Translational lung cancer research最新文献

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.

Background: The effectiveness of different immune checkpoint inhibitors (ICIs) (i.e., pembrolizumab or sintilimab) in combination with chemotherapy in the treatment of resectable non-small cell lung cancer (NSCLC) is unknown. Using propensity score matching (PSM), this study aimed to analyze the preliminary results of using neoadjuvant chemotherapy in combination with sintilimab or pembrolizumab in the treatment resectable NSCLC.

Methods: NSCLC patients who received neoadjuvant pembrolizumab or sintilimab in combination with chemotherapy at two hospitals between June 2018 and March 2024 were recruited for the study. PSM was used to analyze the differences between the two groups in terms of the objective response rate (ORR), pathological complete response (pCR) rate, and operation-related information.

Results: A total of 366 patients were enrolled in the study: 163 in the sintilimab group (SG) and 203 in the pembrolizumab group (PG). Of the patients, 159 (43.4%) achieved a pCR, of whom 70 (42.9%) and 89 (43.8%) belonged to the SG and PG, respectively (P=0.86). No significant differences were observed between the SG and PG in terms of the major pathological response (MPR) rate (108, 66.3% vs. 127, 62.5%, P=0.46) and ORR (116, 71.2% vs. 126, 62.1%, P=0.07). The logistic analyses indicated that treatment with ≥3 cycles of neoadjuvant treatment and squamous cell cancer remained significant promoting factors of pCR. After PSM, the pCR rate and ORR were also similar between the SG and PG (63 of 140, 45.0% vs. 63 of 140, 45.0%, P>0.99; 93 of 140, 66.4% vs. 82 of 140, 58.6%, 17.1%). The 1- and 3-year overall survival (OS) rates of the PG were 98.7% and 79.3%, while those of the SG were 98.1% and 75.6% (P=0.73). After PSM, the 1- and 3-year OS rates of the PG were 95.3% and 77.0%, while those of the SG were 98.8% and 79.4%, respectively (P=0.22).

Conclusions: The combination of sintilimab or pembrolizumab with chemotherapy demonstrated similar effectiveness in terms of achieving a pCR in the neoadjuvant treatment of resectable NSCLC, and yielded comparable treatment outcomes.

Background and objective: Lung cancer remains the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis and therapy resistance. Despite advances in targeted therapies and immunotherapies, the prognosis remains poor. There is a critical need for minimally invasive biomarkers that enable early detection, prognostic stratification and therapeutic monitoring. Exosomes, a subtype of extracellular vesicles, have emerged as promising candidates in this context given their role in intercellular communication and their selective cargo, which reflects the molecular state of tumor cells. This review aims to summarize the current evidence on the potential of exosomes and their cargo, particularly microRNAs (miRNAs), as diagnostic and prognostic biomarkers as well as therapeutic tools in lung cancer.

Methods: A comprehensive literature search was conducted using PubMed/MEDLINE and Scopus databases between January 3 and April 30, 2025. Studies published from January 2000 to April 2024 were included if they addressed the role of exosomes in lung cancer diagnosis, prognosis, or therapy. Two reviewers independently screened titles and abstracts and full texts were assessed based on predefined inclusion criteria. Relevant articles were also identified through reference lists.

Key content and findings: Exosomal miRNAs (microRNAs) have shown potential as biomarkers for early detection, disease subtype classification, prognosis and therapy resistance in lung cancer. Multiple studies have identified specific miRNA signatures associated with tumor burden, histological subtypes and clinical outcomes. Exosomes also contribute actively to oncogenesis through promoting angiogenesis, epithelial-mesenchymal transition, immune evasion and drug resistance. Furthermore, exosomes are being investigated both as therapeutic targets and delivery systems due to their ability to transfer functional biomolecules selectively and safely. Despite these advances, challenges remain regarding standardization of isolation methods, heterogeneity in miRNA signatures and clinical validation.

Conclusions: Exosomes represent a dynamic and promising platform for improving the diagnosis, prognosis and treatment of lung cancer. Although technical and translational hurdles remain, their integration into clinical practice may enhance personalized and precision oncology strategies. Continued research and technological advancements are necessary to fully unlock their potential in routine cancer care.

Background: There is a significant unmet clinical need for accurate target identification in diagnosis and treatment of malignant tumors, including lung cancer. Optical imaging, specifically fluorescence-based, enables real-time tracking during endoscopic or surgical procedures. Here, we aim to investigate the scenario in which the fluorescence signal is possibly not due to the presence of the administered fluorescent agent, using a preclinical transbronchial lung cancer model.

Methods: Pafolacianine is a folate analog conjugated with an indocyanine green-like dye (peak excitation 774-776 nm, detection 794-796 nm). A composite optical fiberscope (COF) with 0.97 mm outer diameter tip was used for laser excitation at 776 nm and imaging. Spectrometer measurements along the same optical axis as the COF were also made to characterize the signal. In a mouse xenograft model, human folate receptor-positive KB tumor cells were inoculated subcutaneously into the flank of immunodeficient (NCr-Foxn1^nu) mice and grown to 8-15 mm diameter. The mice were then infused with 0.025 or 0.25 mg/kg pafolacianine or negative control. At 24 hours after infusion, tumor and contralateral background spectral measurements were acquired using both the COF imaging system and the spectrometer. In a swine peribronchial model, a pafolacianine-infused tumor was placed manually on the outer wall of the swine bronchus by forceps. The COF was inserted into the working channel of a bronchoscope, which was then inserted through an endotracheal tube and navigated close to where the tumor was located. While changing the distance from the COF tip to the bronchial mucosa, transbronchial COF imaging and spectroscopic measurements were acquired separately.

Results: In the in vivo mouse xenograft model, we observed a peak in the spectrometer spectrum at 810 nm that was more intense in the 0.25 mg/kg cohort than in the 0.025 mg/kg pafolacianine cohort. In the swine peribronchial tumor model with negative control tumor, we observed the excitation laser signal (776 nm) with the spectrometer when the COF tip was placed in very close (~1 mm) proximity to the bronchial mucosa but this signal was not detected at 5 or 10 mm distance.

Conclusions: In situations of very close proximity of the COF to the bronchial wall (~1 mm), we detected both excitation and emission signals. When the distance was increased slightly, only the fluorescence emission signal was detected. Although these results are not fully generalizable to all fluorescence bronchoscopy settings, it is important for clinicians to be aware of possible limitations in the filter rejection of excitation light leakage and to avoid extreme proximity between the bronchial mucosa and the fiber tip. We report this to exemplify artefacts that can occur in fluorescence bronchoscopy.