| BackgroundEtiological diagnosis is the key to the treatment of mediastinal disease,which is caused by a variety of etiologies,including primary,secondary benign or malignant tumors.The etiological diagnosis relies on pathological diagnosis,and biopsy sampling is a prerequisite for pathological examination.Currently,the Endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)has been applied clinically for nearly 20 years as one of the main biopsy sampling techniques for abnormal mediastinal lymphadenectasis or midiastinal masses.Despite the excellent performance of EBUS-TBNA for the diagnosis of mediastinal metastasis of lung cancer,it still has the disadvantage of low tissue acquisition,and the biopsy sampling volume is difficult to meet the sample demand for histopathological and molecular analysis,which affects the diagnosis,treatment planning and disease prognosis of benign mediastinal disease and subtype classification of malignant tumors.ObjectiveTo evaluate the diagnostic value and safety of EBUS-TBNA combined with mediastinal cryobiopsy for mediastinal diseases.MethodsThis study was a multicenter,randomized and open-label trial.Inclusion criteria: age ≥15 years,mediastinal lesion diameter ≥ 1 cm uopn chest CT or PET-CT,and completion of biopsy sampling for a definitive etiology.Exclusion criteria: mediastinal cyst or abscess as the nature of the lesion,presence of contraindications to bronchoscopy,severe coagulation abnormalities and cardiopulmonary insufficiency,and participation in other clinical studies within 3 months.After completion of the preoperative evaluation,they were assigned by random assignment table to the combined group: EBUS-TBNA combined with mediastinal cryobiopsy,and the control group:EBUS-TBNA.Intraoperatively,the overall and operative segmental elapsed time,the diameter of the mediastinal lesion,and complications were recorded,and the shortest diameter of the cryobiopsy sample was measured.Postoperatively,patients were guided to complete immediate,24-hour,pre-discharge,1-month,3-month,and6-month postoperative follow-up,including 24-hour postoperative review of chest radiograph,6-month postoperative review of chest CT or PET-CT,as well as subjective feelings of patients,complications,and assessment of postoperative changes in disease diagnosis and treatment.The history data of the patients,the biopsy pathology results of this study,and the new evidence of disease confirmation during the postoperative follow-up were collated.Finally,the statistical analysis was completed,in which the Categorical variables are reported as counts and percentages,and continuous variables as means and standard deviation.Pearson’s Chi-squared or Fisher’s exact test is used to compare proportions appropriate.For continuous data between-group comparisons are performed by Student’s t test or the Mann-Whitney U-test for parametric or non-parametric data,respectively.P<0.05 is considered to denote statistical significance.Based on the pathological findings of the biopsy sampling and the occurrence of complications in this study,the diagnostic yield of biopsy modalities and the occurrence yield of complications between and within groups,as well as the diagnostic value of additional tests were compared.This trial is now complete and is registered with Clinical Trials.gov,NCT04572984.ResultsBetween Oct 12,2020,and Sept 9,2021,297 consecutive patients were assessed for eligibility and 271 were enrolled and randomly assigned to the combined group(n=136)or the control group(n=135).Four participants(two in the combined group and two in the control group)declined all further investigations after discharge and were hence lost to follow-up,The biopsy sampling was completed in all patients.1.Comparison of diagnostic yield between the control group and combined group by interindividual analyses:(1)The overall diagnosis yield was 94%(126/134)in the combined group and 82%(109/133)in the control group,with RR=1.15 [95% CI 1.05-1.26],and the difference was statistically significant(p=0.002).(2)The diagnosis yield of benign lesions in the combined and control groups was 94%(45/48)and 64%(28/44),respectively,with RR=1.47 [95% CI 1.17-1.86],and the difference was statistically significant(p=0.0004).2.Comparison of diagnostic yield between the subgroup EBUS-TBNA and the EBUS-TBNA combined with cryobiopsy group by intraindividual analyses:(1)Comparison of overall diagnostic yield: the overall diagnostic yield by EBUS-TBNA was 82%(110/134)and it increased to 94%(126/134),after combined with mediastinal cryobiopsy,RR=1.15 [95% CI 1.05-1.25] and the difference was statistically significant(p=0.0026).(2)Comparison of the diagnostic yield of benign lesions: the diagnostic yield of benign lesions by EBUS-TBNA was 67%(32/48)and it increased to 94%(45/48)after combined mediastinal cryobiopsy,RR=1.41 [95% CI 1.14-1.74],and the difference was significant(p=0.0009).(3)Comparison of the diagnosis yield of lung cancer: The diagnosis yield of both lung cancer in subgroups was 98%(63/64),RR=1.00 [95% CI 0.96-1.04],and the diagnostic yield for mediastinal lesions did not differ between the combined groups and EBUS-TBNA groups(p=1.00).However,when subgroups were classified by mediastinal cryobiopsy and EBUS-TBNA only within the combined group,60 cases of lung cancer were confirmed by cryobiopsy and 63 cases by EBUS-TBNA,with 3 cases of missed diagnosis by cryobiopsy.3.Comparison of the diagnostic value of additional biopsy samples: 38 non-small cell lung cancer biopsy specimens within the combined group were suitable for PD-L1 or genetic testing,79%(30/38)of EBUS-TBNA supported additional tests,97%(37/38)of mediastinal cryobiopsy supported additional tests,RR=1.23 [95% CI 1.04-1.47],and the difference was statistically significant(p=0.033).8 cases lymphomas were diagnosed within the combined group,the subtype classification was completed in 20%(1/5)of EBUS-TBNA and in 100%(8/8)of combined cryobiopsy,RR=5.00 [95% CI 0.87-28.86],and the difference was statistically significant(p=0.007).4.Comparison of the occurrence yield of complications: No death or serious adverse events were observed in all patients,and there was no difference in the occurrence yield of complications between the control and combined groups,of which 1%(2/135)of grade 3 or higher bleeding occurred by EBUS-TBNA and 2%(3/136)by combined cryobiopsy,RR=0.67[95% CI 0.11-3.96 ],and there was no statistical difference between the two groups(p=1.00).There were no severe complications causing death or disability.ConclusionThe addition of mediastinal cryobiopsy to standard EBUS-TBNA resulted in a significant improvement in diagnostic yield for mediastinal lesions,with a good safety profile.However,among the non-small cell lung cancer cases in the combined group,there were "3 missed cases” by cryobiopsy,the mediastinal cryobiopsy cannot replace the EBUS-TBNA and might be used as an complementary technique for EBUS-TBNA. |
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