues. Emerging targeted therapies and immunotherapies, which exhibit significant efficacy with fewer side effects, still face challenges including partial drug resistance and genetic mutations. In recent years, research on the association between gut microbiota and lung cancer brain metastasis has gained prominence. Its mechanism of action may influence the progression of brain metastasis through multidimensional interactions via the brain-gut axis, involving neuroendocrine and immune pathways. This review examines specific mechanisms by which gut microbiota modulate lung cancer brain metastasis through immune regulation, endocrine-metabolic regulation, and neurotransmitter control via the brain-gut axis, as well as therapeutic and traditional medicine research on regulating gut microbiota in lung cancer brain metastasis. It aims to provide theoretical support and identify potential clinical therapeutic targets for the prevention and treatment of lung cancer brain metastasis.
. 【中文题目：肠道菌群基于脑-肠轴影响肺癌脑转移
的作用机制研究进展】 【中文摘要：肺癌作为全球癌症死亡的主要原因之一，其并发症脑转移（以脑实质为主）严重影响患者的生活质量及预后。传统治疗手段，如手术、放疗及化疗，虽在临床实践中取得了一定疗效，却因毒性和患者耐受性问题而应用受限。新兴的靶向治疗与免疫治疗凭借较少的副作用展现出显著疗效，但仍然面临部分耐药及基因突变等挑战。近年来，肠道菌群与肺癌脑转移之间的关联性研究成为新热点，其作用机制可能通过脑-肠轴介导的神经内分泌-免疫多维度交互途径对肺癌脑转移进程产生影响。本文综述了肠道菌群基于脑-肠轴调控肺癌脑转移的免疫调节、内分泌代谢调节、神经递质调控等具体作用机制，及调节肠道菌群在肺癌脑转移中的治疗和传统医学研究，旨在为肺癌脑转移的防治策略提供理论支撑和临床潜在治疗靶点。
】 【中文关键词：肺肿瘤；肠道菌群；脑转移；脑-肠轴；作用机制】.
The incidence and mortality rates of non-small cell lung cancer (NSCLC) are generally on the rise, and the overall prognosis of patients remains poor. Current clinical treatment strategies have significant limitations. Notably, the bioactive components of traditional Chinese medicine possess unique advantages, including diverse targets of action and low toxicity. Ziyuglycoside II (ZGS II), a major active component of Sanguisorba officinalis L, has been shown to inhibit cancer cell proliferation, migration, and invasion. This property confers potential application value and developmental prospects for its use in cancer therapy. Nevertheless, the effects of ZGS II on NSCLC and the underlying mechanisms remain unclear. This study aimed to investigate the anti-tumor molecular mechanism of ZGS II in NSCLC and to explore the potential of being a novel therapeutic strategy for improving the prognosis of NSCLC patients. First, the cell counting kit-8 (CCK-8) and the colony formation assay were used to detect the changes in the viability and proliferation ability of NSCLC cells after treatment with ZGS II. Wound-healing and Transwell assays were used to evaluate the effects of ZGS II on migration and invasion abilities. Western blot, Lentiviral transfection, wound healing assay, and Transwell assay were used to study the effects of ZGS II on the integrin β4/focal adhesion kinase (ITGB4/FAK) signaling pathway. A rescue experiment was then performed using the FAK agonist ZINC40099027. A nude mouse xenograft model was used to evaluate the inhibitory effect of ZGS II on NSCLC metastasis in vivo. ZGS II inhibited proliferation, migration, and invasion of NSCLC cells and suppressed the protein expression of ITGB4. This inhibitory effect was significantly enhanced upon ITGB4 knockdown. Meanwhile, total FAK expression remained nearly unchanged, but the protein expression level of phosphorylated focal adhesion kinase (p-FAK) was suppressed. Following the addition of an FAK activator, cell migration rate and the number of cells crossing the Transwell membrane increased, reversing the inhibitory effects of ZGS II on cell migration and invasion. Therefore, the anti-tumor effect of ZGS II depends on the reduced activation of the ITGB4/FAK signaling pathway. The nude mouse xenograft experiment results showed that ZGS II effectively inhibited tumor growth in nude mice. ZGS II inhibits proliferation, metastasis, and tumor growth in NSCLC by suppressing the ITGB4/FAK pathway. These findings highlight the potential of ZGS II as a promising drug for treating metastatic NSCLC and lay the foundation for its clinical research. 【中文题目：地榆皂苷II通过ITGB4/FAK信号通路
抑制非小细胞肺癌的进展】 【中文摘要：背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）的发病率和死亡率总体呈现上升趋势，患者整体预后不佳，现有临床治疗手段存在明显的局限性。而中药生物活性成分具有作用靶点多样、毒副作用小的独特优势。地榆皂苷II（ziyuglycoside II, ZGS II）是地榆的一种主要活性成分，可抑制癌细胞的增殖、迁移以及侵袭过程，这一特性使其在癌症治疗领域展现出了潜在的应用价值和发展前景。然而，ZGS II对NSCLC的作用及其可能的机制仍未阐明。本研究旨在探讨ZGS II在NSCLC中抗肿瘤的分子机制，探讨作为改善NSCLC患者预后的一种新的治疗策略的可能性。方法 首先采用细胞增殖与毒性检测试剂盒（cell counting kit-8, CCK-8）和集落形成实验检测ZGS II处理NSCLC细胞后活力和增殖能力的变化。细胞划痕和Transwell实验评估ZGS II对NSCLC细胞的迁移和侵袭能力的影响。利用蛋白印迹法、慢病毒转染、细胞划痕和Transwell等方法研究ZGS II对整合素β4/黏着斑激酶（integrin β4/focal adhesion kinase, ITGB4/FAK）信号通路的作用。随后使用FAK激活剂ZINC40099027进行逆转实验。采用裸鼠异种移植模型评价ZGS II对体内NSCLC转移的抑制作用。结果 ZGS II抑制NSCLC细胞的增殖、迁移和侵袭，并且抑制了ITGB4的蛋白表达，这一结果在敲低ITGB4后抑制作用明显加强。同时发现总FAK的表达几乎不变，但磷酸化黏着斑激酶（phosphorylated focal adhesion kinase, p-FAK）的蛋白表达水平受到抑制。加入FAK激活剂后，细胞的迁移率以及穿过Transwell膜的细胞数量增加，ZGS II对细胞迁移和侵袭能力的抑制作用得到逆转。因此，ZGS II的抗肿瘤作用依赖于ITGB4/FAK信号通路的激活减弱。裸鼠异种移植实验结果表明，ZGS II显著抑制了裸鼠体内肿瘤的生长。结论 ZGS II通过抑制ITGB4/FAK通路抑制NSCLC的增殖、转移和肿瘤生长。这些结果突出了ZGS II作为治疗转移性NSCLC的药物的前景，为其临床研究奠定基础。
】 【中文关键词：肺肿瘤；地榆皂苷II；ITGB4/FAK信号通路；进展】.
Lung cancer remains the leading cause of cancer-related deaths in China. Optimizing lung cancer screening strategies to improve screening efficiency and mitigate associated harms has become a key research focus and priority in current clinical practice. The purpose of this paper is to revise the China national lung cancer screening guideline with low-dose computed tomography (LDCT) (2023 version). The revision work for the 2025 version of this guideline was jointly undertaken by experts from the Chinese Expert Group on Early Diagnosis and Treatment of Lung Cancer and experts from the China Lung Oncology Group. Drawing on recent advances in LDCT lung cancer screening at home and abroad, combined with the epidemiological characteristics of lung cancer in China, the expert panel revised the guideline with the following key updates: (1) In the selection criteria of high-risk population, the exposure duration to occupational lung carcinogens is clearly specified; additionally, if an individual's physical condition cannot tolerate potential lung cancer resection surgery or the individual suffers from a life-threatening disease during annual screening, discontinuation of LDCT screening is recommended. (2) The method for measuring nodule size is updated, with mean diameter adopted as the metric for assessing nodule size. (3) In nodule management, the positive threshold for the mean diameter of solid nodules or the solid components of part-solid nodules in baseline screening is raised to 6 mm, and the follow-up interval for positive solid or part-solid nodules is adjusted from 6 months to 3-6 months. (4) It is recommended that informed consent and shared decision-making be integrated throughout the entire process, including high-risk group identification, screening interval determination, and nodule management. This revision further clarifies and optimizes the selection of high-risk groups and the management of screen-detected nodules. Based on a comprehensive balance between the benefits and potential harms of lung cancer screening, it emphasizes the critical importance of informed consent and shared decision-making. This revised guideline will be more aligned with China's national conditions and enhance the standardization and applicability of LDCT-based lung cancer screening across the country.
. 【中文题目：中国肺癌低剂量CT筛查指南（2025年版）】 【中文摘要：肺癌是导致中国癌症死亡的首要原因。通过优化肺癌筛查策略，提高筛查效率，减少相关危害已成为当前肺癌筛查的研究热点和方向。本文的目的是对2023年中国肺癌低剂量计算机断层扫描（low-dose computed tomography, LDCT）筛查指南进行修订。由国家卫健委指定的中国肺癌早诊早治专家组专家及部分中国西部肺癌研究协作中心专家，共同参与了2025年版中国肺癌LDCT筛查指南的修订工作。专家组根据近年来国内外LDCT肺癌筛 查进展，结合我国肺癌流行病学特征，共同修订了本肺癌筛查指南。本指南对以下内容进行了修订：（1）高危人 群定义中明确了职业暴露年限，另外，如果在年度筛查中发现受检者身体状况无法耐受可能的肺癌切除手术，或罹患其他严重威胁生命的疾病，则建议停止LDCT筛查；（2）更新了结节大小的测量方法，将平均直径作为结节大小的衡量指标；（3）结节管理中，将基线筛查中实性结节或部分实性结节实性成分的平均直径阳性阈值提高至6 mm，并将实性结节或部分实性的阳性结节复查时间由6个月调整为3-6个月；（4）建议将知情同意和共同决策贯穿于高危人群选择、筛查间隔和结节管理环节。本次修订进一步明确和优化了高危人群选择及结节管理，并在对肺癌筛查获益和危害充分权衡基础上，强调了知情同意和共同决策的重要性。本次修订将使得LDCT筛查指南更适应我国国情，并提升了我国肺癌筛查的规范性与适用性。
】 【中文关键词：肺肿瘤；筛查；低剂量计算机断层扫描；指南；中国】.
Lung cancer is the malignant tumor with the highest incidence and mortality rate worldwide. The current treatment methods have limited efficacy, and the prognosis of patients is poor. There is an urgent need to explore new therapeutic targets and strategies. Epigenetic modification disorders are closely related to the occurrence and development of tumors. Among them, histone deacetylase 1 (HDAC1), as a key epigenetic regulatory molecule, participates in the regulation of biological processes such as cell proliferation, differentiation, and apoptosis. HDAC1 is highly expressed in lung cancer, and its expression level is closely related to the malignancy degree, clinical stage, and poor prognosis of lung cancer. Abnormal activation of HDAC1 is also one of the core factors for the resistance of lung cancer to chemotherapy, targeted therapy, and immunotherapy. The development of HDAC1 inhibitors provides a new direction for the treatment of lung cancer, and the combination with chemotherapy, targeted therapy, and immunotherapy can significantly enhance the synergistic anti-tumor effect. This article systematically reviews the structural characteristics and physiological functions of HDAC1, deeply explores its regulatory mechanism in lung cancer, elaborates on its association with lung cancer resistance, and summarizes the research and development progress, clinical trial status, and challenges of HDAC1 inhibitors, with the aim of providing new ideas for the precise treatment of lung cancer.
. 【中文题目：HDAC1在肺癌中的潜在作用机制及研究进展】 【中文摘要：肺癌是全球发病率与死亡率最高的恶性肿瘤。当前治疗手段疗效有限，患者预后不佳，亟需探索新的治疗靶点与策略。表观遗传修饰失调与肿瘤发生发展密切相关，其中组蛋白去乙酰化酶1（histone deacetylase 1, HDAC1）作为关键的表观遗传调控分子，参与调控细胞增殖、分化、凋亡等生物学过程。HDAC1在肺癌中呈高表达，且其表达水平与肺癌恶性程度、临床分期及不良预后密切关联。HDAC1异常激活也是肺癌化疗、靶向治疗及免疫治疗耐药的核心因素之一。HDAC1抑制剂的研发为肺癌治疗提供了新方向，且与化疗、靶向治疗及免疫治疗联用能够显著增强协同抗肿瘤效果。本文系统综述了HDAC1的结构特征与生理功能，深入探讨其在肺癌中的调控机制，阐述其与肺癌耐药的关联，并总结HDAC1抑制剂的研发进展、临床试验现状及面临的挑战，以期为肺癌的精准治疗提供新思路。
】 【中文关键词：肺肿瘤；HDAC1；表观遗传修饰；HDAC1抑制剂】.
Non-small cell lung cancer (NSCLC) is one of the causes of cancer-related deaths worldwide. Although platinum-based chemotherapy is the main treatment method for advanced patients, acquired resistance often leads to treatment failure. Long non-coding RNAs (lncRNAs) play an important role in tumor occurrence and development, but the specific mechanism of their involvement in chemotherapy resistance in NSCLC is not yet fully understood. This study aims to explore the effect of LINC00641 on the microRNA-1306-5p (miR-1306-5p)/fibroblast growth factor receptor 3 (FGFR3) axis on the malignant progression and chemotherapy resistance of NSCLC cell line H1299. The mRNA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR); and the interaction was verified by the dual-luciferase reporter gene assay. H1299 cells were randomly divided into the following groups: CG group (normal culture), sh-NC group (transfected with sh-NC), sh-LINC00641 group (transfected with sh-LINC00641), sh-LINC00641+anti-NC group (transfected with sh-LINC00641 and anti-NC), sh-LINC00641+anti-miR-1306-5p group (transfected with sh-LINC00641 and anti-miR-1306-5p), mimic-NC group (transfected with mimic-NC), miR-1306-5p-mimics group (transfected with miR-1306-5p-mimics), miR-1306-5p-mimics+OE-NC group (transfected with miR-1306-5p-mimics and OE-NC), and miR-1306-5p-mimics+OE-FGFR3 group (transfected with miR-1306-5p-mimics and OE-FGFR3). Then cell proliferation, migration, and invasion were measured by plate colony formation assay, scratch assay, and Transwell assay, respectively. In addition, H1299/DDP cells were grouped as mentioned above. After that, the chemotherapy resistance of H1299/DDP cells was detected by the MTT method. And Western blot was implemented to detect the protein expressions of FGFR3, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 13 (MMP-13), integrin β1 in H1299 cells, and the P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) in H1299/DDP cells. In NSCLC tissues or cells (H1299, H1299/DDP), LINC00641 and FGFR3 were highly expressed, while miR‑1306‑5p was lowly expressed, and the expression trends of these three factors changed more significantly in the drug‑resistant cell line H1299/DDP (P<0.05). LINC00641 could negatively regulate miR‑1306‑5p in a targeted manner; and miR‑1306‑5p could negatively regulate FGFR3 in a targeted manner. Knockdown of LINC00641 (sh‑LINC00641) or overexpression of miR‑1306‑5p reduced the clone number, scratch healing rate, migration number, invasion number, and the expression of PCNA, MMP‑13, and integrin β1 proteins in H1299 cells (P<0.05), and also suppressed the optical density (OD)540 value and the expression of P‑gp and MRP1 proteins in H1299/DDP cells (P<0.05). In addition, inhibition of miR‑1306‑5p or overexpression of FGFR3 could reverse the inhibitory effects of LINC00641 knockdown or miR‑1306‑5p overexpression on the proliferation, migration, invasion, and chemoresistance of H1299 cells (P<0.05). Knockdown of LINC00641 can regulate the miR-1306-5p/FGFR3 axis, inhibit the malignant progression and chemotherapy resistance of NSCLC cells, and provide a new candidate target for molecular intervention of chemotherapy resistance in NSCLC. 【中文题目：LINC00641调节miR-1306-5p/FGFR3轴
对非小细胞肺癌H1299细胞恶性进展
和化疗耐药性的影响】 【中文摘要：背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）是全球癌症相关死亡的原因之一，尽管以铂类为基础的化疗是晚期患者的主要治疗手段，但获得性耐药常导致治疗失败。长链非编码RNA（long non-coding RNA, lncRNA）在肿瘤发生发展中扮演重要角色，但其在NSCLC化疗耐药中的具体机制尚不完全清楚。本研究旨在探讨LINC00641调节微小RNA-1306-5p（microRNA-1306-5p, miR-1306-5p）/成纤维细胞生长因子受体3（fibroblast growth factor receptor 3, FGFR3）轴对NSCLC细胞H1299恶性进展和化疗耐药性的影响。方法 实时荧光定量聚合酶链式反应（quantitative real-time polymerase chain reaction, qRT-PCR）法检测mRNA表达；双荧光素酶报告基因实验验证互作。将H1299细胞随机分为CG组（正常培养）、sh-NC组（转染sh-NC）、sh-LINC00641组（转染sh-LINC00641）、sh-LINC00641+anti-NC组（转染sh-LINC00641+anti-NC）、sh-LINC00641+anti-miR-1306-5p组（转染sh-LINC00641+anti-miR-1306-5p）、mimic-NC组（转染mimic-NC）、miR-1306-5p-mimics组（转染miR-1306-5p-mimics）、miR-1306-5p-mimics+OE-NC组（转染miR-1306-5p-mimics+OE-NC）、miR-1306-5p-mimics+OE-FGFR3组（转染miR-1306-5p-mimics+OE-FGFR3）。平板克隆形成实验、划痕实验检测细胞迁移，Transwell实验检测细胞迁移和侵袭；另将H1299/DDP细胞按上述进行分组，MTT法检测H1299/DDP细胞化疗耐药性；Western blot检测H1299细胞中FGFR3、增殖细胞核抗原（proliferating cell nuclear antigen, PCNA）、基质金属蛋白酶13（matrix metalloproteinase 13, MMP-13）、整合素β1（integrin β1）以及H1299/DDP细胞中P-糖蛋白（P-glycoprotein, P-gp）、多药耐药相关蛋白1（multidrug resistance-associated protein 1, MRP1）蛋白表达。结果 NSCLC组织或细胞（H1299、H1299/DDP）中LINC00641、FGFR3高表达，miR-1306-5p低表达，且耐药细胞H1299/DDP中3个因子表达趋势变化更明显（P<0.05）。LINC00641可以靶向负调控miR-1306-5p；miR-1306-5p可以靶向负调控FGFR3。敲低sh-LINC00641或过表达miR-1306-5p能够降低H1299细胞克隆数、划痕愈合率、迁移数、侵袭数以及细胞中PCNA、MMP-13、integrin β1蛋白表达（P<0.05），并可以抑制H1299/DDP细胞吸光度（optical density, OD）540值以及细胞中P-gp、MRP1蛋白表达（P<0.05）。抑制miR-1306-5p或过表达FGFR3可逆转敲低sh-LINC00641或过表达miR-1306-5p对H1299细胞增殖、迁移、侵袭和化疗耐药性的抑制作用（P<0.05）。结论 敲低LINC00641可以调节miR-1306-5p/FGFR3轴，抑制NSCLC细胞恶性进展和化疗耐药性，为NSCLC化疗耐药的分子干预提供了新的候选靶点。
】 【中文关键词：肺肿瘤；长链非编码RNA00641；微小RNA-1306-5p；成纤维细胞生长因子受体3；恶性进展；化疗耐药性】.
