Safety and efficacy of a novel transbronchial radiofrequency ablation system for lung tumours: One year follow-up from the first multi-centre large-scale clinical trial (BRONC-RFII).

BACKGROUND AND OBJECTIVE: Radiofrequency ablation (RFA) is an emerging treatment of lung cancer, yet it is accompanied by certain safety concerns and operational limitations. This first multi-centre, large-scale clinical trial aimed to investigate the technical performance, efficacy and safety of an innovative transbronchial RFA system for lung tumours. METHODS: The study enrolled patients with malignant lung tumours who underwent transbronchial RFA using an automatic saline microperfusion system between January 2021 and December 2021 across 16 medical centres. The primary endpoint was the complete ablation rate. The performance and safety of the technique, along with the 1-year survival rates, were evaluated. RESULTS: This study included 126 patients (age range: 23-85 years) with 130 lung tumours (mean size: 18.77 × 14.15 mm) who had undergone 153 transbronchial RFA sessions, with a technique success rate of 99.35% and an average ablation zone size of 32.47 mm. At the 12-month follow-up, the complete ablation rate and intrapulmonary progression-free survival rates were 90.48% and 88.89%, respectively. The results of patients with ground-glass nodules (GGNs) were superior to those of the patients with solid nodules (12-month complete ablation rates: solid vs. pure GGN vs. mixed GGN: 82.14% vs. 100% vs. 96.08%, p = 0.007). No device defects were reported. Complications such as pneumothorax, haemoptysis, pleural effusion, pulmonary infection and pleural pain were observed in 3.97%, 6.35%, 8.73%, 11.11% and 10.32% of patients, respectively. Two subjects died during the follow-up period. CONCLUSION: Transbronchial RFA utilizing an automatic saline microperfusion system is a viable, safe and efficacious approach for the treatment for lung tumours, particularly for patients with GGNs.

First in vivo Experiment with PulmValve Endobronchial Valve: Feasibility, Efficiency, and Safety.

INTRODUCTION: Endoscopic lung volume reduction with endobronchial valves has been widely recognized for treating hyperinflation in advanced chronic obstructive pulmonary disease and emphysema patients. The main challenges include the technical complexity of upper lobe implantation and the number of endobronchial valves required. These issues might be addressed by placing larger diameter valves in the lobar bronchus. This study evaluated the feasibility, efficiency, and safety of the new valve PulmValve (model PV-13) in porcine models. METHODS: Six PV-13 valves were bronchoscopically implanted into the caudal lobe bronchus of six healthy pigs. The procedure time, valve deployment, and removability were recorded. Follow-up examinations included blood tests, chest CT scans, and bronchoscopy at 30 min, 14 days, 28 days, and 84 days post-procedure, with necropsy and pathological evaluations after the final follow-up examination. RESULTS: The successful in vivo deployment and removal of PV-13 valves was established, with a median procedure time of 6.5 min. The distal lung volume reduction was evident at 30 min post-operation and was persistently monitored on day 84. No migration or malfunction of any PV-13 valves was detected, but a mild angle deviation was found in 3 cases. Coughing was observed in four pigs within the first 7 days and localized granulation tissue was observed in all pigs. No cases of pneumothorax, diffuse pneumonia, or hemoptysis were detected. CONCLUSIONS: In this study, we report the successful implantation and removal of a new valve PulmValve in a short operation time. Complete lobar atelectasis was induced without device migration, malfunction, or severe complications. Further studies are warranted to evaluate the long-term, sustained effects and potential benefits in human patients.

The Wound Healing of Autologous Regenerative Factor on Recurrent Benign Airway Stenosis: A Canine Experimental and Pilot Study.

INTRODUCTION: Benign airway stenosis (BAS) is a severe pathologic condition. Complex stenosis has a high recurrence rate and requires repeated bronchoscopic interventions for achieving optimal control, leading to recurrent BAS (RBAS) due to intraluminal granulation. METHODS: This study explored the potential of autologous regenerative factor (ARF) for treating RBAS using a post-intubation tracheal stenosis canine model. Bronchoscopic follow-ups were conducted, and RNA-seq analysis of airway tissue was performed. A clinical study was also initiated involving 17 patients with recurrent airway stenosis. RESULTS: In the animal model, ARF demonstrated significant effectiveness in preventing further collapse of the injured airway, maintaining airway patency and promoting tissue regeneration. RNA-seq results showed differential gene expression, signifying alterations in cellular components and signaling pathways. The clinical study found that ARF treatment was well-tolerated by patients with no severe adverse events requiring hospitalization. ARF treatment yielded a high response rate, especially for post-intubation tracheal stenosis and idiopathic tracheal stenosis patients. CONCLUSION: The study concludes that ARF presents a promising, effective, and less-invasive method for treating RBAS. ARF has shown potential in prolonging the intermittent period and reducing treatment failure in patients with recurrent tracheal stenosis by facilitating tracheal mucosal wound repair and ameliorating tracheal fibrosis. This novel approach could significantly impact future clinical applications.

Autologous transplantation of P63+ lung progenitor cells for chronic obstructive pulmonary disease therapy.

Adult lung resident stem/progenitor cells, including P63+ progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63+ progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63+ progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 106 to 5.2 × 106 cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, n = 17; control group, n = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: -17.4%; P = 0.008). Furthermore, participants in the intervention group showed >30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of P63 was associated with treatment efficacy. In conclusion, transplantation of cultured P63+ lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.

Effects of human umbilical cord blood mononuclear cells on ovalbumin-induced asthma in mice.

Background: Umbilical cord blood mononuclear cells (UCMNCs) show broad immune-modulation effects, which may be helpful for treating asthma. Effects of UCMNCs on asthma were investigated with mouse model in present study. Methods: Asthma was induced in BALB/c mice by ovalbumin (OVA) immunization and challenge. Asthmatic mice were then treated on days 7 and 20 with intravenous injections of UCMNCs in doses of 4×105, 2×106, and 107 cells per mouse for the low-dose UCMNC (UCMNCL), medium-dose UCMNC (UCMNCM), and high-dose UCMNC (UCMNCH) groups, respectively. Fetal mouse blood mononuclear cells (FMMNCs) were administered to FMMNC group at a dose of 2×106 cells per mouse as approximate allograft control. Airway hyperresponsiveness (AHR), airway inflammation indexes, and CD4/CD8 T cell subsets were measured at day 25. Results: Compared with the model group, AHR in the UCMNCL group, inflammation score of lung tissue in the UCMNCM group, interleukin (IL)-5 in bronchoalveolar lavage fluid (BALF) in UCMNCL group, IL-5 and IL-13 in BALF in UCMNCM group, and IL-17 in serum in UCMNCH group were significantly inhibited. Compared with the model group, CD4+CD8+ T cells were reduced in the UCMNCL group, while decrease of CD4-CD8- T cells and increase of CD4+CD8- T cells were further strengthened in UCMNCM group. FMMNC treatment significantly reduced the IL-13 and IL-17 in serum, decreased CD4-CD8- and CD4+CD8- T cells, and increased the CD4+CD8+ and CD4-CD8+ T cells in BALF. Conclusions: UCMNCs can modulate AHR, T-helper (Th)2 inflammation, and airway injury in experimental asthma at appropriate dose.

Autologous Airway Basal Cell Transplantation Alleviates Airway Epithelium Defect in Recurrent Benign Tracheal Stenosis.

BACKGROUND: Airway epithelium defects are a hallmark of recurrent benign tracheal stenosis (RBTS). Reconstructing an intact airway epithelium is of great importance in airway homeostasis and epithelial wound healing and has great potential for treating tracheal stenosis. METHODS: An experimental study was conducted in canines to explore the therapeutic effect of autologous basal cell transplantation in restoring airway homeostasis. First, airway mucosae from human patients with recurrent tracheal stenosis were analyzed by single-cell RNA sequencing. Canines were then randomly divided into tracheal stenosis, Stent, Stent + Cells, and Stent + Cells + Biogel groups. Autologous airway basal cells of canines in the Stent + Cells and Stent + Cells + Biogel groups were transplanted onto the stenotic airway after modeling. A biogel was coated on the airway prior to basal cell transplantation in the Stent + Cells + Biogel group. After bronchoscopic treatments, canines were followed up for 16 weeks. RESULTS: Single-cell RNA sequencing demonstrated packed airway basal cells and an absence of normal airway epithelial cells in patients with RBTS. Autologous airway basal cell transplantation, together with biogel coating, was successfully performed in the canine model. Follow-up observation indicated that survival time in the Stent + Cells + Biogel group was significantly prolonged, with a higher (100%) survival rate compared with the other groups. In terms of pathological and bronchoscopic findings, canines that received autologous basal cell transplantation showed a reduction in granulation hyperplasia as well as airway re-epithelialization with functionally mature epithelial cells. CONCLUSIONS: Autologous airway basal cell transplantation might serve as a novel regenerative therapy for airway re-epithelialization and inhibit recurrent granulation hyperplasia in benign tracheal stenosis.

Mechanical stretch promotes apoptosis and impedes ciliogenesis of primary human airway basal stem cells.

BACKGROUND: Airway basal stem cells (ABSCs) have self-renewal and differentiation abilities. Although an abnormal mechanical environment related to chronic airway disease (CAD) can cause ABSC dysfunction, it remains unclear how mechanical stretch regulates the behavior and structure of ABSCs. Here, we explored the effect of mechanical stretch on primary human ABSCs. METHODS: Primary human ABSCs were isolated from healthy volunteers. A Flexcell FX-5000 Tension system was used to mimic the pathological airway mechanical stretch conditions of patients with CAD. ABSCs were stretched for 12, 24, or 48 h with 20% elongation. We first performed bulk RNA sequencing to identify the most predominantly changed genes and pathways. Next, apoptosis of stretched ABSCs was detected with Annexin V-FITC/PI staining and a caspase 3 activity assay. Proliferation of stretched ABSCs was assessed by measuring MKI67 mRNA expression and cell cycle dynamics. Immunofluorescence and hematoxylin-eosin staining were used to demonstrate the differentiation state of ABSCs at the air-liquid interface. RESULTS: Compared with unstretched control cells, apoptosis and caspase 3 activation of ABSCs stretched for 48 h were significantly increased (p < 0.0001; p < 0.0001, respectively), and MKI67 mRNA levels were decreased (p < 0.0001). In addition, a significant increase in the G0/G1 population (20.2%, p < 0.001) and a significant decrease in S-phase cells (21.1%, p < 0.0001) were observed. The ratio of Krt5+ ABSCs was significantly higher (32.38% vs. 48.71%, p = 0.0037) following stretching, while the ratio of Ac-tub+ cells was significantly lower (37.64% vs. 21.29%, p < 0.001). Moreover, compared with the control, the expression of NKX2-1 was upregulated significantly after stretching (14.06% vs. 39.51%, p < 0.0001). RNA sequencing showed 285 differentially expressed genes, among which 140 were upregulated and 145 were downregulated, revealing that DDIAS, BIRC5, TGFBI, and NKX2-1 may be involved in the function of primary human ABSCs during mechanical stretch. There was no apparent difference between stretching ABSCs for 24 and 48 h compared with the control. CONCLUSIONS: Pathological stretching induces apoptosis of ABSCs, inhibits their proliferation, and disrupts cilia cell differentiation. These features may be related to abnormal regeneration and repair observed after airway epithelium injury in patients with CAD.

Long-term efficacy and safety of the Dumon stent for treatment of benign airway stenosis.

BACKGROUND: The long-term efficacy of the Dumon stent in the treatment of benign airway stenosis is unclear. OBJECTIVE: The objective of this study was to evaluate the long-term efficacy and safety of the Dumon stent in patients with benign airway stenosis. METHODS: We retrospectively reviewed patients with benign airway stenosis who were treated with a Dumon stent at the First Affiliated Hospital of Guangzhou Medical University between March 2014 and October 2021. We included patients with successful removal of silicone stents after implantation. The clinical data and information on bronchoscopic interventional procedures and related complications were collected and analyzed. RESULTS: Ninety-nine patients with benign airway stenosis were included. The stent was placed mainly in the trachea (44.4%) and left main bronchus (43.4%). The main type of stenosis was post-tuberculosis bronchial stenosis (57.6%). The overall cure rate was 60.6%. Stent-related complications included retention of secretions (70.7%), granuloma formation (67.7%), stent angulation (21.2%), and stent migration (12.1%). The stent was less effective for left main bronchus stenosis (p = 0.012). Multivariate logistic regression analysis identified that stent placement for more than 13 months, a stent-intervention number of ⩽ 1 predicted a favorable outcome. CONCLUSION: The efficacy and safety of the Dumon stent for benign airway stenosis need improvement. The stent is less effective for left main bronchus stenosis; regular follow-up is required in such cases. Stent placement for > 13 months and no more than once stent intervention within a 6-month period were associated with a favorable outcome.

Enhanced secretion of hepatocyte growth factor in human umbilical cord mesenchymal stem cells ameliorates pulmonary fibrosis induced by bleomycin in rats.

