Brain metastasis has emerged as a significant challenge in the comprehensive management of patients with non-small cell lung cancer (NSCLC), particularly in those harboring driver gene mutations. Traditional treatments such as radiotherapy and surgery offer limited clinical benefits and are often accompanied by cognitive dysfunction and a decline in quality of life. In recent years, novel small molecule tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and other pathways have been developed, effectively penetrating the blood-brain barrier while enhancing intracranial drug concentrations and improving patient outcomes. This advancement has transformed the treatment landscape for brain metastases in NSCLC. Consequently, the Lung Cancer Medical Education Committee of the Chinese Medical Education Association and the Brain Metastasis Collaboration Group of the Lung Cancer Youth Expert Committee of the Beijing Medical Reward Foundation have jointly initiated and formulated the Clinical Practice Guidelines for the Management of Brain Metastases from Non-small Cell Lung Cancer with Actionable Gene Alterations in China (2025 Edition). This guideline integrates the latest research findings with clinical experience, adhering to multidisciplinary treatment principles, and encompasses aspects such as diagnosis, timing of intervention, and systemic and local treatment options for driver gene positive NSCLC brain metastases. Additionally, it proposes individualized treatment strategies tailored to different driver gene types, aiming to provide clinicians with a reference to enhance the overall diagnostic and therapeutic standards for NSCLC brain metastases in China.
.
Humans ; Brain Neoplasms/drug therapy* ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Lung Neoplasms/genetics*

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Thus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V1) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 19 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease.
.
Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/pathology* ; Anaplastic Lymphoma Kinase/metabolism* ; Carcinoma, Squamous Cell/genetics* ; Mutation ; Cytoskeletal Proteins/genetics* ; Lung/pathology* ; Oncogene Proteins, Fusion/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Tumor Suppressor Protein p53/genetics*

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
.
Aminopyridines ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Consensus ; Drug Resistance, Neoplasm/genetics* ; Drug-Related Side Effects and Adverse Reactions/drug therapy* ; Humans ; Lactams ; Lactams, Macrocyclic/adverse effects* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/adverse effects* ; Protein-Tyrosine Kinases/genetics* ; Pyrazoles

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrous interstitial lung disease of unknown etiology. IPF is also considered to be among the independent risk factors for lung cancer, increasing the risk of lung cancer by 7% and 20%. The incidence of IPF complicated with lung cancer, especially non-small cell lung cancer (NSCLC), is increasing gradually, but there is no consensus on unified management and treatment. IPF and NSCLC have similar pathological features. Both appear in the surrounding area of the lung. In pathients with IPF complicated with NSCLC, NSCLC often develops from the honeycomb region of IPF, but the mechanism of NSCLC induced by IPF remains unclear. In addition, IPF and NSCLC have similar genetic, molecular and cellular processes and common signal transduction pathways. The universal signal pathways targeting IPF and NSCLC will become potential therapeutic drugs for IPF complicated with NSCLC. This article examines the main molecular mechanisms involved in IPF and NSCLC and the research progress of drugs under development targeting these signal pathways.
.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Idiopathic Pulmonary Fibrosis/drug therapy* ; Lung Neoplasms/genetics* ; Lung/pathology* ; Signal Transduction

BACKGROUND: Pneumonic-type lung carcinoma is a special type of lung cancer both clinically and radiologically. Here we present our experience on pneumonic-type lung carcinoma in an attempt to investigate the clinical, radiological and pathological features, diagnostic procedures, treatment, and prognosis of this type of tumor. METHODS: Pathologically confirmed lung cancer with a chest CT characterized by ground glass opacity or consolidation was defined as pneumonic-type lung carcinoma. Cases with advanced pneumonic-type lung carcinoma admitted to Peking Union Medical College Hospital (PUMCH) from January 1, 2013 to August 30, 2018 were enrolled. Retrospective analysis of clinical data and survival follow-up of these patients was conducted. RESULTS: A total of 46 cases were enrolled, all of which were adenocarcinoma. Cough (41/46, 89.1%) and expectoration (35/46, 76.1%) were the most prominent symptoms. The most frequent chest CT findings were ground glass attenuation (87.0%), patchy consolidation (84.8%), and multiple ground-glass nodules (84.8%). Multiple cystic changes (40%) and cavitation (13%) were also quite frequent. Ipsilateral and contralateral intrapulmonary metastasis were noted in 95.3% and 84.8% of cases respectively. The median duration from symptom onset to diagnosis was 214 days (95%CI: 129-298). Both surgical lung biopsy and CT-guided percutaneous lung biopsy had a diagnostic yield of 100%. Transbronchial lung biopsy (TBLB) combined with bronchoalveolar lavage (BAL) had a diagnostic yield of 80.9% (17/21). Sputum cytology had a diagnostic yield of 45% (9/20). Twenty-six cases were invasive mucinous adenocarcinoma (26/46, 56.5%) and the remainder were unable to identify pathological subtypes due to lack of adequate biopsy sample size. EGFR mutation was detected in 15.8% (6/38) of patients and ALK rearrangement was detected in 3.0% (1/33) of patients. The median overall survival for these patients was 522 d (95%CI: 424-619). In patients without EGFR mutation or ALK rearrangement, chemotherapy significantly improved survival (HR=0.155, P=0.002,2). The median overall survival was 547 d (95%CI: 492-602 d) with chemotherapy and 331 d (95%CI: 22-919) without chemotherapy. CONCLUSIONS Diagnosis of pneumonic-type carcinoma is usually delayed due to clinical and radiological features mimicking pulmonary infection. TBLB combined with BAL has a quite high diagnostic yield. The most frequent histological type is invasive mucinous adenocarcinoma. The incidence of EGFR mutation or ALK rearrangement is low in pneumonic-type carcinoma. For patients without cancer driver genes, chemotherapy is recommended to improve overall survival.
Aged ; Anaplastic Lymphoma Kinase ; genetics ; metabolism ; Antineoplastic Agents ; therapeutic use ; Carcinoma ; diagnostic imaging ; drug therapy ; genetics ; pathology ; ErbB Receptors ; genetics ; metabolism ; Female ; Gene Rearrangement ; Humans ; Lung Neoplasms ; diagnostic imaging ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Retrospective Studies ; Survival Analysis ; Tomography, X-Ray Computed

