Association between healthy behaviors and healthcare resource use with subsequent positive airway pressure therapy adherence in obstructive sleep apnoea.

BACKGROUND: The healthy adherer effect (HAE) has gained increasing attention as potential source of bias in observational studies examining the association of positive airway pressure (PAP) adherence with health outcomes in obstructive sleep apnea (OSA). RESEARCH QUESTION: Is adherence to PAP associated with healthy behaviors and healthcare resource use prior to device prescription? METHODS: Data from the IRSR Pays de la Loire Sleep Cohort were linked to health administrative data to identify proxies of heathy behaviors (HB) including adherence to cardiovascular (CV) drugs (medication possession ratio, [MPR]), cancer screening tests, influenza vaccination, alcohol and smoking consumption, and drowsiness-related road accidents during the two years preceding PAP onset in OSA patients. Multivariable regression analyses were conducted to evaluate the association of HB with subsequent PAP adherence. Healthcare resource use was evaluated according to subsequent PAP adherence. FINDINGS: We included 2,836 patients who had started PAP therapy between 2012 and 2018 (65% of whom were PAP adherent with mean daily use ≥4h/night). Being adherent to CV active drugs (MPR≥80%) and non-smoker were associated with a higher likelihood of PAP adherence (odds ratio, OR [95% confidence interval]: 1.43 [1.15; 1.77] and 1.37 [1.10; 1.71] respectively). Patients with no history of drowsiness-related road accidents were more likely to continue PAP (OR: 1.39 [1.04; 1.87]). PAP adherent patients used less healthcare resources 2 years before PAP initiation, than non-adherents (mean number of outpatient consultations: 19.0 vs 17.2, P=.003; hospitalization days: 5.7 vs 5.0, P=.04; emergency room visit: 30.7 vs 24.0% P=.0002). INTERPRETATION: Patients who adhere to PAP therapy of OSA were more health seeking and less healthcare users prior to device initiation than non-adherent patients. Until the HAE associated with PAP adherence is better understood, caution is warranted when interpreting the association of PAP adherence with CV health outcomes and healthcare resource use in non-randomized cohorts.

In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicentre study.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. METHODS: MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. RESULTS: Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. CONCLUSION: PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH.

Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. INTERPRETATION: The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. FUNDING: French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Use of a Smartphone Self-assessment App for a Tobacco-Induced Disease (COPD, Cardiovascular Diseases, Cancer) Screening Strategy and to Encourage Smoking Cessation: Observational Study.

BACKGROUND: Patient self-assessment via a mobile app detects actionable symptoms and has been shown to detect lung cancer relapses early, thereby lengthening survival. OBJECTIVE: The purpose of this study was to assess the incidence of chief symptoms associated with the main tobacco-induced pathologies in both current and ex-smokers through a self-assessment smartphone app and to evaluate the app's capacity to encourage users to quit smoking or reduce consumption, as well as its impact on early lung cancer stages at the time of diagnosis. METHODS: Current and ex-smokers were recruited through an advertising campaign in Sarthe county (France) proposing the free download of a smartphone app. App users were asked to answer 13 questions related to symptoms associated with tobacco-induced diseases (chronic obstructive pulmonary disease [COPD], cardiovascular diseases, cancer). In the event of any positive answer, a message was displayed recommending the user to consult a physician. In addition, they were asked about smoking cessation intention before and after answering these 13 questions. Finally, incidence of stage 1 or 2 lung cancers diagnosed during the launch period of our application was evaluated by comparing data from various sources to those from the same period during the previous year. RESULTS: Of the 5671 users who were eligible for evaluation, an alert was sent to the majority (4118/5671, 72.6%), with a higher incidence for current smokers (2833/3679, 77.0% vs 1298/1992, 65.2%; P<.001). The most frequent symptoms triggering the notifications were fatigue (2023/5671, 35.7%), cough (1658/5671, 29.2%), dyspnea (1502/5671, 26.5%), and persistent chest pain (1286/5671, 22.7%). Of the current smokers, 14.0% (515/3679) showed symptoms suggesting COPD, 15.5% (571/3679) showed symptoms suggesting stable angina, 12.4% (455/3679) probably had lower extremity artery disease, and 6.8% (249/3679) had possible cancer. Of the users, 36.5% (1343/3679) claimed that they thought about quitting smoking, and 48.7% (1795/3679) had thought about reducing their consumption. Surgery-eligible stage 1 and 2 lung cancer incidence was 24% (14/58) during the study period versus 9% (5/54) during the previous year in Sarthe county (P=.04), whereas it remained unchanged in the neighboring county of Maine-et-Loire. CONCLUSIONS: A majority of current and ex-smokers showed worrying symptoms, and the use of a self-assessment smartphone app may drive a majority of smokers toward the intention of smoking cessation or decreasing consumption. A randomized study should be performed to confirm this intention and to support the potential increase of symptomatic lung cancer detection at early, surgery-accessible stages. TRIAL REGISTRATION: ClinicalTrials.gov NCT04048954; https://www.clinicaltrials.gov/ct2/show/NCT04048954.

