Citations

Introduction: Incident cardiac arrhythmias are common in hospitalized COVID-19 patients, but the impact of a second incident cardiac arrhythmia during hospitalization on clinical outcomes remain unclear. Hypothesis: The aim of this study was to assess the frequency and prognostic implications of a second incident arrhythmia in hospitalized COVID-19 patients over the pandemic course till vaccine availability. Methods: The multicenter COVID-RHYTHM Registry enrolled hospitalized COVID-19 patients from 3/8/2020 to 1/24/2021. Cardiac arrhythmia included documented atrial fibrillation (AF), atrial flutter (AFL), ventricular tachycardia (VT), severe sinus bradycardia (<40 bpm) or AV block. Outcomes were compared between patients with single vs. more than one incident arrhythmias adjusting for baseline variables. Results: Of 6299 hospitalized COVID-19 patients, 4398 had an had an incident cardiac arrhythmia during hospitalization, of which 822 (19%) had a second incident arrhythmia. Those with >1 incident arrhythmia had a higher baseline prevalence of heart failure, chronic kidney disease, coronary artery disease and sleep apnea (Table). Those with >1 incident arrhythmia had higher in-hospital mortality, need for ICU admission and need for rehab upon discharge. Length of stay was similar between the groups. Conclusions: In hospitalized COVID-19 patients with incident cardiac arrhythmias, a second incident arrhythmia during hospitalization was seen in 19%. Having >1 incident arrhythmia was associated with increased need for ICU admission and reduced survival.

Background: While cardiac involvement in sarcoidosis could be significant, data assessing geographical disparities in cardiovascular deaths (CVDs) among patients with sarcoidosis are limited. Objective: This study aims to determine the mortality attributed to CVDs with comorbid sarcoidosis in different geographic locations in the United States. Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database and performed serial cross-sectional analyses of national death certificate data for CVDs with comorbid sarcoidosis among patients aged 25 and above. Diseases of the circulatory system (ICD-10 I00-I99) were listed as the underlying cause of death, and sarcoidosis (ICD-10 D86) as contributing cause of death. We calculated age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and compared the mortality among census regions and states. Results: In the 22-year study period, 5,630 CVDs with comorbid sarcoidosis in the United States were identified between 1999 and 2020. The South region had the highest AAMRs for CVDs with comorbid sarcoidosis (1.32 [95% CI, 1.26-1.37] per 1,000,000 individuals), followed by Northeast region (1.25 [95% CI, 1.18-1.32] per 1,000,000 individuals), Midwest region (1.24 [95% CI, 1.17-1.30] per 1,000,000 individuals), and West Region (0.92 [95% CI, 0.86-0.98] per 1,000,000 individuals). The AAMRs for CVDs with comorbid sarcoidosis were between 0.57 [95% CI, 0.43-0.75] per 1,000,000 individuals and 1.96 [95% CI, 1.73-2.19] per 1,000,000 individuals throughout the States, except Maryland and the District of Columbia, which recorded 2.79 [95% CI, 2.44-3.14] and 6.01 [95% CI, 4.44-7.94], respectively. Conclusion: The South region, particularly Maryland recorded the highest CVDs in sarcoidosis. Geographical disparities observed in CVDs with comorbid sarcoidosis highlight the need to improve public health measures at state-level.

Background: Sarcoidosis is a multisystem inflammatory disease that could result in debilitating cardiac manifestations. Despites, data on the cardiovascular deaths (CVDs) among patients with sarcoidosis are limited. Objective: This study sought to determine the longitudinal trends in mortality attributed to CVDs with comorbid sarcoidosis by age, sex, and race in the United States. Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database and performed serial cross-sectional analyses of national death certificate data for CVDs with comorbid sarcoidosis among patients aged 25 and above. Diseases of the circulatory system (ICD-10 I00-I99) were listed as the underlying cause of death, and sarcoidosis (ICD-10 D86) as contributing cause of death. We calculated age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and determined the trends over time by estimating the annual percent change using the Joinpoint Regression Program. Results: In the 22-year study period, 5,630 CVDs with comorbid sarcoidosis in the United States were identified between 1999 and 2020. The AAMRs from CVDs with comorbid sarcoidosis increased from 1.03 (95% CI, 0.88-1.17) in 1999 to 1.38 (95% CI, 1.24-1.52) in 2020. Overall, women recorded a higher AAMRs compared to men (1.25 [95% CI, 1.21-1.30] vs. 1.10 [95% CI, 1.06-1.15]). Black individuals had higher AAMRs than White individuals (5.17 [95% CI, 4.97-5.37] vs. 0.68 [95% CI, 0.66-0.71]). A higher percentage of CVDs with comorbid sarcoidosis was seen in the age groups of 55-64 in men (24.68%) and 65-74 in women (22.62%). Conclusion: The CVDs in sarcoidosis have increased over the last two decades, with disparities seen in women and Black individuals. Most CVDs with comorbid sarcoidosis occurred at a younger age compared to general population. This highlights the importance of early screening for cardiovascular diseases in sarcoidosis individuals.

