Translational lung cancer research最新文献

Lung cancer represents one of the most prevalent malignant tumors and the leading cause of mortality from neoplastic diseases worldwide. Despite significant advancements of lung cancer treatment in recent years, thanks to advancements in technologies such as chemotherapy, targeted therapy, immunotherapy, and so on, the development of drug resistance in lung cancer remains a major challenge. Ferroptosis, dependent on iron and accompanied by lipid peroxidation, is a unique form of cell death. Strategies targeting ferroptosis, either by blocking antioxidant defense pathways or activating oxidative pathways, are usually aimed at killing cancer cells or boosting cancer therapy effectiveness. The regulation of ferroptosis entails synergistic interactions among multiple pathways. Core pathways, including the glutathione peroxidase 4 (GPX4)-glutathione (GSH) axis, iron metabolism pathway, lipid metabolism pathway, and non-coding RNAs, are all involved in modulating ferroptosis sensitivity. Here, we describe in detail the mechanisms of ferroptosis and elucidate its promising therapeutic role of modulating ferroptosis in countering lung cancer resistance to conventional therapies, such as chemotherapy, targeted therapy, immunotherapy, and photodynamic therapy. At the same time, we emphasize the challenges and prospect of translating these findings on the use of strategies aimed at reversing lung cancer resistance, and expect that our review will serve as a valuable reference for further research.

Background: De novo post-transplant malignancy (PTM) is a significant complication after transplantation. Limited research exists on the incidence rates in recent lung transplant recipients (LTRs). This study aims to determine the risk spectrum of malignancies in LTRs and analyze their temporal evolution.

Methods: Data on 32,480 LTRs were extracted from the United States (U.S.) Organ Procurement Transplant Network/United Network for Organ Sharing (UNOS) database. We described the annual incidence rates and calculated the standardized incidence ratio (SIR).

Results: Among the 32,480 LTRs, the cancer incidence rate was 23.11%. The incidence of malignancies varied over time, initially increasing and then stabilizing in the first 10 years post-transplant. The overall incidence of cancers excluding non-melanoma skin cancer (NMSC) remained stable, with some tumors linked to viral infections being more common early on. Older age at transplantation and male gender were associated with higher cancer incidence risk. Besides cutaneous squamous cell carcinoma (cSCC) (n=3,706) and basal cell carcinoma (BCC) (n=1,054), the most common malignancies were lung cancer [n=580; incidence rate 455.55 per 100,000 person-years (PY); SIR =4.088] and non-Hodgkin lymphoma (NHL) (n=578; incidence rate 453.98 per 100,000 PY; SIR =13.266).

Conclusions: LTRs have a higher cancer risk compared to the general population. Targeted monitoring based on PTM occurrence patterns is necessary to prevent and detect tumors early. These findings assist in identifying high cancer incidence periods and guide predictions of tumor development.

Background: Lung cancer frequently presents with bilateral multiple pulmonary nodules (BMPNs), whose accurate intraoperative localization during surgery is challenging, making reliable preoperative localization essential. This retrospective study evaluates the safety and efficacy of electromagnetic navigation bronchoscopy-guided dye marking (ENBDM) compared with conventional computed tomography-guided percutaneous dye marking (CTPDM) for localizing BMPNs.

Methods: A retrospective cohort study was conducted on patients with BMPNs who underwent preoperative localization (either ENBDM or CTPDM) followed by video-assisted thoracoscopic surgery (VATS) between January 2020 and September 2024. Patients' characteristics, nodule features, localization procedural details, procedure-related complications, pain scores, and surgical outcomes were compared between the two groups.

Results: A total of 150 patients were evaluated, including 79 patients who underwent ENBDM for preoperative pulmonary nodule localization and 71 patients who underwent CTPDM. Compared to the computed tomography (CT) group, the ENB group localized smaller nodules {6 [interquartile range (IQR), 5-8] vs. 7 (IQR, 6-9) mm, P<0.001} while requiring less localization time [8 (IQR, 7-10.5) vs. 25 (IQR, 20.5-32) min, P<0.001]. The distance between the positioning points marked by ENB and CT and the pulmonary nodules showed no significant difference [12 (IQR, 10-15) vs. 11 (IQR, 6-18) mm, P=0.15]. The ENB group was not exposed to radiation (0 vs. 6.6±1.9, P<0.001). No procedure-related complications, such as pneumothorax, hemothorax, pulmonary hematoma, or other adverse events, were observed in the ENB group. Moreover, the post-procedure pain scores in the CT group were significantly higher than those in the ENB group (3.1±1.5 vs. 0, P<0.001).

