Lung-protective ventilation in acute respiratory distress syndrome (ARDS) can lead to hypercapnia, an independent risk factor for increased mortality. Extracorporeal CO2 removal (ECCO2R) enables further reduction of ventilator intensity, but its routine use is limited due to safety concerns. In the current study, we evaluated the feasibility, efficacy, and safety of minimally invasive ECCO2R (miECCO2R) implemented via a renal replacement therapy (RRT) platform in patients with mild-to-moderate ARDS and refractory hypercapnia. In this prospective single-center observational study, 20 ICU patients with persistent hypercapnia despite escalated ventilation received either standalone miECCO2R (n = 11) or miECCO2R combined with continuous RRT (n = 9). As a primary outcome, efficacy of miECCO2R was assessed. Moreover, ventilator parameters, disease severity, renal function, and adverse events were evaluated as secondary outcome parameters over a time-course of five days upon initiation of miECCO2R. miECCO2R led to a rapid and sustained reduction in PaCO2 levels from 71.4 mm Hg to 51.6 mm Hg within 24 h. This was accompanied by normalization of pH, and the median CO2 clearance rate was 64.5 mL/min. Driving pressure decreased significantly from 22 cm H2O to 15 cm H2O by day 5, while oxygenation remained stable. The standalone miECCO2R treatment group demonstrated faster CO2 reduction, probably due to higher blood flow rates. There were no severe adverse events related to either the device or the therapy. Circuit clotting was managed by system exchange, without clinical consequences for the patients. Platelet counts declined moderately, but no major bleeding complications occurred. miECCO2R delivered via an RRT platform appears to be a safe and effective method of controlling hypercapnia and facilitating lung-protective ventilation in patients with ARDS. These findings need to be supported by further randomized controlled trials that can more definitely demonstrate the impact of miECCO2R on clinical outcomes.
Introduction:Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate comprising the monoclonal antibody telisotuzumab and the monomethyl auristatin E payload. Primary analysis of the phase 2 LUMINOSITY trial (NCT03539536) revealed Teliso-V monotherapy 1.9 mg/kg elicited durable responses and had generally manageable safety in patients with locally advanced or metastatic c-Met protein overexpressing, EGFR wild-type, nonsquamous NSCLC. We present updated outcomes with approximately 6 months longer follow-up and explore the impact of previous therapies. Methods:Patients (≥18 y; had previous therapy including ≤1 chemotherapy) received 1.9 mg/kg Teliso-V every 2 weeks. c-Met protein overexpression (clinical trial assay for MET [SP44] [Roche]) was defined as greater than or equal to 25% tumor cells with 3+ staining intensity (c-Met high: ≥50% 3+; c-Met intermediate: 25 to <50% 3+). Primary end point was the overall response rate by independent central review per the Response Evaluation Criteria in Solid Tumors version 1.1. Results:As of February 21, 2024, 172 patients received at least one dose of Teliso-V; 168 patients (c-Met high, n = 84; c-Met intermediate, n = 84) were evaluable for efficacy. The overall response rate was 29.2% (95% confidence interval [CI]: 22.4-36.7; c-Met high, 34.5% [24.5-45.7]; c-Met intermediate, 23.8% [15.2-34.3]). Median duration of response was 7.2 months (95% CI: 5.5-11.0; c-Met high, 7.2 [95% CI: 4.2-12.0]; c-Met intermediate, 7.2 [95% CI: 4.7-11.5]). Previous therapy (platinum, immune checkpoint inhibitors, or both) did not impact efficacy outcomes. The most common treatment-related adverse event was peripheral sensory neuropathy (any-grade: 31%; grade ≥3: 7%). Conclusions:Teliso-V monotherapy 1.9 mg/kg elicited durable responses, irrespective of the type of previous therapy received, and maintained a manageable safety profile in patients with c-Met protein overexpressing EGFR wild-type, nonsquamous NSCLC. ClinicalTrialsgov ID number:NCT03539536.
In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (EFS) and pathologic complete response in patients with resectable non-small cell lung cancer (R-NSCLC), with a safety profile consistent with the individual agents. We report EFS from a second planned interim analysis, interim disease-free survival (DFS) and overall survival (OS), and safety, after all patients completed/discontinued treatment. In this phase III, double-blind, placebo-controlled study, patients with treatment-naïve R-NSCLC (stage II-IIIB [N2]) were randomly assigned (1:1) to neoadjuvant platinum-based chemotherapy plus durvalumab/placebo (once every 3 weeks, four cycles) presurgery and then adjuvant durvalumab/placebo (once every 4 weeks, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (n = 740; for DFS, its resected subpopulation), which excluded patients with documented EGFR/ALK aberrations. As of May 10, 2024 (median follow-up, 25.9 months [censored patients]), EFS benefit favoring the durvalumab arm remained consistent (hazard ratio [HR], 0.69 [95% CI, 0.55 to 0.88]). Numerical improvement in DFS (HR, 0.66 [95% CI, 0.47 to 0.92]) and OS (HR, 0.89 [95% CI, 0.70 to 1.14]) favored the durvalumab arm. Maximum grade 3/4 adverse events occurred in 15.4% and 10.6% of the durvalumab and placebo arms, respectively, during adjuvant treatment. These results further support perioperative durvalumab plus neoadjuvant chemotherapy as a new treatment option.
Animal models of bronchopulmonary dysplasia (BPD) have allowed the discovery of pathological and disease-management pathways. The laboratory mouse is the go-to model for first-step experimental in vivo studies. BPD encompasses disturbances to lung structure and function, including breathing patterns and gas exchange. Despite advances in quantitative assessment of lung structure in mice, most mouse modeling studies continue to use disordered lung structure as the primary experimental endpoint. Technical challenges associated with lung function studies in neonatal mice have limited enthusiasm for drawing correlations between lung structure and lung function. As this represents a key limitation of mouse BPD models, methodologies were developed here to adapt two established techniques: unrestrained whole body plethysmography (WBP) and the forced oscillation technique (FOT), enabling reliable conscious and anesthetized assessments of lung function in mouse pups. Diseased mice presented with alveolar simplification as well as a reduced tidal volume and breathing frequency, as assessed by WBP. Changes in respiratory mechanics, namely reduced tissue damping and tissue elastance, were revealed by FOT. Alterations to pressure/volume loops suggested an obstructive pattern of disease. In a clinical cohort of 65 patients with BPD, decreased tidal volume but unchanged breathing frequency was noted. Thus, with some exceptions, disturbances to lung function in experimentally modeled elements of BPD in mice paralleled those of infants with BPD. This report serves the dual function of reporting an innovative methodology, describing protocols for using WBP and FOT in neonatal mice, while reporting functional respiratory mechanics outcomes in mice in which BPD was experimentally modeled.NEW & NOTEWORTHY Clinically, respiratory disease in newborns is diagnosed and managed using lung function tests; while in animal models of newborn lung disease, lung structure is the primary experimental endpoint. Here, a comprehensive experimental protocol for assessing lung function in newborn mice is provided. Observed disturbances in lung function were discussed in the context of parallel structural changes to the lung architecture, and comparisons were drawn with clinical lung function studies in infants with BPD.
