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The DEBBRAH study showed promising results for patients with HER2-expressing (including HER2-low) metastatic breast cancer who received the antibody-drug conjugate (ADC) trastuzumab deruxtecan for leptomeningeal disease. ADCs represent a novel tool in the precision biomarker-based armamentarium, including in the tumor-agnostic setting, for targeting highly cytotoxic chemotherapy into cancer cells.

Translation of foundation models from benchmarks to clinical impact has been slow, revealing a fundamental limitation: correlation-based predictions from models trained on observational data miss causal pathways that determine disease course and treatment response. Hybrid models combining deep learning with representations of biological mechanisms will enable causal reasoning and provide mechanistic understanding required for disease intervention.

Background: The dynamic, heterogeneous nature of atrial fibrillation (AF) episodes and poor symptom-rhythm correlation make early AF detection challenging. The optimal screening strategy for early AF detection and its role in stroke prevention are unknown.

Methods: To analyze the impact of screening-mediated AF detection on stroke risk, a Markov-like computer model was created that captured seven clinical states. AF-related atrial remodeling was incorporated, which influenced the age-/sex-dependent transition probabilities between states. Model calibration/validation was performed by replicating clinical studies. The effect of screening strategies on early AF diagnosis and subsequent modulation of stroke rate by simulated oral anticoagulation were assessed.

Findings: The model simulates the entire lifetime of virtual patients with 30-min resolution and provides precise information on the occurrence of AF episodes and clinical outcomes. It replicates numerous age/sex-specific episode- and population-level AF metrics and clinical outcomes. The benefits of intermittent AF screening were frequency and duration dependent, with systematic thrice-daily single electrocardiogram providing the highest detection rates. Screening groups had comparable 5-year and lower 25-year stroke rates than the control group. These differences were increased by more effective anticoagulation therapy, in patients with higher baseline stroke risk, or with delayed clinical AF diagnosis.

Conclusions: We present a novel computational patient-level AF model consistent with a large body of real-world data, enabling for the first time the systematic assessment of AF-management strategies. More frequent and longer screening has higher AF-detection rates, but stroke reduction is highly dependent on patients' and healthcare-systems' characteristics.

Funding: Funding information is shown in the acknowledgments section.

Despite available treatments, patients with lymphoma may still develop relapsed or refractory diseases, highlighting the need for new therapies. Zhang et al.¹ report a phase I dose-escalation study of TQB3617, a novel BET inhibitor, in diverse lymphoma subtypes. The study showed promising safety and efficacy, including T cell and Hodgkin lymphoma, warranting further investigation.

Background: Hereditary hearing loss is one of the most common disabling disorders in children and lacks effective pharmacological treatments. Recent breakthroughs in OTOF gene therapy clinical trials necessitate standardized frameworks to guide emerging therapies. This study aims to establish the first international consensus on the clinical application of gene therapy for hereditary hearing loss.

Methods: A modified Delphi process was conducted from March 2024 to March 2025, involving 46 multidisciplinary experts from several countries across otology, genetics, audiology, gene therapy, and hearing rehabilitation. After a systematic literature review, as well as integration of research and clinical expertise and experience, three iterative voting rounds (two anonymous surveys and one online consensus meeting) were performed. Statements required ≥75% agreement for inclusion.

Findings: From 9,093 publications, 69 were used to draft and support the consensus statements. A total of 30 statements relevant to six domains achieved consensus on gene therapy for hereditary hearing loss, including ethical review (1 statement), patient selection criteria (12 statements), diagnosis and preoperative evaluation (9 statements), gene therapy drug delivery (4 statements), follow-up (3 statements), and post-treatment auditory and speech rehabilitation (1 statement).

Conclusions: This consensus provides the first globally endorsed framework for gene therapy in hereditary hearing loss. It standardizes clinical trial design and patient management, accelerating translation from research to practice while ensuring safety. The guidelines are immediately applicable to OTOF-related hearing loss and adaptable to other genetic forms.

Funding: This work was supported by the National Natural Science Foundation of China, the German Research Foundation (DFG) via the Cluster of Excellence, and others.

IgA nephropathy is in a transformative era, with disease-targeted therapies advancing beyond supportive care. This Trial Watch summarizes recent clinical progress in complement inhibition, endothelin receptor antagonism, and B cell and plasma-cell-directed strategies, highlighting promising reductions in proteinuria, preservation of renal function, and the emerging framework for precision, biomarker-guided treatment.

The phase 3 DIAMOND trial conducted in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) reported comparable 3-year failure-free survival rates between a cisplatin-containing versus a cisplatin-free regimen with radiotherapy, in the backbone of induction, concurrent, and adjuvant anti-programmed death-1 (anti-PD-1) therapy.¹ Reduced cisplatin-related emesis also improved quality of life. DIAMOND challenges the conventional dogma of concurrent cisplatin-radiotherapy in the treatment of LA-NPC.

Intravenous thrombolysis (IVT) remains a cornerstone in the management of acute ischemic stroke (AIS). Since the landmark NINDS and ECASS III trials, numerous randomized controlled trials (RCTs) have expanded IVT indications beyond the initial 4.5-h window. Advanced imaging modalities, including perfusion-based and diffusion/fluid-attenuated inversion recovery (FLAIR) mismatch, have enabled individualized patient selection, leading to positive outcomes in trials such as WAKE-UP, EXTEND, and EXPECTS. Despite these advances, key challenges remain. Patients with large ischemic cores, those on direct oral anticoagulants (DOACs), and those with minor non-disabling strokes lack robust evidence supporting IVT use. Moreover, while alternative thrombolytics like tenecteplase have shown promise, additional data are needed to redefine the standard of care. Adjunctive pharmacologic therapies (e.g., glycoprotein IIb/IIIa or thrombin inhibitors) have yet to demonstrate consistent benefit. This review highlights the progress, limitations, and future directions of IVT, emphasizing a shift from rigid temporal thresholds toward physiology-based, patient-centered stroke reperfusion strategies.

Background: Inflammatory bowel disease (IBD) carries a hereditary risk, which is higher through maternal, rather than paternal, inheritance. Like their mothers, children born to mothers with IBD have an altered microbiome shortly after birth.

Methods: To investigate whether this altered microbiome persists later in life and affects the intestinal mucosa, the fecal microbiome was analyzed in samples from 44 infants ranging from 0 to 10 years of age born to 26 women with IBD. Forty-four age-matched children of 29 women without IBD served as controls. Fecal microbiota transplantation (FMT) to germ-free mice was carried out from 4-year-olds born to mothers with IBD and controls. Markers of inflammation, barrier function, and metabolic changes were investigated.

Findings: Intestinal microbiomes were more similar between women with IBD and their children than between control mothers and their offspring. Microbial changes were noticeable in children from mothers with IBD from the age of 4 years compared to children of controls. No inflammatory response was present in the mucosa of mice receiving FMT from children of mothers with IBD; however, mesenteric lymph node enlargement and decreased expression of barrier genes Zo1 and Ocln were seen in mice receiving FMT from these children compared to controls. Additionally, reduced colonic expression of the immunological tolerance enzyme Ido1 coincided with decreased serum kynurenine/tryptophan ratios.

Conclusions: Fecal microbiomes of children of mothers with IBD exhibit characteristics that reduce epithelial tight junction barrier genes and tolerogenic tryptophan metabolism. Microbiome-induced gut barrier disruptions may contribute to an enhanced IBD predisposition in infants of mothers with IBD.

Funding: This work was funded by ZonMw.