Citations

Introduction: In conjunction with pericardial disease physician specialists, industry experts, and recurrent pericarditis (RP) patients the RESONANCE Registry was designed to collect retrospective and prospective, longitudinal, observational data in real-world clinical practice across the United States (US). We aimed to collect data that were complete and meaningful in terms of patient experience and health related quality of life (HRQoL). Herein, we describe a novel patient-centric research approach to obtain feedback on evaluation tools for incorporation in the RESONANCE Registry (NCT04687358). Methods: Ten adult patients with a self-reported duration of disease ranging from 8 months to 25 years participated in an advisory board during which they provided feedback through a virtual platform. Their feedback informed development of multiple registry aspects. These included selection of patient reported outcomes measures (PROMs), to be collected every three months at prospective data collection timepoints, and design of several questionnaires, including evaluation of specific RP episode characteristics. Results: Prior to finalization, registry case report forms were optimized based on feedback provided by patients. Areas of data-capture informed by patient input included selection of PROMs to be assessed and patient-centric tools used for self-assessment of disease experience and HRQoL. For example, sections of a patient questionnaire were modified to include documentation of the presenting symptom, breathlessness, fear of episodes, and patient management of each episode. Conclusions: This patient-centered research collaboration resulted in enhancements to the RESONANCE Registry that enabled capture of information meaningful to patients’ daily experiences, preferences, and expectations. Patient participation in tangible aspects of research, including registry tools and design, can increase engagement with the communities that have a vested interest in improving patient care. In addition, patient involvement can help to ensure research efforts reflect the needs of not only the healthcare community but of patients alike, with an ultimate goal of improving clinical outcomes.

Background: Cardiac amyloidosis (CA) results from extracellular deposition of insoluble amyloid fibrils in the myocardium, leading to myocardial stiffening, restrictive cardiomyopathy and poor prognosis. Thus, measurements of myocardial stiffness might help with identification of patients with cardiac amyloid deposition. The speed of wave transmission of myocardial stretch (Vm) is a novel measure of myocardial elasticity. Our aim was to investigate the behavior of Vm in the left ventricular (LV) myocardium of patients with CA. We hypothesized this wave speed will be increased in these patients and will partly explain the reduction in systolic myocardial function. Methods: We prospectively studied 23 consecutive patients with systemic amyloidosis, of whom 17 (age 59±13 years) had confirmed cardiac involvement (15 AL, 2 TTR), and compared to 18 control subjects (age 47±13 years) with normal LV function. Comprehensive transthoracic echocardiography was performed. Tissue Doppler cineloops (350-450 frames/s) were acquired from 6 LV walls from 3 standard apical views. Regional and global Vm were measured as the wave speed of the onset of myocardial stretch from LV base to apex (late diastole). Results: Subjects with CA (n=17) had higher Vm compared to normal subjects (2.5±0.8 vs 1.5±0.2 m/s; P<0.001, respectively). They also had lower LV ejection fraction (56±11 vs 65±4%; P=0.02), global longitudinal strain (GLS -14±5 vs -20±2%, P<0.001), and myocardial relaxation (mitral annulus septal e’ velocity 4.7±1.9 vs 9.2±2.4 cm/s; P<0.001) and higher LV mass (150±54 vs 87±18 g/m2; P<0.001), left atrial volume (44±7 vs 27±6 mL/m2; P<0.001), and estimated LV filling pressure (E/e’ 20±9 vs 8±3; P<0.001). There was a strong positive association between Vm and LV wall thickness (R=0.62; P<0.001), GLS (R=0.45; P=0.01) and septal E/e’ (R=0.42; P=0.02) and an inverse correlation between Vm and septal e’ (R=-0.39; P=0.03), but not with ejection fraction (P=0.37). Conclusion: This pilot study indicates that Vm is elevated in patients with CA compared to normal subjects, commensurate with the effects of amyloid deposition on LV structure and function. This novel measurement shows promise for noninvasive assessment of diastolic myocardial stiffness in patients with CA.

