Citations

BACKGROUND: Anthracyclines are a widely used and effective class of chemotherapy. However, a major limitation for their use is cardiotoxicity, manifesting as systolic dysfunction, congestive heart failure, and arrhythmias. The objective of this study was to identify genes and genetic risk variants for doxorubicin-induced arrhythmia. METHODS: We performed genome-wide association studies and meta-analysis across 2 independent nonoverlapping, genetically homogenous data sets from the Molecular Epidemiology Resource (cases N=77, controls N=1184) and Tapestry (cases N=13, controls N=172). Doxorubicin-related arrhythmia was the primary cardiac outcome, followed by investigation of a broader phenotype of cardiac events. Effects of doxorubicin on top-associated genes were assessed by quantitative polymerase chain reaction on RNA extracted from human cardiomyocytes following treatment with doxorubicin and by echocardiography in a zebrafish model of doxorubicin-induced cardiomyopathy. RESULTS: In the meta-analysis, rs12151014 at the KCTD15 locus was associated with doxorubicin-related arrhythmia at the genome-wide significance (minor allele frequency in Molecular Epidemiology Resource cases 0.195 versus 0.069 in controls; Tapestry cases 0.192 versus 0.079 in controls) P =9.01×10 −9 ; odds ratio, 3.61. MMP 16 rs1094199 was associated with the broader phenotype of arrhythmia and heart failure (minor allele frequency in Molecular Epidemiology Resource cases 0.079 versus 0.019 in controls; Tapestry cases 0.038 versus 0.015) P =1.98×10 − 8 ; odds ratio=6.15. In human cardiomyocytes, MMP16 and KCTD15 gene expression was significantly downregulated by doxorubicin, and in a zebrafish MMP16 knockout was protective of doxorubicin-induced decline in left ventricular ejection fraction. CONCLUSIONS: Genetic variants at KCTD15 and MMP16 are associated with doxorubicin-related arrhythmia and cardiac events. MMP16 is a potential cardioprotective therapeutic target.

ABSTRACT Background Coeliac disease is due to an acquired, lifelong gluten‐specific immune response resulting in a gluten‐dependent chronic immune‐mediated enteropathy associated with gastrointestinal and extraintestinal morbidity. Strictly avoiding dietary gluten is the only available management but has never been subjected to rigorous efficacy assessment now required for a pharmaceutical agent. Gluten‐free diet (GFD) is partially and inconsistently effective, but it places a high burden on patients, families, the food industry, and regulators and is defined inconsistently around the world, highlighting the need for effective and convenient adjunctive pharmacological therapies. Aims To summarize key patient, scientific, and regulatory considerations for coeliac disease drug development based on a multi‐stakeholder meeting focused on accelerating clinical trials. Methods A pre‐competitive meeting convened by the Beyond Celiac Coalition (May 2024) included patients with coeliac disease, academic experts, pharmaceutical industry representatives, and participants from the US Food and Drug Administration. Moderated panel addressed patient priorities, symptom and histologic endpoints, biopsy and histology methods, gluten challenge design, clinical trial duration, and regulatory expectations. Themes were synthesized qualitatively with focus on trial design implications and unresolved questions. Results Participants described high symptom burden and psychosocial impact despite gluten‐free diet adherence underscoring unmet therapeutic need in coeliac disease. Regulatory perspectives emphasized the need for clinically meaningful improvement and evidence of intestinal benefit, framed as symptom and histology co‐primary endpoints in clinical trials. These expectations were discussed as most applicable to trial populations with both clinically meaningful symptoms and active histologic injury at baseline; for other phenotypes, it was emphasized that endpoint strategy, the role of gluten exposure, and trial duration should be tailored case by case to the population and mechanism of action. Practical challenges identified included endpoint selection and definition, discordance between symptoms and histology, selecting fit‐for‐purpose symptom measures; standardizing biopsy acquisition and central histology reads to address patchiness and variability, pre‐specifying definitions of meaningful histologic change given ongoing uncertainty about healing, and trial feasibility. Controlled gluten exposure was discussed as a tool to improve interpretability of efficacy outcomes, with careful consideration of dose, duration, patient burden and safety. Discussion addressed the ideal length of the double‐blind period, including a shorter 24‐week double‐blind study with an open‐label extension versus a 52‐week double‐blind design. Trial duration should balance scientific rigour, patient retention, and the need for longer‐term safety and durability data, with flexibility to tailor the approach to context. Conclusions Progress in coeliac disease drug development will require patient‐centred, scientifically robust but feasible trial designs with appropriate endpoints, justified use of gluten exposure, consideration of improved biomarkers to reduce patient burden and early regulatory engagement. Continued multi‐stakeholder collaboration, including dedicated consideration of paediatric drug development, is essential to advance effective therapies.

OBJECTIVE Ganglioneuromas (GNs) are rare benign tumors arising from sympathetic neural crest derivatives, with limited large-scale data guiding management. The objective of this study was to characterize the clinical presentation, imaging features, surgical management, and long-term outcomes of patients with GN treated at a single institution over a 30-year period. METHODS The authors conducted a retrospective review of all patients diagnosed with GN between 1995 and 2025 at a single institution. Clinical data, imaging characteristics, operative details, perioperative complications, and long-term outcomes were abstracted. RESULTS A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified. Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%). The mean tumor dimensions on MRI were 8.5 ± 3.8 × 6.6 ± 3.2 × 5.8 ± 3.7 cm. Most lesions (72%) were incidental findings. Seventy patients underwent 72 surgeries, of which 69.4% had preoperative biopsy confirmation. Gross-total resection (GTR) was achieved in 73.6% of cases (53/72) and subtotal resection (STR) was performed in 26.4% (19/72). Short-term postoperative complications occurred in 43.1% of cases, most commonly neurological deficits (22.2%). The mean hospital length of stay was 4.6 ± 3.7 days. At the final follow-up (mean duration 33.8 ± 42.6 months), 46.5% of patients were stable, 42.3% had improved, and 11.3% had worsened from baseline. Two patients experienced recurrence (2.9%, 2/70). No malignant transformations were observed. Thirty-one patients were managed with observation (mean age 32.3 ± 17.7 years; mean follow-up duration 90.9 ± 151 months). Observation was chosen primarily due to proximity to major vascular or neural structures (74.2%). No patient in the observation group developed new symptoms, and 2 tumors exhibited minimal interval growth (0.08–0.17 cm/year). CONCLUSIONS GNs demonstrate indolent behavior, low recurrence rates, and no observed malignant transformation in this large cohort. GTR is achievable in most cases, but STR provides excellent long-term control when required to avoid morbidity. Observation is safe for asymptomatic tumors, particularly when adjacent to critical structures, with no growth observed on long-term follow-up, except for minimal growth in few cases. These findings support an individualized, risk-based approach to management.

Introduction/Objectives The rise in screening for social drivers of health (SDoH) in primary care settings has led to questions about effective intervention design. A large primary care practice at Mayo Clinic developed a model centered on a full-time Health Equity Coordinator (HEC) to facilitate clinic-community partnerships in 2022. The goal of this analysis was to assess the model on process outcomes, resolution of SDoH needs, and changes in healthcare utilization. Methods Using a cohort study design, we identified primary care patients with unmet SDoH needs at the intervention clinic and two comparator clinics from March 2022 to December 2023. We assessed process outcomes descriptively and resolution of SDoH needs and healthcare utilization using multivariable regression. Results The HEC contacted 348 patients and conducted 748 meetings with community-based organization staff. While there were decreases for SDoH needs and missed or late cancelled appointments in intervention group, there were no significant difference in resolution of SDoH and healthcare utilization relative to comparator groups. Conclusions The HEC model for multi-stakeholder coordination showed promise in referring patients to services and engaging key stakeholders in a primary care setting. Longer term follow up may be needed to identify changes in SDoH needs and healthcare utilization.

Abstract Introduction: Next generation of Theranostics studies are looking at novel combinations with radiation sensitizers to enhance PRRT’s efficacy. Here, we present safety and efficacy data from a multi-center phase 1 study of a [¹⁷⁷Lu]lutetium-dotatate -triapine combination in patients with GEP-NETs. Methods: The study consisted of two phases (dose escalation and expansion) administering the recommended phase 2 doses (RP2D) for the two agents. All patients received 200 mCi of [¹⁷⁷Lu]lutetium-dotatate on day 1 of four 8-week cycles, in combination with oral triapine administered at assigned dose levels (100 mg, 150 mg or 200mg) from days 1 to 14 of each cycle. Results: A total of 31 (A: 15 ; B: 16 ) patients received treatment. Nine patients experienced dose-limiting toxicities; Grade 3 anemia (n=1), Grade 5 cardiac arrest (n=1), and Grade 4 neutropenia (n=7). Based on the overall safety and pharmacokinetics data, a [¹⁷⁷Lu]lutetium-dotatate (200 mCi) plus triapine (150 mg) dose was selected as the RP2D for the expansion phase. Grade ≥3 treatment related adverse events were observed in 77% patients: anemia (23%), nausea and vomiting (3% ), lymphopenia ( 58%), neutropenia ( 35%) and leukopenia ( 39%). The majority of cytopenias were transient and resolved within two weeks. Among the 28 evaluable patients, the objective response rate (ORR) was 21.4% and the median progression-free survival (mPFS) has not been reached (median follow-up period: 23.7 months). Conclusions: The combination of [¹⁷⁷Lu]lutetium-dotatate (200 mCi) and oral triapine (150 mg D1-14) was well tolerated and demonstrated preliminary activity in patients with well-differentiated GEP-NETs. (NCT04234568).

Abstract Cancer outcomes vary widely between individual patients, each accumulating an irregular record of treatments, diagnoses, measurements, and complications. Current prognostic models reduce this complexity into a single snapshot, focus on narrow clinical settings, and rarely generalize across hospitals. Here we introduce Chronicle , an explainable transformer that learns from entire patient trajectories to predict diverse clinical outcomes throughout the disease course while capturing both short- and long-term temporal dependencies. Trained on 53.7 million longitudinal data points from 51,711 patients spanning 67 cancer types, Chronicle operates natively on irregular data without imputation and jointly predicts eight endpoints within a flexible framework adaptable to additional outcomes. Chronicle outperformed cross-sectional models for overall survival prediction (C-index 0.84 vs 0.76-0.79), stratified patients more accurately than established prognostic systems, including TNM stage, and predicted seven adverse event and transfusion endpoints (AUC 0.80-0.92). Applied without retraining to 69,341 patients in Germany, Switzerland, and the United States, Chronicle generalized across healthcare systems and improved further with local fine-tuning. Integrated explainability traced each risk update to patient-specific clinical factors, revealing distinct temporal persistence of prognostic information, with relevance half-lives ranging from weeks for therapies to nearly one year for baseline characteristics. These findings demonstrate that learning from hospital-wide patient trajectories enables interpretable and continuously updated predictions, providing a scalable framework to support individualized treatment decisions.

Background Randomized trials have shown equivocal outcomes between a direct aspiration as first-pass technique (ADAPT) and stent retriever (SR) stroke thrombectomy, yet whether specific patient subgroups benefit differentially from one technique over the other remains unknown. Methods In this retrospective multicenter cohort study, patients with large vessel occlusion were included, and those who underwent ADAPT versus SR first-pass thrombectomy (either as standalone or combined with aspiration) were compared. The primary outcome was a composite of first-pass effect (FPE, modified Thrombolysis In Cerebral Infarction (mTICI) 2c or better with one attempt) with no symptomatic intracranial hemorrhage (sICH). A causal forest model was used to estimate the conditional average treatment effect (CATE) for each patient, with larger CATEs indicating that ADAPT is expected to be more advantageous. Patients were stratified by CATEs, and outcomes were compared between treatment groups. Results Among 6700 included patients, ADAPT (n=3695, 55%) was associated with a higher rate of FPE with no sICH (39.9% vs 26.9%; adjusted OR (aOR) 2.07, 95% CI 1.77 to 2.41, P<0.001). The causal forest identified significant treatment effect heterogeneity (interaction P<0.001), where ADAPT was more advantageous in more recent years and among patients with M1 occlusions presenting in earlier time windows. Low-CATE patients showed no statistically significant difference between techniques (aOR 0.91, 95% CI 0.57 to 1.45, P=0.70), while medium- and high-CATE patients demonstrated progressively larger ADAPT advantages (aOR 2.06, 95% CI 1.67 to 2.55, and aOR 2.99, 95% CI 2.24 to 3.98, respectively, both P<0.001). Conclusions ADAPT may be superior to SR for a majority of patients, particularly in recent years, and among patients with M1 occlusions presenting in earlier time windows.

Background The management of osteochondral lesions of the talus (OLT) is challenging, with 2 main options being conservative and surgical management. Orthobiologic therapies come to bridge the gap between these 2 options; however, inconsistencies in indication, composition, and heterogeneous evidence limit clinical decision-making. To address these challenges, 3 International Congress Meetings on Cartilage Repair of the Ankle were convened in Pittsburgh, USA (2017), Dublin, Ireland (2019), and New York, USA (2025) to establish agreement on the role of conservative management and injectable orthobiologic strategies in the treatment of OLT. Methods Seventy-five multidisciplinary experts from over 25 countries and 1 territory participated in a structured Delphi-based consensus process. Blinded surveys, structured questionnaires, and in-person discussions were used to develop and refine statements, supported by literature review and graded evidence (A1–E). Consensus strength was defined as consensus (51%-74%), strong consensus (75%-99%), or unanimous (100%) Results In total, 29 consensus statements were achieved across the 3 meetings. Strong agreement was reached regarding indications and expected outcomes of conservative management, including the role of immobilization and appropriate timing for surgical intervention. Orthobiologic injections, including platelet-rich plasma, concentrated bone marrow aspirate, and hyaluronic acid, were considered appropriate in select patients with persistent symptoms, although no superiority was demonstrated among formulations, preparation methods, or injection strategies. When used as adjuncts to surgical procedures, orthobiologics may improve radiological outcomes, with limited evidence for improvement in clinical outcomes. Technical considerations, including preferred harvest sites and a lack of standardized preparation protocols, were identified, along with key principles for patient counseling Conclusion These international consensus statements establish a standardized framework for the conservative management and use of injectable orthobiologic therapies in OLT. By clarifying indications, technical considerations, and current limitations, this work aims to improve consistency in clinical practice, guide treatment decision-making, and inform future research.

Radiation oncology is poised for a decade of unusually rapid technological and biological change. Six innovations are converging on the clinic: FLASH radiotherapy, adaptive radiotherapy with advanced imaging, artificial intelligence and machine learning in treatment planning, theranostics with targeted radionuclide therapy, spatially fractionated radiotherapy using GRID and LATTICE techniques, and continuing enhancements in particle therapy with protons and heavy ions. Each is biologically compelling, but they will not reach patients at the same speed or in equal numbers. This review proposes an evidence-and-capital framework for evaluating these innovations along four axes – physical principle, biological rationale, current clinical evidence, and dominant adoption barrier – and ranks them by anticipated population-level impact over the next five years. Capital intensity emerges as the principal determinant of diffusion: innovations layered onto existing linear accelerators (artificial intelligence, spatially fractionated radiotherapy) or onto existing nuclear medicine infrastructure (theranostics) will scale globally, whereas innovations requiring new bunkers, magnetic-shielded vaults, or dedicated accelerators (adaptive radiotherapy, FLASH, particle therapy) will remain concentrated in well-resourced centres. A low anticipated diffusion ranking is not a judgement on intrinsic clinical value: several capital-intensive modalities deliver substantial benefit for selected patients even where population-level reach is limited, and the framework distinguishes throughout between intrinsic efficacy and expected accessibility. The resulting equity gap is not primarily a scientific problem but an infrastructural one. Recognising this asymmetry should inform departmental investment, training curricula, multinational cooperative-group trial design, and health-system policy on capital subsidy and consortium models. The framework is intended for radiation oncologists, medical physicists, and cancer scientists evaluating where to invest finite institutional resources.

ABSTRACT Introduction Cardiogenic shock (CS) carries high morbidity and mortality. However, evidence for mechanical circulatory support (MCS) in non‐ischemic CS remains limited, as prior trials have focused on infarct‐related shock. Methods We performed a retrospective cross‐sectional study using the Nationwide Inpatient Sample (2017–2019), identifying hospitalizations with a principal diagnosis of CS and excluding acute myocardial infarction. Patients were categorized into mutually exclusive groups: no MCS, intra‐aortic balloon pump (IABP) only, Impella only, or extracorporeal membrane oxygenation (ECMO) only. Primary outcomes were in‐hospital mortality, length of stay (LOS), and total hospital cost. Survey‐weighted multivariable models adjusted for demographics, hospital characteristics, and comorbidity burden using Elixhauser and Charlson indices. Results Among 104 045 hospitalizations, 6040 received MCS. IABP was most common, followed by Impella and ECMO. Among patients receiving a single MCS strategy, overall in‐hospital mortality was 29.5%., with lower mortality in the IABP group (19.9%) compared with Impella (37.4%) and ECMO (44.3%). After adjustment, IABP was associated with lower observed in‐hospital mortality versus no MCS (aOR 0.58, 95% CI 0.53–0.64; p < 0.01), whereas Impella and ECMO showed increased aOR. IABP and ECMO were associated with longer LOS, while Impella was not. All MCS strategies were associated with higher costs, with ECMO showing the greatest increase (cost ratio 3.30, 95% CI 3.12–3.50). Conclusion In non‐ischemic CS, MCS strategies demonstrate distinct profiles of mortality and resource utilization. IABP was associated with lower observed in‐hospital mortality, whereas all MCS were linked to higher costs, highlighting heterogeneity in outcomes and the need for further research.