Cancer risk in patients with sleep apnoea following adherent 5-year CPAP therapy.

BACKGROUND: Increasing evidence suggests that obstructive sleep apnoea (OSA) contributes to cancer risk; however, limited data are available on the impact of continuous positive airway pressure (CPAP) therapy on cancer incidence. We aimed to determine whether adherence to CPAP therapy is associated with a reduction in all-cancer incidence compared with nonadherent patients with OSA. METHODS: The study relied on data collected by the multicentre Pays de la Loire Sleep Cohort study, linked to health administrative data, so as to identify new-onset cancer. We included patients who were prescribed CPAP for OSA, with no history of cancer before the diagnostic sleep study or during the first year of CPAP. Patients with documented CPAP use for ≥4 h per night were defined as adherent. Those who discontinued or used CPAP <4 h per night constituted the nonadherent group. A propensity score inverse probability of treatment weighting analysis was performed to assess the effect of CPAP adherence on cancer risk. RESULTS: After a median (interquartile range) follow-up of 5.4 (3.1-8.0) years, 437 (9.7%) out of 4499 patients developed cancer: 194 (10.7%) in the nonadherent group (n=1817) and 243 (9.1%) in adherent patients (n=2682). The final weighted model showed no significant impact of CPAP adherence on all-cause cancer risk (subdistribution hazard ratio 0.94, 95% CI 0.78-1.14). CONCLUSIONS: Adherence to CPAP therapy in OSA patients was not associated with a reduction in all-cancer incidence. Whether adherent CPAP therapy of OSA might reduce the risk of specific cancer sites should be further evaluated.

Association Between Nocturnal Hypoxemia and Cancer Incidence in Patients Investigated for OSA: Data From a Large Multicenter French Cohort.

BACKGROUND: Previous studies have yielded inconsistent findings regarding the association between OSA and cancer in humans. RESEARCH QUESTION: Is there an association between indexes of sleep-disordered breathing severity and cancer incidence in patients investigated for suspected OSA? STUDY DESIGN AND METHODS: Data from a large multicenter cohort of cancer-free patients investigated for OSA were linked to health administrative data to identify new-onset cancer. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association of cancer incidence with OSA severity and nocturnal hypoxemia. RESULTS: After a median follow-up period of 5.8 years (interquartile range, 3.8-7.8), 718 of 8,748 patients (8.2%) had received a diagnosis of cancer. On unadjusted Kaplan-Meier survival analyses, cancer incidence was associated with increasing severity of OSA (log-rank test, P < .0005) and nocturnal hypoxemia (log-rank test, P < .0001 for both oxygen desaturation index and percent night time with oxygen saturation < 90% [T90]). After adjustment for anthropomorphic data, smoking and alcohol consumption, comorbid cardiac, metabolic, and respiratory diseases, marital status, type of sleep study, and study site, only T90 was associated with cancer incidence (adjusted hazard ratio, 1.33; 95% CI, 1.05-1.68 for T90 ≥ 13% vs < 0.01%; P = .02). On stratified analyses, the association between T90 and cancer appeared stronger in older patients with obesity and no adequate OSA therapy. Among the most frequent cancer sites, nocturnal hypoxemia was associated with lung and breast malignancies. INTERPRETATION: Nocturnal hypoxemia was associated with all-cancer incidence in patients investigated for OSA. Whether OSA therapy might reduce the risk of cancer needs further evaluation.

Risk of scleroderma according to the type of immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Among them, ICIs-induced systemic sclerosis (SSc) is poorly known. METHODS: To better characterize this irAE, our comprehensive approach combined the description of ICIs-induced scleroderma cases, the systematic review of the literature and the analysis of VigiBase, the WHO pharmacovigilance database. RESULTS: We identified two cases with underlying limited cutaneous SSc who presented a dramatic increase in the skin thickening following pembrolizumab, associated with scleroderma renal crisis in one case. In the literature, four cases of scleroderma and four cases of morphea have been reported with pembrolizumab or nivolumab. None following ipilimumab, atezolizumab or durvalumab were retrieved. Skin changes appeared or worsened more quickly with pembrolizumab than nivolumab, and had different patterns between both drugs. Patients with generalized skin changes required high-dose prednisone to improve skin thickening. Among the 2527 scleroderma cases identified in VigiBase, 35 were associated with ICIs. Nivolumab and pembrolizumab showed a disproportionality in scleroderma reporting. No disproportionality was found for ipilimumab, atezolizumab or durvalumab. CONCLUSION: The risk of scleroderma or fibrosis extension in SSc patients should be considered when initiating anti-PD-1 agents. It suggests the role of PD-1/PD-L1 interaction in the pathophysiology of SSc.

