Citations

Adenosine boasts promising preclinical and clinical data supporting a vital role in modulating vascular homeostasis. Its widespread use as a diagnostic and therapeutic agent have been limited by its short half‐life and complex biology, though adenosine‐modulators have shown promise in improving vascular healing. Moreover, circulating adenosine has shown promise in predicting cardiovascular (CV) events. We sought to delineate whether circulating plasma adenosine levels predict CV events in patients undergoing invasive assessment for coronary artery disease. Patients undergoing invasive angiography had clinical data prospectively recorded in the Cardiovascular and Percutaneous ClInical TriALs (CAPITAL) revascularization registry and blood samples collected in the CAPITAL Biobank from which adenosine levels were quantified. Tertile‐based analysis was used to assess prediction of major adverse cardiovascular events (MACE; composite of death, myocardial infarction, unplanned revascularization, and cerebrovascular accident). Secondary analyses included MACE subgroups, clinical subgroups and adenosine levels. There were 1,815 patients undergoing angiography who had blood collected with adenosine quantified in 1,323. Of those quantified, 51.0% were revascularized and 7.3% experienced MACE in 12 months of follow‐up. Tertile‐based analysis failed to demonstrate any stratification of MACE rates (log rank, P = 0.83), when comparing low‐to‐middle (hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.68–1.78, P = 0.70) or low‐to‐high adenosine tertiles (HR 0.95, 95% CI 0.56–1.57, P = 0.84). In adjusted analysis, adenosine similarly failed to predict MACE. Finally, adenosine did not predict outcomes in patients with acute coronary syndrome nor in those revascularized or treated medically. Plasma adenosine levels do not predict subsequent CV outcomes or aid in patient risk stratification.

Abstract The role of active antitumor immunity in hormone receptor–positive (HR+) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP+ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP+ (NSG-R) mouse model. Treatment with the antiprogestin mifepristone (MFP) inhibited growth of 59–2-HI tumors with similar kinetics in both animal models. Interestingly, MFP treatment reshaped the tumor microenvironment, enhancing the production of proinflammatory cytokines and chemokines. Tumors in MFP-treated immunocompetent mice showed increased infiltration of F4/80+ macrophages, natural killer, and CD8 T cells, displaying a central memory phenotype. Mechanistically, MFP induced immunogenic cell death (ICD) in vivo and in vitro, as depicted by the expression and subcellular localization of the alarmins calreticulin and HMGB-1 and the induction of an ICD gene program. Moreover, MFP-treated tumor cells efficiently activated immature dendritic cells, evidenced by enhanced expression of MHC-II and CD86, and induced a memory T-cell response, attenuating tumor onset and growth after re-challenge. Finally, MFP treatment increased the sensitivity of HR+ 59–2-HI tumor to PD-L1 blockade, suggesting that antiprogestins may improve immunotherapy response rates. These results contribute to a better understanding of the mechanisms underlying the antitumor effect of hormonal treatment and the rational design of therapeutic combinations based on endocrine and immunomodulatory agents in HR+ breast cancer. Significance: Antiprogestin therapy induces immunogenic tumor cell death in PRA-overexpressing tumors, eliciting an adaptive immune memory response that protects mice from future tumor recurrence and increases sensitivity to PD-L1 blockade.

Abstract Background The prognostic implications of cardiac procedural myocardial injury and infarction (MI) in chronic coronary syndrome patients undergoing elective percutaneous coronary intervention (PCI) is still debated. Objective To determine the optimal cardiac troponin threshold for identifying prognostically important events. Methods Using a pooled dataset of nine registries and one randomized trial, we analysed individual data of 14,433 patients undergoing elective PCI with a normal or moderately elevated baseline pre-PCI cardiac troponin (cTn). A multivariate model was performed to evaluate the associations between post-PCI cTn elevation and 1-year mortality after PCI, including thresholds used by existing procedural myocardial injury definitions (Fourth Universal Definition of MI [UDMI] and Academic Research Consortium 2 [ARC-2] / Society for Cardiovascular Angiography and Interventions (SCAI)). The association between type 4a MI and 1-year mortality was also evaluated. Results Procedural myocardial injury defined by the Fourth UDMI occurred in 52.5% of patients and was not associated with 1-year mortality (adjOR 1.27, 95% CI [0.90–1.81] p=0.18). The association between post-PCI cTn elevation and 1-year mortality was significant above a 3-fold increase above the upper reference limit, and was optimal for a 5.2-fold increase which corresponded to an 18.3% rate of event, and an adjOR of 2.03 (95% CI [1.31–3.14], p=0.002) (figure). Procedural myocardial injury defined by the ARC-2/SCAI definition occurred in 1.3% of the patients, had a strong association with 1-year mortality (adjOR 4.15, 95% CI [1.62–10.64], p<0.01) but lacked sensitivity (5.2% sensitivity). Type 4a MI occurred in 12.7% of patients, was strongly associated with 1-year mortality (adjOR 3.18, 95% CI [1.47–6.90], p=0.002), but could only be evaluated in a subset of patients (n=3 084) with available data on new myocardial ischaemia post-PCI. Conclusions We have demonstrated that a post-PCI cTn elevation ≥5x the 99th percentile URL in CCS patients with normal baseline cTn, represents the optimal threshold for defining prognostically important or “Major” procedural myocardial injury in the absence of evidence for new myocardial ischaemia. Major procedure related myocardial injury and type 4a MI should be considered as a quality metric and endpoints in clinical trials. Adjusted OR of mortality at 1 year Funding Acknowledgement Type of funding source: None

Abstract Introduction Chronic right ventricular pacing (RVP) has been associated with dyssynchrony, leading to increased mortality. However, there have been discrepancies in previous reports in the effect of RVP levels. Objective To sub-stratify mortality risk by age for different RVP level groups within a large real-world ICD cohort. Methods Optum® de-identified electronic health records were linked to the Medtronic Carelink data to identify dual chamber ICD recipients (2007–2017). RVP level was based on median daily pacing during the first 90 days post-implant and categorized either into groups with a cutoff of 40%, or with groups of 0–9%, 10–19%, 20–29%, 30–39%, 40–49%, and 50–100%. The endpoint was death more than 90 days post-implant. Kaplan-Meier survival curves, log-rank tests, and Cox regression were used to analyze the relationship between RVP and risk of death. Results Among 14,832 ICD patients (median age 67; 74.0% male), there were 2,602 deaths within 10 years after implant. In unadjusted comparisons, high RVP (>40%) increased the risk of death relative to low RVP (≤40%) (p<0.001). This effect remained significant in older cohort (≥67 years old at implant) (p<0.001), but not in younger cohort (<67 years old) (p=0.955) (Figure). After controlling for age, gender, pacing mode, MI, SCA, HF hospitalization, diabetes, and renal dysfunction, similar or increased risk was associated with higher pacing groups relative to the 0–9% pacing group in the older cohort, but not in the younger cohort. Conclusions Our data from a large contemporaneous real-world source suggests that older age or characteristics associated with age make patients more sensitive to chronic RVP effects. These results help reconcile differences observed in prior studies. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Medtronic, Inc.

Abstract Background/Introduction TAILOR-PCI is the largest cardiovascular genotype-based randomized trial (NCT#01742117) investigating whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes after percutaneous coronary intervention (PCI). The TAILOR-PCI Digital Sub-Study tests the feasibility of extending original follow-up of 1 year to 2 years using state-of-the-art digital solutions. Deep phenotyping acquired during a clinical trial can be leveraged by extending follow-up in an efficient and cost-effective manner using digital technology. Purpose Our objective is to describe onboarding and engagement of participants initially recruited in a large, pragmatic, international, multi-center clinical trial to a digital registry. Methods TAILOR-PCI participants, within 23 months of their index PCI, were invited by letters containing a URL to the Digital Sub-Study website (http://tailorpci.eurekaplatform.org). These invitations were followed by phone calls, if no response to the letter, to determine reason for non-participation. A NIH-funded direct-to-participant digital research platform (the Eureka Research Platform) was used to onboard, consent and enroll participants for the digital follow-up. Participants were asked to answer health-related surveys at fixed intervals using the Eureka mobile app and desktop platform. To capture hospitalizations, participants could enable geofencing to allow background location tracking, which triggered surveys if a hospitalization was detected. Result(s) Letters were mailed to 893 of 929 eligible participants across 22 sites in the United States and Canada leading to 226 homepage visits and 118 registrations. There were 107 consents (12.0% of invited; mean age: 66.4±9.0; 19 females [18%]): 47 (44%) participants consented after the letter, 36 (34%) consented after the 1st call and 24 (22%) consented after a 2nd call. Among those who consented, 100 were eligible (7 did not have a smartphone) 81 downloaded the study mobile app and 73 agreed for geofencing (Figure 1). Among the 722 invited participants who were surveyed, 354 declined participation: due to lack of time (146; 20.2%), lack of smartphone (125; 17.3%), difficulty understanding (41; 5.7%), concern about using smartphone (34; 4.7%), concern of data privacy (14; 1.9%), concerns of location tracking (6; 0.8%) and other reasons (57; 7.9%). Conclusion Extended follow-up of a clinical trial using a digital platform is feasible but uptake in this study population was limited largely due to lack of time or a smartphone among participants. Based on data from other digital studies, uptake may also have been limited since digital follow-up consent was not incorporated at the time of consent for the main trial. Figure 1. Onboarding of the digital substudy Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institute of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

