Citations

Abstract Use of brentuximab vedotin (BV) and PD-1 monoclonal antibodies (mAbs) before autologous stem cell transplantation (ASCT) could impact the benefit of post-ASCT BV maintenance in relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We identified 1091 patients with R/R cHL who underwent ASCT between 2010-2022. In total, 244 (22%) received a PD-1 mAb and 443 (41%) received BV before ASCT, while 305 (28%) received BV maintenance. We performed 1:1 propensity score matching to assess the efficacy of BV maintenance in different patient subgroups. Among 608 matched patients, the 3-year progression-free survival (PFS) and overall survival were 73% (95% confidence interval [CI], 70-78) and 95% (95%CI, 93-97), respectively. BV maintenance was associated with improved PFS for patients with no exposure to novel agents, especially those with 2+ modified AETHERA risk factors (0-1 factors: hazard ratio (HR), 0.51; 95%CI, 0.24-1.09; P =.083; 2+ factors: HR, 0.40; 95%CI, 0.25-0.65; P< .001). In contrast, BV maintenance was not associated with a significant PFS benefit for any patient subgroup who received novel agents before ASCT (BV-treated, 0-1: HR, 1.43; 95%CI, 0.53-3.81; P =.48; 2+: HR, 0.79; 95%CI, 0.34-1.82; P =.58; PD-1-treated, 0-1 [P>.99], 2+: HR, 0.25; 95%CI, 0.03-2.14; P =.21). In particular, we observed excellent outcomes for patients undergoing ASCT in a complete response after one line of PD-1-based salvage treatment with no significant benefit for BV maintenance observed (2-year PFS 100% vs 95%; P>.99). The benefit of BV maintenance appears to be attenuated for patients receiving novel agents with salvage therapy. Omission of BV maintenance should be considered for patients anticipated to have excellent outcomes.

Abstract Frontline therapy for systemic amyloid light chain (AL) amyloidosis has evolved significantly with the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone, which has significantly improved rates of both hematologic and organ responses. Despite these advances, many patients eventually relapse, and there remains no established standard salvage regimen or optimal timing. In this review, we examine optimal timing of salvage regimens and currently available therapeutic options after daratumumab failure, including next-generation proteosome inhibitors or immunomodulatory drugs, autologous stem cell transplant, BCL-2 inhibitors, and emerging immunotherapeutic agents such as chimeric antigen receptor T-cell therapy and bispecific antibodies.

Abstract Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor (CAR) T-cell therapy approved for relapsed and refractory multiple myeloma (RRMM). Out-of-specification (OOS) CAR T cells not meeting criteria for commercial release are considered an investigational product; the expanded access protocol (EAP) allows release of OOS product for administration. The manufacturing analysis of capability, reliability, and timely delivery of ide-cel in the United States over >3 years since its approval included patients with RRMM who underwent leukapheresis for ide-cel treatment after ≥2 prior lines of therapy between 23 February 2021 and 1 November 2024. Additionally, the BB2121-EAP-001 study evaluated safety and efficacy of OOS ide-cel and included patients who had undergone leukapheresis for commercial ide-cel treatment not meeting commercial release specifications, most commonly due to high CD137 activation or low-infused dose. Primary end point was safety. Secondary end points were overall response rate (ORR) and complete response rate (CRR). At data cutoff (1 November 2024), the manufacturing success rate of ide-cel improved from 95.3% in 2021 to 96.8% in 2024. Turnaround time also improved from 31 days in 2021 to 24 days in 2024. In BB2121-EAP-001, 68 (72.3%) patients experienced ≥1 cytokine release syndrome event (mostly grade 1/2) and 15 (16.0%) had neurological toxicities (2 grade 3, 13 grade 1/2). ORR was 75.4% (95% confidence interval [CI], 63.1-85.2), and CRR was 35.4% (95% CI, 23.9-48.2). The manufacturing success of ide-cel is reliable and consistently high, and when OOS ide-cel products emerged, they demonstrated consistent clinical efficacy and safety. The BB2121-EAP-001 study was registered at www.clinicaltrials.gov as NCT04771078.

PURPOSE Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.

Abstract Background The clinical use and interpretation of cardiac troponins (cTn) in pediatric patients is heterogeneous. Content This review is based on an appraisal and synthesis of the available literature and discussions between International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Biomarkers members and pediatricians, cardiologists, emergency department physicians, and laboratorians. It aims to summarize current knowledge and best practices related to cTn measurements in pediatric patients, including which percentile should be applicable as the upper reference limit, and the influence of age, sex, and physiology on circulating concentrations. Preanalytical and analytical precautions, and a consensus on optimal interpretation of the reported results are discussed. Summary Current studies report high cTn concentrations in healthy infants and newborns. The nadir is reached at 1–3 years at which time concentrations gradually increase, reaching adult levels through puberty. The incidence of myocardial injury is reported to be low and dependent on whether the 97.5th or 99th percentile is chosen as the upper reference limit. The main clinical indication for testing appears to be suspicion of myo/pericarditis or traumatic chest injury. On occasion, cTn is measured in cases of possible heart failure and/or myocardial ischemia. There is heterogeneity among the limited clinical studies published. Most of the data are retrospective, and the current suggestions for clinical practice are thus largely based on expert opinion. More research is needed regarding all aspects of cTn testing in children, and suggestions for future research are included at the end of this review.

