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Abstract Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Previous work has shown age can impact treatment safety and efficacy in patients with inflammatory bowel disease.1 This post hoc analysis investigated the impact of age on the safety and efficacy of etrasimod in patients with UC in the phase 3 ELEVATE UC clinical programme. Methods Data pooled from the ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials were analysed in patients receiving etrasimod 2 mg QD and placebo. ELEVATE UC 52 had a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 was a 12-week induction trial. Proportions and incidence rates (IRs) per 100 patient-years from pooled data of treatment-emergent adverse events (TEAEs) and events of interest were stratified by age (<40 years, 40–59 years, ≥60 years) and analysed in patients who received ≥1 dose of etrasimod or placebo. Efficacy analyses were evaluated in patients with baseline Modified Mayo score (MMS) 5–9 for the primary efficacy endpoint (clinical remission) and select secondary endpoints at Week 12 (both trials) and Week 52 (ELEVATE UC 52) stratified by age. Results There were 787 patients enrolled in the ELEVATE UC programme, of whom 420 (53.4%) were aged <40 years, 276 (35.1%) were aged 40–59 years and 91 (11.6%) were aged ≥60 years. The proportions and IRs of TEAEs and events of interest were mostly similar between age groups and treatment arms (Table). IRs of arthralgia, fatigue, hypertension and pyrexia were higher in older age groups, regardless of treatment arm. Serious AEs and AEs leading to treatment discontinuation were low and consistent across all age subgroups. Serious infections and infection events of interest were balanced across age groups and treatment arms. Regardless of age subgroup, significantly more patients treated with etrasimod 2 mg QD vs placebo achieved the primary and select secondary efficacy endpoints at Week 12 and Week 52 (Figure). Conclusion The safety profile of etrasimod 2 mg QD in the UC population was consistent across age groups, and with no new risks other than the estimated risks associated with increasing age.2 Patients receiving etrasimod in the ELEVATE UC programme showed significant clinical benefit as assessed by clinical remission, symptomatic remission and endoscopic improvement compared with placebo, regardless of age. References 1. Lichtenstein GR et al. Inflamm Bowel Dis 2023; 29: 27–41. 2. Luo J et al. JMIR Med Inform 2016; 4: e30.

Background Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. Methods Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2–5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. Results M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. Conclusions Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

26 Background: Local therapies have the potential to cure a portion of patients with colorectal cancer with liver-only metastatic disease (CRLM). Peri-operative chemotherapy has not been shown to improve overall survival when added to local therapy in CRLM. Circulating-tumor DNA (ct-DNA) may have potential to help guide management decisions following local therapy. Methods: We conducted a retrospective analysis of health records of CRLM patients who had tumor-informed ct-DNA (Signatera) measurement following curative-intent local therapy prior to August 30th, 2023. Disease-free survival (DFS) was defined as the time from ct-DNA test until radiographic evidence of disease. Descriptive characteristics of the cohort, ct-DNA results and their impact on adjuvant therapy decisions were recorded. Survival analysis was carried out using R software v4.3.1 with survival and survminer packages. The Kaplan–Meier method was used to estimate the survival distribution. Log-rank test was used for comparison. A multivariable Cox proportional hazards model was used to assess prognostic factors associated with DFS ( coxph). Results: 27 patients with CRLM underwent local therapy followed by ct-DNA collection. The median age was 61 years, 67% were male, and 85% were White. Molecular characteristics: KRAS 31%, NRAS/BRAF 0%, microsatellite instability 4%. The median time from initial diagnosis to treatment of liver disease was 21.0 months. 63% of patients received less than 6 months of systemic therapy prior to local therapy. ct-DNA was checked prior to definitive therapy in 12 cases and was positive in 5 cases (detection rate of 42%). Liver-directed therapy involved: resection (n=15), ablation (6), radiation (2) or a combination (4). The median follow-up time from liver-directed therapy was 13.2 months. Post-local therapy chemotherapy was initiated prior to recurrence in 59% of cases. ct-DNA results contributed to immediate post-management decisions in 15% of cases. There were 14 radiographic recurrences (11 to liver only, 3 to other sites). Positive ct-DNA on initial testing following local therapy was associated with poorer DFS in univariate analysis and was the only prognostic factor identified on multivariable analysis. Conclusions: ct-DNA positivity following local therapy for CRLM is associated with earlier recurrence. Baseline testing before local therapy may be important for interpretation of testing results post-local therapy, given frequent missed disease detection. Additional clinical trial data is needed to explore ct-DNA-guided treatment decisions in CRLM. [Table: see text]

