Citations

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

Abstract Background Patients with Crohn disease (CD) face an elevated risk of developing small bowel adenocarcinoma (SBA), a malignancy characterized by late-stage diagnosis and poor prognosis. In this study we aimed to characterize surgical management and oncologic outcomes for CD-associated SBA. Methods A retrospective review was conducted across 3 tertiary IBD centers, analyzing 99 patients with CD who underwent surgery for SBA between 1992 and 2025. Data included patient demographics, CD history, surgical details, and oncologic outcomes. Results The median time from CD diagnosis to SBA was 25 years. The SBA diagnosis was incidental in 74.8% of cases, discovered during surgery for other complications. Tumors were predominantly located in the ileum (80.8%) and showed aggressive features: 56.6% were poorly differentiated (grade 3), and 85.9% were pathologically advanced (T3/T4 on TNM staging). Nodal involvement was present in 45.5% of patients, and 18.2% had distant metastases at diagnosis. A complete (R0) resection was achieved in 90.9% of surgeries, with a 30-day morbidity rate of 26.3%. After a median follow-up of 36 months, the distant recurrence rate was 28.3%, and overall mortality was 27.3% (18.2% cancer related). Conclusion In patients with long-standing CD, SBA is typically an incidental diagnosis made at an advanced stage. While high rates of complete surgical resection are possible, the prognosis remains guarded due to aggressive tumor biology and high recurrence rates. These findings highlight a critical need for improved risk stratification to guide surveillance and for the development of evidence-based adjuvant treatment strategies.

ABSTRACT Background Ventricular tachycardia (VT) is a life‐threatening arrhythmia frequently observed in structural heart diseases, including LMNA‐related cardiomyopathy, a genetic disorder associated with high risk of sudden cardiac death and progressive systolic dysfunction. While catheter ablation is an established therapeutic option for VT, its efficacy in cardiac laminopathy remains poorly defined. Objectives To synthesize available evidence on the role and outcomes of VT ablation in patients with cardiac laminopathy. Methods A systematic review and single‐arm meta‐analysis was performed in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane databases were searched for studies reporting VT ablation outcomes in LMNA‐related cardiomyopathy. An inverse variance random‐effects model was applied for meta‐analysis of proportions. Results Seven studies (six cohorts, one abstract) comprising 62 patients (mean age 53.2 ± 9.7 years; 85% male; 88% with implantable cardioverter‐defibrillator) were included. An endocardial/endo‐epicardial approach was used in 93% of cases. Acute procedural success was achieved in 37% (95% CI: 14%–63%; I² = 27.4%), and 28% required multiple procedures. Over a median follow‐up of 26 (9–35) months, VT recurrence occurred in 91% (95% CI: 76%–100%; I² = 37.2%). All‐cause mortality was 54% (95% CI: 39%–70%; I² = 28%), predominantly from cardiac causes (51%, 95% CI: 25%–76%; I² = 53%), and 14% (95% CI: 1%–34%; I² = 42%) underwent heart transplantation. Conclusions In LMNA‐related cardiomyopathy, catheter ablation is associated with high VT recurrence, limited long‐term success, and substantial cardiovascular mortality and transplantation rates, underscoring the importance of ICD implantation and the need for alternative strategies, including variant‐specific and molecularly targeted therapies.