Conclusions: For patients with BMPNs, ENB-guided localization achieved comparable accuracy to CT-guided localization, while offering significantly shorter localization times and a complete absence of complications. ENBDM represents a safe, efficient, and reliable method for preoperative localization of BMPNs.

Background: Targeted therapies such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant lung adenocarcinoma. However, distinguishing TKI-related adverse effects from coexisting systemic diseases can be challenging, especially when symptoms mimic known drug toxicities. Amyloidosis, a rare but serious condition characterized by abnormal protein deposition, may present with cardiac and renal dysfunction-features that overlap with reported toxicities of EGFR-TKIs. Early recognition and differentiation between drug-induced toxicity and systemic diseases like amyloidosis are crucial for accurate diagnosis and timely intervention.

Case description: A 67-year-old East Asian female with EGFR-mutant lung adenocarcinoma was treated with the first-generation EGFR-TKI gefitinib for five years following recurrence after surgery. She was subsequently switched to osimertinib, a third-generation EGFR-TKI, after identification of the T790M resistance mutation. Fifteen months after initiating osimertinib, she developed generalized edema, nephrotic-range proteinuria, and cardiac dysfunction. Initial assessments suggested drug-induced toxicity. Osimertinib was discontinued for several weeks, leading to a reduction in proteinuria without evidence of lung cancer progression. Given these findings, the treatment was cautiously switched to lazertinib. However, renal function deteriorated again shortly thereafter, necessitating the discontinuation of lazertinib as well. Kidney biopsy subsequently revealed amyloidosis with lambda light chain predominance, ultimately requiring hemodialysis. This case highlights the complexity of distinguishing drug-induced toxicity from unrelated but coexisting systemic diseases. While osimertinib-related cardiotoxicity is well recognized, the delayed onset of symptoms and lack of improvement with drug cessation suggested an alternative etiology. Biopsy-proven amyloidosis emphasized the need for thorough evaluation when clinical findings are atypical. Also, whole genome sequencing (WGS) could be helpful to distinguish drug toxicity from disease-related pathology.

Conclusions: When evaluating new symptoms in patients on targeted therapies, clinicians should not assume drug toxicity as the sole cause. A high index of suspicion for underlying systemic diseases, such as amyloidosis, is essential. Timely recognition and accurate diagnosis are critical to ensure appropriate and effective patient care.

Background: Fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) is a useful modality for the diagnosis of various cancers; however, its role in predicting the therapeutic response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains unclear. The effect of metabolic tumor activity on ¹⁸F-FDG accumulation was analyzed to evaluate the efficacy of osimertinib monotherapy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations.

Methods: Sixty-eight patients who underwent ¹⁸F-FDG PET prior to osimertinib initiation were enrolled in this study. The maximum and peak standardized uptake values (SUV_max and SUV_peak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) all based on ¹⁸F-FDG uptake were evaluated to predict the efficacy and clinical outcomes of osimertinib monotherapy.

Results: Bone metastasis was significantly associated with high MTV and TLG values, whereas liver metastasis was associated with elevated values across all four parameters (SUV_max, SUV_peak, MTV, and TLG). Positive programmed death ligand-1 (PD-L1) expression was significantly associated with high SUV_max and SUV_peak values. The objective response rate was 61.8%, and grade 3 or higher adverse events occurred in 22.1% of the patients. There were no significant differences in the therapeutic efficacy or adverse events of osimertinib according to the uptake level of ¹⁸F-FDG. Univariate analysis identified performance status (PS) and MTV as significant predictors of progression-free survival (PFS) and overall survival (OS). Multivariate analysis of PFS identified MTV as a significant prognostic factor.

Conclusions: MTV is a significant marker for predicting outcomes after osimertinib monotherapy in patients with advanced NSCLC harboring EGFR mutations.

Background: Current neoadjuvant strategies for resectable epidermal growth factor receptor (EGFR)-mutation non-small cell lung cancer (NSCLC) yield suboptimal pathological responses, highlighting an unmet need for biologically targeted approaches. This study aimed to evaluate the effectiveness and safety of neoadjuvant BL-B01D1, a first-in-class EGFR/human EGFR 3 (HER3) bispecific antibody-drug conjugate combined with aumolertinib, a third EGFR-tyrosine kinase inhibitor, in individuals with resectable stage II-IIIB NSCLC harboring EGFR mutation.