Non-small cell lung cancer (NSCLC) is associated with a high rate of postoperative recurrence, and conventional tumor-node-metastasis (TNM) staging does not fully reflect its biological heterogeneity. Hypoxia-inducible factor-1alpha (HIF-1α) plays a critical role in tumor progression and remodeling of the tumor immune microenvironment. However, the spatial distribution of HIF-1α and its prognostic significance in the context of different lymph node metastatic states remain unclear. This study aimed to investigate the densities of HIF-1α-expressing tumor cells, CD4+ T cells, and CD8+ T cells in the primary tumors of NSCLC patients, and to assess their associations with lymph node metastasis and postoperative recurrence. 256 formalin-fixed paraffin-embedded primary tumor specimens from NSCLC patients who underwent radical resection at Shandong First Medical University Affiliated Cancer Hospital between January 1, 2014 and December 31, 2018 were retrospectively collected. Tissue microarrays containing both tumor center (TC) and invasive margin (IM) regions were constructed and multiplex immunofluorescence staining [HIF-1α/CD4/CD8/cytokeratin (CK)/4',6-diamidino-2-phenylindole (DAPI)] were performed to quantitatively analyze the densities of HIF-1α-expressing tumor cells (HIF-1α+CK+), HIF-1α+CD4+ T cells and HIF-1α+CD8+ T cells. Mann-Whitney U tests were used to compare cellular density differences between N0 versus N1-2 groups and N1 versus N2 subgroups, while Cox proportional hazards regression models were employed to identify critical recurrence-associated factors. The study ultimately included 256 patients with stage IA-IIIB NSCLC, with a median follow-up duration of 37.05 months, during which 87 cases (34.0%) experienced recurrence. Comparative analysis revealed that in both TC and IM regions, the N1-2 group exhibited significantly higher densities of HIF-1α+CK+ cells (P values: 0.039 and <0.001, respectively) and lower densities of HIF-1α+CD8+ cells (both P values: <0.001) compared to the N0 group, while no statistically significant differences were observed in the densities of HIF-1α+CK+ cells, HIF-1α+CD4+ cells, or HIF-1α+CD8+ cells between N1 and N2 subgroups within either TC or IM regions (all P>0.05). Multivariate Cox regression analysis showed that, among N0 patients, a low density of HIF-1α+CD8+ cells in the TC was an independent risk factor for recurrence in NSCLC patients [hazard ratio (HR)=1.998, 95%CI: 1.077-3.705, P=0.028]. In contrast, among N1 and N2 patients, the densities of HIF-1α+CK+ cells, HIF-1α+CD4+ T cells, and HIF-1α+CD8+ cells in both the TC and IM regions were not significantly associated with NSCLC recurrence. In patients with NSCLC, lymph node metastasis is closely associated with alterations in the densities of HIF-1α-related cellular subpopulations in the primary tumor. A reduced density of HIF-1α+CD8+ cells in the TC of the primary lesion is significantly associated with postoperative recurrence in N0-stage NSCLC patients and may serve as a potential immunological marker for postoperative risk stratification. 【中文题目：非小细胞肺癌中HIF-1α细胞亚群
对淋巴结转移和术后复发的影响】 【中文摘要：背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）术后复发率较高，传统肿瘤原发灶-淋巴结-转移（tumor-node-metastasis, TNM）分期难以充分反映其生物学异质性，乏氧诱导因子-1α（hypoxia-inducible factor-1alpha, HIF-1α）在肿瘤进展及免疫微环境重塑中发挥重要作用，但其在不同淋巴结转移状态下的空间分布特征及对术后复发的预后意义尚不明确。本研究旨在探讨NSCLC患者原发灶中的表达HIF-1α的肿瘤细胞、CD4+ T细胞及CD8+ T细胞的密度差异，以及对淋巴结转移及患者术后复发的影响。方法 回顾性收集2014年1月1日至2018年12月31日在山东第一医科大学附属肿瘤医院行根治性手术的256例NSCLC患者的术后石蜡包埋原发灶组织标本，构建包含肿瘤中心（tumor center, TC）和侵袭边缘（invasive margin, IM）区域的组织微阵列，并应用多重免疫荧光染色技术［HIF-1α/CD4/CD8/细胞角蛋白（cytokeratin, CK）/4',6-二脒基-2-苯基吲哚（4',6-diamidino-2-phenylindole, DAPI）］定量表达HIF-1α的肿瘤细胞（HIF-1α+CK+）、表达HIF-1α的CD4+ T细胞（HIF-1α+CD4+）及表达HIF-1α的CD8+ T细胞（HIF-1α+CD8+）的密度。采用Mann-Whitney U检验分析N0与N1-2组、N1与N2组中的细胞密度差异，Cox比例风险回归模型分析关键复发因子。结果 研究最终纳入256例IA-IIIB期NSCLC患者，中位随访时间为37.05个月，其中87例（34.0%）患者在随访期间复发。在NSCLC患者的TC及IM区域，与N0组相比，N1-2组HIF-1α+CK+细胞密度均更高（P分别为0.039、<0.001），HIF-1α+CD8+细胞密度均更低（P分别为<0.001、<0.001）；与N1组相比，N2组原发灶内TC区域和IM区域HIF-1α+CK+细胞、HIF-1α+CD4+细胞及HIF-1α+CD8+细胞的密度差异均无统计学意义（均P>0.05）。多因素Cox分析显示，在N0组患者中，TC区域低HIF-1α+CD8+密度是NSCLC患者复发的独立危险因素［风险比（hazard ratio, HR）=1.998，95%CI: 1.077-3.705，P=0.028］。在N1、N2组患者中，TC区域和IM区域HIF-1α+CK+密度、HIF-1α+CD4+、HIF-1α+CD8+密度与NSCLC患者复发无统计学关联。结论 在NSCLC患者中淋巴结转移与原发灶HIF-1α相关细胞亚群密度变化密切关联。原发灶TC区域中HIF-1α+CD8+细胞密度降低与N0期NSCLC患者术后复发显著关联，可作为术后风险分层的潜在免疫学指标。
】 【中文关键词：肺肿瘤；无复发生存时间；淋巴结转移；预后；乏氧诱导因子-1α；CD8+ T细胞；肿瘤中心】.
Lung cancer is the leading cause of cancer morbidity and mortality worldwide. A highly complex bidirectional regulatory relationship exists between lung cancer progression and the nervous system. The nervous system is believed to play a pivotal regulatory role in the genesis of lung cancer. It is involved in regulating malignant biological behaviors such as proliferation, local invasion, and distant metastasis of lung cancer cells via core mediating pathways involving neurons, neurotransmitters, and neuroactive molecules. At the same time, lung cancer itself and related therapeutic interventions are capable of inducing reverse structural and functional reprogramming within the nervous system. The emergence of cancer neuroscience as a novel interdisciplinary field offers a new perspective to overcome the current bottlenecks in lung cancer treatment, yet it also faces numerous theoretical and clinical challenges that urgently require resolution. This article systematically reviews the intricate relationship between the nervous system and lung cancer progression, focusing on the potential effects and molecular mechanisms of clinical strategies including local therapies, chemotherapy, immunotherapy, and targeted therapy on the nervous system, with the aim of clarifying research opportunities and key challenges in this field and providing a theoretical foundation and practical reference for optimizing the precision treatment system of lung cancer and improving clinical efficacy.
. 【中文题目：癌症神经科学视角下肺癌演进的
神经调控机制与临床治疗挑战】 【中文摘要：肺癌作为全球发病率与死亡率均居首位的恶性肿瘤，其演变进程与神经系统存在高度复杂的双向调控关系。神经系统在肺癌的起源阶段发挥关键调控作用，可通过神经元、神经递质及神经活性分子等核心介导途径，参与肺癌细胞增殖、局部侵袭及远处转移等恶性生物学行为的调控；与此同时，肺癌本身及相关治疗干预措施亦能反向诱导神经系统的结构重塑与功能重编程。癌症神经科学这一新兴交叉学科的崛起，为突破肺癌治疗瓶颈提供了全新的研究视角，但同时也面临诸多亟待解决的理论与临床挑战。本文系统梳理神经系统与肺癌演进的内在关联，重点剖析局部治疗、化疗、免疫治疗及靶向治疗等临床策略对神经系统的潜在影响及其分子机制，进一步明确该领域的研究机遇与核心挑战，旨在为优化肺癌精准治疗体系、提升临床治疗效能提供理论依据与实践参考。
】 【中文关键词：肺肿瘤；癌症神经科学；神经系统；神经活性分子】.