Introduction: Corticosteroids (CS) are the standard first-line treatment for patients (pts) with chronic graft-versus-host disease (cGvHD), but pts can be unresponsive or become refractory to or dependent on CS (SR/D).Ruxolitinib (RUX), a JAK1/2 inhibitor, is approved for the treatment of pts ≥12 years of age with SR/D-cGVHD, based on the primary outcomes from the randomized, phase III REACH3 (NCT03112603) study, which demonstrated the superior efficacy of RUX vs best available treatment (BAT) in pts with SR/D-cGVHD. Here, we present the final, long-term efficacy and safety outcomes from REACH3. Methods: Pts ≥12 years of age with moderate or severe SR/D-cGVHD were randomized 1:1 to receive either RUX 10 mg twice daily (BID) or investigator-selected BAT and followed for 3 years, till discontinuation or death. The primary analysis was conducted at week 24 (Cycle 7 Day 1 [C7D1]) in randomized pts, then pts entered the extension period (C7-39) in which they continued treatment, switched from BAT to RUX (crossover cohort), or discontinued treatment and entered long-term survival follow-up (FU). Failure-free survival (FFS; key secondary endpoint), duration of response (DOR), overall survival (OS), non-relapse mortality (NRM), malignancy relapse (MR), and safety were analyzed at 3 years (week 156; final data cut off 15 Dec 2022). Overall response rate (ORR) and best overall response (BOR) during the crossover treatment period were analyzed for pts who switched from BAT to RUX on or after C7D1. Results: Of 329 pts randomized, 53 completed the treatment period and 276 discontinued, 115 entered survival FU (RUX: 73/165; BAT:42/164); 70 pts crossed over from BAT to RUX of which 16 completed the crossover treatment period and 24 entered survival FU. Median FFS was longer in the RUX vs BAT arms (38.4 vs 5.7 months; hazard ratio [HR]=0.361, 95% confidence interval [CI]: 0.268, 0.485) with 12-month FFS probabilities of 64.0% (95% CI: 56.1, 70.8) and 28.8% (95% CI: 21.8, 36.1), respectively. Median OS was not reached and there was no difference in risk of death between the arms (HR=0.851, 95% CI: 0.544, 1.331) [Table 1]. Median DOR was 6.4 months (95% CI: 4.9, 11.4) in the BAT arm but was not reached for the RUX arm; notably, the probability of maintaining DOR at 3 years was higher in RUX (59.6%; 95% CI: 50.4, 67.6) vs BAT (26.7%; 95% CI: 18.5, 35.5). NRM event rates were similar between the arms (RUX: 29/165; BAT 34/164), and MR events were similar and low in both arms (13/156 and 11/160, RUX and BAT respectively) up to 3 years. The ORR at week 24 after crossover from BAT to RUX was 50.0% (95% CI: 37.8, 62.2), including complete response (CR) in 4 (5.7%) pts and partial response (PR) in 31 (44.3%) pts. The BOR during crossover was 81.4% (95% CI: 70.3, 89.7), including CR of 7.1% and PR of 74.3%; disease progression only occurred in 1 pt. Almost all pts treated during the main treatment period (RUX: 100%; BAT: 93.7%) experienced ≥1 adverse event (AE) and, in general, AE rates were higher in the RUX vs BAT arms [Table 2], likely due to prolonged FU and exposure to RUX (median exposure to treatment of 52.9 weeks vs. 24.1 weeks for RUX and BAT, respectively).Anemia was the most common AE (RUX: 33.9%; BAT: 15.8%) and grade ≥3 AE for RUX (17.6% vs BAT 9.5%, respectively); grade ≥3 neutropenia, thrombocytopenia, alanine aminotransferase increase, and gamma-glutamyltransferase increase were also ≥5% higher for RUX than BAT. Anemia (24.2%; grade ≥3, 10.3%) and thrombocytopenia (3.8%) were the most common RUX and BAT treatment-related AEs, respectively. Infections, excluding tuberculosis, were the most common AE of special interest (77.6% vs. 68.4%; grade ≥3, 31.5% and 26.6%, for RUX and BAT, respectively). On-treatment deaths were mainly due to cGvHD (n/N, RUX: 10/18; BAT 6/12). Conclusions: After 3 years of treatment in REACH3, the longer FFS and higher DOR with RUX vs BAT indicated that cGVHD was more in control with RUX treatment. Notably, efficacy was demonstrated in pts who switched from BAT to RUX with an ORR similar to that in pts randomized to RUX. RUX was well tolerated with no unexpected toxicities and safety that was consistent with earlier studies. Overall, the long-term control of cGVHD and tolerability of RUX was demonstrated for pts ≥12 years of age with SR/D-cGvHD.

