Integrating artificial intelligence into lung cancer screening: a randomised controlled trial protocol.

INTRODUCTION: Lung cancer (LC) is the most common cause of cancer-related deaths worldwide. Its early detection can be achieved with a CT scan. Two large randomised trials proved the efficacy of low-dose CT (LDCT)-based lung cancer screening (LCS) in high-risk populations. The decrease in specific mortality is 20%-25%.Nonetheless, implementing LCS on a large scale faces obstacles due to the low number of thoracic radiologists and CT scans available for the eligible population and the high frequency of false-positive screening results and the long period of indeterminacy of nodules that can reach up to 24 months, which is a source of prolonged anxiety and multiple costly examinations with possible side effects.Deep learning, an artificial intelligence solution has shown promising results in retrospective trials detecting lung nodules and characterising them. However, until now no prospective studies have demonstrated their importance in a real-life setting. METHODS AND ANALYSIS: This open-label randomised controlled study focuses on LCS for patients aged 50-80 years, who smoked more than 20 pack-years, whether active or quit smoking less than 15 years ago. Its objective is to determine whether assisting a multidisciplinary team (MDT) with a 3D convolutional network-based analysis of screening chest CT scans accelerates the definitive classification of nodules into malignant or benign. 2722 patients will be included with the aim to demonstrate a 3-month reduction in the delay between lung nodule detection and its definitive classification into benign or malignant. ETHICS AND DISSEMINATION: The sponsor of this study is the University Hospital of Nice. The study was approved for France by the ethical committee CPP (Comités de Protection des Personnes) Sud-Ouest et outre-mer III (No. 2022-A01543-40) and the Agence Nationale du Medicament et des produits de Santé (Ministry of Health) in December 2023. The findings of the trial will be disseminated through peer-reviewed journals and national and international conference presentations. TRIAL REGISTRATION NUMBER: NCT05704920.

Lack of correlation between MET and PD-L1 expression in non-small cell lung cancer revealed by comparative study of matched biopsies and surgical resection samples.

INTRODUCTION: Both MET expression and the PD-L1 tumor proportion score (TPS) are companion diagnostics for treatment of advanced non-small cell lung carcinoma (aNSCLC) patients. We evaluated the rate of correlation between MET expression and the PD-L1 TPS in matched biopsies and surgically resected specimens from NSCLC patients. PATIENTS AND METHODS: This retrospective analysis assessed the prevalence and correlation between MET expression (SP44 clone) and the PD-L1 TPS (22C3 clone) by immunohistochemistry together with molecular alterations determined by targeted next-generation sequencing in matched lung biopsy and surgically lung resected specimens from 70 patients with NSCLC. RESULTS: The study found a significant correlation between the MET H-score in surgical samples and matched biopsies (P-value < 0.0001), as well as between the PD-L1 TPS in paired biopsies and surgical samples (P-value < 0.0001). However, there was no significant correlation between the MET H-score or expression subgroups and the PD-L1 TPS in both types of paired samples (P-value = 0.47, and P-value = 0.90). The MET H-score was significantly higher in adenocarcinoma compared to squamous cell carcinoma (P-value < 0.0001). A mutational analysis showed that the MET H-score was significantly higher in NSCLC cases with targetable molecular alterations (P-value = 0.0095), while no significant correlation was found for the PD-L1 TPS. CONCLUSIONS: Our study found no significant correlation between PD-L1 and MET expression in samples from NSCLC patients, highlighting the importance of personalized treatment strategies based on individual expression profiles. These findings provide valuable insight into the development of effective immunotherapy and targeted therapy for NSCLC patients.

Accurate Detection of SARS-CoV-2 by Next-Generation Sequencing in Low Viral Load Specimens.

As new SARS-CoV-2 variants emerge, there is an urgent need to increase the efficiency and availability of viral genome sequencing, notably to detect the lineage in samples with a low viral load. SARS-CoV-2 genome next-generation sequencing (NGS) was performed retrospectively in a single center on 175 positive samples from individuals. An automated workflow used the Ion AmpliSeq SARS-CoV-2 Insight Research Assay on the Genexus Sequencer. All samples were collected in the metropolitan area of the city of Nice (France) over a period of 32 weeks (from 19 July 2021 to 11 February 2022). In total, 76% of cases were identified with a low viral load (Ct ≥ 32, and ≤200 copies/µL). The NGS analysis was successful in 91% of cases, among which 57% of cases harbored the Delta variant, and 34% the Omicron BA.1.1 variant. Only 9% of cases had unreadable sequences. There was no significant difference in the viral load in patients infected with the Omicron variant compared to the Delta variant (Ct values, p = 0.0507; copy number, p = 0.252). We show that the NGS analysis of the SARS-CoV-2 genome provides reliable detection of the Delta and Omicron SARS-CoV-2 variants in low viral load samples.

Ultrafast Gene Fusion Assessment for Nonsquamous NSCLC.

Introduction: Gene fusion testing of ALK, ROS1, RET, NTRK, and MET exon 14 skipping mutations is guideline recommended in nonsquamous NSCLC (NS-NSCLC). Nevertheless, assessment is often hindered by the limited availability of tissue and prolonged next-generation sequencing (NGS) testing, which can protract the initiation of a targeted therapy. Therefore, the development of faster gene fusion assessment is critical for optimal clinical decision-making. Here, we compared two ultrafast gene fusion assays (UFGFAs) using NGS (Genexus, Oncomine Precision Assay, Thermo Fisher Scientific) and a multiplex reverse-transcriptase polymerase chain reaction (Idylla, GeneFusion Assay, Biocartis) approach at diagnosis in a retrospective series of 195 NS-NSCLC cases and five extrapulmonary tumors with a known NTRK fusion. Methods: A total of 195 NS-NSCLC cases (113 known gene fusions and 82 wild-type tumors) were included retrospectively. To validate the detection of a NTRK fusion, we added five NTRK-positive extrathoracic tumors. The diagnostic performance of the two UFGFAs and standard procedures was compared. Results: The accuracy was 92.3% and 93.1% for Idylla and Genexus, respectively. Both systems improved the sensitivity for detection by including a 5'-3' imbalance analysis. Although detection of ROS1, MET exon 14 skipping, and RET was excellent with both systems, ALK fusion detection was reduced with sensitivities of 87% and 88%, respectively. Idylla had a limited sensitivity of 67% for NTRK fusions, in which only an imbalance assessment was used. Conclusions: UFGFA using NGS and reverse-transcriptase polymerase chain reaction approaches had an equal level of detection of gene fusion but with some technique-specific limitations. Nevertheless, UFGFA detection in routine clinical care is feasible with both systems allowing faster initiation of therapy and a broad degree of screening.

Molecular Profiling in Non-Squamous Non-Small Cell Lung Carcinoma: Towards a Switch to Next-Generation Sequencing Reflex Testing.

Molecular diagnosis of lung cancer is a constantly evolving field thanks to major advances in precision oncology. The wide range of actionable molecular alterations in non-squamous non-small cell lung carcinoma (NS-NSCLC) and the multiplicity of mechanisms of resistance to treatment resulted in the need for repeated testing to establish an accurate molecular diagnosis, as well as to track disease evolution over time. While assessing the increasing complexity of the molecular composition of tumors at baseline, as well as over time, has become increasingly challenging, the emergence and implementation of next-generation sequencing (NGS) testing has extensively facilitated molecular profiling in NS-NSCLC. In this review, we discuss recent developments in the molecular profiling of NS-NSCLC and how NGS addresses current needs, as well as how it can be implemented to address future challenges in the management of NS-NSCLC.

A Single Dose of BNT162b2 Messenger RNA Vaccine Induces Airway Immunity in Severe Acute Respiratory Syndrome Coronavirus 2 Naive and Recovered Coronavirus Disease 2019 Subjects.

BACKGROUND: Mucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and therefore virus shedding. Parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior mucosal infection compared with injections of a parenteral vaccine in a mucosally naive subject. We investigated whether this was also the case for the BNT162b2 coronavirus disease 2019 (COVID-19) messenger RNA vaccine. METHODS: Twenty recovered COVID-19 subjects (RCSs) and 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive subjects were vaccinated with, respectively, 1 and 2 doses of the BNT162b2 COVID-19 vaccine. Nasal epithelial lining fluid (NELF) and plasma were collected before and after vaccination and assessed for immunoglobulin G (IgG) and IgA antibody levels to Spike and for their ability to neutralize binding of Spike to angiotensin-converting enzyme-2 receptor. Blood was analyzed 1 week after vaccination for the number of Spike-specific antibody-secreting cells (ASCs) with a mucosal tropism. RESULTS: All RCSs had both nasal and blood SARS-CoV-2-specific antibodies at least 90 days after initial diagnosis. In RCSs, a single dose of vaccine amplified preexisting Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including Delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after 2 vaccine doses compared with RCSs after 1 dose. CONCLUSIONS: Mucosal immune response to the SARS-CoV-2 Spike protein is higher in RCSs after a single vaccine dose compared with SARS-CoV-2-naive subjects after 2 doses.

Multidisciplinary management of tracheobronchial injury.

Tracheobronchial injury is a heterogeneous entity comprising multiple rare and potentially life-threatening scenarios. We performed a systematic literature review focusing on post-intubation tracheal injuries (PiTIs) and post-traumatic tracheobronchial injuries (PTTBIs).PiTIs are often longitudinal lacerations of the middle third of the membranous trachea. Subcutaneous emphysema of the face and trunk following tracheal intubation should immediately trigger the diagnosis. Diagnosis may be suspected on the chest computed tomography (CT) and should be confirmed by bronchoscopic examination. Conservative management is encouraged for a spontaneously breathing or stable patient on noninvasive ventilation. Surgical repair is mandatory when mechanical ventilation is required and if bridging of the injury is impossible.PTTBIs are often associated with other severe injuries. Patients often present with massive subcutaneous emphysema and intractable pneumothorax. Diagnosis may be suspected on the chest CT and should be confirmed by bronchoscopic examination. Early surgical repair is indicated. In selected patients, conservative management can be considered.

Salivary detection of COVID-19: clinical performance of oral sponge sampling for SARS-CoV-2 testing.

BACKGROUND: The current diagnostic standard for coronavirus disease 2019 (COVID-19) is reverse transcriptase-polymerase chain reaction (RT-PCR) testing with nasopharyngeal (NP) swabs. The invasiveness and need for trained personnel make the NP technique unsuited for repeated community-based mass screening. We developed a technique to collect saliva in a simple and easy way with the sponges that are usually used for tamponade of epistaxis. This study was carried out to validate the clinical performance of oral sponge (OS) sampling for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. METHODS: Over a period of 22 weeks, we collected prospectively 409 paired NP and OS samples from consecutive subjects presenting to a public community-based free screening centre. Subjects were referred by their attending physician because of recent COVID-19 symptoms (n = 147) or by the contact tracing staff of the French public health insurance because they were considered as close contacts of a laboratory-confirmed COVID-19 case (n = 262). RESULTS: In symptomatic subjects, RT-PCR SARS-CoV-2 testing with OS showed a 96.5% (95% CI: 89.6-94.8) concordance with NP testing, and a 93.2% (95% CI: 89.1-97.3) sensitivity when using the IdyllaTM platform and a sensitivity of 76.3% (95% CI: 69.4-83.2) on the Synlab Barla laboratory platform. In close contacts the NP-OS concordance (93.8%, 95% CI: 90.9-96.7) and OS sensitivity (71.9%, 95% CI: 66.5-77.3) were slightly lower. CONCLUSION: These results strongly suggest that OS testing is a straightforward, low-cost and high-throughput sampling method that can be used for frequent RT-PCR testing of COVID-19 patients and mass screening of populations.

Evaluation of Sample Pooling for SARS-CoV-2 Detection in Nasopharyngeal Swab and Saliva Samples with the Idylla SARS-CoV-2 Test.

Due to increased demand for testing, as well as restricted supply chain resources, testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to face many hurdles. Pooling several samples has been proposed as an alternative approach to address these issues. We investigated the feasibility of pooling nasopharyngeal swab (NPS) or saliva samples for SARS-CoV-2 testing with a commercial assay (Idylla SARS-CoV-2 test; Biocartis). We evaluated the 10-pool and 20-pool approaches for 149 subjects, with 30 positive samples and 119 negative samples. The 10-pool approach had sensitivity of 78.95% (95% confidence interval [CI], 54.43% to 93.95%) and specificity of 100% (95% CI, 71.51% to 100%), whereas the 20-pool approach had sensitivity of 55.56% (95% CI, 21.20% to 86.30%) and specificity of 100% (95% CI, 25% to 100%). No significant difference was observed between the results obtained with pooled NPS and saliva samples. Given the rapidity, full automation, and practical advantages of the Idylla SARS-CoV-2 assay, pooling of 10 samples has the potential to significantly increase testing capacity for both NPS and saliva samples, with good sensitivity. IMPORTANCE To control outbreaks of coronavirus disease 2019 (COVID-19) and to avoid reagent shortages, testing strategies must be adapted and maintained for the foreseeable future. We analyzed the feasibility of pooling NPS and saliva samples for SARS-CoV-2 testing with the Idylla SARS-CoV-2 test, and we found that sensitivity was dependent on the pool size. The SARS-CoV-2 testing capacity with both NPS and saliva samples could be significantly expanded by pooling 10 samples; however, pooling 20 samples resulted in lower sensitivity.