Abstract Neuromodulation is approved for the treatment of drug‐resistant epilepsy. It has been increasingly utilized over the past two decades with the approval of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in addition to vagus nerve stimulation (VNS)—particularly in patients who are not deemed to be good resective surgical candidates or in case of patient preference. In this seminar in epileptology article, we address learning objective 3.7 “Demonstrate knowledge of indications, limitations and risks for vagal nerve stimulation and other neuromodulation techniques” of the International League Against Epilepsy curriculum for epileptologists. We will review the indications for neuromodulation, device programming, surgical considerations for implantation, side effects, effects on sleep, and mood. This is complemented by case examples that provide perspective for trainees, along with an outlook on future directions for neuromodulation in epilepsy. This article aims to serve as a learning resource for trainees in neurology, clinical neurophysiology, and epileptology by providing guidance in how to navigate the landscape of neuromodulation in epilepsy.

Abstract Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep‐rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14–15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.

Abstract In Vitro testing is widely used to evaluate the hemodynamic performance of transcatheter aortic valves (TAVs). However, many studies assess self-expanding valves using blood analogs matched in viscosity at room temperature, despite the temperature-dependent mechanical behavior of nitinol stent frames. This study investigates the independent and combined effects of temperature and viscosity on the in vitro performance assessment of a self-expanding TAV. Rheological characterization was performed to identify water-glycerin solutions with matched viscosities at room temperature and physiological temperature (37 °C). A patient-specific aortic model was cast in silicone. A self-expanding Medtronic Evolut R valve was deployed within the compliant model and evaluated using a pulse-duplicating left heart simulator under physiological flow and pressure conditions. The transvalvular pressure gradient and effective orifice area (EOA) were calculated. Rheometry identified two fluid conditions with comparable viscosities at room and body temperatures. Heating the blood analog to 37 °C resulted in significantly reduced transvalvular pressure gradient and increased EOA compared to the viscosity-matched room temperature condition (p &lt; 0.0001). At physiological body temperature, the higher viscosity fluid (42% glycerin) yielded further improvements in valve performance relative to the lower viscosity fluid (38% glycerin), with lower pressure drop and larger EOA (p &lt; 0.0001). These results demonstrate that temperature-dependent effects influence the hemodynamic performance of self-expanding nitinol TAVs beyond viscosity matching alone. Combined consideration of temperature and viscosity is therefore necessary to ensure physiologically relevant in vitro assessment of self-expanding TAVs.

Abstract Background Robotic left pancreatectomy (RLP) is increasingly adopted worldwide. Current guidelines suggest a learning curve of 21 cases, yet its impact on major morbidity and oncological quality remains uncertain. Methods A retrospective multicentre international study was undertaken across 10 centres in the UK, Spain, Germany, the USA, and Australia (2014–2025). Consecutive patients undergoing RLP were categorised into competency (first 21 cases per centre) or proficiency phase (&gt;21). The primary outcome was major morbidity (Clavien–Dindo grade ≥ IIIa), and secondary outcome was the R1-margin rate. Mixed-effects logistic regression and risk-adjusted cumulative sum (RA-CUSUM) analyses were performed. Results 521 patients underwent RLP, including 200 (38.4%) in the competency phase and 321 (61.6%) in the proficiency phase. Median age was 63 years (IQR 54–73), and 56.4% were female. Rates of major morbidity were similar between phases (14.5% versus 14.0%, P = 0.981), as were R1 margin rates (21.6% versus 19.7%, P = 0.092). Independent predictors of major morbidity included male sex (OR 1.76, P = 0.037), preoperative pancreatitis (OR 2.23, P = 0.031), and multivisceral resection (OR 2.29, P = 0.034). Among patients with adenocarcinoma (n = 110), prolonged operative time (OR 1.39 per hour, P = 0.004) and nodal positivity (OR 2.62, P = 0.047) predicted R1 resection, while learning phase was not associated with margin status. RA-CUSUM demonstrated no excess morbidity over time in any centre. Conclusions In this first multicentre international analysis, the learning phase of RLP did not increase the risk of major morbidity or compromise oncological quality. These findings support the safe global adoption of RLP with appropriate training and case selection.