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A 75-year-old male was admitted with worsening anemia and spontaneous bruising in the left abdominal wall and paraspinal region. Laboratory workup revealed low factor XIII (FXIII) activity levels. Cryoprecipitate transfusions raised his FXIII level, but still fluctuated drastically, ranging from 4 to 43% was discharged 3 days later once his bleeding was managed. Three days later, he was readmitted for severe pain and new bruising in his latissimus dorsi and lateral right thigh. CT-scan revealed hemothorax and arterial bleeding requiring an urgent angiogram with embolization. Chromogenic and functional FXIII assays were unable to elucidate an inhibitor at this time. Management included FXIII concentrate, rituximab, and prednisone; the patient was discharged 12 days later with FXIII levels of 50%. After prednisone tapering, FXIII levels decreased drastically. This case exemplified that higher levels of FXIII are required to prevent bleeding diatheses rather than the previously reported minimum of 5% activity. Despite the diagnostic uncertainty of laboratory testing, the shortened half-life of FXIII activity following replacement therapy and favorable response to immunotherapy indicates that the bleeding diathesis was caused by an acquired inhibitor.

Abstract Background and Aims Women are underdiagnosed and undertreated for cardiovascular disease (CVD). Automatic quantification of breast arterial calcification (BAC) on screening mammography can identify women at risk for CVD. This study aimed to determine whether artificial intelligence–based automatic quantification of BAC from screening mammograms predicts CVD and mortality beyond PREVENT scores in a large, racially diverse, multi-institutional population. Methods This retrospective cohort study included 123 762 women from two healthcare systems who had screening mammograms. Breast arterial calcification was quantified using a transformer-based neural network for segmentation. Breast arterial calcification severity was categorized as zero (0 mm2), mild (>0–10 mm2), moderate (>10–25 mm2), and severe (>25 mm2). Kaplan–Meier analysis, Cox proportional hazards, and Fine–Gray competing event models were used to examine the association between BAC and major adverse cardiovascular events (MACE). Results Breast arterial calcification was detected in 16.1% (internal cohort) and 20.6% (external cohort) of women and provided significant prognostic value incremental to the PREVENT score. In PREVENT adjusted models, a clear dose–response was observed. Compared with zero BAC, mild [internal: hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.10–1.59; external: HR 1.28, 95% CI 1.17–1.39], moderate (internal: HR 1.75, 95% CI 1.23–2.50; external: HR 1.79, 95% CI 1.55–2.06), and severe BAC (internal: HR 3.29, 95% CI 2.15–5.05; external: HR 2.80, 95% CI 2.36–3.32) were all prognostic for any MACE. Each 1 mm2 increase in BAC conferred an additional 2%–3% risk for MACE (P < .001). Conclusions Automatically quantified BAC is an independent predictor of MACE and mortality, adding prognostic value to the PREVENT score. This approach may provide an opportunistic cardiovascular risk assessment during routine mammography screening without additional radiation exposure to guide earlier and more effective preventive care for women.

Background: A critical component of conducting systematic reviews or meta-analyses is assessing the methodological quality and bias of included studies. Several methodological quality assessment tools have been developed; however, these tools may not be relevant to observational sports medicine research, which carries numerous unique nuances and biases. Purpose: To develop the Sport Publication Observational Research Tool (SPORT), which evaluates and scores the methodological quality of observational sports medicine research. Study Design: Consensus statement. Methods: SPORT was developed through a modified Delphi approach involving members from the Herodicus Society and The FORUM. All active members were invited to participate in the process aimed at building consensus on SPORT content and scoring. After finalizing SPORT, a power analysis led to the independent selection of 55 observational clinical sports medicine studies, which were scored twice by 4 reviewers of varying training levels. Interrater and intrarater reliability for SPORT was assessed using intraclass correlation coefficients (ICCs). The distribution and percentiles for total SPORT score across the 55 studies were calculated. SPORT was also compared with the methodological index for non-randomized studies (MINORS), a commonly utilized quality assessment tool. Results: A total of 51 members participated and achieved 100%, 100%, 98.0%, and 98.0% completion rates for rounds 1 through 4, respectively. The final SPORT included 19 subscores related to methodological quality and bias and achieved 94% consensus approval. Mean SPORT completion time was 6 minutes and 19 seconds per study, which varied significantly by reviewer training level. The subscore "peer review" demonstrated unacceptable reliability and was removed. The remaining 18 subscores exhibited ICC ranges of 0.599 to 0.955 for interrater reliability and 0.530 to 0.936 for intrarater reliability. Total SPORT score demonstrated excellent agreement, for interrater (ICC, 0.967) and intrarater reliability (ICC, 0.966). Median SPORT score across the 55 studies was 20.0 and skewed toward lower scores. There was a moderate significant correlation between SPORT and MINORS ( r [53] = 0.575; P < .001). Conclusion: An objective tool to assess the methodologic quality of observational sports medicine research (SPORT) was successfully developed through a modified Delphi approach with numerous content experts in the field. This tool may be useful in assessing the methodological quality of primary observational sports medicine studies included in systematic reviews and meta-analyses.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