Methods: This phase II, open-label, non-controlled, single-arm, dose escalation and dose expansion study will recruit 40 stage II-IIIB resectable NSCLC patients with EGFR mutation. The study will evaluate the efficacy and safety of neoadjuvant therapy combining BL-B01D1 with aumolertinib prior to surgery and aumolertinib adjuvant treatment post-surgery. The primary endpoint is pathological complete response and major pathological response at the time of resection. Secondary end points include objective response rate, event-free survival, disease-free survival, overall survival, and R0 resection rate in the neoadjuvant setting. Safety, tolerability and biomarkers will also be assessed.

Discussion: This protocol describes the methodology of study in order to identify neoadjuvant therapy of BL-B01D1 and aumolertinib for resectable stage II-IIIB NSCLC with EGFR mutation.

Trial registration: Clinicaltrials.gov identifier: NCT06951464. Registered on April 23, 2025. Protocol version: version 2.0, May 06, 2025.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide, with higher death rates in Asia than in Europe and North America. Programmed cell death protein-(ligand) 1 [PD-(L)1] inhibitors are effective in NSCLC treatment, but their comparative effectiveness in Asian vs. non-Asian populations is unclear. The aim of this systematic literature review (SLR) and meta-analysis was to assess the efficacy of PD-(L)1 inhibitor monotherapy or combination therapy (with platinum-based chemotherapy or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors as first-line (1L), second-line (2L), and later (2L+) treatment for locally advanced or metastatic NSCLC in Asian vs. non-Asian patients.

Methods: Multiregional randomized, controlled studies that included subgroup analyses for Asian patients by ethnicity or region were selected. Studies were excluded if the control arm was not platinum-based chemotherapy or if the primary population did not meet the criteria. Literature searches were undertaken from January 1, 2010, to October 25, 2024 and were performed using the Ovid SP^® platform. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted using random-effects models. Quality and bias were evaluated using the Cochrane Risk of Bias tool and funnel plot and Begg's test.

Results: 1,431 records were screened, and 1L (n=21) and 2L/2L+ (n=10) studies in 10,233 patients with locally advanced or metastatic squamous/non-squamous NSCLC were identified. OS favored 1L PD-(L)1 inhibitor monotherapy or combination therapy (plus platinum-based chemotherapy and/or CTLA-4 inhibitors) in both Asian [HR =0.70; 95% confidence interval (CI): 0.64-0.76] and non-Asian (HR =0.71; 95% CI: 0.65-0.77) patients. Similar findings were observed with PFS in Asian (HR =0.53; 95% CI: 0.47-0.59) and non-Asian (HR =0.58; 95% CI: 0.53-0.64) patients. 1L PD-(L)1 inhibitor monotherapy or combination therapy was extremely effective at improving OS in Asian (HR =0.50; 95% CI: 0.39-0.64) and non-Asian (HR =0.64; 95% CI: 0.55-0.76) patients with tumor cell PD-L1 expression ≥50%, and there was also a greater magnitude of effect on PFS in Asian (HR =0.38; 95% CI: 0.32-0.44) than non-Asian (HR =0.46; 95% CI: 0.37-0.56) patients with tumor cell PD-L1 expression ≥50%.

Conclusions: These data support the global use of PD-(L)1 inhibitors for Asian and non-Asian patients with 1L or 2L/2L+ locally advanced or metastatic NSCLC. However, it was not possible to assess outcomes in all subgroups due to lack of data (e.g., wider PD-L1 subgroups, genetic profiles), warranting further studies by ethnicity.

Background: Primary bronchogenic lung cancer (PBLC) poses a serious threat to human health with its high mortality rate largely attributed to challenges in reliable early detection. Hence, the early identification of PBLC is essential for subsequent patient treatment. Machine learning (ML) models that utilize accessible data, such as routine blood tests and tumor markers, present a promising approach for enhancing early screening rates. This study aims to construct an ML prediction model based on the combined analysis of routine blood tests and tumor markers and to establish an early intelligent screening platform for PBLC through systematic integration and development of technology so as to improve the early screening rate of PBLC.

Methods: This study used samples from the PBLC group and the healthy control (HC) group from 2018 to 2023 (n=1,054). Data from The Affiliated Dazu's Hospital of Chongqing Medical University were used for model construction and internal validation (n=767), and data from the Chongqing Dazu District People's Hospital Medical Community were used for external validation (n=287). After feature selection using the least absolute shrinkage and selection operator (LASSO) algorithm, 14 features were selected, including routine blood tests and tumor markers. Subsequently, 10 ML models were used to establish prediction models using eight evaluation metrics, including accuracy, sensitivity, specificity, and area under the curve (AUC), to develop an early PBLC prediction tool.