Umbilical cord mesenchymal stem cells (UCMSCs) are a reportedly promising choice in the treatment of irreversible pulmonary fibrosis and lethal interstitial lung disease with limited drug treatment options. In this study, we investigated the therapeutic efficacy of UCMSCs overexpressing hepatocyte growth factor (HGF), which is considered one of the main anti-fibrotic factors secreted by MSCs. Adenovirus vector carrying the HGF gene was transfected into UCMSCs to produce HGF-modified UCMSCs (HGF-UCMSCs). Transfection promoted the proliferation of UCMSCs and did not change the morphology, and differentiation ability, or biomarkers. Rats were injected with HGF-UCMSCs on days 7 and 11 after intratracheal administration of bleomycin (10 mg/kg). We performed an analysis of histopathology and lung function to evaluate the anti-fibrotic effect. The results showed that HGF-UCMSCs decreased the Ashcroft scores in hematoxylin and eosin-stained sections, the percentage positive area in Masson trichrome-stained sections, and the hydroxyproline level in lungs. Forced expiratory volume in the first 300 m/forced vital capacity was also improved by HGF-UCMSCs. To explore the possible therapeutic mechanism of HGF-UCMSCs, we detected inflammatory factors in the lungs and performed mRNA sequencing in UCMSCs and HGF-UCMSCs. The data indicated that inhibition of interleukin-17 in the lung may be related to the anti-fibrosis of HGF-UCMSCs, and overexpressed HGF probably played a primary role in the treatment. Collectively, our study findings suggested that the overexpression of HGF may improve the anti-fibrotic effect of UCMSCs through directly or indirectly interacting with interleukin-17-producing cells in fibrotic lungs.

Optimize Initial Freezing Time of Transbronchial Cryobiopsy for the Diagnosis of Interstitial Lung Disease: A Prospective Randomized Parallel Group Study.

BACKGROUND: Transbronchial cryobiopsy (TBCB) is increasingly being identified as a potential alternative for the diagnosis of interstitial lung disease (ILD). The specimen size of TBCB is positively related to the freezing time. However, the proper initial freezing time for the clinical application of TBCB in ILD remains unknown. METHODS: A prospective randomized parallel group study was employed to investigate ILD patients with unclear diagnosis, who were admitted to the First Affiliated Hospital of Guangzhou Medical University from May 2019 to October 2020 and required TBCB. All patients were randomly divided into 4 groups according to the different freezing times of TBCB: 3 s, 4 s, 5 s, and 6 s groups. All operations were performed under intravenous anesthesia with endotracheal intubation, 60-65 bar pressure of freezing gas source, and 1.9-mm cryoprobe. Compare differences among groups in specimen size, complications, pathological diagnosis efficiency, and multidisciplinary discussion (MDD) diagnostic efficiency. RESULTS: A total of 100 patients were recruited and randomly assigned into 4 groups (n = 25 each group). The specimen sizes of TBCB in ILD were positively correlated with the freezing time (r = 0.639, p < 0.05). None of the patients experienced Grade 3 severe bleeding. Pneumothorax occurred in 1 patient in the 4 s, 5 s, and 6 s groups, respectively. The diagnostic yield of MDD in the 3 s, 4 s, 5 s, and 6 s groups were 64%, 88%, 88%, and 96%, respectively (p < 0.05), but showing no significant differences among 4 s, 5 s, and 6 s groups. CONCLUSIONS: The specimen size and diagnostic efficiency of TBCB in ILD increased with a longer freezing time. When the freezing gas pressure is 60-65 bar, we recommended 4 s as the initial freezing time of TBCB, and this time is associated with high diagnostic efficiency and low incidence of complications.

A clinical and canine experimental study in small-airway response to bronchial thermoplasty: Role of the neuronal effect.