Lung cancer is one of the most prevalent and lethal malignant tumors worldwide. In recent years, immune checkpoint inhibitors have significantly improved the survival outcomes of some patients with advanced non-small cell lung cancer; however, primary and acquired resistance remain important barriers limiting their clinical efficacy. Research has revealed that structural remodeling of the tumor microenvironment (TME) is one of the key factors involved in immunotherapy resistance. Efferocytosis is an important process by which tumor-associated macrophages clear apoptotic cells. In the lung cancer TME, the high apoptotic cell burden can lead to persistent activation of efferocytosis. Studies have shown that sustained efferocytosis is not merely a process of cellular debris clearance, but can also induce metabolic reprogramming in macrophages, including dysregulated lipid metabolism and enhanced glycolysis, and promote the secretion of immunosuppressive and tissue-repair-related factors. These changes further promote pathological angiogenesis, activation of cancer-associated fibroblasts, and excessive extracellular matrix deposition, thereby driving structural remodeling of the TME and forming an immune-excluded microenvironment characterized by vascular abnormalities and stromal fibrosis. This process restricts effector T-cell infiltration and impairs the efficacy of immune checkpoint inhibitors. This review describes the molecular mechanisms of macrophage efferocytosis in the lung cancer TME, focusing on its regulatory roles in metabolic reprogramming, pathological angiogenesis, and stromal fibrosis, and discusses potential therapeutic strategies targeting efferocytosis-related signaling pathways and TME structural remodeling, aiming to provide new insights into overcoming immunotherapy resistance in lung cancer.
. 【中文题目：巨噬细胞胞葬驱动肺癌微环境结构重塑
与血管生成的机制及临床干预前景】 【中文摘要：肺癌是全球发病率和死亡率均居首位的恶性肿瘤。近年来免疫检查点抑制剂显著改善了部分晚期非小细胞肺癌患者的生存预后，但仍有相当比例患者存在原发性或继发性免疫耐药。肿瘤微环境（tumor microenvironment, TME）结构重塑被认为是影响免疫治疗疗效的重要因素。胞葬是肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）清除凋亡细胞的重要过程，在维持炎症消退和组织稳态的同时，可诱导巨噬细胞发生显著的代谢重编程及分泌谱改变。持续活化的胞葬作用通过调控脂质代谢和糖酵解等代谢途径，促进多种免疫抑制及组织修复因子的分泌，从而驱动异常血管生成、激活肿瘤相关成纤维细胞并促进细胞外基质沉积，导致肿瘤基质结构重塑，形成免疫排斥型TME，限制效应T细胞浸润并降低免疫治疗疗效。本文综述胞葬作用在TME中的分子机制，重点阐述其在代谢重编程、血管生成异常及基质纤维化中的作用，并探讨靶向胞葬相关信号通路及TME结构重塑的潜在治疗策略，并进一步探讨胞葬相关指标在免疫检查点抑制剂疗效预测的潜在价值，以期为肺癌免疫治疗耐药的精准干预提供新的研究思路。
】 【中文关键词：肺肿瘤；巨噬细胞；胞葬；肿瘤微环境；代谢重编程；血管生成】.
The prognosis for non-small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is extremely poor. However, in oncogene addicted patients, the emergence of targeted therapies with high central nervous system (CNS) penetration is significantly reshaping the treatment landscape. Existing guidelines, which often favor conservative strategies, are no longer sufficient to meet the demands of precision medicine. To address this challenge, the Metastasis Lung Cancer Collaboration Group, Youth Specialists Committee of Beijing Medical Reward Foundation convened multidisciplinary experts from Medical Oncology, Radiology, Pathology, Radiotherapy, and Neurosurgery. Based on evidence-based medicine from the past decade and clinical practice experience, they have developed the Chinese expert consensus on clinical management of oncogene addicted NSCLC with leptomeningeal metastasis (2026 edition). This consensus emphasizes that the diagnosis of LM should be based on a comprehensive assessment of clinical symptoms, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cytology. It also highlights the critical role of CSF molecular liquid biopsy in clarifying driver gene status and assessing treatment efficacy. In terms of treatment, this consensus advocates for a fundamental paradigm shift: therapy should be led by a multidisciplinary team (MDT), with high-CNS-penetration targeted therapies as the first-line intervention, while local treatments (such as intrathecal injection and radiotherapy) are positioned as supplementary measures. The consensus provides a series of expert recommendations on key aspects, including the selection of high-CNS-penetration tyrosine kinase inhibitors (TKIs), the application of intrathecal chemotherapy, the timing of radiotherapy, and palliative surgery. It aims to establish proactive, individualized treatment standards for patients with NSCLC LM in China, based on molecular subtyping and MDT collaboration, thereby improving patient survival outcomes.
. 【中文题目：驱动基因阳性非小细胞肺癌脑膜转移
临床诊疗中国专家共识（2026版）】 【中文摘要：非小细胞肺癌（non-small cell lung cancer, NSCLC）脑膜转移（leptomeningeal metastasis, LM）的预后极差，然而在驱动基因阳性患者中，高中枢神经系统（central nervous system, CNS）渗透性靶向药物的出现，正显著重塑治疗格局。现有指南多倾向于保守策略，已难以满足精准医学的需求。为应对此挑战，北京医学奖励基金会肺癌医学青年专家委员会转移性肺癌协作组组织肿瘤内科、影像学、病理学、放疗及神经外科等多学科专家，基于近10年的循证医学证据及临床实践经验，制定了《驱动基因阳性非小细胞肺癌脑膜转移临床诊疗中国专家共识（2026版）》。本共识强调，LM诊断应综合临床症状、磁共振成像（magnetic resonance imaging, MRI）及脑脊液（cerebrospinal fluid, CSF）细胞学结果进行判断，并突出CSF分子活检在明确驱动基因状态及疗效评估中的关键作用。在治疗方面，本共识倡导根本性范式转变：由多学科诊疗（multidisciplinary team, MDT）团队主导治疗，以高CNS渗透性靶向治疗作为一线干预措施，局部治疗（如鞘内注射及放疗）则定位为辅助手段；共识针对高CNS渗透性酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）的选择、鞘内化疗的应用、放疗时机及外科姑息治疗等关键环节，提供了一系列专家推荐，旨在为中国NSCLC LM患者确立基于分子分型和MDT协作的积极个体化治疗规范，从而提升患者生存水平。
】 【中文关键词：肺肿瘤；脑膜转移；驱动基因；靶向治疗；临床诊疗指南】.
Combined small cell lung cancer (CSCLC) is a cancer that mixes small cell lung cancer (SCLC) with non-small cell lung cancer (NSCLC) components according to the World Health Organization's 2015 New Pathologic Classification of Lung Cancer. Composed of a mixture of SCLC and NSCLC components, CSCLC is classified as a subtype of SCLC in neuroendocrine tumors. Currently, research on SCLC mainly focuses on single-component pure SCLC, with relatively few studies on CSCLC, which is clinically rare and has no standardized treatment protocols and lacks a unified perception of the clinicopathological features and prognostic predictive indexes of CSCLC. Further observation of efficacy and prognosis is needed. We report the treatment course of a case of CSCLC and provide a literature review of the current status of research on CSCLC.