Results: Among multiple ML models for early prediction of PBLC in patients, the Xtreme Gradient Boosting (XGBoost) model achieved an AUC above 0.980 in both internal and external validation. Basophils, lymphocytes, and carcinoembryonic antigen (CEA) ranked highest in feature importance for early PBLC prediction, suggesting that the indicators from routine blood tests and tumor markers jointly influence the predictive performance, thereby underscoring the practicality of integrating these two types of indicators in model development.

Conclusions: The ML models developed possess substantial application value in the early screening of PBLC, which is beneficial for the prompt detection and treatment of individuals diagnosed with PBLC.

Background: Completion lobectomy (CL) is occasionally required after segmentectomy for malignant lung tumors, particularly in cases of local recurrence at the resection margins. However, evidence of its technical feasibility and long-term outcomes remains limited. This study aimed to evaluate the surgical feasibility and oncologic outcomes of CL following segmentectomy for malignant lung tumors in a multi-institutional cohort.

Methods: This multi-institutional retrospective study included 18 patients who underwent CL after segmentectomy for malignant lung tumors between 2000 and 2023. The surgical procedures, perioperative outcomes, and long-term survival were evaluated. An exploratory post-hoc analysis was also performed to compare clinical and radiological features of true local recurrence and granuloma.

Results: The most common indication for CL, based on preoperative clinical diagnosis, was local recurrence at the segmental resection margin (72.2%). Video-assisted thoracic surgery (VATS) was performed in 27.8% of patients, with no conversions to thoracotomy. Pulmonary artery (PA) injury occurred in 11.1% and postoperative complications in 27.8%, with prolonged air leak being the most common. Perioperative mortality was not observed. On final pathological diagnosis, 50.0% of patients had local recurrence, 27.8% had metachronous primary lung cancer, and 22.2% had granuloma. Among 13 patients clinically diagnosed with local recurrence preoperatively, 3 were ultimately diagnosed with granuloma. The 5-year overall survival (OS) rate after CL for local recurrence was 58.3%, with a median OS of 87.2 months. An exploratory analysis suggested that features such as interval tumor shrinkage and absence of vascular/bronchial involvement may aid in distinguishing recurrence from granuloma.

Conclusions: CL after segmentectomy is a feasible and safe procedure when performed with careful planning and may provide encouraging long-term outcomes. Preoperative differentiation between local recurrence and granuloma remains a challenge and requires thorough imaging and tissue confirmation.

Background: For patients with resectable epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), the optimal neoadjuvant regimen remains undefined. In this multicenter retrospective cohort study, we explored the efficacy and safety of immunochemotherapy, tyrosine kinase inhibitors (TKIs), and chemotherapy as perioperative treatments for patients with resectable NSCLC harboring EGFR mutations.

Methods: Patients with untreated stage IIA-IIIB NSCLC and EGFR mutations were enrolled in the study. Neoadjuvant treatment comprised immunotherapy combined with chemotherapy, chemotherapy or TKI followed by surgery and optional adjuvant treatment. The primary endpoint was pathological response, including the pathological complete response (pCR) rate and major pathological response (MPR). The secondary endpoints included event-free survival (EFS), objective response rate (ORR), lymph node downgrade rate, and safety.

Results: Between January 13, 2020, and September 1, 2023, of 64 patients screened, 41 patients from seven centers were included in the final efficacy analysis. The ORR of the immunochemotherapy group, the TKI group, and the chemotherapy group was 63.0% [95% confidence interval (CI): 42.4-80.6%], 41.7% (95% CI: 15.2-72.3%), and 100% (95% CI: 15.8-100%), respectively. A total of 40 patients (97.5%) underwent definitive surgery, and 55.9% of the patients achieved lymph node downgrade. Among all 40 patients receiving definitive surgery, 10 patients achieved MPR, and the MPR rate was 25.0% (95% CI: 12.7-41.2%). The pCR rate was 10.0% (95% CI: 2.8-23.7%). For the immunochemotherapy group, the MPR rate was 30.8%, and for the TKI group, the MPR rate was 8.3% (P=0.08). The pCR rates of the immunochemotherapy group and the TKI group were 15.4% and 0%, respectively (P=0.18). With a follow-up of 24.0 months, the median EFS was not reached, and the 12-month and 24-month EFS rates were 94.2% and 75.8%, respectively. Treatment-related adverse events were manageable.

Conclusions: The combination of immunotherapy and chemotherapy as neoadjuvant treatment demonstrated a promising pathological response among patients with EGFR-mutant NSCLC.