BACKGROUND: The effects of bronchial thermoplasty (BT) on smooth muscle (SM) and nerves in small airways are unclear. METHODS: We recruited 15 patients with severe refractory asthma, who received BT treatment. Endobronchial optical-coherence tomography (EB-OCT) was performed at baseline, 3 weeks' follow-up and 2 years' follow-up to evaluate the effect of BT on airway structure. In addition, we divided 12 healthy beagles into a sham group and a BT group, the latter receiving BT on large airways (inner diameter >3 mm) of the lower lobe. The dogs' lung lobes were resected to evaluate histological and neuronal changes of the treated large airways and untreated small airways 12 weeks after BT. RESULTS: Patients receiving BT treatment had significant improvement in Asthma Control Questionnaire (ACQ) scores and significant reduction in asthma exacerbations. EB-OCT results demonstrated a notable increase in inner-airway area (Ai) and decrease in airway wall area percentage (Aw%) in both large (3rd-to 6th-generation) and small (7th-to 9th-generation) airways. Furthermore, the animal study showed a significant reduction in the amount of SM in BT-treated large airways but not in untreated small airways. Protein gene product 9.5 (PGP9.5)-positive nerves and muscarinic receptor 3 (M3 receptor) expression in large and small airways were both markedly decreased throughout the airway wall 12 weeks after BT treatment. CONCLUSIONS: BT significantly reduced nerves, but not SM, in small airways, which might shed light on the mechanism of lung denervation by BT.

Long-term efficacy and safety of the Dumon stent for benign tracheal stenosis: a meta-analysis.

BACKGROUND: The short-term efficacy of Dumon stent has been well demonstrated. Across years, however, due to insufficient sample size and absent of the randomized controlled trial, no reliable conclusion could be reach for Dumon stent's long-term efficacy. So, we conducted the first meta-analysis to evaluate the long-term efficacy and safety of the Dumon stent for benign tracheal stenosis. METHODS: Data on related trials were obtained by doing a literature search in PubMed, Web of Science and Cochrane Library. Random-effect and fixed-effect models were used to calculate the efficacy and incidence of complication of Dumon stent placement. RESULTS: A total of 395 patients from 8 studies were included in this study, revealing that the stability rate was 41.12% (95% CI, 34.85-48.52%) of Dumon stenting. Further, a curative rate of 40.74% (95% CI, 34.92-47.53%), and efficacy of 75.49% (95% CI, 70.89-80.39%) were obtained from this study. Analysis of the incidence of complications indicated 25.04% of migration (95% CI, 17.52-35.79%), 15.66% granulation (95% CI, 9.39-26.11%) and 23.82% of mucus retention 23.82% (95% CI, 13.77-41.20%). CONCLUSIONS: Dumon stent has a moderate efficacy for treating benign tracheal stenosis with approximately 20% incidence of complication, regular bronchoscopy follow-up should be conducted. Thus, further research is required to modified Dumon stenting.

The application of transbronchial cryobiopsy in interstitial lung disease: a prospective, multicenter, real-world study.

BACKGROUND: Transbronchial cryobiopsy (TBCB) has been widely used to diagnose interstitial lung disease (ILD). Existing reports on TBCB in ILD are mostly single-center prospective or retrospective studies but rarely multicenter prospective real-world studies. We explored the diagnostic efficiency and safety of TBCB in ILD in a real world setting. METHODS: A prospective, multicenter, real-world study was conducted to analyze the data of patients with unclarified ILD who underwent TBCB in 20 hospitals in China from October 2018 to October 2019. The results of the pathological and multidisciplinary discussion (MDD) diagnosis and complications related to TBCB were then analyzed. RESULTS: A total of 373 patients were enrolled in this study, including 194 males and 179 females, with an average age of 52.6±12.4 years. None of the patients had severe hemorrhaging, and the incidence of pneumothorax was 4.8%. The proportions of definitive, possible, and unclassified pathological diagnoses were 62.5%, 5.6%, and 31.9%, respectively. The overall diagnostic yield of MDD was 63.5%. There were 237 patients with a definitive diagnosis of MDD and 136 patients with an unclarified MDD diagnosis. The cooling gas pressure, freezing durations, number of specimens, maximum lengths of specimens, and specimen sizes varied significantly between the definitive and unclarified MDD diagnoses. CONCLUSIONS: In China, the application of TBCB in ILD is generally safe, and its diagnostic efficiency is acceptable. Using a 1.9-mm cryoprobe to collect five samples would achieve a better positive diagnostic rate for TBCB in ILD, without a significant increase in complication risk. TRIAL REGISTRATION: ClinicalTrials.gov; date of registration: 09/25/2018; registration number: NCT03704233; URL: clinicaltrials.gov.

Complete chloroplast genome sequence of Acer sutchuenense subsp. tienchuanenge (Sapindaceae).