Abstract Background Guidelines recognize the role of exercise stress testing in evaluating functional capacity in patients with asymptomatic severe aortic stenosis (AS). Exercise stress echocardiography (ESE) allows the detection of pulmonary congestion with B-lines by lung ultrasound (LUS). Aim To identify the prevalence, determinants, and functional correlates of B-lines during ESE in asymptomatic severe AS. Methods We enrolled 35 asymptomatic patients (age= 69±16 years, 69% male) with severe AS, aortic valve area (AVA) &lt;0.6 cm2/m2, mean aortic gradient (MAG) ≥ 40 mmHg, left ventricular ejection fraction ≥55%. All patients were referred for ESE (treadmill in 1, bicycle in 34 patients) in 7 experienced centers from 4 countries between 2021-2022. ESE assessment at rest and peak stress included global longitudinal strain (GLS), left atrial volume index (LAVI) and cardiac output (CO). B-lines were assessed by simplified LUS from 4 lung zones across the third intercostal space (2 on each side). Heart rate reserve (HRR) was measured as the peak/rest heart rate. CO reserve was calculated as the difference between peak stress CO and rest CO. Results B-lines (≥2) were present in 2 patients at rest and in 15 patients during ESE (6% vs 43%, p&lt;0.001). When compared to patients without B-lines during ESE (Group 1, n=20), patients with B-lines during ESE (Group 2, n=15) were older (Group 1= 64±18 vs Group 2=75±8 years, p=0.030) had larger LAVI, higher logNT-pro-BNP and a trend to higher systolic pulmonary artery pressures (SPAP), see Table. The 2 groups showed similar values of resting AVA (Group 1= 0.52±0.11 vs Group 2=0.47±0.15 cm2/m2, p=0.311), stress AVA (Group 1= 0.45±0.09 vs Group 2=0.49±0.13 cm2/m2, p=0.663), resting MAG (Group 1= 45±15 vs Group 2=46±10 mm Hg, p=0.491), and stress MAG (Group 1= 59±19 vs Group 2=58±11 mm Hg, p=0.665). Patients with B-lines during ESE showed lower HRR and CO reserve, with a trend towards lower peak GLS, see Table. Conclusions Exercise-induced pulmonary congestion as evidenced by development of sonographic B- lines on LUS were present commonly (43%) among patients with "asymptomatic" severe AS undergoing ESE. Patients with exercise-induced B-lines have larger resting LAVI, higher NT-pro-BNP levels, lower CO reserve, and blunted HRR. Exercise-induced B-lines might provide an early sign of cardiac decompensation in "asymptomatic" patients with severe AS, which is an important factor to consider in the decision to intervene.TableFigure

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Abstract Background and aims Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE. Methods A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. Results The TRI-SCORE was low (≤3) in 32%, intermediate (4–5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P &lt; .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively). Conclusions Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.

Abstract Background Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. In vitro mechanistic studies have demonstrated that the anti-tumor activity of lymphoid and myeloid cell populations is mediated by metabolite availability and signaling in the TME, raising the possibility that the immune response and metabolism of ccRCC tumors coevolve and jointly influence the likelihood that a patient responds to therapy.. However, both the broad patterns of coordination between metabolite abundance and TME cellular composition, as well as the precise cell populations producing metabolic phenotypes of interest, remain unknown. Methods To study IMH, we multiregionally profiled the metabolome, transcriptome, and genome of 187 tumor/normal regions from 31 clear cell renal cell carcinoma (ccRCC) patients. Using these measurements and additional multimodal metabolomic/transcriptomic profiling of ccRCC and other diseases, we developed computational models that can be used to understand RNA-metabolite covariation and ultimately impute metabolite levels from RNA sequencing data. Results Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, and especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we deployed and benchmarked a machine learning method (MIRTH) to impute metabolite levels directly from RNA sequencing data of primary and metastatic ccRCC tumors. We inferred metabolomic profiles from RNA sequencing data of ccRCC patients enrolled in 6 clinical trials, ultimately identifying specific metabolite biomarkers associated with response to anti-angiogenic agents. Conclusions Local metabolic phenotypes therefore emerge in tandem with the immune microenvironment and associate with therapeutic sensitivity. CDMRP DOD Funding: yes

AbstractThe liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta‐Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well‐established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.

Abstract Background Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. Methods Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. Results Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. Conclusions BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.