Introduction: Based on an established classification system of Apert syndrome subtypes, we aim to directly analyze the correlation between segmented airway volume changes and different skull suture synostosis, so as to provide individualized surgical planning for each subgroup of Apert patients. Methods: CT scans of 44 unoperated Apert syndrome and 53 controls were included and subgrouped as: type I. Bilateral coronal synostosis; type II. Pansynostosis; type III. Perpendicular combinations of cranial vault synostosis. CT scans were measured using Mimics and 3-matics software. Results: Type I developed a 41% ( P = .116) reduction in the nasal cavity, yet a normal sized pharyngeal airway. The reduced nasal airway was linked to the decreased cross sectional area ( r = 0.598, P = .001), vertical dimension ( r = 0.719, P < .001), and narrower width ( r = 0.727, P < .001). Type II developed proportionally reduced nasal airway and pharyngeal airway volumes (both 47%, P = .113 and P = .041), along with the proportionally restricted cross sectional areas at choana and condylion levels by 62 to 65%. This reduction is related to the cranial base length ( r = 0.712, P = .048), and also cranial base angulation ( r = 0.780, P = .023). Nasal and pharyngeal airway developed normal volume in type III. However, the cross sectional areas at the gonion level diminished by 74% ( P < .001). Conclusion: Airway development is influenced by subtype of Apert suture synostosis. Type II pansynostosis Apert patients developed synchronous reduced nasal and pharyngeal airways, which is correlated with the slightly flattened cranial base. Type I bicoronal patients have a smaller nasal cavity, but normally sized hypopharynx. Yet, type III patients developed normal nasopharyngeal airway volume overall.

Background: The use of prescribed medications during pregnancy is a challenge and an underestimated source of treatment burden. Levothyroxine (LT4) for the treatment of overt and subclinical hypothyroidism is extensively prescribed during pregnancy. To this end, we aimed to explore the patients' perceived benefits and risks, knowledge, beliefs, attitudes, and related burden of LT4 therapy during pregnancy. Methods: In this cross-sectional study, we surveyed pregnant women who were treated with LT4 during pregnancy from January 1, 2019, to December 31, 2019, in a tertiary academic medical center of the United States. The anonymous online survey included questions to gather demographic data and multiple-choice questions regarding the benefits and risks, knowledge, beliefs, attitudes, and burden related to LT4 use during pregnancy. Results: Sixty-four pregnant women (mean age 31.5 years) completed the study survey (response rate: 96%): 62% were diagnosed with hypothyroidism more than 12 months before pregnancy, 16% less than or about 12 months before pregnancy, and 22% during pregnancy. We found that one-third of pregnant women using LT4 had a feeling of uneasiness/anxiety due to their hypothyroidism diagnosis. About half of the respondents (45%) reported that they did not receive an explanation by their clinician regarding the maternal/fetal risks of uncontrolled hypothyroidism or the benefits of adequate control. Finally, two in three patients expressed various concerns of LT4-related treatment burden. Conclusions: Our findings support the need for increased effective communication and tailored counseling to address fears, anxiety, and uncertainties about the benefits and risks of LT4 use in pregnancy. For patients with clear benefits from LT4 treatment in pregnancy, it could help to overcome their concerns, promote adherence, and decrease adverse maternal/fetal outcomes. For patients with no clear benefits established, clinicians need to be aware of LT4-related treatment burden in pregnancy and implement patient-centered approaches in their clinical practices.