17 Background: Age-appropriate colon cancer screening has long demonstrated effectiveness in reducing colon cancer incidence and mortality. However, despite a gradual rise in compliance with colon cancer screening, significant disparities remain, particularly among patients with limited English proficiency (LEP). Multitarget stool DNA (MT-sDNA) testing (Exact Sciences, Madison, WI) has been available over the past decade in the United States as a lower-cost and non-invasive option for screening. In 2019, Exact Sciences began to offer patient navigation services comprising outbound phone, text, and e-mail reminders, and inbound phone support (>200 languages) with all MT-sDNA orders. In this study, we aimed to evaluate the disparity in successful MT-sDNA testing between LEP and EP patients in a time frame when patient navigation services were active. Methods: We performed a retrospective cohort study of patients 45-75 years old enrolled in the primary care setting of our institution who received an order for MT-sDNA screening during a period in which patient navigation services began to be offered. A multi-state Cox model was constructed with time to MT-sDNA or other CRC screening predicted by English proficiency accounting for age and gender. Wald tests were used to test the association of CRC screening completion and English proficiency. Rates of completion of MT-sDNA screening and other CRC screening following MT-sDNA test ordering were calculated using the Kaplan-Meier method. Results: Of the 5016 patients evaluated and referred for multitarget stool DNA testing from May 1st, 2021, and May 1st, 2022, 154 patients were of LEP, and 4862 were English proficient (EP). At 180 days following a MT-sDNA test order the rate of completion for the LEP patients was 50.2% (95% CI: 42.8-58.7%) versus 70.3% (95% 69.1-71.6%) for EP individuals (p=0.001). A small portion of individuals also completed another type of CRC screen, 3.3% for LEP and 2.5% for EP (p=0.99). Conclusions: This study is consistent with the existing research demonstrating LEP as a significant demographic group linked with decreased participation in cancer screening. Our findings indicated that despite the availability of patient navigation services, individuals with LEP were still less likely to complete an MT-sDNA test successfully when compared to those with EP. [Table: see text]

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled “Clinical N0 Disease, Locally Advanced MCC.” This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term “nonsurgical” by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

PURPOSE Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA). Here, we examined the pattern of use of a tumor-informed ctDNA assay in CRC MRD monitoring in routine clinical practice at Mayo Clinic, Rochester. METHODS We conducted a retrospective analysis of health records of patients with CRC who had at least one tumor-informed ctDNA assay from May 2019 through July 1, 2022. Recurrence was defined as radiographic evidence of disease. Descriptive characteristics of the cohort, ctDNA results, and subsequent interventions were recorded. RESULTS Of the 120 patients included, the median age at diagnosis was 67 years, 46% were female, and 94% were White. At diagnosis, 10 patients had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. Of 476 ctDNA assays performed, 70% were performed in patients who had recurrent disease most commonly to monitor the effectiveness of therapeutic interventions and 16% resulted in a change in clinical decision making. There were 110 recurrences identified in 62 patients, as some patients experienced more than one recurrence over time. Compared with serum carcinoembryonic antigen levels, ctDNA results correlated better with radiologic imaging. CONCLUSION Routine ctDNA monitoring for MRD detection has been adopted in clinical practice; however, 84% of ctDNA assays performed did not result in a change in clinical management. This suggests the need for further clinical research data to guide routine clinical use of ctDNA MRD testing in CRC.

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with >5 sites of disease had a higher risk of progression, and every site of disease >5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs.

AbstractOver the past several decades, molecular genetic testing volumes have grown and testing has expanded from single‐gene assays to multigene panels, exome sequencing, and genome sequencing. The number of molecular genetic variants that require manual interpretation has grown simultaneously, resulting in an increased demand for education on molecular variant evaluation (MVE). To meet this growing need, a team of genetic counselors and educational experts undertook a quality improvement (QI) initiative with the objectives of assessing, standardizing, and scaling access to MVE education, without increasing instructor time to deliver the education. Using the Six Sigma define–measure–analyze–improve–control (DMAIC) framework, a flipped learning course with a series of standardized online modules was developed to deliver MVE education in an enduring and accessible format for a diverse group of learners. Outcome measures included the number of online modules developed, the number of individual learners and unique learner groups accessing MVE education, and direct instruction time required to deliver MVE education. Countermeasures to ensure maintenance of educational quality included post‐course learner satisfaction scores and performance on competency assessments. Both the total number of learners and the number of unique learner groups accessing MVE education increased, while instructor time required to deliver content per learner decreased. Learner satisfaction scores remained constant and performance on competency assessments improved. The QI initiative successfully scaled MVE education to a diverse group of learners without decreasing learner outcomes or satisfaction. The flipped learning format provides a scalable and flexible educational model for instructors and learners in a rapidly changing environment that often includes remote work and education.

While congenital heart disease historically was a pathology primarily restricted to specialized pediatric centers, advances in technology have dramatically increased the number of people living into adulthood, the number of complications faced by these patients, and the number of patients visiting non-specialized emergency departments for these concerns. Clinicians need to be aware of the issues specific to patients’ individual congenital defects but also have an understanding of how typical cardiac pathology may manifest in this special group of patients. This manuscript attempts to provide an overview of this diverse but increasingly common group of adult patients with congenital heart diseases, including a review of their anatomical variants, the complications they face at the highest rates, and ways that emergency physicians may need to manage these patients differently to avoid causing harm.

Abstract Study Objectives Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson’s disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)—henceforth “neurotrauma” (NT)—increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. Methods Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). Results RBD + NT reported earlier RBD symptom onset (37.5 ± 11.9 vs. 52.2 ± 15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. Conclusions This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.