Citations

Abstract Introduction Multiple pulmonary nodules (MPNs) are commonly encountered in patients at elevated risk for thoracic malignancy and represent a spectrum of disease states and stages. We evaluated the safety, and procedural outcomes of a combined robotic assisted bronchoscopy (RaB) and linear endobronchial ultrasound (EBUS) approach to patients with MPNs during a single bronchoscopic procedure. Methods This multicenter observational registry included patients who underwent RaB for evaluation of MPNs. Data were prospectively collected from six centers between 2019 and 2025. Demographics, imaging characteristics, safety events, and procedural outcomes were analyzed and associated with final diagnosis. Results A total of 191 patients underwent RaB with biopsy of MPN during a single procedure; 167 patients also underwent linear EBUS lymph node sampling. The strict per nodule diagnostic yield was 71.5% overall (first nodule 70.7%, second 74.3%, third 71.4%). At least one malignant nodule was identified in 127 patients (66.8%), and 85 patients (44.5%) had two or more malignant nodules; 15 patients (17.6%) demonstrated heterogeneous histopathology between malignant nodules. Among patients with non–small cell lung cancer, adequate cellularity for next generation sequencing was achieved in 82.6% of nodules. Malignant lymph nodes were identified in 10.8% (18/167). No patients with two pure ground glass nodules (0/8) had malignant nodal involvement. Pneumothorax occurred in 7.3% of cases, with 2.1% requiring chest tube placement; unplanned admissions occurred in 3.7%. Conclusion This study provides a large multisite registry evaluation of performance of simultaneous bronchoscopic sampling of multiple pulmonary nodules with EBUS staging during a single anesthesia event demonstrating an acceptable safety profile and adequacy for molecular profiling.

Abstract Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263 ), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies ranging from relatively indolent well-differentiated neuroendocrine tumors (NETs) to more aggressive poorly differentiated neuroendocrine carcinomas (NECs). The advent of somatostatin receptor (SSTR)–targeting therapies, particularly radioligand therapy (RLT), has transformed the therapeutic landscape of NETs. Ongoing efforts are aimed at maximizing the therapeutic benefit of RLT and include retreatment and combination strategies as well as novel α-emitter–based radiopharmaceuticals. The increasing use of molecular profiling has led to the identification of recurrent canonical alterations in pancreatic NETs, including in MEN1 , ATRX / DAXX , PI3K/Akt/mTOR, and angiogenic signaling pathways, facilitating the development of effective targeted therapies. However, despite the addition of newer targeted therapies to the therapeutic armamentarium, resistance remains inevitable and highlights the need for improved predictive markers to inform therapy sequencing and novel biomarker-selected therapies. In addition, the development of novel therapeutic strategies including SSTR antagonists, nonpeptide drug conjugates, and novel radiopharmaceutical constructs highlights the potential of biomarker-informed therapies in this space. By contrast, treatment options for NECs remain limited, with modest therapeutic benefit of platinum-based chemotherapy. The identification of delta-like ligand 3 (DLL3) as a therapeutic target in high-grade NENs has led to the development of novel targeted therapies such as T-cell engagers, which have demonstrated promising activity in early phase clinical trials. In addition, other DLL3-targeting agents such as antibody-drug conjugates, trispecific engagers, and cellular therapies remain under investigation. Collectively, these advances underscore the potential of biomarker-informed treatment approaches to personalize treatment decisions and improve long-term outcomes across the NEN spectrum.

Abstract TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer’s disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.

