Citations

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2. Critically, combining mRNA-N with the clinically proven S-expressing mRNA vaccine (mRNA-S+N) induced robust protection against both Delta and Omicron variants. In the hamster models of SARS-CoV-2 VOC challenge, we demonstrated that, compared to mRNA-S alone, combination mRNA-S+N vaccination not only induced more robust control of the Delta and Omicron variants in the lungs but also provided enhanced protection in the upper respiratory tract. In vivo CD8 + T cell depletion suggested a potential role for CD8 + T cells in protection conferred by mRNA-S+N vaccination. Antigen-specific immune analyses indicated that N-specific immunity, as well as augmented S-specific immunity, was associated with enhanced protection elicited by the combination mRNA vaccination. Our findings suggest that combined mRNA-S+N vaccination is an effective approach for promoting broad protection against SARS-CoV-2 variants.

BACKGROUND Ibrutinib, an irreversible Bruton tyrosine kinase inhibitor, has been associated with an increased risk of bleeding. There is a paucity of data on the risk of bleeding in patients on ibrutinib undergoing dermatologic surgery. OBJECTIVE To determine the frequency of bleeding complications associated with ibrutinib in patients undergoing dermatologic surgery. MATERIALS AND METHODS A retrospective, single-center, case–control study of patients on ibrutinib undergoing skin surgery between January 2013 and March 2020 compared with sex, disease, and age-matched control patients undergoing cutaneous surgeries. RESULTS A total of 75 surgeries performed on 37 case patients and 116 surgeries performed on 64 control patients were included. Ibrutinib was associated with a statistically significant increased rate of bleeding events (6/75 [8%] vs 1/116 [0.8%], p -value = .02). Compared with ibrutinib patients who did not have a bleeding event, those on ibrutinib who suffered bleeding were all men, older (mean age 82.7 vs 73.0, p -value= .01), and had lower mean platelet counts (104.0 vs 150.5 K/μL, p -value = .03). CONCLUSION Ibrutinib may be associated with increased risk of bleeding in patients with hematologic malignancies, particularly older men with lower platelet levels and on multiple anticoagulants. Transient discontinuation of ibrutinib should be considered for dermatologic surgeries.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P &amp;lt; .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P &amp;lt; .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P &amp;lt; .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Abstract Same day processing of biospecimens such as blood is not always feasible, which presents a challenge for research programs seeking to study a broad population or to characterize patients with rare diseases. Recruiting sites may not be equipped to process blood samples and variability in timing and technique employed to isolate peripheral blood mononuclear cells (PBMCs) at local sites may compromise reproducibility across patients. One solution is to send whole blood collected by routine phlebotomy via overnight courier to the testing site under ambient conditions. Determining the impact of shipping on subsequent leukocyte responses is a necessary prerequisite to any experimental analysis derived from transported samples. To this end, whole blood was collected from healthy control subjects and processed fresh or at 6, 24 and 48 hours after collection and handling under modeled shipping conditions. At endpoint, whole blood was assessed via a complete blood count with differential and immunophenotyped using a standardized panel of antibodies [HLADR, CD66b, CD3, CD14, CD16]. PBMCs and neutrophils were isolated from whole blood and subjected to ex vivo stimulation with lipopolysaccharide and heat-killed Staphylococcus aureus. Stimulated release of cytokines and chemokines was assessed by cytometric bead array. RNA was also isolated from PBMCs to analyze transcriptional changes induced by shipping. The complete blood count with differential revealed that most parameters were maintained in shipped blood held for 24 hours at ambient temperature. Immunophenotyping indicated preservation of cellular profiles at 24 hours, although with broadening of some populations and a decrease in CD16 intensity on classical monocytes. At the transcriptional level, RNAseq analysis identified upregulation of a transcription factor module associated with inflammation in unstimulated PBMCs derived from whole blood shipped overnight. However, these changes were limited in both scale and number of impacted genes. Ex vivo stimulation of PBMCs further revealed preservation of functional responses in cells isolated from shipped blood held for 24 hours at ambient temperature. However, neutrophil responses were largely abrogated by this time. By 48 hours neither cell population responded within normal parameters. These findings indicate that robust immunophenotyping and PBMC stimulated response profiles are maintained in whole blood shipped overnight and processed within 24 hours of collection, yielding results that are representative of those obtained from the sample immediately following venipuncture. This methodology is feasible for many patient recruitment sites to implement and allows for sophisticated immunological analysis of patient populations derived from large geographic areas. With regard to rare disease research, this meets a universal need to enroll patients in sufficient numbers for immunoprofiling and discovery of underlying pathogenic mechanisms.

Abstract BTK plays an important role in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in primary CNS lymphomas, and hence represents an excellent therapeutic target. Ibrutinib, a first-generation BTKi, was evaluated in phase 1/2 trials for R/R PCNSL, SCNSL, and PVRL, showing limited survival benefit. GB5121 is a novel, orally available, covalent BTKi with superior specificity, CNS penetration, and CNS target occupancy in preclinical testing versus other BTKis including ibrutinib. GB5121 is well-suited for evaluation in CNS lymphoma. This is a phase 1b/2 open-label study of GB5121 in adults with R/R PCNSL, isolated SCNSL or PVRL and will be conducted in three parts: phase 1b dose-escalation, expansion, and phase 2. Eligibility criteria for phase 1b dose-escalation and expansion (N≈30 for each) include age ≥18 years, ECOG≤2, R/R PCNSL, R/R SCNSL with CNS-only relapse, or R/R PVRL. Patients with newly diagnosed PCNSL who cannot tolerate standard high-dose methotrexate-based therapies are also eligible. Patients with prior allogeneic stem cell transplant are excluded. A Bayesian optimal interval design will be employed to perform dose escalation to determine the recommended phase 2 dose (RP2D). In the absence of dose-limiting toxicity (DLT), dose levels will increase sequentially according to a modified Fibonacci approach. Safety, tolerability, PK/PD, DLT, maximum tolerated dose, and preliminary therapeutic activity will be assessed to determine the optimal biological dose informing the RP2D. Phase 1b expansion will further explore therapeutic activity and characterize safety and tolerability of GB5121 at the RP2D. Phase 2 will initiate following RP2D determination. This is a single-arm, open-label study to investigate GB5121 safety and efficacy in patients with R/R PCNSL. Adverse events will be graded per CTCAE v5.0. Clinical response will be determined using International Primary CNS Lymphoma Collaborative Group criteria. Progression-free and overall survival will be evaluated. Enrollment begins May 2022 (NCT05242146).

AbstractEnteral nutrition (EN) is a vital component of nutrition around the world. EN allows for delivery of nutrients to those who cannot maintain adequate nutrition by oral intake alone. Common questions regarding EN are when to initiate and in what scenarios it is safe. The answers to these questions are often complex and require an evidence‐based approach. The Board of Directors of the American Society for Parenteral and Enteral Nutrition (ASPEN) established an Enteral Nutrition Committtee to address the important questions surrounding the indications for EN. Consensus recommendations were established based on eight extremely clinically relevant questions regarding EN indications as deemed by the Enteral Nutrition Committee. These consensus recommendations may act as a guide for clinicians and stakeholders on difficult questions pertaining to indications for EN. This paper was approved by the ASPEN Board of Directors.

Abstract Background Measurement of cholesterol within lipoprotein subfractions may aid in cardiovascular disease prediction. Simple, homogenous enzymatic assays for the direct measurement of lipoprotein subfractions have been developed to measure small dense low-density lipoprotein cholesterol (sdLDL-C), high-density lipoprotein-3 cholesterol (HDL3-C), and triglyceride-rich lipoprotein (TRL-C) cholesterol. The objective of this study was to determine biological variability for sdLDL-C, HDL3-C, and TRL-C in a healthy reference population to facilitate interpretation of these analytes. Methods Serum samples were collected from 24 healthy subjects (n = 14 female/10 male) daily for 3 days while non-fasting, and daily for 5 days, weekly for 4 weeks, and monthly for 6 months after overnight fasting. sdLDL-C, HDL3-C, and TRL-C cholesterol were measured by homogenous enzymatic assays. Sources of variability (between-subject, within-subject, and analytical) were calculated using random-effects regression models. Reference change value (RCV) and index of individuality (II) for each time period were determined from the variance components. Results Analytic variability (daily, weekly, and monthly CVA) was &lt;3% for each analyte. Monthly within-subject variability (CVI) was 17.1% for sdLDL-C, 7.4% for HDL3-C, and 25.7% for TRL-C. Most of the monthly variation was attributed to between-subject variation for all 3 analytes. Overall RCVs for monthly measurements were 18.1 mg/dL for sdLDL-C, 6.1 mg/dL for HDL3-C, and 16.0 mg/dL for TRL-C. IIs were &lt;0.6 for sdLDL-C and HDL3-C, and 0.81 for TRL-C. Conclusions sdLDL-C, HDL3-C, and TRL-C showed moderate within-subject variability, but high between-subject variability, in a healthy reference population. Given the high individuality of each analyte, population-based reference intervals may be inadequate to detect clinically significant changes.

Accurate and precise monitoring of kidney function is critical for a timely and reliable diagnosis of chronic kidney disease (CKD). The determination of kidney function usually involves the estimation of the glomerular filtration rate (eGFR). We recently reported the clinical performance of a new eGFR equation (GFRNMR) based on the nuclear magnetic resonance (NMR) measurement of serum myo-inositol, valine, and creatinine, in addition to the immunoturbidometric quantification of serum cystatin C, age and sex. We now describe the analytical performance evaluation of GFRNMR according to the Clinical and Laboratory Standards Institute guidelines. Within-laboratory coefficients of variation (CV%) of the GFRNMR equation did not exceed 4.3%, with a maximum CV% for repeatability of 3.7%. Between-site reproducibility (three sites) demonstrated a maximum CV% of 5.9%. GFRNMR stability was demonstrated for sera stored for up to 8 days at 2–10°C and for NMR samples stored for up to 10 days in the NMR device at 6 ± 2°C. Substance interference was limited to 4/40 (10.0%) of the investigated substances, resulting in an underestimated GFRNMR (for glucose and metformin) or a loss of results (for naproxen and ribavirin) for concentrations twice as high as usual clinical doses. The analytical performances of GFRNMR, combined with its previously reported clinical performance, support the potential integration of this NMR method into clinical practice.