A rapid near-patient RT-PCR test for suspected COVID-19: a study of the diagnostic accuracy.

BACKGROUND: Management of large numbers of reverse transcriptase-polymerase chain reactions (RT-PCR) for diagnosis of coronavirus 2019 disease (COVID-19) requires robust infrastructures, located in dedicated premises with a high standard of biosafety procedures, and well-trained personnel. The handling of a "run-of-river sample" to obtain rapid reporting of results is challenging. METHODS: We studied the clinical performance of the Idylla™ SARS-CoV-2 Test (index test) on a platform capable of fully automated nucleic acid testing including extraction, amplification, and detection in a single-use cartridge to establish the diagnosis of COVID-19. The study was conducted on a prospective cohort of 112 volunteers with recent symptoms and an unknown SARS-CoV-2 status who came to free screening centers of the Nice metropolitan area. All subjects underwent bilateral nasopharyngeal sampling. One sample was processed using the index test, the other using the standard of care RT-PCR. Samples were treated blind. RESULTS: Most of the participants (70%) were sampled within 4 days of symptom onset. Forty-five (40.2%) were positive for COVID-19. No clinical symptoms were distinguished between SARS-CoV-2 RT-PCR positive and negative subjects except anosmia and dysgeusia. Positive and negative agreement between the index and the standard of care test was 100%. CONCLUSIONS: The Idylla™ SARS-CoV-2 Test is very sensitive, specific, rapid and easy to use in a near-patient RT-PCR approach to distinguish between symptomatic SARS-CoV-2 positive and negative patients in selected settings.

Detection of ALK fusion transcripts in plasma of non-small cell lung cancer patients using a novel RT-PCR based assay.

BACKGROUND: Detection of genomic rearrangements, like anaplastic lymphoma kinase (ALK) fusions, is a pivotal requirement in non-small cell lung cancer (NSCLC) for the initiation of a targeted treatment. While tissue testing remains the gold standard, detection of these alterations using liquid biopsies is an unmet need. To enable the detection of ALK rearrangements from circulating-free RNA (cfRNA) from NSCLC patients, we have evaluated a novel reverse transcription PCR (RT-PCR) based assay. METHODS: Sixty-six patients with advanced stage NSCLC were included in the study. ALK status was determined by immunohistochemistry (IHC) and/or FISH on tissue sections. For the detection of ALK rearrangements from 2ml plasma collected in EDTA or Streck BCT DNA tubes, cfRNA was extracted using a prototype cfRNA sample preparation method and tested by a novel multiplex ALK/RET RT-PCR assay (Roche). RESULTS: Of the forty-two patients with an ALK rearrangement, 30 (71%) were included at baseline. In 10 of the baseline patients, an ALK rearrangement was detected by RT-PCR [baseline sensitivity 33.33% (95% CI: 17.29-52.81%)]. All 24 negative ALK IHC/FISH-negative patients were negative using the RT-PCR based assay (specificity =100%). CONCLUSIONS: The prototype Roche ALK/RET RT-PCR assay was able to detect ALK fusion transcripts in the plasma of NSCLC patients at baseline as well as at disease progression with limited sensitivity but high specificity. Consequently, this assay could potentially be considered to select patients for an ALK-targeting therapy when tissue samples are lacking.

A machine learning approach to predict extreme inactivity in COPD patients using non-activity-related clinical data.

Facilitating the identification of extreme inactivity (EI) has the potential to improve morbidity and mortality in COPD patients. Apart from patients with obvious EI, the identification of a such behavior during a real-life consultation is unreliable. We therefore describe a machine learning algorithm to screen for EI, as actimetry measurements are difficult to implement. Complete datasets for 1409 COPD patients were obtained from COLIBRI-COPD, a database of clinicopathological data submitted by French pulmonologists. Patient- and pulmonologist-reported estimates of PA quantity (daily walking time) and intensity (domestic, recreational, or fitness-directed) were first used to assign patients to one of four PA groups (extremely inactive [EI], overtly active [OA], intermediate [INT], inconclusive [INC]). The algorithm was developed by (i) using data from 80% of patients in the EI and OA groups to identify 'phenotype signatures' of non-PA-related clinical variables most closely associated with EI or OA; (ii) testing its predictive validity using data from the remaining 20% of EI and OA patients; and (iii) applying the algorithm to identify EI patients in the INT and INC groups. The algorithm's overall error for predicting EI status among EI and OA patients was 13.7%, with an area under the receiver operating characteristic curve of 0.84 (95% confidence intervals: 0.75-0.92). Of the 577 patients in the INT/INC groups, 306 (53%) were reclassified as EI by the algorithm. Patient- and physician- reported estimation may underestimate EI in a large proportion of COPD patients. This algorithm may assist physicians in identifying patients in urgent need of interventions to promote PA.

Endobronchial Coil System versus Standard-of-Care Medical Management in the Treatment of Subjects with Severe Emphysema.

BACKGROUND: Bronchoscopic lung volume reduction using endobronchial coils is a new treatment for patients with severe emphysema. To date, the benefits have been modest and have been suggested to be much larger in patients with severe hyperinflation and nonmulti-comorbidity. OBJECTIVE: We aimed to evaluate the efficacy and safety of endobronchial coil treatment in a randomized multicenter clinical trial using optimized patient selection. METHOD: Patients with severe emphysema on HRCT scan with severe hyperinflation (residual volume [RV] ≥200% predicted and RV/total lung capacity [TLC] >55%) were randomized to coil treatment or control. Primary outcome measures were differences in the forced expiratory volume in 1 s (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score at 6 months. RESULTS: Due to premature study termination, a total of 120 patients (age 63 ± 7 years, FEV1 29 ± 7% predicted, RV 251 ± 41% predicted, RV/TLC 67 ± 6%, and SGRQ 58 ± 13 points), instead of 210 patients, were randomized. At study termination, 91 patients (57 coil and 34 control) had 6-month results available. Analyses showed significantly greater improvements in favor of the coil group. The increase in FEV1 was greater in the coil group than that in the control group by + 10.3 [+4.7 to +16.0] % and in SGRQ by -10.6 [-15.9 to -5.4] points. At study termination, there were 5 (6.8%) deaths in the coil cohort reported. CONCLUSION: Despite early study termination, coil treatment compared to control results in a significant improvement in the lung function and quality of life benefits for up to 6 months in patients with emphysema and severe hyperinflation. These improvements were of clinical importance but were associated with a higher likelihood of serious adverse events.

Prospective Multicenter Validation of the Detection of ALK Rearrangements of Circulating Tumor Cells for Noninvasive Longitudinal Management of Patients With Advanced NSCLC.

INTRODUCTION: Patients with advanced-stage NSCLC whose tumors harbor an ALK gene rearrangement benefit from treatment with multiple ALK inhibitors (ALKi). Approximately 30% of tumor biopsy samples contain insufficient tissue for successful ALK molecular characterization. This study evaluated the added value of analyzing circulating tumor cells (CTCs) as a surrogate to ALK tissue analysis and as a function of the response to ALKi. METHODS: We conducted a multicenter, prospective observational study (NCT02372448) of 203 patients with stage IIIB/IV NSCLC across nine French centers, of whom 81 were ALK positive (immunohistochemistry or fluorescence in situ hybridization [FISH]) and 122 ALK negative on paraffin-embedded tissue specimens. Blood samples were collected at baseline and at 6 and 12 weeks after ALKi initiation or at disease progression. ALK gene rearrangement was evaluated with CTCs using immunocytochemistry and FISH analysis after enrichment using a filtration method. RESULTS: At baseline, there was a high concordance between the detection of an ALK rearrangement in the tumor tissue and in CTCs as determined by immunocytochemistry (sensitivity, 94.4%; specificity 89.4%). The performance was lower for the FISH analysis (sensitivity, 35.6%; specificity, 56.9%). No significant association between the baseline levels or the dynamic change of CTCs and overall survival (hazard ratio = 0.59, 95% confidence interval: 0.24-1.5, p = 0.244) or progression-free survival (hazard ratio = 0.84, 95% confidence interval: 0.44-1.6, p = 0.591) was observed in the patients with ALK-positive NSCLC. CONCLUSIONS: CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs revealed promise for real-time patient monitoring and improved delivery of molecularly guided therapy in this population.

Setting-Up a Rapid SARS-CoV-2 Genome Assessment by Next-Generation Sequencing in an Academic Hospital Center (LPCE, Louis Pasteur Hospital, Nice, France).

Introduction: Aside from the reverse transcription-PCR tests for the diagnosis of the COVID-19 in routine clinical care and population-scale screening, there is an urgent need to increase the number and the efficiency for full viral genome sequencing to detect the variants of SARS-CoV-2. SARS-CoV-2 variants assessment should be easily, rapidly, and routinely available in any academic hospital. Materials and Methods: SARS-CoV-2 full genome sequencing was performed retrospectively in a single laboratory (LPCE, Louis Pasteur Hospital, Nice, France) in 103 SARS-CoV-2 positive individuals. An automated workflow used the Ion Ampliseq SARS-CoV-2 panel on the Genexus Sequencer. The analyses were made from nasopharyngeal swab (NSP) (n = 64) and/or saliva (n = 39) samples. All samples were collected in the metropolitan area of the Nice city (France) from September 2020 to March 2021. Results: The mean turnaround time between RNA extraction and result reports was 30 h for each run of 15 samples. A strong correlation was noted for the results obtained between NSP and saliva paired samples, regardless of low viral load and high (>28) Ct values. After repeated sequencing runs, complete failure of obtaining a valid sequencing result was observed in 4% of samples. Besides the European strain (B.1.160), various variants were identified, including one variant of concern (B.1.1.7), and different variants under monitoring. Discussion: Our data highlight the current feasibility of developing the SARS-CoV-2 next-generation sequencing approach in a single hospital center. Moreover, these data showed that using the Ion Ampliseq SARS-CoV-2 Assay, the SARS-CoV-2 genome sequencing is rapid and efficient not only in NSP but also in saliva samples with a low viral load. The advantages and limitations of this setup are discussed.

Circulating tumour cells as a potential biomarker for lung cancer screening: a prospective cohort study.

BACKGROUND: Lung cancer screening with low-dose chest CT (LDCT) reduces the mortality of eligible individuals. Blood signatures might act as a standalone screening tool, refine the selection of patients at risk, or help to classify undetermined nodules detected on LDCT. We previously showed that circulating tumour cells (CTCs) could be detected, using the isolation by size of epithelial tumour cell technique (ISET), long before the cancer was diagnosed radiologically. We aimed to test whether CTCs could be used as a biomarker for lung cancer screening. METHODS: We did a prospective, multicentre, cohort study in 21 French university centres. Participants had to be eligible for lung cancer screening as per National Lung Screening Trial criteria and have chronic obstructive pulmonary disease with a fixed airflow limitation defined as post-bronchodilator FEV1/FVC ratio of less than 0·7. Any cancer, other than basocellular skin carcinomas, detected within the previous 5 years was the main exclusion criterion. Participants had three screening rounds at 1-year intervals (T0 [baseline], T1, and T2), which involved LDCT, clinical examination, and a blood test for CTCs detection. Participants and investigators were masked to the results of CTC detection, and cytopathologists were masked to clinical and radiological findings. Our primary objective was to test the diagnostic performance of CTC detection using the ISET technique in lung cancer screening, compared with cancers diagnosed by final pathology, or follow up if pathology was unavailable as the gold standard. This study is registered with ClinicalTrials.gov identifier, number NCT02500693. FINDINGS: Between Oct 30, 2015, and Feb 2, 2017, we enrolled 614 participants, predominantly men (437 [71%]), aged 65·1 years (SD 6·5), and heavy smokers (52·7 pack-years [SD 21·5]). 81 (13%) participants dropped out between baseline and T1, and 56 (11%) did between T1 and T2. Nodules were detected on 178 (29%) of 614 baseline LDCTs. 19 participants (3%) were diagnosed with a prevalent lung cancer at T0 and 19 were diagnosed with incident lung cancer (15 (3%) of 533 at T1 and four (1%) of 477 at T2). Extrapulmonary cancers were diagnosed in 27 (4%) of participants. Overall 28 (2%) of 1187 blood samples were not analysable. At baseline, the sensitivity of CTC detection for lung cancer detection was 26·3% (95% CI 11·8-48·8). ISET was unable to predict lung cancer or extrapulmonary cancer development. INTERPRETATION: CTC detection using ISET is not suitable for lung cancer screening. FUNDING: French Government, Conseil Départemental 06, Fondation UNICE, Fondation Aveni, Fondation de France, Ligue Contre le Cancer-Comité des Alpes-Maritimes, ARC (Canc'Air Genexposomics), Claire de Divonne-Pollner, Enca Faidhi, Basil Faidhi, Fabienne Mourou, Michel Mourou, Leonid Fridlyand, cogs4cancer, and the Fondation Masikini.