Abstract Objective To examine the influence of demographics on organ damage in a broad, multiethnic cohort of patients with Behçet’s syndrome (BS). Methods In this cross-sectional ancillary analysis of the PROBE project, the investigated demographic variables were sex, age, education level and geographic area of residence. Damage was measured by the BS Overall Damage Index (BODI). Multivariate linear (β) and logistic (adjusted odds ratio [adjOR]) regression analyses examined associations between demographics and the extent and prevalence of damage. Results A total of 970 patients were enrolled. The median (interquartile range) age was 40 (31–50) years; 56.5% were males; 21.4% had a low level of education. The median BODI score was 1 (0–3), with 65.6% of patients having a BODI ≥1. Males had higher damage (β 0.103) and a higher prevalence of total (adjOR 1.7, per 10 years), ocular (adjOR 1.6), and vascular (adjOR 2.1) damage. Age was associated with greater damage (β 0.104), and a higher prevalence of overall (adjOR 1.4), neuropsychiatric (adjOR 1.2) and miscellaneous (adjOR 2.0) damage. Low education was associated with a greater frequency of overall (adjOR 1.9) and ocular (adjOR 1.6) damage. North African patients experienced greater damage than South European (β 0.400) and Middle Eastern (β 0.314) patients, as well as a higher risk of overall damage (adjOR 13.9 and 10.7, respectively) across all organ domains, except for the reproductive and gastrointestinal systems. Conclusions This study demonstrates how the extent, prevalence and characteristics of damage in BS vary with demographic factors, underscoring their importance in research and personalized management.

Background α‐Klotho is a multifunctional protein implicated in vascular aging. Declining Klotho levels are associated with arterial stiffness, endothelial dysfunction, and vascular calcification. We investigated the associations between circulating klotho, aortoiliac calcification, endothelial progenitor cells, and 10‐year survival. Methods In this retrospective cohort, blinded clinicians scored calcification on computed tomography (0–10 scale: aorta 6 points, iliac 4 points). Plasma klotho was measured by ELISA; endothelial progenitor cell subsets were quantified via flow cytometry. Mortality data were obtained from the Minnesota Death Registry. Results This study included 148 participants (mean age 72.4±9.6 years; 41% female). Median calcification score was 3 (interquartile range, 1–5). Patients with low calcification had higher Klotho levels (669 [567–841] versus 556 [457–678] pg/mL; P <0.01), with Klotho inversely correlated with calcification (r=−0.315, P <0.01). Stratified by calcification location and severity, the highest Klotho levels were seen in patients without aortic or iliac calcification ( P =0.015). Over 10 years, low Klotho was independently associated with higher mortality (hazard ratio [HR], 3.056 [95% CI 1.288–7.878]; P =0.014). Klotho inversely correlated with mature osteocalcin‐positive EPCs; B=−0.16 (95% CI, −0.29 to −0.02; P =0.027). Immunohistochemistry and immunofluorescence confirmed endothelial Klotho expression in internal mammary artery. Conclusions Lower circulating Klotho levels are associated with increased aortoiliac calcification and higher 10‐year mortality, supporting a role for Klotho in vascular aging.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

ABSTRACT Background We recently published the first real‐world multicenter and multi‐institutional study of cisplatin, gemcitabine, and durvalumab in patients with advanced biliary tract cancer (BTC). Here we present an expanded patient cohort with an increased sample size and longer median follow‐up. Methods The study population included patients with advanced BTC, who received cisplatin/gemcitabine plus durvalumab at 55 centers across 12 countries in Europe, the United States, and Asia. The primary endpoints of the study were progression‐free survival (PFS) and overall survival (OS). Secondary endpoints were overall response rate (ORR) and safety. Results Overall, 1358 patients were enrolled. Median PFS was 7.6 months (95% CI: 7.2–8.1), and median OS was 15.6 months (95% CI: 14.8–16.5). ORR was 35.6%, and DCR was 82.7%. Any grade AEs occurred in 1213 patients (89.3%). Grade 3–4 AEs occurred in 597 patients (43.2%). The rate of immune‐related AEs (irAE) was 20.3%. Grade 3–4 irAE occurred in 3.0% of patients. At the multivariate analysis for OS, normal albumin level (HR 0.68, 95% CI 0.57–0.81, p < 0.0001), CEA levels within normal ranges (HR 0.68, 95% CI 0.57–0.82, p < 0.0001), NLR < 3 (HR 0.62, 95% CI 0.52–0.74, p < 0.0001), ECOG PS 0 (HR 0.51, 95% CI 0.42–0.61, p < 0.0001), and prior surgery (HR 0.80, 95% CI 0.65–0.99, p = 0.036) were positive prognostic factors. Conclusion The updated findings, derived from an expanded cohort, further support the adoption of durvalumab in combination with gemcitabine and cisplatin in routine clinical practice, reinforcing the efficacy and safety outcomes demonstrated in the phase III TOPAZ‐1 trial.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR‐CM compared with heart failure. Methods In this multicenter, observational study, patients with ATTR‐CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all‐cause death alone or combined with heart failure hospitalization. Results Patients with ATTR‐CM (median age, 76 [interquartile range, 72–83] years, 98% men, left ventricular (LV) ejection fraction 30% [26–33]) showed greater QRS shortening after CRT implantation ( P =0.012), but not after a median of around 1 year ( P =0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P =0.124), or to the last echo ( P =0.796), which was performed after 1.3 years in patients with ATTR‐CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR‐CM had a shorter survival than controls ( P <0.001 for both end points). Patients with ATTR‐CM experiencing an early improvement in LV ejection fraction had a longer survival (log‐rank, 4.3; P =0.038). Conclusions Following CRT implantation, patients with ATTR‐CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all‐cause death.

The primary purpose of this study was to examine the acute effects of a multi-ingredient preworkout supplement (MIPS) on isometric, concentric, and eccentric peak torque and electromyographic (EMG) responses of the leg extensors during a fatiguing isokinetic protocol. Thirteen male subjects (mean age ± SD = 22.9 ± 2.2 years) were assigned in crossover fashion to ingest an MIPS or placebo before an isokinetic protocol that consisted of 30 maximal, concentric and eccentric muscle actions with EMG signals recorded from the vastus lateralis, rectus femoris, and vastus medialis muscles. Immediately before (PRE) and after (POST) the isokinetic fatigue protocol, subjects were assessed for isometric peak torque. The MIPS condition resulted in greater isometric (205 ± 48 vs. 185 ± 44 N·m, p = 0.04) and concentric (121 ± 34 vs. 103 ± 27 N·m, p = 0.015) torque values versus placebo (collapsed across time). For eccentric peak torque as well as EMG amplitude and frequency values, there were no significant (p > 0.05) interactions or main effects for each condition. These findings indicated that acute ingestion of the MIPS enhanced isometric and concentric peak torque of the leg extensors, which was not explained by changes in the EMG signal.

Abstract Berubicin is a unique anthracycline engineered to have the ability to cross the blood-brain barrier (BBB). Herein we present the primary results from a large global trial of Berubicin vs. Lomustine randomizing patients with progressive disease after only one prior therapy, all being IDH WT and stratified for MGMT methylation. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rates (ORR) of complete (CR) and partial (PR) responses. Eligibility was determined radiologically by central reads based on progression of disease, and in 2.5 years 252 patients were enrolled with 168 randomized to Berubicin and 84 to Lomustine. Safety assessment showed that Berubicin was well tolerated and myelosuppressive side effects were manageable with growth factors. Importantly, although anthracyclines are known to cause cardiotoxicity, evaluation with frequent troponin measurements, ECG and ECHO testing revealed no evidence of impact on cardiac function. The primary endpoint, OS, showed Berubicin and Lomustine had similar outcomes. Median overall survival for Berubicin was 8.7 months (6.7, 9.9) and for Lomustine was 9.3 months (6.7, 10.7) with a Hazard Ratio of 1.13 (p = 0.5351). PFS of Berubicin and Lomustine were also similar (1.5 vs, 1.6 months). There were no responses in the Lomustine arm and stable disease in 35.2% of patients while Berubicin had a response rate of 5.8% (PR) and stable disease of 33.6% with a combined disease control rate (DCR) of 39.4%. Additional data will be presented and discussed. Anthracyclines are characteristically used in combination for systemic therapy (e.g. leukemia, lymphoma, certain breast cancers), so there is promise that combination therapy will be the next pertinent approach to treatment of GBM. Evaluation of activity against a range of pediatric brain tumors is being pursued and preliminary results will be presented at the time of the conference.