Background: Cellular transplantation has emerged as promising approach for treating cardiac diseases. However, a poor engraftment rate limits our understanding on how transplanted cardiomyocytes contribute to cardiac function in the recipient’s heart. Methods: The CRISPR/Cas9 technique was employed for stable and constitutive gene expression in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Myocardial infarction was induced in adult immunodeficient mice, followed by intramyocardial injection of hiPSC-CMs expressing either CCND2/channelrhodopsin 2 (hiPSC-CCND2OE/ChR2OECMs) or CCND2/luciferase (hiPSC-CCND2OE/LuciOECMs). Six months later, hemodynamics and intramural electrocardiogram were recorded upon blue light illuminations in anesthetized, open-chest mice. Results: Blue light resets automaticity of spontaneously beating hiPSC-CCND2OE/ChR2OECMs in culture, but not that of hiPSC-CCND2OE/LuciOECMs. Response to blue light was also observed in mice carrying large (>106 cells) intracardiac grafts of hiPSC-CCND2OE/ChR2OECM but not in mice carrying hiPSC-CCND2OE/LuciOECMs. The former exhibited single premature ventricular contractions upon light illumination or ventricular quadrigeminy upon second-long illuminations. At the onset of premature ventricular contractions, maximal systolic ventricular pressure decreased while ventricular volume rose concomitantly. Light-induced changes reversed upon resumption of sinus rhythm. Conclusions: We established an in vivo model for optogenetic-based modulation of the excitability of donor cardiomyocytes in a functional, reversible, and localized manner. This approach holds unique value for studying electromechanical coupling and molecular interactions between donor cardiomyocytes and recipient hearts in live animals.

Abstract Background: FGFR gene amplifications are found in 18% of breast cancers (BCs), with FGFR1 amplifications occurring in ≈10% of cases, predominantly in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) MBCs. FGFR1 amplifications are associated with resistance to endocrine therapy, and in preclinical experiments, FGFR pathway inhibition has been shown to overcome resistance to hormone therapy in BC harboring FGFR1 amplifications. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown preclinical activity in BC xenograft models harboring FGFR1/2 amplifications. In a phase 1 study, futibatinib showed promising clinical activity and tolerability across tumor types, including MBC, harboring various FGFR aberrations. A multicohort phase 2 trial (FOENIX-MBC2; NCT04024436) was designed to evaluate futibatinib alone (cohorts 1-3) or in combination with fulvestrant (cohort 4) in patients with MBC harboring FGFR2 or FGFR1 amplifications, respectively. Here, we report preliminary safety data from cohort 4 of FOENIX-MBC2, including data from a safety lead-in. Methods: Cohort 4 of FOENIX-MBC2 enrolled adult patients with HR+ HER2− MBC harboring high levels of FGFR1 amplification (FGFR1:CEN8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell), Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function. Patients were fulvestrant naive and had previously received 1-2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a CDK4/6 inhibitor (if eligible). Cohort 4 began with a safety lead-in to assess dose-limiting toxicities (DLTs) during the first treatment cycle. Patients received oral futibatinib 20 mg once daily continuously, and intramuscular fulvestrant 500 mg was administered on days 1 and 15 of cycle 1 and day 1 of every subsequent 28-day cycle. Patients were treated until disease progression, unacceptable toxicity, or another discontinuation criterion was met. Results: As of data cutoff (March 31, 2021), cohort 4 had enrolled 8 female patients with HR+ HER2− MBC harboring high-level FGFR1 amplification. The median age was 55.5 years (range: 31-62 years), and all patients had received ≥2 prior therapies for advanced/metastatic BC. The median duration of treatment was 8.0 weeks (range: 3.0-32.7 weeks); 3 of 8 patients (38%) were continuing treatment at time of data cutoff. All patients experienced treatment-related adverse events (TRAEs; grade ≥3: 25%). The most common TRAE was hyperphosphatemia (88%), followed by constipation (62%), transaminase elevation (50%), dry mouth (38%), and alopecia (38%). Among these TRAEs, grade ≥3 events were only reported for hyperphosphatemia (12%), and no serious adverse events were reported. In this cohort, TRAEs led to dose reductions in 4 patients, dosing interruptions in 3 patients, and treatment discontinuation in 1 patient; no patients died due to TRAEs. DLTs were evaluated in 5 patients following 1 treatment cycle (1 patient was enrolled after data cutoff, and 4 of 9 patients were not evaluable for DLTs); DLTs were not experienced by any of the 5 evaluable patients. Conclusions: Based on these preliminary safety results, the combination of futibatinib and fulvestrant appears to be safe and tolerable in patients with HR+ HER− MBC harboring high-level FGFR1 amplification. The safety profile was consistent with the individual profiles of both drugs, and the treatment combination did not appear to result in synergistic toxicity. As no DLTs were observed in 5 evaluable patients, the recommended futibatinib dose in combination with fulvestrant is 20 mg once daily. Efficacy will be evaluated in the complete 28-patient post-lead-in cohort, in which enrollment is ongoing. Citation Format: Senthil Damodaran, Nisha Unni, Karthik V. Giridhar, Brooke Daniel, Sacha Howell, Luis Costa, Marta Ferreira, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Futibatinib in combination with fulvestrant in patients with metastatic breast cancer (MBC) harboring high-level FGFR1 amplification: Preliminary data from a phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-35.

Object We sought to determine the safety and efficacy in secondary stroke prevention of carotid endarterectomy (CEA) in patients with symptomatic non-stenotic carotid artery disease (SyNC). Methods This was a single-centre retrospective case series. All patients who underwent CEA for unilateral anterior circulation cerebrovascular events with ipsilateral <50% carotid stenosis from 2002 to 2020 were included. Imaging hallmarks including the degree of luminal stenosis and the presence of various vulnerable plaque characteristics (eg, intraplaque haemorrhage (IPH) on MR angiography, ulceration or low-density plaque on CT angiography) were assessed. The presence of vulnerable plaque characteristics was compared between arteries ipsilateral to the ischaemic event and contralateral arteries. The prevalence of perioperative/intraoperative complications, as well as recurrent ischaemic events at follow-up was determined. Results Thirty-two patients were included in the analysis, of which 25.0% were female. Carotid arteries ipsilateral to an ischaemic event had a significantly higher prevalence of IPH when compared with contralateral arteries (80.0% vs 0.0%; p<0.001). There were no intraoperative complications. One patient (3.1%) developed symptoms of transient ipsilateral ischaemia 1 day following CEA which resolved without treatment. In a median follow-up of 18.0 months (IQR 5.0–36.0), only one patient (3.1%) experienced a transient neurologic deficit with complete resolution (annualised rate of recurrent stroke after CEA of 1.5% for a total follow-up of 788 patient-months following CEA). All other patients (31/32, 96.9%) were free of recurrent ischaemic events. Conclusion CEA appears to be safe and well-tolerated in patients with SyNC. Additional studies with larger cohorts and longer follow-up intervals are needed in order to determine the role of CEA in this patient population.

Skeletal muscle is highly plastic and dynamically regulated by the body’s physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina’s Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, FSTL3, and RP11-624M8.1. Of the 90 decreased DMCs, 9 were within the genes CNGA1, FCGR2A, KIF21A, MEIS1, NT5DC1, OR4D1, PRPF4B, SLC26A7, and ZNF280C. Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.

AbstractAimsThe MicraTM transcatheter pacing system (TPS) (Medtronic) is the only leadless pacemaker that promotes atrioventricular (AV) synchrony via accelerometer‐based atrial sensing. Data regarding the real‐world experience with this novel system are scarce. We sought to characterize patients undergoing MicraTM‐AV implants, describe percentage AV synchrony achieved, and analyze the causes for suboptimal AV synchrony.MethodsIn this retrospective cohort study, electronic medical records from 56 consecutive patients undergoing MicraTM‐AV implants at the Mayo Clinic sites in Minnesota, Florida, and Arizona with a minimum follow‐up of 3 months were reviewed. Demographic data, comorbidities, echocardiographic data, and clinical outcomes were compared among patients with and without atrial synchronous ventricular pacing (AsVP) ≥ 70%.ResultsSixty‐five percent of patients achieved AsVP ≥ 70%. Patients with adequate AsVP had smaller body mass indices, a lower proportion of congestive heart failure, and prior cardiac surgery. Echocardiographic parameters and procedural characteristics were similar across the two groups. Active device troubleshooting was associated with higher AsVP. The likely reasons for low AsVP were small A4‐wave amplitude, high ventricular pacing burden, and inadequate device reprogramming. Importantly, in patients with low AsVP, subjective clinical worsening was not noted during follow‐up.ConclusionWith the increasing popularity of leadless pacemakers, it is paramount for device implanting teams to be familiar with common predictors of AV synchrony and troubleshooting with MicraTM‐AV devices.

AbstractOur phase III trial reported that autograft‐absolute lymphocyte count (A‐ALC) improved survival post‐autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) for a short‐term follow‐up of 2 years. We evaluated retrospectively in our phase III trial patients that the A‐ALC still confers survival benefit with a longer follow‐up. With a median follow‐up of 127.6 months, patients infused with an A‐ALC ≥ 0.5 × 109 cells/kg experienced better overall survival (HR = 0.392, 95% confidence of interval [CI]: 0.224–0.687, p < 0.001) and progression‐free survival (HR = 0.413, 95% CI: 0.253–0.677), p < 0.0004). This study supports that A‐ALC provides long‐term survival benefit post APBHSCT.

AbstractThe Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID‐19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish‐speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health‐care services and to aid caregivers of Latinos living with AD.

Background and objectives Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia.