Daily Respiratory Research Analysis

BACKGROUND: The aim of this study was to explore the biological impact of chemotherapy during epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in individuals with non-small cell lung cancer (NSCLC). METHODS: Plasma and tumor tissue specimens were prospectively collected from NSCLC patients with EGFR activating mutations who participated in a randomized phase III study comparing EGFR-TKI therapy with or without inserted chemotherapy (JCOG1404/WJOG8214L). The specimens were analyzed for genetic mutations by droplet digital polymerase chain reaction analysis and next-generation sequencing. RESULTS: Two hundred patients were enrolled in this biomarker study, with 113 and 87 individuals receiving EGFR-TKI monotherapy and EGFR-TKI treatment plus inserted chemotherapy, respectively. Although progression-free survival (PFS) for EGFR-TKI monotherapy was shorter in patients with than in those without detectable EGFR activating mutations in cell-free DNA at baseline, inserted chemotherapy improved PFS compared with EGFR-TKI monotherapy for the former patients (median, 17.5 vs. 11.8 months). Inserted chemotherapy suppressed the number of alleles positive for activating and T790M mutations of EGFR in cell-free DNA at disease progression. The benefit of inserted chemotherapy relative to EGFR-TKI monotherapy was more apparent in patients with (median PFS, 18.8 vs. 13.5 months) than in those without detectable concurrent mutations of TP53. CONCLUSIONS: Chemotherapy has the potential to suppress the development of EGFR-TKI resistance as well as to inhibit tumor growth for NSCLC positive for EGFR activating mutations. Our results provide biological insight into combination treatment with EGFR-TKIs and chemotherapy for such patients.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is the most common category of epilepsy-related mortality. Centrally mediated respiratory dysfunction has been observed to lead to death in the majority of cases of SUDEP. SUDEP also mainly occurs during nighttime sleep. This study seeks to identify sleep EEG and sleep-related respiratory biomarkers of SUDEP risk. METHODS: In this case-control study, we compared demographic, clinical, EEG, and respiratory data from people with epilepsy who later died of SUDEP (the SUDEP group) with data from age and sex-matched living people with epilepsy, classified as high risk of SUDEP (with ≥1 generalised tonic-clonic seizure [GTCS] per year), low risk of SUDEP (no history of GTCS), and non-epilepsy controls. These data were prospectively collected as part of a multicentre National Institutes of Health study. We analysed sleep macroarchitecture and microarchitecture features and measured sleep homoeostasis by calculating overnight change in slow wave activity (SWA; 0·5-4·0 Hz) in non-rapid eye movement (NREM) sleep during seizure-free nights using linear regression models. We also analysed sleep respiratory metrics, including inter-breath interval variability. We used receiver operating characteristic analysis to assess the individual discriminative performance of demographic, clinical, sleep EEG, and sleep-related respiratory features to predict the risk of SUDEP. FINDINGS: Between Sept 1, 2011, and Oct 15, 2022, 41 participants who later died of SUDEP and 123 matched controls (41 people living with epilepsy at hight risk of SUDEP, 41 people living with epilepsy at low-risk of SUDEP, and 41 non-epilepsy controls) were enrolled. The SUDEP group showed an abnormal lack of overnight decline and an increase in the slope of SWA power compared with the other groups (SUDEP group mean 0·005 standardised error of the mean [SEM] 0·003; high-SUDEP risk group -0·005, 0·002; low-SUDEP risk group -0·003, 0·002; non-epilepsy controls -0·007, 0·003; p=0·017). The overnight increase in the SWA slope was more pronounced in males compared with females (males mean 0·012, SEM 0·001; females 0·001, 0·002; p=0·005). The variability of the inter-breath interval was significantly higher in the SUDEP (coefficient of variation mean 0·15, SD 0·09; SD mean 0·54 s SD 0·35 s) and high-SUDEP risk groups (0·11, 0·03; 0·46 s, 0·19 s) compared with low-SUDEP risk group (0·08, 0·03; 0·30 s, 0·14 s) and non-epilepsy controls (0·08, 0·02; 0·31 s, 0·11 s; p<0·0001). The coefficient of variation of inter-breath interval had the greatest predictive power of SUDEP risk (between-group point estimate difference 0·30, AUC 0·80; 95% CI 0·70-0·90; p<0·0001). INTERPRETATION: This study identifies impaired sleep homoeostasis in the form of altered SWA progression during NREM sleep overnight in people with epilepsy who later died of SUDEP, and an increase in respiratory variability during NREM sleep in people with epilepsy who later died of SUDEP and in people with epilepsy at high risk of SUDEP. Multiday polysomnography studies are needed to validate sleep homoeostasis and respiratory variability during sleep as potential biomarkers of SUDEP risk. Further studies are required to explore possible sleep interventions that could mitigate SUDEP risk. FUNDING: National Institutes of Health-National Institute of Neurological Disorders and Stroke.

BACKGROUND: Neuromuscular electrical stimulation (NMES) has been investigated for various cardiopulmonary conditions; however, its effects on interstitial lung disease (ILD) remain poorly understood. OBJECTIVE: To investigate the effects of NMES on exercise capacity, muscle strength, quality of life, and physical activity in ILD patients. METHODS: This was a prospective, randomized, controlled, triple-blinded study. Nineteen patients in the NMES group received NMES on the bilateral quadriceps femoris (QF) at 40 Hz for 20 min, three times a week for six weeks, along with daily respiratory exercises. Eighteen patients in the control group performed respiratory exercises alone for six weeks. Outcomes measured before and after included: 6-min walk test (6MWT), incremental shuttle walk test (ISWT), maximum inspiratory and expiratory pressures (MIP, MEP), QF muscle strength, quality of life (SGRQ, LCQ), physical activity, dyspnea (MMRC scale), and fatigue (FSS). RESULTS: The NMES group demonstrated significant improvements in 6MWT distance, MMRC, energy expenditure, physical activity duration, and daily step count, with increased FSS scores compared to the control group (p = 0.025). No significant differences were observed between groups for ISWT, MIP/MEP, SGRQ, or LCQ scores (p > 0.05). While 6MWT distance improved (p = 0.002), QF muscle strength was preserved within the NMES group but decreased within the control group (p = 0.018). CONCLUSION: NMES is a feasible and effective intervention for enhancing exercise capacity and physical activity levels, while preserving muscle strength and reducing dyspnea in patients with ILD. This implies that incorporating NMES into the rehabilitation programs of ILD patients may enhance their overall physical performance and quality of life.