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BACKGROUND:ORCHARD (NCT03944772) was a phase II platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations following progressive disease (PD) on first-line osimertinib. Datopotamab deruxtecan (Dato-DXd) is an anti-TROP2 antibody-drug conjugate approved as monotherapy in EGFR-mutated advanced non-small-cell lung cancer (NSCLC). We report final data from the osimertinib plus Dato-DXd module. METHODS:Eligible patients had EGFR-mutated advanced NSCLC and PD on first-line osimertinib. Patients received oral osimertinib (80 mg once daily) plus intravenous Dato-DXd (4 or 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. RESULTS:Sixty-nine patients received study treatment. Among patients in the 4 mg/kg (N = 35) and 6 mg/kg (N = 34) cohorts, respectively, confirmed ORR was 43% [80% confidence interval (CI) 32% to 55%] and 36% (80% CI 25% to 49%); median PFS was 9.5 months (95% CI 7.2-9.8 months) and 11.7 months (95% CI 8.3-21.7 months); median DoR was 6.3 months (95% CI 3.8-8.1 months) and 20.5 months [95% CI 6.2 months-not calculable (NC); estimated median of at least 16 months]; and median OS was 19.8 months (95% CI 13.5-23.3 months) and 26.2 months (95% CI 14.8 months-NC; estimated median greater than or equal to the 4 mg/kg cohort). In the 4 mg/kg and 6 mg/kg cohorts, respectively, grade ≥3 adverse events (AEs) were reported in 49% and 76% of patients; AEs leading to Dato-DXd dose reduction in 23% and 59%; and adjudicated interstitial lung disease/pneumonitis in 3% and 15%. CONCLUSIONS:Osimertinib plus Dato-DXd demonstrated clinical benefit in patients with EGFR-mutated advanced NSCLC who progressed on first-line osimertinib. AEs in the 6 mg/kg cohort were of higher frequency and severity but could be managed with prophylaxis, careful monitoring, and dose reduction. The safety profile was consistent with the known profiles of the individual drugs. Considering the overall benefit-risk profile, 6 mg/kg is suggested as the preferred Dato-DXd starting dose for combining with osimertinib 80 mg. CLINICAL TRIAL NUMBER:ClinicalTrials.govNCT03944772.
BACKGROUND:Central retinal artery occlusion can result in permanent vision loss. Effective treatment is lacking. METHODS:We conducted a phase 3, double-blind, double-dummy, randomized, controlled trial involving adults with acute, nonarteritic central retinal artery occlusion who had symptom onset within 4.5 hours before treatment. Patients were assigned, in a 1:1 ratio, to receive intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight) and oral placebo or intravenous placebo and oral aspirin (at a dose of 300 mg). The primary end point was vision recovery, defined as a best corrected visual acuity (BCVA) in the affected eye at 30 days of up to 0.7 logMAR (logarithm of the minimum angle of resolution; equivalent to ≥20/100). Key secondary visual end points were a BCVA of up to 0.5 logMAR (equivalent to ≥20/63), mean improvement in BCVA, and perimetry score at 30 days. Key safety end points included symptomatic intracranial hemorrhage, major bleeding, and death. RESULTS:A total of 78 patients at 16 sites in six countries underwent randomization, with 40 assigned to receive tenecteplase and 38 to receive aspirin. At 30 days, 8 patients (20%) in the tenecteplase group and 9 patients (24%) in the aspirin group had vision recovery (risk difference, -3.7 percentage points; 95% confidence interval, -22.0 to 14.7; P = 0.69). The outcomes with regard to the secondary visual end points did not differ substantially between the groups. There was a greater incidence of adverse events in the tenecteplase group, including one fatal intracranial hemorrhage. CONCLUSIONS:Intravenous tenecteplase administered within 4.5 hours after onset of central retinal artery occlusion did not result in significantly greater vision recovery at 30 days than oral aspirin but was associated with serious safety concerns. (Funded by Oslo University Hospital and others; TenCRAOS ClinicalTrials.gov number, NCT04526951; EU Clinical Trials number, 2024-517606-29-00.).
INTRODUCTION:The Pediatric Inventory for Parents measures the frequency and difficulty of parental disease-related stress. We describe the psychometric properties and evaluation of the Norwegian version for mothers of infants with CHD. MATERIALS:The Pediatric Inventory for Parents contains 42 items within four domains: (1) communication, (2) emotional functioning, (3) medical care, and (4) role function. Participants assessed the frequency and difficulty of disease-related stressful events over the previous seven days. Data were collected from 48 Norwegian-speaking mothers of infants with CHD one month after hospital discharge. The psychometric properties of the frequency subscale were explored using exploratory factor analysis, and the discriminant and concurrent validity of the total scale were examined. RESULTS:Factor analysis revealed that some items had poor loadings in our sample of mothers of infants with CHD. Cronbach's alpha in domains was between 0.69 and 0.90. The Pediatric Inventory for Parents discriminated between stress levels in CHD severity in both subscales and all domains (p-values 0.03 to 0.001). Difficulty of disease-related stress and symptoms of depression were moderately correlated (r = 0.56 to 0.63). CONCLUSION:The domains on the frequency subscale were multidimensional, and some items had lack of relevance to the population studied. Despite this, the Pediatric Inventory for Parents differentiated between stress in different CHD severity groups and correlated moderately with symptoms of depression. We recommend developing an infant version of the instrument. If the original version is used in mixed populations, lack of relevance of some items to infants should be accounted for.
BACKGROUND:Adrenal crisis is a life-threatening emergency. Despite preventive strategies, previous reports suggest increasing incidence and substantial mortality, but robust validated data are limited. OBJECTIVE:To assess temporal trends in adrenal crisis incidence and identify associated risk factors. METHODS:We studied 1040 patients with autoimmune or idiopathic primary adrenal insufficiency enrolled in the Norwegian Addison Registry. Medical records were reviewed for crisis-related hospitalizations between 2000 and 2023. Overt adrenal crisis was defined by acute clinical deterioration with hemodynamic or biochemical abnormalities, whereas incipient crisis was defined by typical symptoms without objective abnormalities. RESULTS:During a median follow-up of 15 years, 660 patients (63%) experienced crisis-related hospitalizations, and 265 (25%) had an overt adrenal crisis after diagnosis. The incidence of overt crises was 3.2 per 100 person-years and that of incipient crises was 6.9 per 100 person-years. Admission rates for incipient crises increased significantly over time (p < 0.001), whereas overt crisis rates remained stable. Among 1754 admissions, five deaths (0.3%) were attributed to adrenal crisis. Both younger and older age (p < 0.001) and type 1 diabetes (incidence rate ratio 2.09, 95% confidence interval 1.45-3.01; p < 0.001) were associated with increased overt crisis risk. Daily corticosteroid dose was not associated with crisis risk. Prehospital stress dosing was used in about 50% of admissions. CONCLUSIONS:Overt adrenal crisis was uncommon and crisis-related in-hospital mortality was exceptionally low. Crisis risk was independent of replacement dose but increased in patients with type 1 diabetes. Strengthening education and implementation of prehospital stress dosing may further reduce the burden of adrenal crises.
