Citations

Extracorporeal membrane oxygenation (ECMO) represents an established modality of intraoperative circulatory and respiratory support during lung transplantation (LTx). Systemic anticoagulation with unfractionated heparin (UFH) remains essential to prevent circuit thrombosis; however, the optimal monitoring strategy during this procedure remains uncertain. Conventional assays, including antifactor Xa activity (anti-Xa), activated partial thromboplastin time (aPTT), aPTT ratio (aPTTr), and activated clotting time (ACT), demonstrate variable sensitivity and reliability, particularly at low UFH concentrations where ACT is often inadequate. This study aimed to evaluate the interrelationship between standard coagulation monitoring methods and to assess the feasibility of using viscoelastic testing, specifically the ROTEM INTEM/HEPTEM clotting time ratio (I/Hr), as a bedside alternative to ACT. A total of 79 patients undergoing LTx with intraoperative ECMO support were analyzed. Unfractionated heparin was administered in all cases, and coagulation parameters were assessed preoperatively, before ECMO cannulation, and during ECMO support. A strong correlation was observed between I/Hr and anti-Xa, with satisfactory agreement with aPTT and aPTTr. Bland–Altman analysis confirmed narrower limits of agreement for I/Hr-derived versus ACT-derived anti-Xa predictions. These findings support I/Hr as a reliable and practical bedside surrogate for UFH monitoring during ECMO-assisted LTx.

ABSTRACT Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.

Cholangiocarcinoma (CCA) represents a biologically and clinically heterogeneous group of biliary tract malignancies. Growing evidence underscores that the 3 major anatomic subtypes—intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)—are distinct tumor entities rather than a single disease. Each subtype differs in embryologic origin, carcinogenesis mechanisms, molecular landscape, and immunogenic profile, all of which contribute to variability in diagnosis, treatment responsiveness, and prognosis. The importance of understanding these distinctions is reinforced by the rising global incidence of CCA, which highlights the need for precision medicine approaches based on these subtypes. Recent advances have deepened our insight into subtype-specific risk factors, including chronic biliary diseases and metabolic conditions, while artificial intelligence–driven tools are improving diagnostic accuracy and risk stratification. Surgical innovations now allow for more tailored resections and perioperative care, and therapeutic strategies are increasingly guided by molecular and immune profiling. Emerging strategies for early diagnosis and chemoprevention in high-risk populations further emphasize the significance of recognizing the unique biology of each subtype. In this review, we provide a comprehensive overview of the distinct anatomic subsets of CCA, integrating their molecular and biological foundations with clinical management to inform practice and guide future research.

Abstract Background Coronary computed tomography angiography (CCTA) is a non-invasive diagnostic modality for assessing coronary artery disease (CAD), with a growing global trend favouring a "CT-first" approach. However, this strategy strains healthcare systems as demand for CCTA increases. Pre-test probability (PTP) models for obstructive CAD are used to optimize the usage of CCTA. However, these models perform inconsistently across different subpopulations and offer limited discriminatory accuracy, with low positive predictive values (PPV). This study aims to enhance the PTP models with explainable artificial intelligence (XAI) on electrocardiogram (ECG) data. Methods Patients who underwent CCTA for suspected CAD with both CAD-Reporting and Data System (CAD-RADS) classification and Coronary Artery Calcium Score (CACS) were included. Obstructive CAD was defined as CAD-RADS 3 or above. Missing values were imputed. The Risk Factor Weighted Clinical Likelihood (RF-CL) model, based on clinical variables (age, sex, symptom type, smoking, hypertension, dyslipidaemia, diabetes, and family history) was computed. Two gradient descent decision tree models, "AI-ECG" and "AI-CAC," were developed for the pilot study. AI-ECG used clinical risk factors and ECG classification as abnormal, borderline or normal, while AI-CAC further incorporated CACS. We used a cutoff value of 15%, reflecting current guidelines. Comparative analysis was performed using area under the curve (AUC) analysis, the DeLong test for statistical comparison, and feature importance using SHAP values. We intend to develop and present a model based on ECG signal data during the conference. Pilot results We identified 6 178 patients who underwent CCTA between 2022 and 2024 at the Cardiology Centers Netherlands (CCN), of which 2 083 were included (mean age 57.4 ± 10.2 years; 48.1% male). Obstructive CAD was found in 413 (19.8%) patients. The RF-CL model was outperformed by both AI-ECG (AUC: 0.69 vs. 0.80, p<0.001) and AI-CACS (AUC: 0.69 vs. 0.90, p<0.001). Sensitivity increased in both AI models, from 0.46 to 0.87 for AI-ECG and to 0.83 for AI-CACS, while PPV improved only in the AI-CACS model (from 0.37 to 0.61). Key predictive features were CACS, age, sex, ECG classification, and family history. Conclusion and Discussion Our pilot study shows that integrating XAI with clinical risk factors and ECG classification enhances PTP estimation for obstructive CAD. Implementing this model can better stratify patients at risk of obstructive CAD, support more focused CCTA use and reduce unnecessary testing. Nonetheless, further external validation is needed to assess model performance in real-world, prospective clinical settings. Additionally, models based on raw ECG signals have the potential to extract more detailed information.Reciever Operating Characteristic CurvesFeature Importance

Abstract Aims Left bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodeling. However, not all patients with LBBB develop cardiomyopathy, and dyssynchrony can occur without conduction defects. The role of microvascular dysfunction remains uncertain. We aimed to assess how mechanical dyssynchrony and perfusion heterogeneity relate to LV remodeling and function in patients with and without LBBB. Methods and results We retrospectively analyzed 233 patients with isolated LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), myocardial blood flow (MBF), coronary vascular resistance (CVR), myocardial flow reserve (MFR), septal-to-lateral MBF ratio (SLR) for perfusion heterogeneity, LV volumes, and ejection fraction (EF). Compared to controls, patients with LBBB had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all p <0.001), and had higher stress CVR (37 vs. 34 mmHg/mL·min⁻¹·g⁻¹), lower stress MBF (2.4 vs. 2.6 mL/min/g), reduced MFR (2.4 vs. 2.6), and lower SLR (0.95 vs. 1.00) (all p <0.05). Among patients with dyssynchrony, SLR<1.0 identified those with more adverse remodeling. In multivariable regression, phase entropy and SLR independently predicted LV volumes and EF, with adverse effects of SLR reduction amplified in LBBB (interaction p <0.01). In the Cox proportional hazards analysis, phase entropy (HR:1.02, p =0.01), MFR (HR:0.62, p <0.001), and LVEF (HR:0.97, p <0.001) were independently associated with mortality and heart failure hospitalization, whereas LBBB was not. Conclusions Mechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodeling, irrespective of LBBB. Integrated imaging enhances cardiomyopathy stratification.

Heart failure (HF) remains a major cause of morbidity and mortality worldwide, with its prevalence continuing to rise due to an aging population and the increasing burden of cardiometabolic diseases. Advances in understanding HF pathophysiology—neurohormonal, inflammatory, and metabolic mechanisms—have led to significant improvements in diagnosis and management, emphasizing earlier detection and patient-centered approaches. Novel biomarkers have the potential to enhance risk assessment beyond traditional natriuretic peptides. Imaging advances can enhance structural and functional assessment, enabling more accurate phenotyping, disease characterization, and risk stratification. Recent advances and real-world data have been used to implement and optimize guideline-directed medical therapy (GDMT) for HF to reduce HF hospitalizations and cardiovascular mortality across the spectrum of HF etiologies. Adjunctive therapies are reserved for select patients with persistent symptoms or high-risk features despite optimal GDMT. Device- and transcatheter-based interventions include established and emerging technologies that address persistent symptoms, structural abnormalities, and hemodynamic abnormalities despite optimal GDMT, thereby expanding treatment options for high-risk patients. Collectively, these advancements highlight a paradigm shift toward precise, personalized approaches to HF management, thereby improving long-term outcomes across the spectrum of HF etiologies.

TPS646 Background: SSTR-targeted RPT has transformed the treatment landscape for NETs, significantly improving clinical outcomes in phase 3 studies versus other targeted therapies. Nevertheless, disease progression and renal toxicity after treatment highlight the need for further improvement. Use of the α-emitter 225 Ac as the radioactive component has shown promising results in clinical studies: initial data from ACTION-1 suggest promising efficacy for RYZ101, a first-in-class, highly potent α-emitting RPT, in patients with SSTR+ GEP-NETs progressing after 2–4 cycles of 177 Lu-somatostatin analogs. RYZ401 is a cyclic 6-amino acid SSTR-targeting peptide agonist conjugated to a DOTA chelator bound to 225 Ac. Preclinical data have shown an improved therapeutic window versus DOTATATE. RYZ401 has the potential to deliver higher radiation doses to tumors, with improved renal clearance and lower kidney absorbed dose, potentially eliminating the need for amino acid infusion. Methods: RYZ401-101 is a global, multicenter, phase 1, first-in-human, dose-escalation/-expansion study designed to determine the recommended phase 2 dose (RP2D) and optimal treatment regimen, safety and tolerability, and preliminary efficacy of RYZ401 in patients with NETs and other selected solid tumors expressing SSTRs. Key eligibility criteria: histologically confirmed metastatic or unresectable well-differentiated NETs; WHO grade 1–3 (Ki-67 ≤55%); ≥1 SSTR PET-positive measurable lesion; and disease progression after ≥1 prior treatment line. In dose escalation, 6–18 patients will receive escalating doses of RYZ401 (2.0–11.1 MBq IV Q6W × 2–4 cycles); no amino acid co-infusion is planned. In dose expansion, approximately 80 patients will receive RYZ401 at the RP2D, 40 patients with well-differentiated GEP-NETs (cohort A) and 40 with other SSTR+ tumors including non-GEP-NETs (cohort B). Primary endpoints: dose-limiting toxicities in weeks 1–4 of treatment (dose escalation) and safety (dose expansion). Secondary endpoints: safety, pharmacokinetics, and efficacy outcomes (dose escalation and expansion). RYZ401 dosimetry will be evaluated in a sub-study of 10−16 patients. Enrollment is ongoing in the USA. Clinical trial information: NCT07165132 .

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .