Citations

Background/Objectives: Performing endoscopic retrograde cholangiopancreatography (ERCP) in surgically altered gastrointestinal anatomy remains challenging, frequently necessitating the use of forward-viewing endoscopes. Given the challenge in endoscope selection based on the type of altered anatomy, the aim of this study was to examine ERCP success rates by specific endoscopes for different anatomy types. Methods: This single-center retrospective study examined ERCPs performed in patients with surgically altered gastrointestinal anatomy during an 18-year period. Enteroscopy success, cannulation success, and intervention success rates were compared between the different anatomy and endoscope types. Results: This study included a total of 334 adult patients (665 total ERCPs) with altered anatomy. The pediatric colonoscope was most frequently utilized (32.2%), and the majority of procedures were performed for biliary indications. Enteroscopy success was 82.2% in Roux-en-Y gastric bypass (RYGB), 97% in Billroth II, 91.5% in Whipple, and 93.2% in Roux-en-Y hepaticojejunostomy (RYHJ). Cannulation success was 90.5% in RYGB, 90.5% in Billroth II, 83.6% in Whipple, and 90.6% in RYHJ. Intervention success was 88.2% in Billroth II, 65.1% in RYGB, 81.6% in Whipple, and 87.5% in RYHJ. In patients with RYGB and RYHJ, SBE was utilized most frequently, with rotational enteroscopy having the highest success rates. The overall adverse event rate was 5.1%, with the majority of these being mild in severity. Conclusions: This large retrospective study found ERCP with forward-viewing endoscopes to be safe and effective for a variety of surgically altered anatomy types. Despite recent advances seen with endoscopic ultrasound-guided drainage procedures, this study advocates for ERCP as the initial approach for pancreaticobiliary access in surgically altered anatomy.

Abstract Pancreatic neuroendocrine neoplasm (panNEN) is a rare malignancy and the second most common type of pancreatic cancer after pancreatic ductal adenocarcinoma (PDAC), but its etiology is poorly understood. We investigated whether the risk factors of panNEN are concordant with those known for PDAC. We performed the largest case-control study to date on panNENs, comprising 927 sporadic nonfunctional panNEN cases and 1807 frequency-matched controls, using data from the Mayo Clinic Biospecimen Resource for Pancreas Research. We assessed associations for obesity, first-degree family history of pancreatic cancer, cigarette smoking, overall type II diabetes mellitus (T2DM), new-onset T2DM (<1 year before panNEN diagnosis), longstanding T2DM (≥5 years), alcohol intake and aspirin use. Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). Our results show that overall T2DM (OR = 1.71, 95% CI: 1.37–2.14) and new-onset T2DM (OR = 2.65, 95% CI: 1.92–3.69) are associated with higher odds of panNEN, but not longstanding T2DM (OR = 1.29, 95% CI: 0.94–1.75). A non-significant elevated odds of panNEN was observed among participants with a positive family history of pancreatic cancer (OR = 1.44, 95% CI: 0.96–2.14). Alcohol use was inversely related to panNEN (OR = 0.52, 95% CI: 0.42–0.66, ever-vs-never). No association was observed for smoking, obesity or aspirin use. These findings indicate that overall T2DM and new-onset T2DM are associated with higher odds of panNEN. Unlike PDAC, alcohol use was inversely related to panNEN, and we found no associations for cigarette smoking, obesity or aspirin use. These results indicate differences in the risk factor profiles of panNEN and PDAC.

ABSTRACT Rituximab, gemcitabine, and oxaliplatin (R‐GemOx) is a commonly used chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), but there are limited real‐world data. In a multicenter retrospective study from a cohort of eight US academic centers (LEO CReWE), we evaluated 183 patients with R/R DLBCL and high‐grade B cell lymphoma treated with R‐GemOx, including subgroups treated without intent for consolidation with autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T cell therapy ( n = 100), those utilizing R‐GemOx as a bridge to ASCT or CAR T ( n = 83), and those aged 70 and older ( n = 71). Overall response rates (ORRs) for all patients treated with R‐GemOx were 45% with a complete response (CR) rate of 29%. The median event‐free survival (EFS) was 2.3 months, and the median overall survival (OS) was 13.5 months. Patients receiving R‐GemOx without intent for ASCT or CAR T had ORR and CR rates of 33% and 18%, respectively, with median EFS and OS of 2.0 and 9.5 months, respectively. Patients receiving R‐GemOx as a bridge to ASCT or CAR T had ORR and CR rates of 57% and 36%, respectively, with median EFS and OS of 3.5 and 17.4 months, respectively. Patients receiving R‐GemOx aged 70 and older had ORR and CR rates of 53% and 33%, respectively, with median EFS and OS of 2.2 and 13.9 months, respectively. These data provide a benchmark for R‐GemOx in the rapidly evolving landscape of R/R DLBCL therapies.

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.

Background: Previous studies have linked pericoronary artery adipose tissue attenuation to major adverse cardiac event (MACE). However, the association between pericarotid artery fat and prognosis remains underexplored. This study aimed to investigate the association between preoperative pericarotid fat characteristics and the subsequent prognosis in patients undergoing carotid endarterectomy (CEA). Methods: This study included patients with preoperative computed tomography angiography (CTA) followed by CEA. Preoperative neck CTA images were obtained and analyzed with novel methods using 3D Slicer software. We segmented the common and internal carotid arteries. The segment was horizontally trimmed, isolating the region around the bifurcation, extending 15 mm above and 10 mm below. Pericarotid fat was defined as adipose tissue within a 5 mm radial distance from the outer vessel wall, with Hounsfield units (HU) between -190 and -30 (Figure 1, carotid segmentation [green] and pericarotid fat [yellow]) . For each patient, we calculated the HU average and the volume (mm3) of the pericarotid fat. MACE was defined as a composite of all-cause mortality, myocardial infarction, and cerebrovascular events. The relationship between both pericarotid fat characteristics and MACE was investigated. Results: Of the 43 patients initially included, one was excluded due to an inability to perform segmentation caused by chronic total occlusion, leaving 42 patients (age 73 [67-78] years, 33 [76.7%] male). The comparison of mean pericarotid fat HU between the ipsilateral and contralateral sides showed no significant difference (-60.3±11.0 HU vs. -60.9 ±11.3 HU, p=0.437). However, the median ipsilateral fat volume was significantly higher than the contralateral volume (528 [248, 1100] mm3 vs. 328 [184, 697] mm3, p=0.020). When comparing patients with and without MACE, those with MACE had a significantly lower ipsilateral fat density (-59.4±10.2 HU vs. -66.8 ±11.1 HU, p=0.022) and a higher fat volume (468 [233, 746] mm3 vs. 845 [458, 1451] mm3, p=0.044). Kaplan-Meier analysis revealed that higher volume and lower fat density than the median were significant predictors of MACE (log-rank p=0.015 and p=0.042, respectively) (Figure 2). Conclusions: Assessment of pericarotid fat using a novel CTA analytic method in patients undergoing CEA identified ipsilateral lower fat density and higher fat volume as predictors of adverse outcomes.

Background: Atherosclerotic carotid artery disease is associated with a high risk of major adverse cardiac events (MACE) even with optimal risk factor management and surgical interventions such as carotid endarterectomy (CEA). Aortic stenosis (AS) is an age-related valve disease that is associated with a high rate of MACE. An artificial intelligence-based AS estimation algorithm (AI-AS) can identify AS with high accuracy using electrocardiogram. This study evaluates the prognostic value of AI-AS in patients with carotid artery disease undergoing CEA. Methods: We included patients with carotid artery disease undergoing CEA at Mayo Clinic from 2002-2023 if they had >30 days of follow-up and an electrocardiogram within one year before CEA. The electrocardiogram closest to the CEA date was used to calculate AI-AS (AS probability ranging from 0-1). MACE was defined as the composite of cardiac events, ischemic cerebrovascular accidents, and all-cause mortality during follow-up after CEA. A receiver operating characteristic curve and the Youden index were used to identify the optimal AI-AS cut-off value for predicting MACE. Kaplan Meier plot was used to depict MACE-free survival. Regression models were used to evaluate the predictive value of AI-AS for future MACE adjusting for clinical covariates. Results: A total of 665 patients with a median age of 72 [IQR:66, 78] years and 438 (65.9%) males were included. Over a median follow-up time of 7.1 [IQR:2.7, 11.5] years, MACE occurred in 419 (63%) of the patients, including 187 (44.6%) mortality, 161 (38.4%) cardiac events, and 71 (16.9%) cerebrovascular accidents. Median AI-AS was 0.32 [IQR:0.09, 0.55] in the total cohort, 0.34 [IQR:0.12, 0.56] in patients with MACE, and 0.30 [IQR:0.07, 0.53] in patients without MACE (P=0.038). AI-AS was a significant predictor of MACE (HR:2.38, 95%CI:1.64-3.46, P<0.001) in univariate Cox regression analysis. The optimal cut-off value of AI-AS for MACE was 0.419 (area under the curve: 0.55). Patients with high AI-AS (≥0.419) had a significantly lower MACE-free survival in the Log-rank test ( Figure 1 ) and in the multivariable Cox regression model adjusted for covariates compared to low AI-AS (<0.419) patients ( Table 1 ). Conclusion: AI-AS is an independent predictor of MACE in patients with carotid artery disease after CEA and can be used as a risk-stratifying tool in this patient population. Additional studies are needed to elucidate the mechanistic link between AS and MACE in these patients.

Background: Previous research has suggested pericarotid fat density to be significantly linked to atherosclerotic plaque components and cerebrovascular events. Inflammatory markers within the plaques are critical in the pathogenesis and progression of carotid artery disease. However, the association between pericarotid fat and inflammatory processes within atherosclerotic plaques remains underexplored. This study hypothesizes that pericarotid fat density is directly associated with the levels of inflammatory markers within atherosclerotic plaques. Methods: Carotid plaques were prospectively collected from patients with carotid artery disease undergoing carotid endarterectomy (CEA). The levels of inflammatory plaque cytokines (MCP-1, IL-8, IFN-γ, IL-10, IL-1β, IL-6, PDGF-AA, PDGF-AB/BB, TNF-α, VEGF) were measured in tissue homogenates using a customized 10-plex Luminex assay. Baseline demographics and clinical data of our population were extracted from electronic health records. We analyzed preoperative neck computed tomography angiography (CTA) images placing regions-of-interest (ROI) in the pericarotid fat on the slice showing maximal stenosis. For each patient, we calculated the average of Hounsfield Units (HU) within the ROI. Spearman correlation test was used to assess the correlation between variables. Results: Among the 43 patients included, the median age was 73 (67, 78) years, and 33 (76.7%) patients were male. Plaque levels of PDGF-AA and VEGF showed significant positive correlations with HU (r=0.330, p=0.030; r=0.380, p=0.011, respectively), as illustrated in Figure 1 . Although plaque levels of IFN-γ demonstrated a significant negative correlation with HU (r=-0.390, p=0.010), the most cases exhibited values close to zero. Conclusions: The assessment of pericarotid fat density on CTA may allow for the estimation of plaque inflammation, suggesting that more fat density is associated with increased inflammatory activity within atherosclerotic plaques.