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Background: The most effective method for improving the prognosis of lung cancer is the application of low-dose computed tomography (LDCT) for pulmonary nodule screening in populations at high risk. Timely diagnosis and treatment of early-stage lung cancer can contribute to higher long-term survival rates. However, it remains difficult to differentiate malignant from benign pulmonary nodules measuring 8–15 mm, and avoid overtreatment on the one hand and delayed diagnosis on the other hand. In this consensus paper, we aimed to clarify the definition of “high-risk indeterminate pulmonary nodules (IPNs)” and discuss appropriate evaluation and management to facilitate timely diagnosis of lung cancer to improve lung cancer outcome. Direction for future research was discussed. Methods: A multi-disciplinary panel of doctors and IT experts from Asia, Canada and the U.S. were invited to participate. Published evidence and consensus guidelines were used to develop this consensus was clarified. Their evaluation and management were discussed. Findings: The experts believed that the prevalence of pulmonary nodules was very high, and it that was difficult to diagnose early-stage lung cancer due to the small size of the nodules, often leading to delayed diagnosis or overtreatment. To address this issue and to improve long-term outcome, the panel considered important to revise the classification of high-risk IPNs, (1) as pulmonary nodules that cannot be clearly diagnosed with non-surgical biopsy procedures, but is highly suspicious for early-stage lung cancer. The panel also recommends the most responsible should arrange imaging evaluations and follow-ups, taking new technologies into account. Artificial intelligence (AI) assessment based on the Medical Internet of Things (MIoT) can be combined with expert opinion to form a human–computer multidisciplinary team (MDT) that can fully implement the three core procedures of the MIoT, namely, comprehensive perception, reliable transmission, and intelligent processing. This will help to upgrade the non-standard diagnosis and treatment, the so-called “handicraft workshop model”, to a modern assembly-line model that meets international standards. The MIoT technology, which has the potential to realize “simplification of complex problems, digitalization of simple problems, programming of digital problems, and systematization of programming problems”, can promote the homogeneous evaluation of pulmonary nodules by enhancing both the sensitivity and the specificity of detecting early-stage lung cancer, in order to avoid delayed diagnosis and overtreatment. Conclusion: To optimize the evaluation of early-stage lung cancer, and to avoid delayed diagnosis and overtreatment, it is necessary to propose and promote the concept of “high-risk IPNs”. The application of current technologies, AI, and a human–computer MDT, will facilitate improvement in nodule evaluation, transforming the current diagnosis and treatment model, which is akin to production in handicraft workshops, into a modern assembly-line model that meets international standards, and will ultimately result in better prognosis.

Robotic‐assisted bronchoscopy (RAB) is a newly developed bronchoscopic technique for the diagnosis of peripheral pulmonary lesions (PPLs). The objective of this meta‐analysis was to analyze the diagnostic yield and safety of RAB in patients with PPLs. Five databases (PubMed, Embase, Web of Science, CENTRAL, and ClinicalTrials.gov) were searched from inception to April 2023. Two independent investigators screened retrieved articles, extracted data, and assessed the study quality. The pooled diagnostic yield and complication rate were estimated. Subgroup analysis was used to explore potential sources of heterogeneity. Publication bias was assessed using funnel plots and the Egger test. Sensitivity analysis was also conducted to assess the robustness of the synthesized results. A total of 725 lesions from 10 studies were included in this meta‐analysis. No publication bias was found. Overall, RAB had a pooled diagnostic yield of 80.4% (95% CI: 75.7%–85.1%). Lesion size of >30 mm, presence of a bronchus sign, and a concentric radial endobronchial ultrasound view were associated with a statistically significantly higher diagnostic yield. Heterogeneity exploration showed that studies using cryoprobes reported better yields than those without cryoprobes (90.0%, 95% CI: 83.2%–94.7% vs. 79.0%, 95% CI: 75.8%–82.2%, p < 0.01). The pooled complication rate was 3.0% (95% CI: 1.6%–4.4%). In conclusion, RAB is an effective and safe technique for PPLs diagnosis. Further high‐quality prospective studies still need to be conducted. [ABSTRACT FROM AUTHOR]

