Hospital Clínic de Barcelona

Rationale: Excessive stress (distending pressure), strain (volume deformation), and drop in inspiratory alveolar pressure are proposed mechanisms for patient self-inflicted lung injury. Objectives: To dissect the influence of inspiratory effort, respiratory mechanics, and ventilation mode on lung stress, strain, and drop in inspiratory alveolar pressure; and explore their impact on oxygenation and lung compliance. Methods: International cohort study analyzing respiratory recordings (esophageal pressure) of patients with acute hypoxemic respiratory failure. Association between muscular pressure (Pmus), surrogates of stress (driving trans-alveolar pressure), strain (tidal volume), and inspiratory alveolar pressure relative to PEEP were explored with mixed-models, including interactions for ventilation mode, respiratory system elastance, and synchrony. Association between these and changes in oxygenation and lung compliance were explored. Measurements and main results: 60 patients from 15 centers represented 528 recordings (339,796 breaths). For each cmH(2)O Pmus increase there was an increase in driving trans-alveolar pressure (median[CI 95%] 0.28[0.27-0.29]cmH(2)O) and tidal volume (0.16[0.16-0.17]ml/kg of predicted body weight) and decrease in alveolar pressure (-0.25[0.24-0.6]cmH(2)O, p<0.001). Volume-control ventilation showed less increase in stress and strain surrogates than pressure-targeted modes, but more drop in alveolar pressure (p<0.001, Pmus:mode interaction). Breath-stacking was infrequent and associated with higher stress. Lower inspiratory alveolar pressure relative to PEEP was associated with subsequent worsening oxygenation (p=0.04) and higher stress with worsening lung compliance (p=0.023). Conclusion: Strong efforts are associated with high surrogates for lung stress, strain, and lower inspiratory alveolar pressure relative to PEEP, differently according to the mode of ventilation, being associated with subsequent worsening oxygenation and lung compliance.

Spondylodiscitis is a severe infection associated with considerable morbidity and mortality. The prevalence of gram-negative infections is on the rise, posing significant therapeutic challenges. Cefepime/enmetazobactam constitutes a novel antibiotic combination that offers broad-spectrum activity against resistant gram-negative organisms. However, its pharmacokinetic profile within spinal tissues remains unknown. To dynamically assess unbound steady-state concentrations of cefepime/enmetazobactam in healthy vertebral cancellous bone, intervertebral disc, and paravertebral muscle after both short-term and continuous infusions. 16 pigs were randomised to receive either short-term infusion (3 doses of 2 g/0.5 g cefepime/enmetazobactam administered over 2 h, repeated every 8 h) or continuous infusion (1 g/0.25 g loading dose administered over 15 min, followed by 6 g/1.5 g administered over 15 h and 45 min). Steady state was assumed during the third dosing interval (16–24 h). Microdialysis was employed to sample interstitial fluid from spondylodiscitis-relevant tissues: vertebral cancellous bone, intervertebral disc and paravertebral muscle, at steady state for 8 h. The unbound concentrations of cefepime and enmetazobactam were quantified by LC–MS/MS. The primary endpoint was to determine the time above relevant MIC (T > MIC) for cefepime (0.125, 4, 8, and 32 mg/L) and the time above relevant concentration threshold (T > Ct) for enmetazobactam (2 and 8 mg/L). For both cefepime and enmetazobactam, there were no differences in T > MIC and T > Ct when comparing dosing regimens, applying the conventional targets of MIC 0.125, 4, and 8 mg/L, and Ct of 2 mg/L. Only when applying the aggressive targets of MIC 32 mg/L and Ct 8 mg/L did continuous infusion yield longer T > MIC and T > Ct compared with short-term infusion in both the vertebral cancellous bone and intervertebral disc. Both cefepime and enmetazobactam consistently reached theoretically effective unbound steady-state tissue levels in relevant target tissues for spondylodiscitis, irrespective of the dosing regimen.

