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Background & aim We investigated the combination of rapid antigen detection (RAD) and RT-qPCR assays in a stepwise procedure to optimize the detection of COVID-19. Methods From August 2020 to November 2020, 43,399 patients were screened in our laboratory for COVID-19 diagnostic by RT-qPCR using nasopharyngeal swab. Overall, 4,691 of the 43,399 were found to be positive, and 200 were retrieved for RAD testing allowing comparison of diagnostic accuracy between RAD and RT-qPCR. Cycle threshold (Ct) and time from symptoms onset (TSO) were included as covariates. Results The overall sensitivity, specificity, PPV, NPV, LR-, and LR+ of RAD compared with RT-qPCR were 72% (95%CI 62%–81%), 99% (95% CI95%–100%), 99% (95%CI 93%–100%), and 78% (95%CI 70%–85%), 0.28 (95%CI 0.21–0.39), and 72 (95%CI 10–208) respectively. Sensitivity was higher for patients with Ct ≤ 25 regardless of TSO: TSO ≤ 4 days 92% (95%CI 75%–99%), TSO > 4 days 100% (95%CI 54%–100%), and asymptomatic 100% (95%CI 78–100%). Overall, combining RAD and RT-qPCR would allow reducing from only 4% the number of RT-qPCR needed. Conclusions This study highlights the risk of misdiagnosing COVID-19 in 28% of patients if RAD is used alone. A stepwise analysis that combines RAD and RT-qPCR would be an efficient screening procedure for COVID-19 detection and may facilitate the control of the outbreak.

Purposes Following a hospitalization for COPD, dual and triple therapies were compared in terms of persistence and relations with outcomes (exacerbations, health care resource use and costs). Methods This was a historical observational database study. All patients aged ≥45 hospitalized for COPD between 2007 and 2015 were identified in a 1/97th random sample of French claims data. Patients receiving dual therapy within 60 days after hospitalization were compared to patients receiving triple therapy, after propensity score matching on disease severity. Results Of the 3,089 patients hospitalized for COPD, 1,538 (49.8%) received either dual or triple therapy in the 2 months following inclusion, and 1,500 (48.6%) had at least 30 days of follow-up available; 846 (27.4%) received dual therapy, and 654 (21.2%) received triple therapy. After matching, the number of exacerbations was 2.4 per year in the dual vs 2.3 in the triple group (p=0.45). Among newly treated patients (n=206), persistence at 12 months was similar in the dual and triple groups (48% vs 41%, respectively, p=0.37). As compared to patients on dual therapy, more patients on triple therapy received oral corticosteroids (49.1 vs 40.4%, p=0.003) or were hospitalized for any reason (67% vs 55.8%, p=0.0001) or for COPD (35.3 vs 25.1%, p=0.0002) during follow-up. Cost of care was higher for patients on triple than for those on dual therapy (€11,877.1 vs €9,825.1, p=0.01). Conclusion Following hospitalizations for COPD, patients on dual and triple therapy experienced recurrent exacerbations, limited adherence to therapies and high cost of care. Patients on triple therapy appeared more severe than those on dual therapy, as reflected by exacerbations and health care resource use.

Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and 1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary. Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.

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BackgroundDiagnosing SARS CoV-2 infection with certainty is essential for appropriate case management. We investigated the combination of rapid antigen detection (RAD) and RT-qPCR assays in a stepwise procedure to optimize the detection of COVID-19.MethodsFrom August 2020 to November 2020, 43,399 patients were screened in our laboratory for COVID-19 diagnostic by RT-qPCR using nasopharyngeal swab. Overall, 4,691 of the 43,399 were found to be positive, and 200 were retrieved for RAD testing allowing comparison of diagnostic accuracy between RAD and RT-qPCR. Cycle threshold (Ct) and time from symptoms onset (TSO) were included as covariates.ResultsThe overall sensitivity, specificity, PPV, NPV, LR-, and LR+ of RAD compared with RT- qPCR were 72% (95%CI 62%–81%), 99% (95% CI95%–100%), 99% (95%CI 93%–100%), and 78% (95%CI 70%–85%), 0.28 (95%CI 0.21-0.39), and 72 (95%CI 10-208) respectively. Sensitivity was higher for patients with Ct ≤ 25 regardless of TSO: TSO ≤ 4 days 92% (95%CI 75%–99%), TSO > 4 days 100% (95%CI 54%–100%), and asymptomatic 100% (95%CI 78-100%). Overall, combining RAD and RT-qPCR would allow reducing from only 4% the number of RT-qPCR needed.ConclusionThis study highlights the risk of misdiagnosing COVID-19 in 28% of patients if RAD is used alone. Thus, negative results from RAD needs to be confirmed by RT-qPCR prior to making treatment decisions. A stepwise analysis that combines RAD and RT-qPCR would be an efficient screening procedure for COVID-19 detection and may facilitate the control of the outbreak.

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.

Background One of the major challenges in treating OSA is to achieve adequate CPAP adherence. Telemonitoring has the potential to provide individualized management and early recognition of problems during treatment. Research Question What is the effect of a multimodal telemonitoring intervention on treatment adherence, quality of life, and functional status in symptomatic patients with OSA and low cardiovascular risk? Study Design and Methods In a multicenter, randomized controlled trial, patients newly diagnosed with OSA were randomly assigned to multimodal telemonitoring for 6 months vs usual care (UC). Telemonitoring consisted of built-in electronic alert algorithms for early adjustment of CPAP treatment in case of side effects, leaks, or persistent residual events. The primary outcome was CPAP adherence (in hours per night). Secondary outcomes included daily symptoms such as fatigue and sleepiness, and quality of life measured by using self-reported questionnaires. Results A total of 206 patients with OSA and a median age of 50.6 years (interquartile range [IQR], 42.1; 58.1 years) were included in the study; they were predominantly male (63%) with a median BMI of 30.6 kg/m2 (IQR, 26.8; 35.1 kg/m2) and a median apnea-hypopnea index of 45.2 events/h (IQR, 34.0; 60.0 events/h). Of these, 102 received UC and 104 received telemonitoring. After 6 months of treatment, CPAP adherence was similar in the two groups when assessed either by mean duration of usage (4.73 ± 2.48 h per night in the telemonitoring group and 5.08 ± 2.44 h per night in the UC group; P = .30) or in percentage of patients adherent to treatment (> 4 h usage per night, > 70% nights; 64% in the telemonitoring group vs 72% in the UC group; P = .24). There was no significant difference between the groups in effect size of improvement in fatigue and sleepiness. Interpretation In patients with severe OSA and low cardiovascular risk, multimodal telemonitoring did not increase CPAP adherence. For both the telemonitoring and UC groups, similar improvements in daytime symptoms were achieved. Trial Registry ClinicalTrials.gov; No.: 01796769; URL: www.clinicaltrials.gov

BackgroundPD1/L1 Immune Checkpoint Inhibitors (ICI) have significantly improved long-term outcome in about 20% of advanced Non Small Cells Lung Cancer (NSCLC) patients (pts), but 80% present primary or secondary resistance. The PIONeeR project (NCT03493581) aims to predict the response/resistance to PD1/L1 ICIs in advanced NSCLC pts through a comprehensive agnostic multiparametric and longitudinal biomarkers assessment. Data presented here are a focus on the quantification of tumor infiltration by lymphocytes, their activation as potential markers of the resistance to treatment by ICI.MethodsAdvanced NSCLC pts with available archived tumor tissue at screening visit (VS), treated with standard PD1/L1 ICIs (nivolumab, pembrolizumab or atezolizumab), alone (2nd line or more) or combined with chemotherapy (1st line), were re-biopsied at 6 weeks (V2) of treatment. PD1/L1 ICIs overall response rate (ORR) was assessed by RECIST 1.1 every 6 weeks. The multiplex IHC test ”Immunoscore® CR T Cells Exhaustion” (IS TCE) quantifies cytotoxic lymphocytes expressing three checkpoints: PD1, LAG3, TIM3, extrapolating their exhaustion status, both in the stroma and parenchyma. The unsupervised neural-network-based machine learning algorithm SOM (Self-Organizing Maps) was used to classify samples based on the 27 IS TCE variables. Statistical significance of survival differences between groups was evaluated using the log-rank test.ResultsAmong the first 100 pts, (male (64%), smokers (91,8%), ConclusionsIS TCE test may help stratifying and predicting responders to anti PD1/L1 therapy through checkpoint expressing lymphocytes quantification and spatial distribution. Additional tests performed on the PIONeeR cohort to explore other aspects of the immune response to cancer should complete these results.AcknowledgementsThis work is supported by French National Research Agency (ANR-17-RHUS-0007), a partnership of AMU, APHM, AstraZeneca, Centre Léon Bérard, CNRS, HalioDx, ImCheck Therapeutics, Innate Pharma, Inserm, Institut Paoli Calmettes and sponsored by AP HM. Drug supply is funded by AstraZeneca. Special thanks to patients and families.Trial RegistrationNCT03493581Ethics ApprovalThe study is conducted in accordance with Good Clinical Practice and the French applicable regulatory requirements (Public Health Code, article L.1121-1/La loi n° 2012–300 du 5 mars 2012 relative aux recherches impliquant la personne humaine (dite loi Jardé), the applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinski. The study was approved by the French Ethic Committee, CPP Ouest II - Angers, ref. CPP: 2028/08, Ref ANSM (French competent authority) 2018020500208, 2018072600120, 2019083000148. Freely given written informed consent was signed and obtained from each individual participating in the study, before any study specific procedure was undertaken and after the provision of information about the study by the investigator during a physician-patient consultation and sufficient time for reflection.