Abstract Background Recurrent pericarditis (RP) predominantly shows features consistent with IL-1-mediated chronic autoinflammatory disease (1-4). A recent analysis suggested that supplementing anakinra with colchicine incrementally reduced pericarditis recurrence vs. anakinra alone (5). Rilonacept (a weekly IL-1α and IL-1β cytokine trap with 6-week washout) prevents engagement with IL-1 receptor, inhibiting both IL-1α and IL-1β activity (6). The Phase 3 trial RHAPSODY demonstrated rilonacept efficacy in two independent analyses: Randomized Withdrawal (RW) and Long-Term Extension (LTE) periods (7,8). Purpose Assess long-term recurrence-free persistence with rilonacept as monotherapy in pts with RP during the combined RW and LTE periods of RHAPSODY. Methods Post-hoc analysis. Freedom from recurrence on rilonacept monotherapy was quantified using the Kaplan-Meier (KM) method from RW start (if randomized to rilonacept) or from initiation of bailout rilonacept (if randomized to placebo) until the end of treatment. Prespecified recurrence adjudication criteria were pericarditis pain (numerical rating scale [NRS]) ≥4 plus C-reactive protein (CRP) ≥1 mg/dL. Per RHAPSODY protocol, background therapies were discontinued during the Run-In Period before randomization. In pts treated with rilonacept, concomitant colchicine was not added during the RW period. In the LTE, 6.8% (5/74) of pts added colchicine: one for 2 days of chest pain without CRP elevation, 4 in the absence of chest pain, CRP elevation, or recurrence; these 5 pts were censored in the KM curve at 6 days after last rilonacept dose or at colchicine initiation (whichever was first). One additional pt added colchicine prophylactically before an intentional rilonacept treatment interruption for elective cardiac surgery and experienced a recurrence after this interruption; this pt was not censored from the recurrence-free persistence analysis at colchicine initiation in order to capture this event. Results 74 pts (mean [SD] age 43.9 [15.7] years, 83.8% idiopathic pericarditis, mean [SD] disease duration 2.5 [3.2] years) were analyzed over three years. Rilonacept was well tolerated. Recurrence-free persistence was 95.9% (n=71/74) while receiving rilonacept as monotherapy (Figure 1). The three observed adjudicated recurrences were each associated with temporary interruptions of 1-3 doses of rilonacept. Conclusions Rilonacept as monotherapy provided recurrence-free persistence over the three-year trial duration when used continuously without interruption; pericarditis recurrences occurred only after interruptions. These findings support evidence-based use of rilonacept as monotherapy, minimizing the need for adjunctive treatments and reducing polypharmacy in long-term RP management. Further investigations are warranted to address how to assess pts as candidates for long-term treatment with rilonacept and when to cease rilonacept treatment.

Abstract Background Recurrent pericarditis (RP) is an IL-1-mediated chronic autoinflammatory disease (1,2). The phase 3 trial RHAPSODY demonstrated that rilonacept (IL-1α and IL-1β cytokine trap), the first and only FDA-approved treatment for RP, was effective in treating RP not only as a third-line agent (3L; after corticosteroids) but also as a second-line agent (2L; instead of corticosteroids) and reduced recurrence risk as monotherapy (3). The REgiStry Of the NAtural history of recurreNt periCarditis in pEdiatric and adult patients (RESONANCE) has been collecting long-term combined prospective and retrospective data from US-based pericardial-disease-dedicated programs since 2020 (4). Purpose To assess the efficacy of rilonacept in RP in a real-world setting, extending the clinical trial findings of RHAPSODY. Methods Database cut-off (DCO) was 05 February 2025. Data on RP management were collected and analyzed from pts with ≥2 years of observation in RESONANCE. Disease duration at DCO was defined as time from RP diagnosis to either disease resolution (no disease flares while off all RP treatments for ≥6 months before DCO) or last follow-up (for pts with ongoing treatment at DCO). Pericarditis recurrences (investigator-assessed) were confirmed based on RP symptom data and/or objective findings. Annualized recurrence rates were calculated per RP treatment regimen as total pericarditis recurrences divided by total patient-years (PY) while receiving that treatment. Wilcoxon signed-rank test was utilized to analyze the significance in change of annualized recurrence rates before and after rilonacept initiation. Results At DCO, 81 pts had ≥2 years of follow-up data in RESONANCE; mean (SD) age was 51.0 (16.8) years; most (66.7%) were female; 84% had idiopathic etiology; median (Q1-Q3) disease duration was 3.1 (2.6-3.7) years; and median observation was 2.93 (2.54-3.38) years. Patient-year treatment exposures per treatment were: NSAIDS ± colchicine (n=79; 187.8 PY), corticosteroids (n=30; 61.1 PY), anakinra (n=1; 1.2 PY) and rilonacept (n=35; 72.8 PY). Of the 35 pts treated with rilonacept for any duration (median observation: 3.2 years; median time on rilonacept: 2.08 years), the most common reason for rilonacept initiation was chest pain/recurrence on prior treatment (n=28). The annualized recurrence rate while receiving rilonacept was significantly lower versus all combined prior lines of treatment (4.00 vs. 0.02 events per PY; p=0.002); this outcome was consistent across line of treatment for rilonacept use (2L: 3.73 vs. 0.06 events per PY, p=0.02; 3L: 4.14 vs. 0 events per PY, p&lt;0.001; Table 1). Conclusions This first report of real-world outcomes from RESONANCE shows that rilonacept-containing regimens for RP as 1st, 2nd, or 3rd line therapy reduced recurrence risk over long- term (&gt;2 year) treatment, supporting prolonged management during RP natural history.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

PURPOSE Detection of molecular residual disease using circulating tumor DNA (ctDNA) may enable postoperative risk stratification and guide adjuvant therapy. We evaluated the prognostic value of a tissue-free, epigenomic ctDNA assay in patients with stage III colon cancer (CC) enrolled in a phase III adjuvant chemotherapy trial. METHODS Plasma samples were collected after surgery and before adjuvant infusional fluorouracil, leucovorin, and oxaliplatin alone or combined with cetuximab. ctDNA was analyzed using a tissue-free assay; in ctDNA-positive patients, tumor fraction (TF) was quantified and genotyping was performed with a 739-gene panel. Associations with disease-free survival (DFS), time to recurrence (TTR), and overall survival (OS) were assessed using multivariable Cox models adjusted for covariates. RESULTS Among 2,260 evaluable patients, 461 (20.4%) were ctDNA-positive with significantly higher detection in advanced T-/N-stage, high-grade, obstruction/perforation, and BRAF V600E tumors. At a median follow-up of 6.1 years, ctDNA positivity was independently associated with shorter TTR (hazard ratio [HR], 5.96 [95% CI, 5.11 to 6.96]), DFS (HR, 5.03 [95% CI, 4.36 to 5.81]), and OS (HR, 4.45 [95% CI, 3.76 to 5.27]; all P < .0001). The 5-year DFS was 27.7% (95% CI, 23.8 to 32.2) v 77.1% (95% CI, 75.1 to 79.1) in ctDNA-positive versus ctDNA-negative patients, and adverse prognostic impact was greater in lower T/N stage, low-risk, and dMMR subsets (interaction P = .0012-.041). Among ctDNA-positive patients, TF was nearly double in those who recurred or died ( P = .0002) and stratified patients for TTR, DFS, and OS (all adjusted P < .002). Genotyping identified mutations in FLT1 (OR, 8.99) and PREX2 (OR, 7.73) genes that were most strongly associated with recurrence ( P < .03). CONCLUSION Evaluation of ctDNA in resected stage III CC using a tissue-free assay provided robust and independent prognostic value. Higher ctDNA burden, dMMR, and specific mutations defined poor prognostic groups among ctDNA-positive patients.

Introduction: Embolic stroke of undetermined source (ESUS) is a clinical construct encompassing heterogenous possible mechanisms of incident stroke, potentially with variable responsiveness to anticoagulation and antiplatelet treatment. This study aims to identify differences in recurrent stroke risk based on phenotypic clusters in an ESUS population, and whether some clusters may benefit relatively more from anticoagulation over antiplatelet therapy. Methods: We identified patient phenotypes from a multicenter, retrospective cohort study of 1909 ESUS patients by dividing them into groups using Partitioning Around Medoids (PAM) with correlation-weighted Gower distance over 23 baseline demographic, clinical, laboratory, radiographic, and cardiac features. We confirmed optimal clustering at 3 groups. We assessed cluster associations with time to recurrent stroke using Kaplan-Meier survival analysis. We then employed a causal survival forest to estimate conditional average treatment effects (CATE) of anticoagulation versus antiplatelet therapy using the same baseline features as predictors with a 365-day horizon for restricted mean survival time differences. Finally, we used best linear projection to identify baseline features predictive of treatment effect and assessed whether effects differed significantly by cluster. Results: Cluster 1 (n=542) identified a low-risk, younger sample with minimal baseline disability and comorbidity burden. Cluster 2 (n=743) comprised a moderate-risk phenotype with intermediate comorbidity. Cluster 3 (n=626) represented the oldest and highest-risk phenotype. Kaplan-Meier analysis demonstrated significant differences in stroke-free survival across patient clusters (p < 0.001), where Cluster 1 experienced the lowest recurrent stroke rate and Cluster 3 had the highest. The clustering algorithm successfully identified clinically meaningful phenotypes with distinct risk profiles. While CATE varied across clusters, the differences were not statistically significant. Conclusion: In a multicenter ESUS population, we identified 3 distinct phenotypic clusters, each comprising nearly one-third of the sample and with a differential risk of recurrent stroke. Although cluster was not a significant effect modifier, substantial CATE variability by cluster was observed. Future clinical trials may consider evaluating secondary stroke prevention therapies among phenotypically similar patients who may respond differentially to novel therapies.