BACKGROUND AND PURPOSE:Grading meningioma guides treatment choices from follow-up to surgical resection with adjuvant radiation. Radiomics may offer a non-invasive alternative to biopsies. We assessed radiomic features (RFs) for distinguishing Grade 1 and Grade 2 meningiomas on preoperative multiparametric MRI. METHODS:Presurgical T1-weighted (T1), T2-weighted (T2), T2 gradient echo-weighted (T2GRE), fluid-attenuated inversion recovery (FLAIR), apparent diffusion coefficient (ADC), and T1-weighted contrast-enhanced (T1CE). MRI sequences of histopathologically diagnosed meningiomas were collected retrospectively. Each volume had 75 RFs extracted from semimanually segmented tumors using MintLesion Research (Version 3.10). The Lasso method selected variables from imputed data, and 10-fold cross-validation determined the optimal regularization parameter. For Lasso-retained variables, multivariate effects were estimated. RESULTS:Out of 150 patients (67.3% women), 110 (73.3%) had Grade 1 meningiomas, and 40 (26.7%) Grade 2. The strongest metrics to distinguish meningiomas Grade 1 versus Grade 2 were intensity histogram coefficient of variation on T1CE (odds ratio [OR] 0.47, 95% confidence interval [CI] 0.23-0.88; p = 0.028), maximum histogram gradient on T1 (OR 2.11, 95% CI 1.18-4.82; p = 0.043), and intensity histogram quartile coefficient of dispersion on FLAIR (OR 0.53, 95% CI 0.31-0.89; p = 0.021). The combined RFs achieved an area under the curve of 0.814 (95% CI, 0.732-0.896) for grading differentiation. Texture features and metrics extracted from T2, T2GRE, and ADC sequences did not discriminate meningioma grading. CONCLUSIONS:Histogram-based first-order RFs from T1, FLAIR, and T1CE may predict meningioma grades preoperatively. Larger, multicenter studies are needed to confirm these findings, providing insights for clinical decision-making and personalized treatment.

ABSTRACT:Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed/refractory (R/R) mantle cell lymphoma (MCL) based on the ZUMA-2 cohort 1 (ClinicalTrials.gov identifier: NCT02601313) study in which brexu-cel demonstrated a 93% objective response rate (ORR) and 67% complete response (CR) rate in patients with R/R MCL and previous BTKi therapy (N = 60). Here, we report the primary results of ZUMA-2 cohort 3 (brexu-cel in patients with BTKi-naive R/R MCL). Adults received brexu-cel at 2 × 106 anti-CD19 CAR T cells per kilogram. The primary end point was ORR assessed by independent radiology review committee (IRRC). As of 26 November 2023, 95 patients were enrolled, and 86 received brexu-cel; median follow-up was 15.5 months. The primary end point was met, with a 91% ORR (95% confidence interval [CI], 82.5-95.9; P< .0001; N = 86) and a CR rate of 73% (95% CI, 62.6-82.2). Estimated 12-month progression-free survival (PFS), duration of response, and overall survival (OS) rates were 75%, 80%, and 90%, respectively. Among 95 enrolled patients, the ORR was 82%, the CR rate was 66%, and the 12-month PFS and OS rates (95% CI) were 73% (62.1-80.8) and 85% (75.6-90.7), respectively. Most patients (88%) experienced treatment-related grade ≥3 adverse events, including 4 treatment-related grade 5 events. Consistent with cohort 1, brexu-cel demonstrated a high ORR and similar safety profile. These results support the continued use of brexu-cel in patients with R/R MCL, and consideration in some patients without previous BTKi therapy who have high-risk disease. This trial was registered at clinicaltrials.gov as #NCT04880434.

BACKGROUND:Withdrawal of prolonged nucleos(t)ide analogue (NA) treatment results in hepatitis B surface antigen (HBsAg) loss in some subjects with chronic hepatitis B (CHB), potentially revealing immune correlates of functional cure. OBJECTIVE:We investigated whether baseline or longitudinal changes in humoral immunity correlated with outcome of discontinuing prolonged NA treatment. DESIGN:Global memory B cells (MBC) and T follicular helper cells (Tfh) were analysed by flow cytometry. HBs (small surface)/HBc (core)-MBC were quantified by ex-vivo bait staining and function assessed by cultured ELISpots (enzyme-linked immunosorbent spots). Immune parameters assessed at end-of-treatment (EOT), 12 and 48 weeks after treatment withdrawal (and at 4-8 years in a subset) were correlated with intrahepatic and longitudinal serum viral markers and alanine transaminase (ALT). RESULTS:Individuals on prolonged NA had comparable frequencies of HBc-MBC and HBs-MBC, although the latter were PD-1hi and functionally defective. Following treatment withdrawal, increases in class-switched HBc-MBC were frequently temporally linked with hepatic flares. Subjects achieving HBsAg loss had an increase in activated global MBC detectable at EOT that become more marked by week 48, accompanied by significant increases in plasmablasts. HBs-MBC in those with HBsAg loss showed significant reductions in PD-1, trends to increased activation (CD71) and function and a more robust correlation with Tfh, compared with HBsAg persistence. MBC changes were maintained 4-8 years after HBsAg seroconversion. CONCLUSION:Differences in global and HBs-specific B cell immunity associate with HBsAg loss, whereas HBc-MBC temporally associates with flares, following withdrawal of prolonged NA treatment. Our results underscore the need to further explore the potential of B cell targets for monitoring and enhancing HBV functional cure in larger cohorts.