Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions—International Pediatric Low-Grade Glioma Coalition

Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry

ObjectiveInterim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS).MethodsFrom September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit.ResultsAt the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0–79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician’s global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout.ConclusionData from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.Novartis Pharma A

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Structural elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle

p23 is a co-chaperone of Hsp90 but its mode of action is mechanistically not well understood. Here, the authors combine in vitro and yeast in vivo assays, biochemical measurements and NMR experiments to characterize p23 and identify two conserved helical elements in the intrinsically disordered C-terminal tail of p23 that together with the folded domain of p23 regulate the Hsp90 ATPase activity and affect the binding and maturation of Hsp90 clients