Citations

ABSTRACT Background Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal‐derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored. Objective We investigate whether archaic alleles influence PBC risk. Design Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE‐mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia. Results A Neanderthal‐derived variant in TNPO3 (rs12531711), previously reported by Cordell et al. showed strong association in CANUK ( p = 2.04 × 10 −26 ) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating IRF5 and downregulating TNPO3 in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000–3000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single‐variant association, the heritability explained by NIMs was not significantly different from that of non‐NIM variants. Conclusion A Neanderthal‐derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen‐driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.

Abstract BCMA-directed CAR T-cell and T-cell engager (TCE) therapies produce high response rates in relapsed multiple myeloma, yet most patients progress. Prior work identified TNFRSF17 alterations mediating antigen escape in up to 43% of TCE progressions. To evaluate the generalizability of these findings and examine antigen-loss-independent resistance, we performed whole-exome sequencing on 32 paired pre- and post-treatment progression bone marrow samples from 15 patients (5 CAR T, 10 TCE); two patients received both agents. TNFRSF17 alterations were infrequent and restricted to TCE recipients (one concurrent frameshift and missense mutation; two heterozygous copy-number losses); no biallelic loss or CAR T-associated events were observed. In contrast, deleterious/loss-of-function variants in NF-κB, PI3K-AKT-mTOR, and MAPK/ERK pathways were universal in pre-treatment samples and acquired or clonally enriched in 80% of patients at progression. Acquired events included loss-of-function alterations in CYLD , activating mutations in KRAS , NRAS and BRAF , and acquired TP53 mutations. In this series, antigen escape via TNFRSF17 /BCMA alteration was uncommon. Instead, pre-existing, acquired and clonally enriched pathogenic variants in NF-κB, PI3K-AKT-mTOR and MAPK cascades, together with TP53 mutation, emerged as a frequent finding. These alterations suggest that deregulation of BCMA-downstream survival signaling, enhanced proliferative fitness, and elevation of apoptotic threshold constitute antigen-loss-independent mechanisms of resistance.

Introduction Clinical Research Coordinators (CRCs) serve as the frontline staff for research participants in studies on frontotemporal degeneration (FTD), directly influencing participant experience. The training adequacy, job satisfaction, and retention of FTD CRCs have not been systematically examined. Methods The Association for Frontotemporal Degeneration (AFTD) administered an anonymous cross-sectional online survey to CRCs affiliated with research networks across the USA and Canada. Results Thirty-seven CRCs responded. Most had more than 3 years of experience, yet 62% reported encountering situations for which they felt inadequately prepared. Information on genetics, symptom management, and brain donation were identified as critical training gaps. Retention was linked to competitive pay and clear career advancement opportunities. Discussion The findings highlight a critical need for formalized, disease-specific onboarding and emotional support systems tailored to CRCs that engage with FTD patients and families. AFTD is developing a modular training curriculum to standardize CRC competency.

Abstract Background Optimal treatment following first-line immunotherapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study evaluated futibatinib, a pan-FGFR inhibitor, combined with pembrolizumab in previously treated patients with FGF19-expressing HCC. Methods Eligible patients were ≥18 years old with advanced HCC, prior systemic therapy, Child-Pugh A-B7 liver function, ECOG 0–2, and FGF19 overexpression. Patients received futibatinib 20 mg orally daily plus pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included overall survival (OS), objective response rate (ORR), quality of life, and safety. Results Between August 2021 and March 2024, 14 patients enrolled and 13 were evaluable. Median age was 72 years (range, 60–87), 53.8% were male, 92.3% had Child-Pugh A liver function, and all had received prior immunotherapy. Median progression-free survival was 15 weeks (95% CI, 9.0–NE), with a PFS6 rate of 23.1% (95% CI, 8.6–62.3%). ORR was 0% (95% CI, 0–24.7%), while stable disease was observed in 53.9% of patients. Median OS was 55.7 weeks (95% CI, 47.3–NE). Grade ≥3 adverse events occurred in 69.2% of patients, and grade ≥4 adverse events in 15.4%. One grade 5 event (acute-on-chronic kidney injury) was deemed unrelated to treatment. Common adverse events included hyperphosphatemia, fatigue, diarrhea, elevated transaminases, dry eye, nail changes, rash, and oral mucositis. Conclusions Futibatinib plus pembrolizumab demonstrated an acceptable safety profile but did not meet efficacy thresholds supporting further study in FGF19-expressing HCC. Effective post-immunotherapy treatment strategies remain an unmet need.

ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.

Abstract Objective Rituximab causes B‐cell depletion and hypogammaglobulinemia, increasing risk for infections. This study aims to determine the incidence of chronic rhinosinusitis (CRS) in patients following rituximab therapy. Study Design Retrospective cohort study using chart review of patients prescribed rituximab between January 2019 and January 2025. Setting Multisite study across Mayo Clinic Enterprise locations in Arizona, Florida, Minnesota, and Wisconsin. Methods Patients with documented rituximab use were included; those with pre‐existing CRS were excluded. Demographic and clinical data—including timing and duration of rituximab therapy, CRS diagnosis, comorbidities (asthma, allergic rhinitis, GERD), and need for sinus surgery—were collected. Descriptive statistics summarized patient characteristics. Group comparisons were performed using t ‐tests, Mann‐Whitney U , and chi‐square tests. Analyses were conducted using SPSS v28. Results Among 17,851 patients prescribed rituximab (median age 64.0 years, M:F ratio 1.1:1), 1105 (6.2%) developed CRS, with an annual incidence of 1.03% (1032 cases per 100,000 person‐years). The median duration of rituximab therapy for those diagnosed with CRS was 5.9 months (IQR, 0.5‐42.6). Most CRS cases occurred after rituximab discontinuation (62.7%, n = 693) compared to during active treatment (37.3%, n = 412). The median delay between rituximab discontinuation and CRS diagnosis was 17.0 months (IQR, 4.3‐41.7). Conclusions This study demonstrates an annual incidence of 1.03% for CRS diagnoses following rituximab. While prior studies report varying CRS incidences in the general population (0.25%‐0.73%), our findings suggest increased risk among rituximab users. Most CRS diagnoses occurred after rituximab discontinuation, emphasizing the need for a comprehensive medication history review during CRS evaluation.

Background Despite advances in cervical cancer screening, cervical cancer rates have been increasing in the last decade. Hispanic women have higher cervical cancer incidence and mortality rates compared to non-Hispanic women in the United States. These disparities are primarily due to language barriers experienced in this Spanish-preferred population. Our study aims to improve cervical cancer screening rates among Spanish-preferred patients through a Spanish-language multimedia presentation on cervical cancer screening. Methods In patients not adherent to U.S. cervical cancer screening guidelines, we conducted a non-randomized study comparing standard care in Family Medicine (FM) to standard care plus a multimedia presentation with Spanish voiceover intervention in Internal Medicine (IM). We evaluated whether baseline characteristics differed between the two study arms using the Wilcoxon rank sum test and either the Chi-Square test or Fisher’s exact test. For the primary goal, we examined whether there was a difference in screening scheduling rates between the intervention and standard care groups using the Chi-Square test. Using descriptive statistics, we investigated whether there was a difference in characteristics for those who scheduled screening and those who did not. Results We had 52 patients in IM and 58 in FM, differing in age and insurance status, with median ages of 45.5 and 40.0, and percent insured of 65.4% and 82.8%. Post-study, 25.0% (13/52) in IM and 15.5% (9/58) in FM scheduled cervical screening appointments, which was not significantly different, p=0.21. Patients who scheduled screening had higher rates of insurance coverage, at 95.5% compared to 69.3%. Conclusion No statistically significant difference in scheduling rates among Spanish-preferred patients was observed in this study. Further efforts should include larger samples and randomization.

Background Prognostic staging systems in transthyretin amyloid (ATTR) cardiomyopathy were developed before the introduction of disease‐modifying treatment. We therefore evaluated contemporary risk stratification according to different staging systems in patients with ATTR cardiomyopathy. Methods All patients with newly diagnosed ATTR cardiomyopathy and baseline biomarker measurements from 2019 to 2023 were included from Mayo Clinic, Rochester, MN. Prognostic outcomes were calculated with Kaplan–Meier analysis for 3e staging systems in the main analysis: the National Amyloidosis Centre (NAC) staging system; a modified Mayo staging system using hsTNT (high‐sensitivity troponin T) cutoff >65 ng/L; the extended NAC model with a fourth stage (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] >10 000 ng/L). Results The study population consisted of 441 patients with a median age of 76 years, 93% were men, 85% were initiated on tafamidis, and 94% had wild‐type ATTR. Median follow‐up was 3.4 years, and 109 deaths occurred during follow‐up. The 3‐year survival for the Mayo stages were 92.3% (88.7–95.9) for stage I, 71.6% (63.0–81.3) for stage II, and 43.5% (32.4–58.5) for stage III. For the NAC system, 3‐year survival were 92.0% (89.0–95.7), 67.5% (59.0–77.3), and 47.0% (34.7–63.5) for stages I, II, and III, respectively. The 3‐year survival by the extended NAC system was 92.0 (69.0–79.2), 69.0% (60.1–79.2), 53.2% (39.9–70.8) and 34.4% (17.4–68.0) for stages I, II, III, and IV, respectively. Conclusions In a contemporary cohort of patients with ATTR cardiomyopathy, the NAC and modified Mayo staging systems remained equally effective in delineating clinically meaningful prognostic groups, whereas the extended NAC system identified a stage IV subgroup with high mortality.

Abstract Background AL amyloidosis and multiple myeloma are plasma cell dyscrasias characterized by excess light-chain production leading to cardiac amyloid deposition and organ dysfunction. While effective, proteasome inhibitor–based therapy and stem cell transplantation are often limited in advanced disease. Daratumumab provides durable and well-tolerated plasma cell suppression and enables assessment of long-term cardiac outcomes. Purpose To evaluate the long-term effects of daratumumab therapy on cardiac biomarkers and myocardial amyloid burden, assessed by artificial intelligence- based electrocardiographic (AI-ECG) and echocardiographic measures, in patients with AL amyloidosis and cardiac involvement. Methods Following IRB approval, we conducted a retrospective review of patients with AL amyloidosis and cardiac involvement treated with daratumumab at Mayo Clinic Rochester since 2015, with a minimum follow-up of 6 months. Demographic, clinical, cardiac biomarker, electrocardiographic, and echocardiographic data were collected at baseline and last follow-up. Paired comparisons were performed using the Wilcoxon signed-rank test. Results Overall, 67 patients with AL amyloidosis were included (mean age at diagnosis 59 ± 10 years; 47 [70%] male; concomitant multiple myeloma 13 (19%) patients, mean left ventricular ejection fraction 61 ± 7%), with a mean follow-up duration of 8.3 ± 5.4 years. At diagnosis, the most common organ involvements were renal and cardiac, affecting 78% and 67% of patients, respectively. Free light-chain isotype was λ in 52 patients (75%) and κ in 17 (25%) and immunoglobulin heavy-chain was identified in 26 patients. Among patients with available baseline staging data, Mayo Clinic revised cardiac staging (2012) classified 32% as stage I, 14% as stage II, 21% as stage III, and 32% as stage IV. Most patients were NYHA class II (62%), with 27% in class III–IV. Baseline creatinine clearance &lt;60 ml/min was observed in 48% of patients. No significant changes were observed in conventional echocardiographic parameters during follow-up. In contrast, cardiac biomarkers improved significantly with high-sensitivity troponin T decreased from a baseline median of 59 [25, 104.5] ng/L to 30.5 [14.5, 58.75] ng/L at follow-up (p = 0.003), and NT-proBNP declined from 1,053 [423.5, 6,211.5] pg/mL to 729 [299, 2,328] pg/mL (p = 0.02). Interestingly, artificial intelligence–based electrocardiographic analysis demonstrated a marked reduction in the predicted likelihood of cardiac amyloidosis, decreasing from 55.8% [5.1, 99.6] at baseline to 19.3% [4.3, 68.4] at follow-up (p &lt; 0.0001). Conclusions Long-term daratumumab therapy was associated with significant reductions in cardiac biomarkers and AI-ECG derived measures of myocardial amyloid burden. These findings support the hypothesis that sustained suppression of pathogenic light-chain production may permit gradual improvement in amyloid cardiomyopathy over time.