Acer sutchuenense subsp. tienchuanenge (Sapindaceae: Acer) is an endangered deciduous arbor species and endemic to China. Being obtained by using genome Illumina pair-end sequencing data, the complete chloroplast genome of A. sutchuenense subsp. tienchuanenge had a typical quadripartite structure, with 156,063 bp long, including a large single-copy (LSC) region of 85,772 bp, a small single-copy (SSC) region of 18,117 bp, and a pair of inverted repeats (IRs) (each 26,087 bp in length). A total of 136 genes were annotated, of which 113 are unique genes, including 30 tRNAs, 4 rRNAs, and 79 protein-coding genes. The overall GC content was 37.9%. The phylogenetic analysis suggested that A. sutchuenense subsp. tienchuanenge was the most closely related to A. griseum and A. triflorum. The complete chloroplast genome of A. sutchuenense subsp. tienchuanenge is valuable for assessment and conservation of genetic resources and further for phylogenetic study of Acer L.

PD-(L)1 inhibitors vs. chemotherapy vs. their combination in front-line treatment for NSCLC: An indirect comparison.

We comprehensively compared the therapeutic effects and safety of PD-1/L1 antibodies (I), chemotherapy (C) or their combination (I + C) as first-line treatments for advanced NSCLC. Online databases were searched to identify RCTs. Survival outcomes and safety events were pooled by indirect treatment comparison. Main subgroup analyses were conducted according to PD-L1 expression. A total of 11 RCTs involving 6,731 patients were included. Overall, PD-1/L1 inhibitors showed no difference to chemotherapy in PFS (HR 0.90, 0.65-1.24) and OS (HR 0.84, 0.64-1.09), while I + C was superior to chemotherapy both in PFS (HR 0.64, 0.58-0.71) and OS (HR 0.74, 0.62-0.89). I + C also showed advantages over PD-1/L1 in PFS (HR 0.71, 0.51-0.99) but not OS (HR 0.88, 0.64-1.22). In the PD-L1 < 1% subgroup, I + C was beneficial both in OS (HR 0.78, 0.67-0.90) and PFS (HR 0.72, 0.65-0.80) than chemotherapy. In PD-L1 ≥ 50% population, PD-1/L1 had longer OS than chemotherapy (HR 0.71, 0.60-0.84); I + C also had longer OS (HR 0.61, 0.49-0.77) and PFS (HR 0.41,0.34-0.49) than chemotherapy. In indirect analysis (PD-L1 ≥ 50%), I + C was superior to PD-1/L1 in terms of PFS (HR 0.54, 0.35-0.82), but not OS (HR 0.86, 0.65-1.14). Both treatment-related and immune-mediated adverse events occurred most frequently in the combination therapy group. We suggest that a combination regimen is preferable as first-line treatment for NSCLC patients with different PD-L1 expression, in the meanwhile, in cautious of side effects.

Incidence and risk of thromboembolism associated with bevacizumab in patients with non-small cell lung carcinoma.

BACKGROUND: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is effective for the treatment of advanced non-small cell lung cancer (NSCLC). However, severe adverse events (AEs) have been reported in NSCLC patients treated with bevacizumab. Currently, the contribution of Bevacizumab to thromboembolism is still controversial. We conducted a study to determine the overall risk and incidence of thromboembolism with bevacizumab in NSCLC patients. METHODS: Electronic databases such as the PubMed, Web of Science and Cochrane Library were searched for related trials. Statistical analyses were conducted to calculate the overall incidence rates, odds ratios (ORs), and 95% confidence intervals (CIs) by using either random-effect or fixed-effect models depending on the heterogeneity. We also used trial sequence analysis (TSA) to verify the pooled result. RESULTS: A total of 3,555 subjects from nine studies were included. The overall incidence of thromboembolism events in NSCLC patients treated with bevacizumab was 4.8% (95% CI: 1.9-7.7%). Without bevacizumab, this incidence was 2.9% (95% CI: 0.6-5.1%). Bevacizumab use was associated with a significantly increased risk in thromboembolism events (OR =1.74; 95% CI: 1.15-2.62; P=0.008). Subgroup analysis based on the doses showed that bevacizumab administered at 15 mg/kg (OR =1.81; 95% CI: 1.14-2.86; P=0.012), but not 7.5 mg/kg (OR =1.32; 95% CI: 0.78-2.24; P=0.296), increased the risk of thromboembolism. CONCLUSIONS: Bevacizumab is associated with a significantly increased risk of thromboembolism development in NSCLC patients. It may have dose-toxicity relationship and low dose of bevacizumab may be a better choice for NSCLC patients, with equal efficacy and low hazard of thromboembolism events.