Citations

ABSTRACT Background Although Percutaneous Coronary Intervention (PCI) is the cornerstone treatment acute myocardial infarction (AMI), its use in the elderly, specifically nonagenarians patients, is not well studied. This study sought to compare the outcomes and complications of nonagenarian patients who experienced AMI between those who underwent PCI and those who underwent medical treatment only. Methods We evaluated 301,440 nonagenarian (ages 90−99) patients who presented to the hospital with AMI who were listed in the National Inpatient Sample from 2016 to 2021. AMI was defined according to the ICD‐10 Diagnostic Codes. Multivariable logistic regression analysis was used to examine the association of PCI with primary outcomes of mortality and secondary outcomes. The temporal trend of both the incidence of PCI in nonagenarian patients as well as the mortality rate between 2016 and 2021 were expressed as percentages over time. Results Of the total ( n = 301,440) nonagenarian patients with AMI, 33,035 patients underwent PCI while 268,406 did not undergo PCI and rather, just utilized optimized medical therapy (OMT). Of these, 3290 (9.96%) died in the PCI group, and 43580 (16.24%) died in the OMT group. All of the secondary outcomes were significantly different between the PCI and OMT groups. Comparing the two groups, the PCI group was associated with decreased mortality (OR 0.63 [95% CI, 0.58−0.69]; p < 0.001), acute heart failure (OR 0.88 [95% CI, 0.82−0.95] p < 0.001), and AKI (OR 0.75 [95% CI, 0.70−0.79]; p < 0.001), and increased cardiogenic shock (OR 3.06 [95% CI, 2.77−3.38]. The temporal of PCI in nonagenarian patients showed an increase in frequency from about 8.3 in 2016 to about 13.7% in 2021. Furthermore, comparing the mortality between the PCI and OMT groups showed a significant difference with a decreased mortality in the PCI group. Conclusions Nonagenarian patients experiencing AMI who underwent PCI is associated with a significant mortality decrease compared to those who underwent OMT only. The PCI group was also associated with a significant decrease in multiple secondary complications including acute heart failure, AKI, acute stroke, and an increase in cardiogenic shock. Temporally, we have seen an increase in PCI being used in nonagenarian patients over the interval.

Myocardial Bridging (MB) is typically a benign congenital coronary anomaly. MB can infrequently result in complications such as myocardial ischemia, arrhythmias, and sudden cardiac death. Recent studies suggest an underlying genetic component for MB involving DES, FBN1, SCN2B, or NOTCH1. The role of percutaneous coronary intervention (PCI) in managing MB, compared to optimal medical therapy (OMT), remains uncertain. Our study used the National Inpatient Sample (NIS) Database to identify patients aged 18 or older with myocardial bridging who were managed with PCI versus medical therapy. We compared the outcomes between both groups including in-hospital mortality, the trend of management of MB and other in-hospital outcomes or complications. Our results showed no statistically significant difference between both subgroups when comparing in-hospital mortality and secondary outcomes of cardiac arrest and the development of an acute kidney injury (AKI). Patients with myocardial bridging treated with PCI had a higher risk of developing cardiogenic shock, requiring LVAD, and requiring the use of intra-aortic balloon pump (IABP) compared to the medical therapy subgroup. Our study suggests the decision to perform PCI in myocardial bridging patients should be individualized such as in patients with refractory symptoms despite medical therapy or those with known high-risk features.

Abstract Objectives IBM is characterized by slowly progressive muscle weakness making it challenging to detect significant changes in weakness during a clinical trial. Trial participants receiving placebo may behave differently from in natural history studies. We aimed to quantify the change in muscle strength and IBM Functional Rating Scale (IBMFRS) of IBM patients receiving placebo during clinical trials. Methods Several databases were searched. Randomized, double-blinded, placebo-controlled trials without treatment intervention on the placebo group were included. Standardized mean differences (SMD) for change in muscle strength and mean differences for IBMFRS were used to calculate pooled effects, using DerSimonian-Laird continuous random effect models. Meta-regression determined change in muscle strength. Heterogeneity was evaluated using the I2 indicator. Results Eleven eligible trials were identified with 257 participants receiving placebo and a low risk of bias per the Cochrane Collaboration Risk of Bias 2 (RoB2) tool. Participants receiving placebo on average had a measurable decline in muscle strength with a mean effect size of –0.398 (95% CI –0.652, –0.144) (P = 0.002). SMD changed by –0.009 (–0.016, –0.002) points per week (P = 0.015). Manual muscle testing was associated with higher heterogeneity (I2 = 67.68%) compared with quantitative muscle testing (I2 = 0%). Only three studies reported IBMFRS results. The pooled change in IBMFRS at 12 months was –2.189 points (–3.893, –0.485) on this 0 to 40-point scale (P = 0.012), with relatively high heterogeneity. Conclusion Participants with IBM displayed a measurable decline in their muscle strength and IBMFRS during clinical trials, in keeping with the disease’s slowly progressive nature. These estimates can inform sample size calculations in future studies.