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Background: Somatic mutations in the IDH genes are common in acute myeloid leukemia (AML). Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and enasidenib (IDH2), have shown improved clinical outcomes in patients with relapsed/refractory IDH-mutant AML and are approved for use in this setting, while investigations in combination with chemotherapy are underway in de novo AML. The prognostic significance of IDH mutations remains controversial. We hypothesize that refining our understanding of IDH-mutated AML will contribute to risk-adapted treatment strategies, including optimal use of IDH-targeted agents. The objective of our study was to identify characteristics that affect outcome in de novo IDH-mutated AML across the age spectrum utilizing a large cohort of patients enrolled on several pediatric and adult trials. Methods: The total cohort (N=3588) included patients age &lt;1 month - 88 years. Pediatric and young adult (YA) patients were treated on recent CCG/COG AML trials (CCG2961, COG 03P1, 0531, 1031, N=2231) and YA/adult patients were treated on SWOG S0106 (N=396), ECOG E1900 AML trials (N=398), Beat AML (N=363), or included in the TCGA biology study (N=200; outcomes not evaluated for this group). Patients were analyzed according to three defined age groups: "younger" 0-29 years of age (N=2401), "intermediate" 30-59 years of age (N=819) and "older" 60 years of age and above (N=319). Data regarding clinical characteristics and treatment outcomes were collected and evaluated according to the standard practices of each cooperative or research groups for the respective studies. Mutational profiling was performed by targeted sequencing for patient samples from COG trials, Beat-AML, ECOG, and SWOG; whole-genome or whole-exome sequencing for the TCGA cohort. Prevalence of IDH mutations, co-occurring mutations, and outcomes (5-year event-free survival [EFS]) were analyzed across the defined age groups. Results: The prevalence of IDH mutations among the entire cohort was 8.6% (N=276). Analysis according to mutation type demonstrated that IDH2 mutations comprised 57% (N=158) and IDH1 mutations 43% (N=118). The prevalence of IDH mutations was strongly correlated with increased age (Fig 1A); according to the age-defined cohorts was 4.0% (N=82) in younger, 15.2% (N=126) in intermediate, and 20.3% (N=65) in older patients (p&lt;0.001). The co-occurring mutational profile demonstrated that IDH mutations commonly co-occurred with NPM1,DNMT3A, and FLT3-ITD mutations (Fig 1B). Among IDH-mutant patients, 48% (N=132) harbored dual mutations (IDHmut/NPM1mut); 11.6% (N=32) triple mutations (IDHmut/NPM1mut/DNMT3Amut), the latter particularly prevalent in intermediate-aged adults (N=27/32, 85%). Analysis of the cohort with outcome data (N=2824) demonstrated that IDHmut and IDH-WT patients experienced similar EFS of 39% vs. 40%, respectively (p=0.723). Given the favorable prognostic significance of NPM1, we subsequently analyzed outcomes of this dual mutant group and found that NPM1 mutations retained favorable prognostic impact in the context of IDH mutant patients (Fig 2A). Notably, this effect was age-dependent, as those with IDHmut/NPM1mut had a favorable EFS compared to IDHmut/NPM1-WT for younger (76% vs. 24%, p&lt;0.001) and intermediate patients (43% vs. 15%, p=0.001, Fig 2B) but this favorable effect was lost in older patients (29% vs. 34%, p=0.456, Fig 2C). Among intermediate age patients, outcome was further stratified by DNMT3A status, and IDHmut/NPM1mut/DNMT3Amut patients experienced an inferior EFS of 25% vs. 57% in IDHmut/NPMmut (p=0.003, Fig 2D). Conclusion: Analysis of this large patient cohort provides the most comprehensive description of IDH mutations in AML across the age spectrum. We confirm age-associated prevalence of IDH mutations and frequent co-occurrence with NPM1 mutation in all ages and in further combination with DNMT3A mutation in intermediate-aged adults. We definitively demonstrate that IDH mutation status is not an independent prognostic determinant of outcome in any age group. Co-occurrence of NPM1 and IDH mutations favorably impacts outcome in patients &lt; 60 years of age with AML, particularly in the absence of DNMT3A mutation. Our data support that IDH inhibitors may be of particular interest in older adults and in patients &lt;60 according to co-occurring NPM1 and DNMT3A mutations. Disclosures Othus: Marck: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Radich:Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Tallman:UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Cellerant: Research Funding; Orsenix: Research Funding. Atallah:Jazz: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Hoffman La Roche: Research Funding. Levine:Novartis: Consultancy; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Gilead: Honoraria; Lilly: Consultancy, Honoraria; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).