The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

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Background In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health‐related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. Materials and Methods In a prospective observational cohort study (2014–2016), outpatients with stage IV lung cancer completed demographic and EQ‐5D‐3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT‐brain (FACT‐Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). Results Of 519 patients with 1,686 EQ‐5D‐3L‐derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT‐Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK‐rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT‐Br and tests of NCF. Conclusion Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene‐addicted tumors have superior HUS. Implications for Practice In the setting of EGFR mutations or ALK rearrangement non‐small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ‐5D questionnaire is associated with measures of health‐related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.

Introduction BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741, BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. Methods Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed. Results Carrying the homozygous variants of both polymorphisms (“double homozygotes”, DH) when compared with those carrying the double wild-type, was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95%CI: 1.9–4.0). This was confirmed in the BR.24 trial (aHR 8.97, 95%CI: 3.3–18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (p<0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH. Conclusion Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival.