Citations

AbstractObjectiveThis study sought to determine if single‐chamber operation and/or loss of rate response (RR) during elective replacement indicator (ERI) in patients with dual‐chamber pacemakers lead to increased symptom burden, healthcare utilization, and atrial fibrillation (AF).BackgroundDual‐chamber pacemakers often change from dual‐ to single‐chamber pacing mode and/or lose RR functionality at ERI to preserve battery. Single‐chamber pacing increases the incidence of heart failure, AF, and pacemaker syndrome suggesting these changes may be deleterious.MethodsA retrospective analysis of 700 patients was completed. Three comparisons were analyzed: Comparison 1: mode change and RR loss versus no change; Comparison 2: RR loss only versus no change; Comparison 3: mode change only versus no change (in patients with no RR programmed at baseline).ResultsIn Comparison 1, 121 (46%) patients with setting changes experienced symptoms (most often dyspnea and fatigue/exercise intolerance) versus 3 (4%) without setting changes (p < .0001). Similar results were noted in Comparisons 2 and 3 (p = .0016 and p = .0001, respectively). In Comparison 1, patients with setting change sought provider contact more than patients without setting changes (p = .0001). A significant difference was not noted in Comparison 2 or 3. Overall 14 (2%) patients were hospitalized, all of whom had setting changes.ConclusionsSetting changes at ERI including a change from dual‐ to single‐chamber pacing and/or loss of RR results in a significantly increased symptom burden and increased healthcare utilization.

Abstract Ventricular electrical storm (VES) is a clinical scenario characterized by the clustering of multiple episodes of sustained ventricular arrhythmias (VA) over a short duration. Patients with VES are prone to psychological disorders, heart failure decompensation, and increased mortality. Studies have shown that 10–28% of the patients with secondary prevention ICDs can sustain VES. The triad of a susceptible electrophysiologic substrate, triggers, and autonomic dysregulation govern the pathogenesis of VES. The rate of VA, underlying ventricular function, and the presence of implantable cardioverter-defibrillator (ICD) determine the clinical presentation. A multi-faceted approach is often required for management consisting of acute hemodynamic stabilization, ICD reprogramming when appropriate, antiarrhythmic drug therapy, and sedation. Some patients may be eligible for catheter ablation, and autonomic modulation with thoracic epidural anesthesia, stellate ganglion block, or cardiac sympathetic denervation. Hemodynamically unstable patients may benefit from the use of left ventricular assist devices, and extracorporeal membrane oxygenation. Special scenarios such as idiopathic ventricular fibrillation, Brugada syndrome, Long and short QT syndrome, early repolarization syndrome, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular cardiomyopathy, and cardiac sarcoidosis have been described as well. VES is a cardiac emergency that requires swift intervention. It is associated with poor short and long-term outcomes. A structured team-based management approach is paramount for the safe and effective treatment of this sick cohort.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

AbstractBackgroundRelatively few cutaneous head and neck melanoma (CHNM) patients with were included in the multicenter selective lymphadenectomy trial II (MSLT‐II). Our objective was to investigate whether immediate completion lymph node dissection completion of lymph node dissection (CLND) was associated with survival benefit for sentinel lymph node (SLN) positive CHNM using the National Cancer Database.MethodsSLN positive patients with CHNM from 2012 to 2014 were retrospectively analyzed. Patients were divided into two groups: those who underwent SLN biopsy (SLNB) only versus those who underwent SLNB followed by CLND (SLNB + CLND). The primary outcome was 5‐year overall survival (OS).ResultsAmong 530 SLNB + patients, 342 patients underwent SLNB followed by CLND (SLNB + CLND). The SLNB only group had fewer positive SLN, less advanced pathologic stage, and a lower rate of adjuvant immunotherapy. There was no significant difference in 5‐year OS between the two groups (51.0% vs 67%; P = .56). After adjusting for pathologic stage, there remained no difference in 5‐year OS among patients with stage IIIA (63.0% vs. 73.6%, P = 0.22) or IIIB/IIIC disease (39.1% vs 57.8%; P = .52).ConclusionsUsing a large nationwide database, CLND was not shown to be associated with improved OS for patients with SLNB positive CHNM, validating the results of MSLT‐II.

AbstractIntroductionVenous stenosis is a well‐recognized complication of transvenous leads (TVLs) that is encountered during lead revisions or device upgrades. We here report the outcomes of TVL placement facilitated by fibroplasty or tunneling (TUN) procedure.MethodsWe conducted a single‐center retrospective cohort study of all patients undergoing TVL implantation requiring fibroplasty or TUN from 2005 to 2017. Medical records and procedure reports were reviewed for relevant data. Outcomes for fibroplasty and TUN to facilitate TVL placement were compared.ResultsSixty patients had fibroplasty and thirty‐five patients had a TUN procedure. There was no difference in procedure success rates between the two groups (97% fibroplasty vs. 100% TUN; p = .98). The fluoroscopy time was longer (fibroplasty = 39.7 ± 21.5 min vs. TUN = 29.2 ± 21.3 min; p = .01) and the total procedural time was shorter in the fibroplasty group (fibroplasty = 247 ± 77.8 min vs. TUN = 287 ± 77.1 min; p = .01). TUN was associated with a significantly higher incidence of acute complications (fibroplasty = 0 vs. TUN = 8; p = .002) most requiring invasive intervention and/or transfusion with blood products. Long‐term complications requiring additional device‐related procedures were comparable between the two groups (fibroplasty = 6 vs. TUN = 6; logrank p = .21).ConclusionsFor patients with venous stenosis requiring additional TVL, balloon fibroplasty is associated with similar rates of success and a significantly decreased incidence of acute complications when compared with subcutaneous TUN.

ObjectiveTo compare the diagnostic performance of an artificial intelligence deep learning system with that of expert neuro‐ophthalmologists in classifying optic disc appearance.MethodsThe deep learning system was previously trained and validated on 14,341 ocular fundus photographs from 19 international centers. The performance of the system was evaluated on 800 new fundus photographs (400 normal optic discs, 201 papilledema [disc edema from elevated intracranial pressure], 199 other optic disc abnormalities) and compared with that of 2 expert neuro‐ophthalmologists who independently reviewed the same randomly presented images without clinical information. Area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity were calculated.ResultsThe system correctly classified 678 of 800 (84.7%) photographs, compared with 675 of 800 (84.4%) for Expert 1 and 641 of 800 (80.1%) for Expert 2. The system yielded areas under the receiver operating characteristic curve of 0.97 (95% confidence interval [CI] = 0.96–0.98), 0.96 (95% CI = 0.94–0.97), and 0.89 (95% CI = 0.87–0.92) for the detection of normal discs, papilledema, and other disc abnormalities, respectively. The accuracy, sensitivity, and specificity of the system's classification of optic discs were similar to or better than the 2 experts. Intergrader agreement at the eye level was 0.71 (95% CI = 0.67–0.76) between Expert 1 and Expert 2, 0.72 (95% CI = 0.68–0.76) between the system and Expert 1, and 0.65 (95% CI = 0.61–0.70) between the system and Expert 2.InterpretationThe performance of this deep learning system at classifying optic disc abnormalities was at least as good as 2 expert neuro‐ophthalmologists. Future prospective studies are needed to validate this system as a diagnostic aid in relevant clinical settings. ANN NEUROL 2020;88:785–795

AbstractIntroductionThe best management strategy for patients with atrial fibrillation (AF) with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) is unknown.Methods and ResultsThis cohort study was conducted in Olmsted County, Minnesota, with resources of the Rochester Epidemiology Project. Patients with incident AF occurring between 2000 and 2014 with a prior or concurrent HF were included. Patients with LVEF ≥ 50% were designated as HF and preserved ejection fraction (HFpEF) and those with LVEF < 50% were designated as HF and reduced ejection fraction (HFrEF). Rhythm control in the first year after AF diagnosis was defined as prescriptions for an antiarrhythmic drug, catheter ablation, or maze procedure. The primary endpoint was all‐cause mortality. The secondary endpoints were cardiovascular death, cardiovascular hospitalization, and stroke or transient ischemic attack. Of 859 patients (age, 77.2 ± 12.1 years; 49.2%, female), 447 had HFpEF‐AF, and 412 had HFrEF‐AF. There was no difference in all‐cause mortality (10‐year mortality, 83% vs 79%; p = .54) or secondary endpoints between the HFpEF‐AF and HFrEF‐AF, respectively. Compared with the rate control strategy, rhythm control in HFpEF‐AF patients (n = 40, 15.9%) offered no survival benefits (adjusted HR, 0.70; 95% CI, 0.42–1.16; p = .16), whereas rhythm control in HFrEF‐AF patients (n = 52, 22.5%) decrease cardiovascular mortality (HR, 0.38; 95% CI, 0.17–0.86; p = .02).ConclusionsPatients with HFpEF‐AF and HFrEF‐AF had similar poor prognoses. Rhythm control strategy was seldom adopted in community care in patients with HF and AF. A rhythm control strategy may provide survival benefit for patients with HFrEF‐AF and the benefit of rhythm control in patients with HFpEF‐AF warrants further study.

Drug resistance is an obstacle in the therapy of acute lymphoblastic leukemia (ALL). Whether the physical properties such as the motility of the cells contribute to the survival of ALL cells after drug treatment has recently been of increasing interest, as they could potentially allow the metastasis of solid tumor cells and the migration of leukemia cells. We hypothesized that chemotherapeutic treatment may alter these physical cellular properties. To investigate the motility of chemotherapeutics-treated B-cell ALL (B-ALL) cells, patient-derived B-ALL cells were treated with chemotherapy for 7 days and left for 12 h without chemotherapeutic treatment. Two parameters of motility were studied, velocity and migration distance, using a time-lapse imaging system. The study revealed that compared to non-chemotherapeutically treated B-ALL cells, B-ALL cells that survived chemotherapy treatment after 7 days showed reduced motility. We had previously shown that Tysabri and P5G10, antibodies against the adhesion molecules integrins α4 and α6, respectively, may overcome drug resistance mediated through leukemia cell adhesion to bone marrow stromal cells. Therefore, we tested the effect of integrin α4 or α6 blockade on the motility of chemotherapeutics-treated ALL cells. Only integrin α4 blockade decreased the motility and velocity of two chemotherapeutics-treated ALL cell lines. Interestingly, integrin α6 blockade did not affect the velocity of chemoresistant ALL cells. This study explores the physical properties of the movements of chemoresistant B-ALL cells and highlights a potential link to integrins. Further studies to investigate the underlying mechanism are warranted.

4508 Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.