Onze Lieve Vrouwe Gasthuis

The risk of relapse among high-risk patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission (CMR) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy is 20% to 25%. Here, we evaluated whether consolidation with the programmed cell death ligand 1 checkpoint inhibitor atezolizumab could reduce the relapse risk. In this phase 2, open-label trial, patients with DLBCL with an International Prognostic Index (IPI) score of ≥3 and CMR after R-CHOP received 1200 mg atezolizumab every 3 weeks for 18 cycles. The primary end point was disease-free survival (DFS) at 2 years, with the aim of improving it to 89% compared to historical 79%. Secondary end points included overall survival (OS) and safety (Common Terminology Criteria for Adverse Events version 4.0). Analyses were on an intention-to-treat principle. Of 109 patients, 65% completed treatment. The cohort was 59% males, with 63% having high-intermediate risk IPI scores. At a median follow-up of 36.4 months, 15 relapses occurred (median, 8.2 months). The 2-year DFS was 87.9% (90% confidence interval [CI], 81.5-92.1), and the 2-year OS was 96.3% (90% CI, 91.7-98.3), meeting the primary objective. Treatment with salvage chemotherapy resulted in 10 of 13 patients achieving a second CMR. OS was significantly better among atezolizumab-treated patients than in a population-based matched control cohort from the Netherlands Cancer Registry. Adverse events (AEs) affected 79% of patients, with 18% developing immune-related AEs, including 4.5% grade 3 to 4. Atezolizumab consolidation significantly improved DFS in high-risk patients with DLBCL compared to historical cohorts. OS was significantly better than a population-based control cohort. These findings warrant further validation and assessment of immune checkpoint inhibitors as consolidation strategy in DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT03463057.

The npmA gene, encoding a 16S rRNA methyltransferase, confers resistance to all clinically available aminoglycosides, posing a significant threat to effective antibiotic therapy. We analyze 1,932,812 bacterial genomes to investigate the distribution and mobilization of npmA variants. npmA is not found in Gram-negative bacteria, where it was originally described, but is identified among Gram-positive bacteria, predominantly as the npmA2 variant in the globally distributed Clostridioides difficile ST11 lineage. We also detect npmA2 in two vancomycin-resistant Enterococcus faecium isolates from a Dutch hospital. Upon sequencing and phenotypic analysis, we determine that E. faecium isolates are pan-resistant to aminoglycosides. Genomic characterization links npmA2 to a composite transposon, Tn7734, which is integrated within a previously uncharacterized Integrative and Conjugative Element (ICE) Tn7740, present in both npmA2-carrying C. difficile and E. faecium clinical isolates. Tn7740-like, but not npmA2, appears across diverse taxa, including human microbiome members. Here, we show that Tn7740 likely facilitates cross-species npmA2 mobilization between these Gram-positive bacteria and emphasize the risk of mobile genetic elements transferring pan-aminoglycoside resistance between clinically important bacterial pathogens.

Liberation from invasive mechanical ventilation is a milestone in critical care, but approaches vary. This survey aimed to describe current ventilator liberation practices, relate them to available evidence, and identify areas for improvement.

A survey was performed among Dutch intensive care unit (ICU) sites. The survey evaluated practice in seven domains of ventilator liberation: protocol availability, transition from controlled to assisted ventilation, spontaneous breathing trials (SBT), cuff-leak test, postextubation support, weaning failure and tracheostomised weaning.

The survey response rate was 93% (132/142), representing 97% (69/71) of Dutch ICUs. Protocols for postextubation support and weaning failure were available in less than half of the ICUs (44% and 49%, respectively). The transition from controlled to assisted ventilation is regularly evaluated daily in 78% of ICUs. Assisted ventilation tolerance is mainly assessed by clinical signs, respiratory parameters and non-invasive manoeuvres that assess respiratory drive (P0.1). SBTs are regularly performed in 58% of ICUs, using one or more of the following methods: T-piece (52%), pressure support+positive end expiratory pressure (32%) and continuous positive airway pressure (28%). Cuff-leak tests are seldom performed (1.4%), predominantly in cases of intubation for upper-airway obstruction (92%). Postextubation respiratory support with high-flow nasal oxygen or non-invasive ventilation is used at least as often with therapeutic (43%/13%) rather than preventive (35%/4%) of facilitative intent (29%/3%). Delirium screening (87%) and reconsidering sedation (84%) are frequently assessed in case of weaning failure. Regular use of closed-loop ventilation is reported in a minority of ICUs throughout the process of ventilator liberation (3–9%).

Various aspects of ventilator liberation practices show only limited alignment with existing guidelines. The results of this survey pinpoint areas to prioritise in guideline and practice improvement.