Non‐diagnostic findings are common in transbronchial lung biopsy (TBLB) and endobronchial ultrasound‐guided transbronchial lung biopsy (EBUS‐TBLB). One of the challenges is to improve the detection of lung cancer using these techniques. To address this issue, we utilized an 850 K methylation chip to identify methylation sites that distinguish malignant from benign lung nodules. Our study found that a combination of HOXA7, SHOX2 and SCT methylation analysis has the best diagnostic yield in bronchial washing (sensitivity: 74.1%; AUC: 0.851) and brushing samples (sensitivity: 86.1%; AUC: 0.915). We developed a kit comprising these three genes and validated it in 329 unique bronchial washing samples, 397 unique brushing samples and 179 unique patients with both washing and brushing samples. The panel's accuracy in lung cancer diagnosis was 86.9%, 91.2% and 95% in bronchial washing, brushing and washing + brushing samples, respectively. When combined with cytology, rapid on‐site evaluation (ROSE), and histology, the panel's sensitivity in lung cancer diagnosis was 90.8% and 95.8% in bronchial washing and brushing samples, respectively, and 100% in washing + brushing samples. Our findings suggest that quantitative analysis of the three‐gene panel can improve the diagnosis of lung cancer using bronchoscopy. [ABSTRACT FROM AUTHOR]

Rationale: Endobronchial ultrasound (EBUS) combined with a guide sheath (GS) as an instrument for confirming the proximity of the bronchoscope and its relationship to the lesion can increase the diagnostic yield when conducting transbronchial lung biopsy of peripheral pulmonary nodules (PPNs). A novel electromagnetic navigational bronchoscopy (ENB) system comprising a thinner locatable sensor probe as a guidance instrument was developed to be suitable for a thin bronchoscope with a working channel 2 mm in diameter. The diagnostic efficacy of EBUS-GS with or without this ENB system has not been confirmed. Objectives: To compare the diagnostic value and safety of EBUS-GS with or without the ENB system for diagnosing PPNs. Methods: A prospective, multicenter, randomized controlled clinical trial was designed and conducted at three centers. Patients with PPNs suspected to be malignant were enrolled and randomly assigned to the ENB-EBUS-GS group or the EBUS-GS group. The primary endpoint was the diagnostic yield in each group. The secondary endpoint was the procedural time and other factors affecting diagnostic yield. The safety endpoint was procedural complications. Results: Four hundred participants were enrolled from July 2018 to October 2019, and 385 patients were analyzed, 193 in the ENB-EBUS-GS group and 192 in the EBUS-GS group. The mean nodule size was 21.7 ± 5.3 mm. The diagnostic yields were 82.9% (95% confidence interval [CI], 77.6-88.2%) in the ENB-EBUS-GS group and 73.4% (95% CI, 67.2-79.7%) in the EBUS-GS group. The difference between the two groups was 9.5% (95% CI, 2.6-16.3%), with an adjusted difference of 9.0% (95% CI, 2.3-15.8%) after adjusting for the stratification factors and center. The time to find lesions in the ENB-EBUS-GS group was shorter than in the EBUS-GS group (213.2 ± 145.6 vs. 264.8 ± 189.5 s; P = 0.003). Intraoperative hemorrhage occurred 3.6% of subjects in the ENB-EBUS-GS group and 3.1% in the EBUS-GS group, without significant differences between the two groups. Conclusions: The novel ENB system combined with EBUS-GS demonstrated improved ability to locate PPNs, achieving a high diagnostic yield for PPNs compared with EBUS-GS alone in a safe and efficient procedure. Clinical trial registered with www.clinicaltrials.gov (NCT03569306). [ABSTRACT FROM AUTHOR]