. 【中文题目：1例复合性小细胞肺癌病例及文献复习】 【中文摘要：复合性小细胞肺癌（combined small cell lung cancer, CSCLC）是根据世界卫生组织2015年肺癌新病理分类，将SCLC与非小细胞肺癌（non-small cell lung cancer, NSCLC）成分混合而成的癌症，在神经内分泌肿瘤中被归类为SCLC的亚型。目前对于SCLC的研究主要集中于单一成分的纯SCLC，对于CSCLC的研究相对较少，且CSCLC临床罕见，尚无规范的治疗方案，对于CSCLC的临床病理特征及预后预测指标缺乏统一的认知，需要进一步观察疗效和预后。现报告1例CSCLC患者的诊疗经过，并对CSCLC的研究现状进行文献回顾。
】 【中文关键词：肺肿瘤；复合性小细胞肺癌；鳞癌；病例报告；文献复习】.
The low response rate to immunotherapy can be partially attributed to tumor immune escape mechanisms arising from the heterogeneous tumor microenvironment. This study aims to determine the impact of inflammatory non-small cell lung cancer (NSCLC) on the efficacy of neoadjuvant immunotherapy combined with chemotherapy at the histological level, and to investigate the predictive value of specific CD8+ and CD4+ T cell numbers, as well as spatial interactions, in treatment response. A retrospective study included 43 patients with NSCLC who underwent neoadjuvant immunotherapy combined with chemotherapy at Shandong Cancer Hospital from January 2021 to June 2023. Preoperative biopsy specimens were collected and subjected to multiplex immunofluorescence staining [CD8/programmed cell death protein 1 (PD-1)/T cell immunoglobulin and mucin-domain containing protein 3 (TIM-3)/CD4/ forkhead box protein 3 (FoxP3)/cytokeratin (CK)/4',6-diamidino-2-phenylindole (DAPI)]. InForm software was used to perform tissue segmentation (epithelial and stromal regions) and quantify the density and spatial proximity of tumor cells, CD8+ T cells and their subsets (cytotoxic, pre-exhausted and exhausted), as well as CD4+ T cells and their subsets (conventional and regulatory). NSCLC was classified into three subtypes based on the relative infiltration levels of CD8+ T cells in both the epithelial and stromal compartments: inflamed (both compartments>10/1000), excluded (epithelial compartment<10/1000 and stromal compartment>10/1000), and desert (both compartments<10/1000). The Kolmogorov-Smirnov test, Fisher's exact test, Mann-Whitney U test and Logistic regression were used to identify factors associated with major pathological response (MPR). Inflamed, excluded, and desert NSCLC accounted for 65.1%, 27.9% and 7.0%, respectively. Compared with patients with non-inflamed NSCLC, those with inflamed NSCLC exhibit a higher MPR rate (71.4% vs 33.3%, P=0.016). Both univariate and multivariate Logistic regression analyses confirmed that the inflamed subtype is an independent protective factor against the acquisition of MPR in NSCLC patients (OR=0.20, 95%CI: 0.05-0.74, P=0.020; adjusted OR=0.17, 95%CI: 0.03-0.80, P=0.030). Analysis of the spatial distance between CD8+ and CD4+ T cells within the epithelial regions of inflamed NSCLC revealed that the effective density of cytotoxic CD8+ T cells within a 30 μm radius of regulatory CD4+ T cells was lower in the MPR group than in the non-MPR group (0.00 vs 0.33, P=0.037). Patients with inflamed NSCLC demonstrate superior efficacy when receiving neoadjuvant immunotherapy combined with chemotherapy. This may be due to reduced proximity between regulatory CD4+ T cells and cytotoxic CD8+ T cells. 【中文题目：免疫分型对非小细胞肺癌新辅助疗效
的影响及机制】 【中文摘要：背景与目的 免疫治疗反应率低，可部分归因于异质性肿瘤微环境导致的肿瘤免疫逃逸机制，本研究旨在通过组织学层面确定炎症型非小细胞肺癌（non-small cell lung cancer, NSCLC）对新辅助免疫联合化疗疗效的影响，并探究特定CD8+ T及CD4+ T细胞的数量和空间接近性在疗效预测中的价值。方法 回顾性纳入2021年1月至2023年6月在山东省肿瘤医院接受新辅助免疫联合化疗的43例NSCLC患者，收集术前活检标本并进行多重免疫荧光染色［CD8/程序性细胞死亡受体1（programmed cell death protein 1, PD-1）/T细胞免疫球蛋白及黏蛋白结构域蛋白 3（T-cell immunoglobulin and mucin-domain containing protein 3, TIM-3）/CD4/叉头框蛋白3（forkhead box protein 3, FoxP3）/细胞角蛋白（cytokeratin, CK）/4',6-二脒基-2-苯基吲哚（4',6-diamidino-2-phenylindole, DAPI）］。使用InForm软件行组织分割（上皮区和间质区），并量化肿瘤细胞、CD8+ T细胞及分群（细胞毒性、预耗竭和耗竭）、CD4+ T细胞及分群（常规和调节性）的密度及其空间接近性。基于CD8+ T细胞在上皮及间质区中的相对浸润程度，将NSCLC分为炎症型（上皮区及间质区均>10/1000）、排除型（上皮区<10/1000，间质区>10/1000）和荒漠型（上皮区及间质区均<10/1000）。使用Kolmogorov-Smirnov检验、Fisher's精确检验、Mann-Whitney U检验及Logistic回归确定与主要病理缓解（major pathological response, MPR）有关的因素。结果 炎症型、排除型及荒漠型NSCLC分别占65.1%、27.9%和7.0%。与非炎症型NSCLC患者相比，炎症型MPR率更高（71.4% vs 33.3%, P=0.016）。单因素以及多因素Logistic回归分析均证实炎症型是NSCLC患者获得MPR的独立保护因素（OR=0.20，95%CI: 0.05-0.74，P=0.020；校正后OR=0.17，95%CI: 0.03-0.80，P=0.030）。在炎症型NSCLC上皮区内分析CD8+ T与CD4+ T细胞空间距离时发现，MPR组上皮区内调节性CD4+ T细胞30 μm半径内细胞毒性CD8+ T细胞的有效密度低于non-MPR组（0.00 vs 0.33, P=0.037）。结论 炎症型NSCLC患者接受新辅助免疫联合化疗的疗效更佳，这可能与调节性CD4+ T细胞与细胞毒性CD8+ T细胞接近性减弱有关。
】 【中文关键词：肺肿瘤；免疫浸润分型；新辅助免疫治疗；空间接近性】.
Leptomeningeal metastasis (LM) is a devastating complication of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), with a poor prognosis. While high-dose third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can enhance drug concentrations in the central nervous system, their efficacy as monotherapy remains limited. Intrathecal Pemetrexed (IP) offers a promising local treatment approach by bypassing the blood-brain barrier and acting directly within the cerebrospinal fluid. However, clinical data on the efficacy and safety of combining high-dose third-generation EGFR-TKIs Furmonertinib (160 mg/d) with IP in EGFR-mutant NSCLC-LM patients are still scarce. Therefore, this study aims to evaluate the efficacy and safety of this combination regimen in this population to provide real-world data support for clinical practice. In this retrospective study, 40 patients with EGFR-mutant NSCLC-LM were enrolled at Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University between June 2021 and December 2024. All patients received oral Furmonertinib (160 mg/d) combined with IP. Primary endpoints were intracranial progression-free survival (iPFS), overall survival (OS), overall response rate (ORR) and adverse events. Survival analysis was performed using the Kaplan-Meier method, and prognostic factors were assessed via Cox proportional hazards regression by collecting the clinical data and follow-up information of the patients. After a median follow-up of 20.0 months, the combination therapy demonstrated significant efficacy. The ORR was 85.0%, with a median iPFS of 9.6 months and a median OS of 12.6 months. The 6-, 12- and 24-month OS rates were 79.9%, 53.9% and 27.0%, respectively. Multivariate analysis identified combination therapy with Bevacizumab as an independent protective factor [hazard ratio (HR)=0.283, 95%CI: 0.114-0.702, P=0.006], while a poor baseline Karnofsky performance status (KPS) score was an independent risk factor (HR=3.069, 95%CI: 1.313-7.170, P=0.010). Adverse events were primarily grade 1-2, including myelosuppression (42.5%), elevated transaminases (22.5%), and gastrointestinal reactions (nausea and/or vomiting, 20.0%). Only one case of grade 4 myelosuppression was reported and resolved after supportive care. High-dose Furmonertinib combined with IP is an effective and well-tolerated regimen for EGFR-mutant NSCLC-LM. The addition of Bevacizumab may further improve outcomes, offering a promising strategy for refractory patients. 【中文题目：高剂量伏美替尼联合培美曲塞鞘内化疗治疗EGFR突变型非小细胞肺癌软脑膜转移
的疗效与安全性分析】 【中文摘要：背景与目的 软脑膜转移（leptomeningeal metastasis, LM）是表皮生长因子受体（epidermal growth factor receptor, EGFR）突变型非小细胞肺癌（non-small cell lung cancer, NSCLC）的严重并发症，预后极差。第三代EGFR-酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitors, EGFR-TKIs）增加剂量虽可提升中枢神经系统药物浓度，但其单药疗效仍不足以有效控制疾病进展。培美曲塞鞘内注射（intrathecal Pemetrexed, IP）能够绕过血脑屏障，直接作用于脑脊液，为LM的局部治疗提供了新途径。然而，目前关于高剂量第三代EGFR-TKIs伏美替尼（160 mg/d）联合IP治疗EGFR突变型NSCLC-LM的临床疗效与安全性的研究数据仍较缺乏。因此，本研究旨在评估该联合方案在此类难治性患者中的有效性及安全性，以期为临床实践提供真实世界证据。方法 选择2021年6月至2024年12月南京大学医学院附属鼓楼医院收治的40例EGFR突变型NSCLC-LM患者，其治疗方案均为高剂量伏美替尼（160 mg/d）联合IP治疗。通过系统收集患者的临床病例资料及随访信息，分析其颅内无进展生存期（intracranial progression-free survival, iPFS）和总生存期（overall survival, OS）、总体反应率和不良事件。生存分析采用Kaplan-Meier法，预后影响因素通过Cox比例风险回归进行多变量分析。结果 中位随访时间20.0个月，高剂量伏美替尼联合IP治疗在EGFR突变型NSCLC-LM患者中展现出显著疗效：总体反应率为85.0%，iPFS为9.6个月，中位OS为12.6个月，6、12和24个月的OS率分别为79.9%、53.9%和27.0%。多因素分析表明，联合贝伐珠单抗治疗是独立的保护性预后因素［风险比（hazard ratio, HR）=0.283, 95%CI: 0.114-0.702, P=0.006］，而基线卡氏体能状态（Karnofsky performance status, KPS）评分较差是独立危险因素（HR=3.069, 95%CI: 1.313-7.170, P=0.010）。安全性方面，主要不良事件为骨髓抑制（42.5%）、转氨酶升高（22.5%）和消化道反应（恶心和/或呕吐20.0%），多数为1-2级。仅报告1例4级骨髓抑制，经支持治疗后好转。结论 高剂量伏美替尼联合IP在EGFR突变型NSCLC-LM患者中表现出显著疗效和可控的安全性，联合贝伐珠单抗可能进一步增加临床获益，为难治性患者提供了有前景的治疗策略。
】 【中文关键词：肺肿瘤；软脑膜转移；表皮生长因子受体；伏美替尼；培美曲塞鞘内化疗】.
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a newly defined type of epithelial tumor in the 2021 World Health Organization (WHO) fifth edition classification of thoracic tumors, with a low incidence. Currently, its treatment and prognosis remain unclear. Pathologically, it can be distinguished from SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) based on histological morphology and immunohistochemistry, yet whether there are differences in their clinical features, sensitivity to radiotherapy, and prognosis remains unknown. This study aimed to analyze the clinical characteristics of patients with SMARCA4-UT and SMARCA4-dNSCLC and to identify prognostic factors. A retrospective analysis was performed on pathologically confirmed SMARCA4-UT and SMARCA4-dNSCLC patients with complete follow-up data who were admitted to Shandong First Medical University Affiliated Tumor Hospital from June 2022 to February 2025. The differences in clinicopathological characteristics and imaging findings between the two groups were statistically analyzed, and the impacts of surgery, radiotherapy, immunotherapy, and clinicopathological factors on the prognosis of patients in both groups were assessed. A total of 27 SMARCA4-UT patients and 40 SMARCA4-dNSCLC patients were enrolled. Both groups showed similar biological characteristics in terms of gender, age, smoking history, tumor size, symptoms, stage, presence of pleural metastasis, neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII). However, there were differences in the predilection sites: SMARCA4-UT occurred more frequently in the mediastinal pleura (22.22%) and right lower lobe (25.93%), while SMARCA4-dNSCLC occurred more frequently in the right upper lobe (25.00%) and left upper lobe (22.50%) (P<0.05). Furthermore, SMARCA4-UT more often presented with local invasion into adjacent structures and more extensive lymph node metastasis (proportion with metastasis in ≥5 lymph node stations: 55.56% vs 27.50%). Both types showed high sensitivity to radiotherapy, with a 6-month local control rate (LCR) of 84.62% vs 83.33% after radiotherapy; the objective response rate (ORR) of immunotherapy was 91.67% vs 68.18% (P>0.05). Regarding survival, the two groups did not show significant differences in progression-free survival (PFS) or overall survival (OS). Cox multivariate regression analysis indicated that surgery could improve the prognosis of both types, while a high NLR (≥3.57) was a predictor of poor prognosis. SMARCA4-UT and SMARCA4-dNSCLC share similar clinical characteristics and survival outcomes, with minor differences in local invasion, mediastinal lymph node metastasis, and primary tumor location. Surgery improved survival in both groups. Although both tumor types exhibited high sensitivity to radiotherapy, this did not translate into a significant survival benefit for the patients. Pretreatment NLR is a potential prognostic indicator. 【中文题目：胸部SMARCA4缺失性未分化肿瘤与
SMARCA4缺失性非小细胞肺癌临床特征
及预后分析】 【中文摘要：背景与目的 胸部SMARCA4缺失性未分化肿瘤（thoracic SMARCA4-deficient undifferentiated tumor, SMARCA4-UT）是2021年世界卫生组织（World Health Organization, WHO）第5版胸部肿瘤分类中新定义的一种上皮性肿瘤类型，发病率低，目前对其治疗及预后尚不明确。病理上可通过组织学形态、免疫组化与SMARCA4缺失性非小细胞肺癌（SMARCA4-deficient non-small cell lung cancer, SMARCA4-dNSCLC）相鉴别，但其临床特征、对放疗的敏感性以及预后是否有差异仍未可知。本研究通过分析SMARCA4-UT及SMARCA4-dNSCLC患者的临床特征，明确预后相关影响因素。方法 回顾性分析2022年6月至2025年2月山东第一医科大学附属肿瘤医院收治的SMARCA4-UT及SMARCA4-dNSCLC患者，患者均经病理确诊，且随访资料完整。统计分析两组患者临床病理特征及影像学表现的差异，并评估手术、放疗、免疫治疗及临床病理因素对两组患者预后的影响。结果 共27例SMARCA4-UT及40例SMARCA4-dNSCLC患者入组，两组患者在性别、吸烟史、年龄、肿瘤最大径、症状、分期、是否有胸膜转移及中性粒细胞/淋巴细胞计数比值（neutrophil to lymphocyte ratio, NLR）、系统免疫炎症指数（systemic immune-inflammation index, SII）方面均表现出相似的生物学特性。但两者好发部位有所差异，SMARCA4-UT更易发生在纵隔胸膜（22.22%）、右肺下叶（25.93%），而SMARCA4-dNSCLC更易发生在右肺上叶（25.00%）及左肺上叶（22.50%）（P<0.05）；SMARCA4-UT更常表现为局部浸润侵犯邻近结构且淋巴结转移更广泛（淋巴结转移≥5站者55.56% vs 27.50%）。两者对放疗的敏感性均高，放疗后6个月局部控制率（local control rate, LCR）分别为84.62% vs 83.33%，免疫治疗的客观缓解率（objective response rate, ORR）分别为91.67% vs 68.18%，均无统计学差异（P>0.05）。生存方面，两组患者在无进展生存期（progression-free survival, PFS）与总生存期（overall survival, OS）方面均未表现出显著差异。Cox多因素回归分析显示，手术可以改善这两类患者的预后，而NLR≥3.57为其预后不良预测因子。结论 SMARCA4-UT与SMARCA4-dNSCLC具有相似的临床特征，生存预后相似，在局部浸润侵犯邻近结构、纵隔淋巴结转移及肿瘤原发部位上略有不同。手术可以改善两组患者的生存，且两者对放疗均表现出高的敏感性，但放疗未表现出患者的生存获益。治疗前NLR值可作为预后预测指标。
】 【中文关键词：肺肿瘤；SMARCA4缺失；临床特征；免疫治疗；放射治疗；局部控制率】.
Lung cancer is the malignant tumor with the highest morbidity and mortality, and it is usually diagnosed with advanced metastasis. Tumor metastasis is an important factor affecting treatment resistance and poor prognosis of lung cancer, among which bone metastasis is a common metastatic pattern of lung cancer and is associated with a particularly dismal prognosis. Meanwhile, bone metastasis frequently causes skeletal-related events such as bone pain, pathological fractures, nerve compression, and hypercalcemia. Exosomes are extracellular vesicles with a diameter of 40-160 nm that are released from the fusion of intracellular multivesicular bodies and the cell membrane. Carrying proteins, lipids, and nucleic acids, they mediate communication between tumor cells and their surrounding matrix, immune cells, and the bone microenvironment. So, it has attracted increasing attention from researchers. This paper aims to summarize and organize the latest research advances on exosomes promoting lung cancer bone metastasis, focusing on their key mechanisms and signaling pathways. These include promoting tumor cells proliferation, invasion and metastasis at the primary lesion, as well as participating in energy metabolism reprogramming, pre-metastatic niche remodeling, immune microenvironment regulation, and interactions with osteocytes, stromal cells, and other cells during distant bone metastasis colonization. In addition, this review analyzes the potential clinical translational value of exosomes in the early diagnosis, treatment, and prognosis of lung cancer bone metastasis. 【中文题目：外泌体参与肺癌骨转移的机制研究
及其相关临床诊疗进展】 【中文摘要：肺癌是发病率和死亡率最高的恶性肿瘤，诊断时通常已形成晚期转移。肿瘤发生转移是其治疗效果差、生存期短的重要影响因素，其中骨转移是肺癌常见的转移形式，常引起骨痛、病理性骨折、神经压迫和高钙血症等骨相关事件，严重影响患者生活质量且预后极差。外泌体是由细胞内多囊泡体与细胞膜融合后，释放到细胞外形成的直径为40-160 nm的细胞外囊泡。其携带蛋白质、脂质和核酸等物质介导肿瘤细胞与基质细胞、免疫细胞及骨微环境之间的信息传递，在肿瘤发生发展及侵袭转移过程中发挥重要调控作用，因此日益受到研究者们的关注。本文旨在总结并梳理外泌体促进肺癌骨转移的最新研究进展，重点阐述其关键机制与信号通路，包括在原发灶促进肿瘤细胞增殖和侵袭转移，在远处骨转移定植过程中参与的能量代谢重编程、转移前微环境塑造、免疫微环境调控和骨细胞、基质细胞等互作，并进一步分析外泌体在肺癌骨转移早期诊断、治疗及预后等方面的潜在临床转化价值。
】 【中文关键词：外泌体；肺肿瘤；骨转移；诊疗】.
Stage III non-small cell lung cancer (NSCLC) accounts for approximately 30% of newly diagnosed NSCLC cases, and the vast majority of these patients present with unresectable disease. Its unresectable nature makes definitive chemoradiotherapy the cornerstone of treatment. In recent years, with immune checkpoint inhibitors (ICIs) becoming a major research focus in lung cancer, increasing evidence demonstrates that the combination of radiotherapy and immunotherapy (iRT) can significantly enhance antitumor efficacy through synergistic mechanisms. The groundbreaking results of the landmark PACIFIC trial further established consolidation immunotherapy following concurrent chemoradiotherapy as the standard of care. However, controversies persist regarding optimal radiotherapy strategies, timing of immune intervention, management of adverse reactions, and exploration of biomarkers. This review aims to systematically elucidate the synergistic mechanisms of iRT, summarize clinical trial advances under different iRT treatment modalities (concurrent, consolidation and induction), and provide an in-depth analysis of key issues in current clinical practice along with future research directions.
. 【中文题目：放疗联合免疫治疗在不可切除III期
非小细胞肺癌中的临床研究进展及未来展望】 【中文摘要：III期非小细胞肺癌（non-small cell lung cancer, NSCLC）约占初诊NSCLC的30%，且绝大多数患者无法手术切除，其不可手术特性使根治性放化疗成为核心治疗手段。近年来，随着免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）成为肺癌领域的研究热点，越来越多的研究表明放疗联合免疫治疗（combination of radiotherapy and immunotherapy, iRT）能通过协同机制显著提升抗肿瘤疗效，PACIFIC研究的突破性进展更确立了同步放化疗后免疫巩固治疗的标准地位。然而，最佳放疗策略、免疫介入时机、不良事件管理和生物标志物探索等问题仍存争议。本综述旨在系统阐述iRT的协同作用机制，梳理不同iRT治疗模式下（同步、巩固、诱导）的临床试验进展，并对当前临床实践中的关键问题与未来研究方向进行深入探讨。
】 【中文关键词：肺肿瘤；放疗；免疫治疗；免疫检查点抑制剂；生物标志物】.