Abstract Background Calcium release channel deficiency syndrome (CRCDS) arises from loss-of-function variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) despite normal exercise testing. Previously, a novel homozygous RYR2 duplication causing ~ 80% RyR2 reduction was associated with exertion-related SCD. However, how Ca2+ homeostasis is maintained despite RyR2-loss remains unknown, as RYR2-/- animals are non-viable. Purpose To generate a RYR2-knockout (RYR2-KO-/-) induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model to dissect compensatory mechanisms sustaining Ca2+ homeostasis and identify arrhythmogenic pathways predisposing to SCD. Methods CRISPR/Cas9 editing was used to introduce a homozygous c.163delT variant into a wild-type iPSC line (control), generating a RYR2-KO-/- model. A patient-derived RYR2-duplication (RYR2-DUP+/+) iPSC line was used for comparison. RyR2 expression was assessed by western blot (WB) and immunofluorescence (IF). Proteome and phospho-proteome were assessed using omics approaches. Intracellular Ca2+ handling was evaluated by Fluo-4 AM imaging (0.5 Hz and long-burst–long-pause [LBLP] protocol). Electrophysiological properties (action potential [AP], and sarcolemmal currents [ICaL, INa and INCX]) were assessed by patch-clamp. Results Despite complete RyR2-loss in RYR2-KO-/- iPSC-CMs as confirmed by WB and IF, contractility and contractile machinery expression was preserved. Ca2+ transient amplitude (ΔF/F0) was reduced markedly in RYR2-KO (0.14±0.01, p<0.01) and RYR2-DUP (0.27±0.2, p<0.01) compared to control (0.52±0.02). Proteomics revealed a significant NCX1 up-regulation and IP3R-interacting protein (ITPRIP) down-regulation in RYR2-KO compared to control, with pathway-analyses showing significant up-regulation of IP3-related pathways. Pharmacological IP3Rs block (2-APB, 10μM) abolished Ca2+ transient generation in RYR2-KO iPSC-CMs (Amplitude: baseline: 0.15±0.01, 2-APB: 0.06±0.01, p<0.01). RyR2-ablation induced electrical remodeling (pA/pF), including ICaL reduction, INCX up-regulation and hyperpolarization of the INa window current in RYR2-KO (ICaL [at 0mV]: -8.5±1.6; INCX [at -110mV]: -4.1±1.1) as compared to control (ICaL:-7.5±3.7, p<0.01; INCX:-1.5±0.5, p=0.02). RYR2-KO CMs demonstrated increased delayed after-depolarizations and beat-to-beat variability as compared to control. Despite Ca2+ sparks abolishment, RYR2-KO CMs displayed higher erratic beating (at 0.5Hz) and arrhythmogenic propensity than control, showing ventricular tachycardia-like events during LBLP stimulation. Conclusions Genetic RYR2-ablation disrupts physiological Ca2+ cycling and triggers electrical remodeling, including INCX up-regulation, overall promoting arrhythmogenesis. Compensatory IP3Rs activation sustains Ca2+ transient generation, revealing a mechanism preserving excitation-contraction coupling that may paradoxically promote arrhythmogenesis in CRCDS.RYR2-KO: Generation and CharacterizationElectrophysiological Assessment

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

Abstract Extramedullary disease (EMD) is increasingly recognized in relapsed/refractory multiple myeloma (MM), with central nervous system involvement (CNS-MM) representing a rare but highly aggressive manifestation associated with dismal outcomes. Data on its incidence and optimal management, particularly in the era of cellular and bispecific therapies, remain limited. We conducted a retrospective analysis of patients with MM with pathology-confirmed EMD treated at our institution between January 2000 and December 2023. CNS-MM was defined by parenchymal or leptomeningeal involvement. Clinical features, cytogenetics, treatments, and outcomes were analyzed, with predictors of CNS involvement evaluated among patients with EMD. Among 304 patients with EMD, 20 (6.5%) had CNS-MM. CNS involvement occurred a median of 19.2 months after MM diagnosis, though 15% presented at diagnosis. CNS-MM was strongly associated with high-risk cytogenetics (odds ratio [OR], 3.7) and additional visceral EMD (OR, 4.6). Median overall survival (OS) from CNS-MM diagnosis was 4.2 months. Outcomes were significantly improved in patients receiving chimeric antigen receptor T-cell therapy or bispecific antibodies, with a median OS of 19.2 months vs 1.2 months in those who did not receive immune effector therapies. Intrathecal (IT) chemotherapy demonstrated limited and transient benefit. In conclusion, CNS-MM is an aggressive complication enriched in high-risk, multifocal EMD with extremely poor prognosis. Cellular and bispecific therapies show promising activity and may meaningfully improve survival, whereas IT therapy appears to have limited efficacy. Prospective studies are needed to define optimal treatment strategies for CNS-MM.

Background: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD. Review Summary: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy. Conclusion: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.

Abstract Aims Transcatheter mitral valve replacement (TMVR) with the Tendyne Mitral Valve System is a treatment option for patients with severe symptomatic mitral regurgitation (MR) unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). This study sought to evaluate the safety and effectiveness of TMVR through 5-year follow-up. Methods and Results The Tendyne Expanded Clinical Study is a prospective, single-arm, multicentre study that enrolled patients between November 2014 and June 2020. The study enrolled 191 patients (mean age 74.1 ± 8.0 years, 62.8% male, 70.2% New York Heart Association Class (NYHA) class III/IV, 88.5% secondary MR), of whom 186 (97.4%) underwent TMVR with Tendyne. MR grade decreased from ≥3+ in 99.5% patients at baseline to grade ≤1+ in 95.3% at 5 years. In those patients surviving to 5 years (n = 49), durable symptomatic improvement was evidenced by 73.5% patients being in NYHA class I/II at 5 years. The Kansas City Cardiomyopathy Questionnaire overall summary score increased from 48.5 ± 22.5 points at baseline to 67.6 ± 21.5 points at 5 years. Serious adverse events that occurred through 5 years included life-threatening bleeding (11.5%), fatal bleeding (2.6%), renal insufficiency/failure (28.8%), endocarditis (7.3%), device thrombosis (5.8%), and new onset atrial fibrillation (13.1%). No structural device degeneration or device embolism occurred through 5 years. Conclusions The Tendyne TMVR was effective at achieving immediate and sustainable elimination of MR, which was associated with symptomatic improvement and absence of structural valve degeneration in a high-risk cohort over 5 years. These findings support TMVR with the Tendyne System as an alternative for patients with appropriate mitral valve anatomy and symptomatic secondary MR unsuitable for mitral surgery or TEER.