BACKGROUND: Advanced epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma had a high overall incidence of brain metastasis during the full course, and local brain radiotherapy combined with systemic targeted therapy may be a better strategy. This study aimed to identify the prognostic factors of EGFR-mutant brain-metastatic lung adenocarcinoma patients who received EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in combination with gamma knife radiosurgery. METHODS: Retrospective analysis of EGFR-mutant lung adenocarcinoma patients with brain metastases which developed at initial diagnosis or during EGFR-TKIs treatment period were performed. Intracranial progression free survival (PFS) was statistically analyzed between different subgroups to find out the prognostic factors including gender, age, smoking history, extracranial metastasis, EGFR mutation type, size and number of intracranial lesions, carcino-embryonic antigen (CEA) level, lung-molGPA score and so on. RESULTS: A total of 74 EGFR-mutant brain-metastatic lung adenocarcinoma patients were enrolled in this study, with median intracranial PFS of 14.7 months. One-year intracranial-progression-free rate was 58.5%, and two-year rate was 22.2%. Univariate survival analysis showed that patients with lower CEA level at initial diagnosis (<10 ng/L)(16.9 months vs 12.6 months, P=0.012) and smaller intracranial lesions (<2 cm)(15.4 months vs 10.8 months, P=0.021) and higher lung-molGPA score (>3)(15 months vs 12.6 months, P=0.041) were prone to have a superior intracranial PFS. Multivariate analysis showed that CEA≥10 ng/mL and intracranial lesion≥2 cm were the independent risk factors of intracranial PFS. CONCLUSIONS EGFR-TKIs in combination with gamma knife radiosurgery was an efficient treatment option to control the cranial tumor lesion. CEA≥10 μg/L at initial diagnosis and intracranial lesion≥2 cm were the risk factors of EGFR-mutant brain-metastatic lung adenocarcinoma patients receiving EGFR-TKIs in combination with gamma knife radiosurgery.
Adenocarcinoma of Lung ; drug therapy ; pathology ; radiotherapy ; therapy ; Adult ; Aged ; Brain Neoplasms ; secondary ; Combined Modality Therapy ; ErbB Receptors ; antagonists & inhibitors ; genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Prognosis ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Radiosurgery ; Retrospective Studies

BACKGROUND: Small cell lung cancer (SCLC) is characterized by poor differentiation, high malignancy and rapid growth fast, short double time, early and extensive metastatic malignancy. In clinical, chemotherapy is the main treatment method, while resistance to multiple chemotherapy drugs in six to nine months has been a major clinical challenge in SCLC treatment. Therefore, It has important clinical value to building SCLC aninimal model which is similar to patients with SCLC. Animal model of xenotransplantation (PDX) from the patients with small cell lung cancer can well retain the characteristics of primary tumor and is an ideal preclinical animal model. The study is aimed to establish SCLC PDX animal model and induce the chemoresistance model to help to study the mechanism of chemoresistance and individual treatment. METHODS: Fresh surgical excision or puncture specimens from SCLC patients were transplanted into B-NSGTM mice subcutaneous tissues with severe immunodeficiency in one hour after operation the B-NSGTM mice subcutaneous in 1 hour, and inject chemotherapy drugs intraperitoneally after its tumor growed to 400 mm³ with EP which is cisplatin 8 mg/kg eight days and etoposide 5 mg/kg every two days until 8 cycles. Measure the tumor volum and mice weights regularly, then re-engrafted the largest tumor and continue chemotherapy. RESULTS: Nine cases were conducted for B-NSG mice modeling. Three of nine cases could be engrafted to new B-NSG mice at least two generation. The SCLC PDX animal models have been established successfully. After adopting chemotherapy drugs, the chemoresistance PDX models have been established. High homogeneity was found between xenograft tumor and patient's tumor in histopathology, immunohistochemical phenotype (Syn, CD56, Ki67). CONCLUSIONS The SCLC PDX animal model and the chemoresistance PDX animal model have been successfully constructed, the success rate is 33%, which provides a platform for the clinical research, seeking for biological markers and choosing individual treatment methods of SCLC.
Animals ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Cisplatin ; administration & dosage ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Etoposide ; administration & dosage ; Female ; Humans ; Interleukin Receptor Common gamma Subunit ; deficiency ; genetics ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Small Cell Lung Carcinoma ; drug therapy ; metabolism ; pathology ; Transplantation, Heterologous ; methods ; Xenograft Model Antitumor Assays

The aim of this paper was to observe the effect of gambogenic acid on angiogenesis of lung cancer and its preliminary mechanism. After culturing lung adenocarcinoma A549 cells, the conditioned medium was treated with gambogenic acid and then used to culture human umbilical vein endothelial cells (HUVECs) to establish the indirect contact cell co-culture system. A two-dimensional culture model of HUVEC was established with matrigel to observe the effect of gambogenic acid on angiogenesis. DAPI staining was used to observe the morphological changes in HUVEC cells after treatment with gambogenic acid under the fluorescence microscope. Annexin V-FITC/PI staining and flow cytometry analysis were used to determine gambogenic acid's effect on HUVEC cell apoptosis rate. The protein expressions of PI3K, p-PI3K, Akt, p-Akt were measured by Western blot. PTEN-siRNA was transfected into cells, and RT-PCR was used to detect the expression levels of PI3K and Akt genes. Gambogenic acid can significantly inhibit angiogenesis, and its inhibitory effect was dose-dependent. DAPI staining showed apoptotic morphological features of HUVEC cells under fluorescence microscope. Annexin V-FITC/PI staining showed that gambogenic acid induced apoptosis in HUVECs. The results of Western blot showed that the expressions of p-PI3K and p-Akt protein were down-regulated with gambogenic acid, while the expressions of PI3K and Akt protein was insignificant. The results of RT-PCR indicated that the expressions of PI3K and Akt protein were up-regulated by PTEN siRNA. Gambogenic acid can inhibit angiogenesis in lung cancer in vitro, and the mechanism of inhibiting angiogenesis may be related to the PI3K/Akt signaling pathway.
A549 Cells ; Apoptosis ; Coculture Techniques ; Human Umbilical Vein Endothelial Cells ; drug effects ; Humans ; Lung Neoplasms ; drug therapy ; pathology ; Neovascularization, Pathologic ; pathology ; PTEN Phosphohydrolase ; genetics ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Transfection ; Xanthenes ; pharmacology

BACKGROUND: There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or Kelch-like ECH-associated protein 1 (Keap1) in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different "driver gene" is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients. METHODS: Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type. RESULTS: The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P<0.05), but not with age, smoking, differentiation and subtype of lung adenocarcinoma (P>0.05). The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05). The progression -free survival (PFS) and overall survival (OS) of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05). Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05). CONCLUSIONS The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly correlated with PFS and OS of EGFR-TKIs. Therefore, Nrf2 may be a biomarker for predicting response of EGFR-TKIs and a potential target for overcoming resistance of EGFR-TKIs.
Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; Adenocarcinoma of Lung ; Adult ; Aged ; Aged, 80 and over ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Kelch-Like ECH-Associated Protein 1 ; genetics ; metabolism ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Mutation ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Neoplasm Staging ; Protein Kinase Inhibitors ; therapeutic use ; Young Adult

In recent years, series of driver genes, such as EGFR, KRAS/NRAS, BRAF, PIK3CA, ALK and ROS1 and so on, have been found in non-small cell lung cancer (NSCLC) one after another with the development of molecular detecting technology. Targeted drugs bring benefits for these NSCLC patients with driver gene variations. However, some NSCLC did not have any known driver gene variations; we called it pan-negative lung cancer. In this paper, we summarize the concept, clinical pathological characteristics, the epidemiological characteristics, treatment and prognosis of pan-negative NSCLC.
Carcinoma, Non-Small-Cell Lung ; diagnosis ; drug therapy ; genetics ; pathology ; Humans ; Lung Neoplasms ; diagnosis ; drug therapy ; genetics ; pathology ; Mutation ; Prognosis