Phenotype and Outcomes of Pulmonary Hypertension Associated with Neurofibromatosis Type 1.

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1.Objectives: To describe characteristics and outcomes of PH-NF1.Methods: We reported the clinical, functional, radiologic, histologic, and hemodynamic characteristics, response to pulmonary arterial hypertension (PAH)-approved drugs, and transplant-free survival of patients with PH-NF1 from the French PH registry.Measurements and Main Results: We identified 49 PH-NF1 cases, characterized by a female/male ratio of 3.9 and a median (minimum-maximum) age at diagnosis of 62 (18-82) years. At diagnosis, 92% were in New York Heart Association functional class III or IV. The 6-minute-walk distance was 211 (0-460) m. Pulmonary function tests showed low DlCO (30% [12-79%]) and severe hypoxemia (PaO2 56 [38-99] mm Hg). Right heart catheterization showed severe precapillary PH with a mean pulmonary artery pressure of 45 (10) mm Hg and a pulmonary vascular resistance of 10.7 (4.2) Wood units. High-resolution computed tomography images revealed cysts (76%), ground-glass opacities (73%), emphysema (49%), and reticulations (39%). Forty patients received PAH-approved drugs with a significant improvement in functional class and hemodynamic parameters. Transplant-free survival at 1, 3, and 5 years was 87%, 54%, and 42%, respectively, and four patients were transplanted. Pathologic assessment showed nonspecific interstitial pneumonia and major pulmonary vascular remodeling.Conclusions: PH-NF1 is characterized by a female predominance, a low DlCO, and severe functional and hemodynamic impairment. Despite a potential benefit of PAH treatment, prognosis remains poor, and double-lung transplantation is an option for eligible patients.

Effect of mandibular advancement therapy on inflammatory and metabolic biomarkers in patients with severe obstructive sleep apnoea: a randomised controlled trial.

Systemic inflammation and metabolic disorders are among the mechanisms linking obstructive sleep apnoea (OSA) and cardiovascular disease (CVD). In 109 patients with severe OSA and no overt CVD, biomarkers of inflammation (C reactive protein, interleukin-6, tumour necrosis factor-α and its receptors, adiponectin, leptin and P-selectin), glucose and lipid metabolism, and N-terminal pro-brain natriuretic peptide, were measured before and after 2 months of treatment with a mandibular advancement device (MAD) (n=55) or a sham device (n=54). MAD reduced the Apnoea-Hypopnoea Index (p<0.001) but had no effect on circulating biomarkers compared with the sham device, despite high treatment adherence (6.6 hour/night). TRIAL REGISTRATION NUMBER: NCT01426607.

Customized adjuvant phase II trial in patients with non-small-cell lung cancer: IFCT-0801 TASTE.

PURPOSE: Surgical resection plus adjuvant platinum-based chemotherapy is considered standard care for stage II to III non-small-cell lung cancer (NSCLC), but its efficacy is limited, and it involves toxic risks, justifying patient-tailored treatment. Excision repair cross-complementation group 1 (ERCC1) was shown to predict cisplatin-based chemotherapy response; EGFR mutations were predictive of epidermal growth factor receptor inhibition response. PATIENTS AND METHODS: This prospective randomized phase II trial enrolled 150 patients with completely resected non-squamous cell stage II or IIIA (non-N2) tumors. Patients in the control arm (n = 74) were treated with four standard-dose courses of cisplatin plus pemetrexed (CP). In the customized treatment arm (n = 76), patients with activated EGFR mutations received erlotinib 150 mg for 1 year; ERCC1-negative patients received four CP courses, whereas ERCC1-positive patients underwent follow-up. The trial sought to demonstrate the feasibility of customized adjuvant chemotherapy based on timely biomarker analysis within a 2-month postsurgery delay. Secondary objectives were tolerability, compliance with adjuvant therapy, and biomarker distribution. RESULTS: In arm A, all patients received CP; in arm B, seven received erlotinib, 53 were administered CP, and 16 underwent follow-up. Median erlotinib exposure was 344 days. Of the 127 patients allocated to CP, 82% received four cycles with good tolerability. The overall success rate of the trial (ie, percentage of patients with complete biomarker status able to start adjuvant treatment within 2 months of surgery) was 80%. CONCLUSION: The primary end point of the trial was met, demonstrating the feasibility of a national biology-driven trial in the adjuvant NSCLC setting. Nevertheless, the phase III part was canceled because of the unreliability of the ERCC1 immunohistochemical readouts.

Comorbidities of COPD.

By 2020, chronic obstructive pulmonary disease (COPD) will be the third cause of mortality. Extrapulmonary comorbidities influence the prognosis of patients with COPD. Tobacco smoking is a common risk factor for many comorbidities, including coronary heart disease, heart failure and lung cancer. Comorbidities such as pulmonary artery disease and malnutrition are directly caused by COPD, whereas others, such as systemic venous thromboembolism, anxiety, depression, osteoporosis, obesity, metabolic syndrome, diabetes, sleep disturbance and anaemia, have no evident physiopathological relationship with COPD. The common ground between most of these extrapulmonary manifestations is chronic systemic inflammation. All of these diseases potentiate the morbidity of COPD, leading to increased hospitalisations and healthcare costs. They can frequently cause death, independently of respiratory failure. Comorbidities make the management of COPD difficult and need to be evaluated and treated adequately.

Major changes in lung cancer over the last ten years in France: the KBP-CPHG studies.

The incidence of lung cancer has dramatically increased in ten years, being now the most commonly diagnosed cancer in males and the fourth most commonly diagnosed cancer in females. Considering social and scientific evolution, the aim of the present study conducted by the French College of General Hospital Respiratory Physicians (CPHG) was to compare patient and lung cancer characteristics at a ten-year interval. Two epidemiological studies, KBP-2000-CPHG and KBP-2010-CPHG, were conducted at a ten-year interval. These prospective multicentre studies included all patients ≥ 18 years of age with primary lung cancer diagnosed between 1st January and 31st December 2000 or 2010, and managed in the respiratory departments of one of the participating general hospitals. A standardised form was completed for each patient. A steering committee checked recruitment exhaustiveness. Respectively, in 2000 and 2010, 137 and 104 centres included 5667 and 7051 patients. Compared to 2000, patients in 2010 were significantly older (65.5 ± 11.3 vs. 64.3 ± 11.5 years, p < 0.0001), more frequently women (24.3% vs. 16.0%, p < 0.0001) and never-smokers (10.9% vs. 7.2%, p < 0.0001). In 2010, adenocarcinoma was the most common tumour (45.4%, vs. 29.0% in 2000, p < 0.0001). The adenocarcinoma rate increased irrespective of sex, age, or smoking status (relative risk [RR] before and after adjustment, RR = 2.07 [1.92-2.24], p < 0.0001 and 2.06 [1.90-2.23], p < 0.0001). In ten years, lung cancer characteristics have therefore changed: more women, more never-smokers, and more adenocarcinomas. The particular high increase in adenocarcinoma rate deserves further analysis.

Independent association between obstructive sleep apnea severity and glycated hemoglobin in adults without diabetes.

OBJECTIVE: We tested the hypothesis of an independent cross-sectional association between obstructive sleep apnea (OSA) severity and glycated hemoglobin (HbA(1c)) in adults without known diabetes. RESEARCH DESIGN AND METHODS: HbA(1c) was measured in whole-blood samples from 2,139 patients undergoing nocturnal recording for suspected OSA. Participants with self-reported diabetes, use of diabetes medication, or HbA(1c) value ≥6.5% were excluded from this study. Our final sample size comprised 1,599 patients. RESULTS: A dose-response relationship was observed between apnea-hypopnea index (AHI) and the percentage of patients with HbA(1c) >6.0%, ranging from 10.8% for AHI <5 to 34.2% for AHI ≥50. After adjustment for age, sex, smoking habits, BMI, waist circumference, cardiovascular morbidity, daytime sleepiness, depression, insomnia, sleep duration, and study site, odds ratios (95% CIs) for HbA(1c) >6.0% were 1 (reference), 1.40 (0.84-2.32), 1.80 (1.19-2.72), 2.02 (1.31-3.14), and 2.96 (1.58-5.54) for AHI values <5, 5 to <15, 15 to <30, 30 to <50, and ≥50, respectively. Increasing hypoxemia during sleep was also independently associated with the odds of HbA(1c) >6.0%. CONCLUSIONS: Among adults without known diabetes, increasing OSA severity is independently associated with impaired glucose metabolism, as assessed by higher HbA(1c) values, which may expose them to higher risks of diabetes and cardiovascular disease.