Background: Endobronchial microwave ablation via flexible catheter offers the potential for local therapy for inoperable peripheral lung cancer. The study aimed to evaluate the feasibility and safety of navigation bronchoscopy‐guided water‐cooled microwave ablation catheter for nonsurgical peripheral lung cancer. Methods: This was a prospective single arm pilot study. Patients with early stage or multiple primary peripheral lung cancer who were nonsurgical candidates for surgery were enrolled in the study. Bronchoscopic microwave ablation was performed via a flexible water‐cooled microwave ablation antenna under the guidance of navigation bronchoscopy. Radial probe endobronchial ultrasound combined with fluoroscopy was used to confirm the position. Treatment outcomes were evaluated based on follow‐up chest CT and positron emission tomography scans. Primary endpoints were technical success and safety. Secondary endpoints were complete ablation rate, 2‐year local control rate, and progression‐free survival. Results: Thirteen patients were enrolled in the study from April 2018 to July 2019. A total of 19 sessions of microwave ablation were performed on 14 tumors under the guidance of navigation bronchoscopy. The technical success was 100%. Treatment‐related complications occurred in two patients. The complete ablation rate was 78.6% (11/14). The 2‐year local control rate was 71.4%. Median progression‐free survival was 33 months for all patients. Conclusions: In this pilot study, bronchoscopic microwave ablation appears to be feasible with acceptable occurrence of complication in the treatment of peripheral lung cancer under the guidance of navigation bronchoscopy. [ABSTRACT FROM AUTHOR]

Background: Early lung cancer detection remains a clinical challenge for standard diagnostic biopsies due to insufficient tumor morphological evidence. As epigenetic alterations precede morphological changes, expression alterations of certain imprinted genes could serve as actionable diagnostic biomarkers for malignant lung lesions. Results: Using the previously established quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) method, elevated aberrant allelic expression of imprinted genes GNAS, GRB10, SNRPN and HM13 was observed in lung cancers over benign lesions and normal controls, which were pathologically confirmed among histologically stained normal, paracancerous and malignant tissue sections. Based on the differential imprinting signatures, a diagnostic grading model was built on 246 formalin-fixed and paraffin-embedded (FFPE) surgically resected lung tissue specimens, tested against 30 lung cytology and small biopsy specimens, and blindly validated in an independent cohort of 155 patients. The QCIGISH diagnostic model demonstrated 99.1% sensitivity (95% CI 97.5–100.0%) and 92.1% specificity (95% CI 83.5–100.0%) in the blinded validation set. Of particular importance, QCIGISH achieved 97.1% sensitivity (95% CI 91.6–100.0%) for carcinoma in situ to stage IB cancers with 100% sensitivity and 91.7% specificity (95% CI 76.0–100.0%) noted for pulmonary nodules with diameters ≤ 2 cm. Conclusions: Our findings demonstrated the diagnostic value of epigenetic imprinting alterations as highly accurate translational biomarkers for a more definitive diagnosis of suspicious lung lesions. [ABSTRACT FROM AUTHOR]

Background: Despite advances in technology, the bronchoscopic diagnosis of parenchymal pulmonary lesions (PPLs) remains difficult to achieve. Transbronchial lung cryobiopsy (TLCB) offers the potential for larger samples with improved diagnostic yield; however, a paucity of data exists describing its safety and usefulness for the diagnosis of PPL.Research Question: What is the safety profile of TLCB for PPL?Study Design and Methods: An observational, retrospective, multicenter cohort study enrolled patients without endobronchial disease undergoing TLCB of PPL from 2015 through 2019. All procedures were performed using both rigid and flexible bronchoscopy with a flexible cryoprobe. Complication rates, including bleeding and pneumothorax rates, were collected. Bleeding was graded on a scale from 0 (trace) to 4 (requiring surgical intervention) with a grade of ≥ 3 considered clinically significant. Pneumothorax, tube thoracostomy placement, diagnostic yield, and need for subsequent interventions were recorded.Results: One thousand twenty-four patients underwent TLCB. One hundred eighty-eight patients (18%) experienced bleeding; in 36 patients (3.5%), the bleeding was clinically significant. Sixty-eight patients (6.6%) demonstrated a pneumothorax and 64 patients (6.3%) required drainage with tube thoracostomy. All chest drains were removed within 4 days, and no cases of prolonged air leak occurred. A definitive diagnosis was achieved in 932 patients (91%). Adenocarcinoma (46%) and metastatic disease (21%) were the most common diagnoses.Interpretation: TLCB showed an acceptable safety profile and diagnostic yield for the evaluation of PPL in this large retrospective cohort. Prospective clinical trials are underway to validate these findings further. [ABSTRACT FROM AUTHOR]

Background: Transbronchial lung biopsy (TBLB) is usually performed to obtain a definitive diagnosis for peripheral pulmonary lesions (PPLs). Ultrathin bronchoscopy combined with virtual bronchoscopic navigation (VBN) and radial endobronchial ultrasound (R‐EBUS) are generally considered appropriate diagnostic methods for PPLs; however, they have not yet been explored in combination with fluoroscopy. Therefore, the present prospective randomized controlled trial determined the role of fluoroscopy in ultrathin bronchoscopy combined with VBN and R‐EBUS for the diagnosis of PPLs. Methods: Patients with potentially malignant PPLs were enrolled in the study and randomized into fluoroscopy or nonfluoroscopy groups. In both groups, a 3.0‐mm outer and 1.7‐mm internal diameter ultrathin bronchoscope was used for transbronchial lung biopsy combined with R‐EBUS and VBN. In addition, the fluoroscopy group (FG) underwent fluoroscopy, while the nonfluoroscopy group (NFG) did not. Results: A total of 126 patients were enrolled and randomized in the study. Among them, 120 patients (60 in the NFG and 60 in the FG) were analyzed. The mean lesion sizes were 26.3 ± 11.4 mm and 29.0 ± 11.3 mm in the NFG and FG, respectively. The diagnostic yield was 73.3% (44/60) in the NFG and 81.7% (49/60) in the FG without statistically significant difference (p = 0.38). No obvious complications occurred in either group. Conclusions: Ultrathin bronchoscope combined with VBN and R‐EBUS without fluoroscopy is a feasible and safe diagnostic method for PPLs. [ABSTRACT FROM AUTHOR]

Background: Lung cancer screening using low-dose computed tomography (LDCT) often leads to unnecessary biopsy because of the low specificity among patients with pulmonary nodules ≤10 mm. Circulating genetically abnormal cells (CACs) can be used to discriminate lung cancer from benign lung disease. To examine the diagnostic value of CACs in detecting lung cancer for patients with malignant pulmonary nodules ≤10 mm. Methods: In this prospective study, patients with pulmonary nodules ≤10 mm who were detected at four hospitals in China from January 2019 to January 2020 were included. CACs were detected using fluorescence in-situ hybridization. All patients were confirmed as lung cancer or benign disease by further histopathological examination. Multivariable logistic regression models were established to detect the presence of lung cancer using CACs and other associated characteristics. Receiver operating characteristic analysis was used to evaluate the performance of CACs for lung cancer diagnosis. Results: Overall, 125 patients were included and analyzed. When the cutoff value of CACs was >2, the sensitivity and specificity for lung cancer were 70.5 and 86.4%. Male (OR = 0.330, P = 0.005), maximum solid nodule (OR = 2.362, P = 0.089), maximum nodule located in upper lobe (OR = 3.867, P = 0.001), and CACs >2 (OR = 18.525, P < 0.001) met the P < 0.10 criterion for inclusion in the multivariable models. The multivariable logistic regression model that included the dichotomized CACs (>2 vs. ≤2) and other clinical factors (AUC = 0.907, 95% CI = 0.842–0.951) was superior to the models that only considered dichotomized CACs or other clinical factors and similar to the model with numerical CACs and other clinical factors (AUC = 0.913, 95% CI = 0.850–0.956). Conclusion: CACs presented a significant diagnostic value in detecting lung cancer for patients with pulmonary nodules ≤10 mm. [ABSTRACT FROM AUTHOR]

Background: Percutaneous cryoablation has been used for the treatment of lung cancer and has been shown to be safe and effective. However, some lung cancer lesions cannot be reached by percutaneous puncture; using bronchoscopy cryoablation is necessary in these cases. Purposes: To examine the efficiency and security of a flexible cryoprobe, we measured the size and temperature distribution of the frozen area (ice ball) in ex vivo pig lung and liver and the temperature of the bronchoscope. Methods: We evaluated flexible cryoprobe cryoablation using a bronchoscope in ex vivo pig lung and a flexible cryoprobe alone in ex vivo pig liver. Seven temperature sensors were positioned at the surface of the cryoprobe and at distances of 0.3, 0.6, 0.9, 1.2, 1.5, and 1.8 cm from the cryoprobe. Two temperature sensors were positioned at the surface of the bronchoscope. The ex vivo pig lung and liver were perfused with 37°C saline and the former was inflated using a ventilator to simulate in vivo lung conditions. The whole operation is usually 2–3 freezing cycles. Results: In ex vivo pig liver, probes made ice balls of 33.2 ± 0.2 mm in diameter. In ex vivo pig lung, probes made ice balls of 35.1 ± 1.7 mm in diameter. The temperature at the surface of the bronchoscope at distances of 1 and 10 cm from the cryoprobe reached 21.1 ± 0.1 and 10.5 ± 0.2°C. Conclusion: A flexible cryoprobe using a bronchoscope in ex vivo pig lung and liver was a sufficiently safe treatment method. [ABSTRACT FROM AUTHOR]

We have recently developed a flexible catheter electrode used for bronchoscopic radiofrequency ablation (RFA). Two patients with nonsurgical stage IA peripheral lung cancer and 1 with lung metastasis underwent treatment with flexible catheter RFA utilizing navigation bronchoscopy. Chest computed tomography (CT) and positron emission tomography/CT (PET/CT) were performed before and after RFA to assess the ablation response of the patients. One patient's tumor had no prior PET uptake and therefore no follow-up PET was obtained. The first and the third patient obtained partial response to RFA, and the second patient obtained complete response 3 months after RFA. The first patient developed progressive disease 6 months after RFA. The second and the third patient achieved one-year progression-free survival. No significant complications occurred in the 3 patients. Navigation bronchoscopy-guided RFA is a safe and feasible procedure for poor surgical candidates with stage IA lung cancer or lung metastasis. [ABSTRACT FROM AUTHOR]

• A blood-based ctDNA methylation sequencing assay, LUNG-TRAC, was developed. • LUNG-TRAC showed promising result in differentiating benign from malignant nodule. • LUNG-TRAC outperformed Mayo and VA model in validation and single-center test set. With the popularization of computed tomography, more and more pulmonary nodules (PNs) are being detected. Risk stratification of PNs is essential for detecting early-stage lung cancer while minimizing the overdiagnosis of benign nodules. This study aimed to develop a circulating tumor DNA (ctDNA) methylation-based, non-invasive model for the risk stratification of PNs. A blood-based assay ("LUNG-TRAC") was designed to include novel lung cancer ctDNA methylation markers identified from in-house reduced representative bisulfite sequencing data and known markers from the literature. A stratification model was trained based on 183 ctDNA samples derived from patients with benign or malignant PNs and validated in 62 patients. LUNG-TRAC was further single-blindly tested in a single- and multi-center cohort. The LUNG-TRAC model achieved an area under the curve (AUC) of 0.810 (sensitivity = 74.4 % and specificity = 73.7 %) in the validation set. Two test sets were used to evaluate the performance of LUNG-TRAC, with an AUC of 0.815 in the single-center test (N = 61; sensitivity = 67.5 % and specificity = 76.2 %) and 0.761 in the multi-center test (N = 95; sensitivity = 50.7 % and specificity = 80.8 %). The clinical utility of LUNG-TRAC was further assessed by comparing it to two established risk stratification models: the Mayo Clinic and Veteran Administration models. It outperformed both in the validation and the single-center test sets. The LUNG-TRAC model demonstrated accuracy and consistency in stratifying PNs for the risk of malignancy, suggesting its utility as a non-invasive diagnostic aid for early-stage peripheral lung cancer. www.clinicaltrials.gov (NCT03989219). [ABSTRACT FROM AUTHOR]

Highlights • Guided bronchoscopy was related to an increased diagnostic yield of SPNs. • VBN could not increase the diagnostic yield of peripheral lesions. • Application of VBN could shorten the bronchoscope arrival time. Abstract Background The rate of detection of pulmonary nodules on computed radiography (CR) is approximately 0.09–0.2%, so rapid identification of the nature of solitary pulmonary nodules (SPNs) with a likelihood of malignancy is a critical challenge in the early diagnosis of lung cancer. Objective We conducted this study to compare the diagnostic yield and safety of endobronchial ultrasonography with a guide sheath (EBUS-GS), and the combination of EBUS-GS and virtual bronchoscopic navigation (VBN). Methods This was a prospective, multicenter, multi-arm, randomized controlled trial involving a total of 1010 subjects. All the patients recruited underwent a chest CT scan which found SPNs that needed to be diagnosed. The subjects were randomly divided into one of three groups: a traditional, non-guided, bronchoscopy biopsy group (NGB group), an EBUS-GS guided bronchoscopy biopsy group (EBUS group), and a guided bronchoscopy biopsy group that combined EBUS-GS with VBN (combined group). The primary endpoint was to investigate the differences between the diagnostic yields of the three groups. Results There was no significant difference in the diagnostic yield between the EBUS group (72.3%) and the combined group (74.3%), but the diagnostic yield for the NGB group was 41.2%. The time required to reach biopsy position was significantly less in the combined group (7.96 ± 1.18 min in the combined group versus 11.92 ± 5.37 min in the EBUS group, p < 0.05). However, the bronchoscope operation time was the same in the EBUS-GS and combined groups. The diagnostic yield for peripheral pulmonary lesions (PPLs) >20 mm in diameter was significantly higher than for those <20 mm in diameter. Conclusion The results of our study suggest that guided bronchoscopy could increase the diagnostic yield in the context of peripheral lesions. There was no significant difference in the diagnostic yield between the EBUS and combined groups, but use of EBUS-GS with VBN could significantly shorten the bronchoscope arrival time. [ABSTRACT FROM AUTHOR]

Objectives Genetic profiles of primary and metastatic lung tumor have been investigated by previous studies. However, whether they can be replaced by each other to guide treatment remains controversial. Moreover, it is unclear that whether genetic profiles of plasma can reflect genetic divergence between primary and metastatic lesions. Materials and methods In this prospective study, we collected 35 pairs of matched primary tumor tissue, metastatic lymph nodes and plasma from treatment-naïve patients with advanced non-squamous non-small cell lung cancer (NSCLC) and applied to capture-based sequencing using a panel consisting 56 NSCLC-related genes to interrogate the heterogeneity and similarity among the 3 sites. Results We observed 62.0% (67/108) by-variant concordance rate among primary tumor, metastatic lymph nodes and plasma as well as 76.4% (81/106) by-variant concordance rate between primary tumor and metastatic lymph nodes. When the analysis restricted to driver genes, we achieved 60.9% (28/46) and 77.3% (34/44) concordance, respectively. Furthermore, there is no statistically significant difference in progression-free survival (PFS) of 17 patients who used matched targeted therapy between patients having 100% concordance rate between primary tumor and metastatic lymph nodes and patients having partially matched mutational profiles. Conclusion Collectively, our study revealed a similar genetic profile shared between primary tumor and metastatic lymph nodes. The limited discordance observed can be partially reflected by plasma. Sequencing results obtained from either site can be utilized for providing treatment guidance. [ABSTRACT FROM AUTHOR]