Introduction: Data on outcomes between unfractionated heparin and bivalirudin anticoagulation during percutaneous coronary intervention (PCI) in acute coronary syndromes remain inconclusive. We aimed to systematically analyze PCI outcomes by comparing unfractionated heparin and bivalirudin. Methods: We systematically searched Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception in 1966 through January 2024 for studies evaluating PCI outcomes comparing unfractionated heparin and bivalirudin. Two investigators independently reviewed the data. Conflicts were resolved through consensus. Random-effects meta-analyses were used. Results: A total of 10 prospective trials were identified that enrolled 42,253 individuals who presented with an acute coronary syndrome. Our analysis found that heparin when compared to bivalirudin was associated with an increased risk of trial-based definition of major bleeding [relative risk (RR): 1.68, 95% confidence interval (CI): 1.29–2.20], nonaccess site complications (RR: 4.6, 95% CI: 1.75–12.09), thrombolysis in myocardial infarction major bleeding (RR: 1.70, 95% CI: 1.20–2.41), major bleeding risks (RR: 1.87, 95% CI: 1.49–2.36), cardiovascular disease death (RR: 1.26, 95% CI: 1.02–1.57), and thrombocytopenia (RR: 1.67, 95% CI: 1.07–2.62). There were no statistically significant differences between heparin and bivalirudin for all-cause mortality, major adverse cardiovascular event, stroke, reinfarction, target vessel revascularization, and acute or stent thrombosis. Conclusions: The present meta-analysis demonstrates bivalirudin reduces major bleeding when used for anticoagulation during PCI in patients with acute coronary syndromes and is not associated with an increased risk of stent thrombosis or major adverse cardiovascular event.

OBJECTIVE Patients with autosomal dominant polycystic kidney disease (ADPKD) have been identified to have a significantly increased risk of developing intracranial aneurysms (IAs). These patients are diagnosed at younger ages and are also at increased risk for IA rupture. The objective of this systematic review and meta-analysis was to identify risk factors associated with IA detection during screening of asymptomatic ADPKD patients. METHODS The authors searched for studies reporting the prevalence of IA among patients with ADPKD screened using MRA, CTA, or DSA on PubMed, Embase, Google Scholar, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov prior to August 2023 by using individualized standardized search strategies. Eligibility of all retrieved studies was assessed according to the PRISMA guidelines. Risk of bias of the included observational studies was assessed using the Newcastle-Ottawa Scale. Meta-analysis was performed using a random-effects model. RESULTS Twenty-four observational studies involving 5907 patients with ADPKD were identified for quantitative analysis. The authors observed an overall prevalence of IA of 12.6%. They identified several risk factors for IA with statistically significantly increased odds for unruptured IA (UIA) detection, including female sex (18 studies, OR 1.63, 95% CI 1.37–1.94, I 2 = 0%), family history of either IA or subarachnoid hemorrhage (SAH) (12 studies, OR 2.17, 95% CI 1.68–2.81, I 2 = 0%), family history of SAH (3 studies, OR 2.67, 95% CI 1.25–5.71, I 2 = 66.0%), stage 3 or greater chronic kidney disease (CKD) (4 studies, OR 2.55, 95% CI 1.84–3.54, I 2 = 0%), and hypertension (13 studies, OR 1.41, 95% CI 1.04–1.91, I 2 = 34%). Age > 45 years, family history of ADPKD, smoking status, and presence of liver cysts did not reach statistical significance as risk factors during this meta-analysis. CONCLUSIONS The results of the authors’ meta-analysis suggest increased risk of UIA detection in screening of ADPKD patients who are female, have a family history of IA or SAH, have hypertension, or have moderate or more severe CKD. Given the increased prevalence of IA in ADPKD patients with these risk factors, these patients may stand to benefit from screening for IA early in treatment or at time of diagnosis, even if neurologically asymptomatic.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

Abstract Background: ASXL1 is one of the three most frequently mutated genes in age-related clonal hematopoiesis (CH), with the others being DNMT3A and TET2. CH frequently progresses to myeloid malignancies including chronic monomyelocytic leukemia (CMML), and is also strongly associated with inflammatory cardiovascular disease and all-cause mortality in humans. DNMT3A and TET2 regulate DNA methylation and demethylation pathways respectively, and loss-of-function mutations of both genes reduce DNA methylation in heterochromatin. In contrast, the mechanisms that connect mutant ASXL1 and CH are not yet fully understood. ASXL1 is a regulatory component of the ASXL1-BAP1 deubiquitinase complex, which removes ubiquitin from mono-ubiquitinated H2A lysine 119 (H2AK119Ub). Recurrent frameshift and nonsense ASXL1 mutations in CH and CMML generate C-terminally truncated proteins that improve BAP1 enzymatic activity. Methods: To relate ASXL1 mutations to CH, we performed the protein immunoprecipitation followed by a mass spectrum to identify proteins interacting with mutant ASXL1. Utilizing a heterozygous Asxl1 mutant knock-in mouse model to recapitulate ASXL1-driven clonal hematopoiesis, we characterized alterations in histone modifications within expanded myeloid populations using CUT&RUN, with Drosophila S2 cells as spike-ins for normalization. Differential gene expression and transposable elements (TEs) activity were quantified in ASXL1-mutant chronic myelomonocytic leukemia (CMML) patients using RNA sequencing (RNA-seq) to assess the broader impact of ASXL1 mutations on transcriptional regulation. Results: Here we show that ASXL1 mutant proteins interact with the EHMT1-EHMT2 methyltransferase complex, which generates H3K9me1 and me2, the latter a repressive modification in constitutive heterochromatin. Compared to cells from age-matched wildtype mice, we found that expanded myeloid cells from old Asxl1 mutant mice display genome-wide decreases of H3K9me2, H3K9me3 and H2AK119Ub as well as an associated increase in expression of transposable elements (TEs) and satellite repeats. Increased TE expression was also observed in monocytes from ASXL1-mutant CMML patients compared to monocytes from healthy controls. Our data suggest that mutant ASXL1 proteins compromise the integrity of both constitutive and facultative heterochromatin in an age-dependent manner, by reducing the levels of H3K9me2/3 and H2AK119Ub. This increase in TE expression correlated with increased expression of nearby genes, including many interferon-inducible (inflammation-associated) genes (ISGs). Conclusion: Our findings provide new insights into how ASXL1 gain-of-function mutations might contribute mechanistically to the progression of CH and myeloid malignancies in aging. We show that even heterozygous expression of truncated ASXL1 proteins can lead to reduced levels of heterochromatin-associated histone modifications, weakening heterochromatin integrity and promoting increased expression of transposable elements that are normally silenced in heterochromatin. Citation Format: Zhen Dong, Hugo Sepulveda, Leo Josue Arteaga Vazquez, Mrinal Patnaik, Samuel A Myers, Anjana Rao. A mutant ASXL1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B001.

AbstractAutoimmune pancreatitis (AIP) is identified as a severe chronic immune‐related disorder in pancreas, including two subtypes. In this study, pancreatic lesions in patients diagnosed as either type 1 AIP or type 2 AIP are examined, and these patients’ peripheral blood at single‐cell level. Furthermore, flow cytometry, immunofluorescence, and functional assays are performed to verify the identified cell subtypes. In type 1 AIP, there is a notable increase in the amount of B cells and plasma cells, and IgG4+ plasma cells are key pathogenic cells of AIP. The differentiation path of naïve‐stage B cells into IgG4+ produced plasma cells is observed, and an increased amount of T helper cells and T follicular helper (Tfh) cells. This study also reveals that HIF‐1α, an activated transcriptional factor, can directly bind to promoter site of NAMPT, promoting higher levels of visfatin production in HIF1A+ classical monocytes. Pancreatic stellate cells can be activated by extracellular visfatin and promote the development of fibrotic response in pancreatic lesions across both AIP subtypes. The current findings shed light on the exploration of dynamic alterations in peripheral blood cells and cell subgroups in pancreatic lesions of AIP, while elucidating a pathogenic cell subset and potential fibrosis mechanism of AIP.

Abstract Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (&lt;28 days vs ≥28 to &lt;40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt &lt;28 days (odds ratio [OR], 0.61) or ≥28 to &lt;40 days (OR, 0.66) and significantly worse overall survival than V2Vt &lt;28 days (hazard ratio [HR], 1.33) or ≥28 to &lt;40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to &lt;40 days or ≥40 days compared with &lt;28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.