BMC Medicine最新文献

Background: This phase II clinical trial evaluated the R2-GemOx-PD1i regimen, a combination of penpulimab (a modified PD1 inhibitor) with lenalidomide and rituximab, gemcitabine, and oxaliplatin, in treating refractory or relapsed (R/R) diffuse large B-cell lymphoma (DLBCL).

Methods: Patients received an induction treatment of up to six cycles of R2-GemOx-PD-1i at standard doses every 2 weeks, followed by pembrolizumab and lenalidomide as maintenance or autologous stem cell transplantation (ASCT) as consolidation. The primary objective was to evaluate the complete response rate (CRR) after the induction phase.

Results: Fifty-four patients were included, including subgroups treated without intent for consolidation with ASCT (N = 38) and those utilizing R2-GemOx-PD1i as a bridge to ASCT (N = 16). The overall response rate (ORR) for all patients was 66.7%, with a CRR of 57.4%. The median progression-free survival (PFS) was 30.4 months, and the median overall survival (OS) was not reached for all patients. Patients receiving R2-GemOx-PD1i without intent for ASCT had ORR and CRR of 63.2% and 52.6%, respectively, with median PFS and OS of 21.2 months and not reached, respectively. Patients receiving R2-GemOx-PD1i as a bridge to ASCT had ORR and CRR of 75.0% and 68.8%, respectively, with median PFS and OS of both not reached, respectively. The most frequent treatment-related adverse events were neutropenia (36, 66.6%) and anemia (32, 59.2%). Hypothyroidism was the most common immune-related adverse event (20 [37.0%]).

Conclusion: The R2-GemOx-PD1i regimen demonstrated encouraging antitumor activity with manageable toxicity in R/R DLBCL, providing some reassurance about its safety and tolerability.

Trial registration: ClinicalTrials.gov, NCT05186558 (Dec 23, 2021).

Background: While diabetes-related complications have been widely investigated, the burden of infectious diseases across the diabetes spectrum remains relatively understudied.

Methods: We developed a Bayesian approach to compare infection risk across 9,476 patients with type 1 diabetes (T1D), 74,270 with type 2 diabetes (T2D), and 32,095 with prediabetes.

Results: Patients with T1D, T2D, and prediabetes had multifold increased risk for all organ system- and pathogen-based composite infection outcomes. We also quantified risk for 1,401 individual infection outcomes, finding increased risk for most infections among patients with either T1D, T2D, or prediabetes. Patients had increased risk for well-established diabetes-associated infections (e.g., mucormycosis) and less commonly associated infections (e.g., West Nile Virus encephalitis). Finally, we found disparities in risk across sociodemographic subgroups (i.e., age, sex, ethnicity, ancestry, and insurance status).

Conclusions: Our comprehensive findings advance previous research by quantifying risk for wide-ranging infection outcomes across diverse patients with T1D, T2D, and prediabetes through an innovative Bayesian approach.

Background: Frailty is highly prevalent in patients with atrial fibrillation (AF) and is associated with adverse outcomes compared with non-frail individuals. This study aimed to explore whether the effects of ablation versus drug therapy on clinical outcomes and quality of life (QoL) differ according to frailty status in patients with AF.

Methods: This is a post hoc analysis of the Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. The frailty index (FI) was calculated using 30 items, with an FI ≥ 0.21 defined as frailty. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. The secondary outcomes included all-cause death and heart failure (HF) hospitalization. QoL was assessed periodically over 60 months using the Mayo AF-Specific Symptom Inventory (MAFSI).

Results: In this study, a total of 2189 and 2070 patients were included in the intention-to-treat (ITT) and per-protocol (PP) populations, respectively. Over a median follow-up of 1440 (IQR, 900-2880) days, 184 patients experienced the primary endpoint, 122 died, and 174 experienced HF hospitalizations. Compared with drug therapy, catheter ablation did not significantly reduce the risk of clinical outcomes, with no significant difference observed across frailty strata. Regarding QoL, patients with AF and frailty in the ablation group experienced significant improvement compared with those in the drug group: a mean difference among all follow-ups of - 1.58 (- 2.11 to - 1.06; P < 0.001) in the MAFSI frequency score and - 1.26 (- 1.69 to - 0.84, P < 0.001) in the MAFSI severity score. However, patients with AF and without frailty in the ablation group showed no significant QoL improvement compared with those in the drug group.

Conclusions: There is no significant difference in the effectiveness of reducing clinical outcomes of catheter ablation according to frailty status in patients with AF compared with drug therapy, while patients with AF and frailty could derive a higher QoL improvements from catheter ablation therapy. These findings highlight the potential role of catheter ablation in improving QoL for patients with AF and frailty.

Background: Numerous emerging systemic therapies, including monoclonal antibodies and Janus kinase (JAK) inhibitors, are effective for atopic dermatitis (AD). However, their effects on the incidence of airway comorbidities like asthma and allergic rhinitis in AD patients remain unclear. This network meta-analysis evaluates and compares the risks of these adverse events among patients with AD receiving different biologics and systemic JAK inhibitors.

Methods: PubMed, Cochrane Library, Embase, and Web of Science were searched for randomized controlled trials (RCTs) evaluating asthma and allergic rhinitis in AD patients receiving JAK inhibitors or biologics, from inception to January 4, 2025. Data synthesis employed a Bayesian network meta-analysis with random-effects modeling, using relative risk (RR) and 95% credible intervals (CI) as effect measures. Meta-regression assessed the impact of study design and participant characteristics on intervention effectiveness. The surface under the cumulative ranking curve (SUCRA) ranked intervention safety profiles, and methodological quality was appraised via the Cochrane ROB 2.0 tool.

Results: A total of 26 randomized clinical trials (13,069 participants) met inclusion criteria, with 9530 receiving JAK inhibitors/biologics and 3540 assigned to placebo. Compared to nemolizumab 90 mg, dupilumab 300 mg (RR = 0.1, 95% CI: 0.01, 0.93) and tralokinumab 150 mg (RR = 0.03, 95% CI: 0, 0.77) were associated with a significantly lower risk of asthma. SUCRA analysis identified ISB 830 600 mg (SUCRA = 8.0%) as the highest for asthma-related adverse events and tralokinumab 150 mg (SUCRA = 95.1%) as the lowest. For allergic rhinitis, abrocitinib 100 mg had the highest adverse event incidence (SUCRA = 10.3%) and dupilumab 200 mg the lowest (SUCRA = 93.8%). Cluster analysis confirmed dupilumab 200 mg as associated with the lowest combined risk of both conditions, while abrocitinib 100 mg had the highest.

Conclusions: Among patients with AD receiving biologics or JAK inhibitors, dupilumab was associated with the lowest risk of asthma and allergic rhinitis in our analysis. Owing to confounding between dose and patient factors (age, disease severity, etc.) in included trials, no specific dose recommendations can be made. These findings warrant confirmation by future large-scale RCTs stratified by age and dose.

Trial registration: PROSPERO (CRD42024595904).

Background: Brincidofovir (BCV) is a novel nucleoside phosphonate analogue with unique dual antiviral and anti-tumor properties.

Methods: The activity of BCV was evaluated in 44 cell-line models, including T/NK-cell non-Hodgkin lymphoma (T/NK-NHL, n = 25) and B-cell lymphoma (BCL, n = 19), and their respective NOD/SCID mice xenograft models. The potential immunogenic effects were examined in a syngeneic EL4-C57BL/6 murine lymphoma model.

Results: BCV demonstrated potent anti-tumor activity across the majority of cell lines regardless of EBV positivity, with IC50 values within clinically achievable human plasma concentrations (2 µg/ml) in 17 of 25 (68.0%) T/NK-NHL and in 13 of 19 (68.4%) BCL. In vivo treatment significantly inhibited tumor growth in all xenograft models compared to vehicle control. Notably, RNAseq analysis demonstrated BCV downregulated MYC-target pathways in T/NK-NHL models. BCV evoked S-phase cell cycle arrest, replication stress, DNA damage, and apoptosis while triggering STING pathway-mediated interferon responses, PD-L1 expression, and immunogenic cell death. In the EL4-C57BL/6 model, BCV in combination with anti-PD1 significantly inhibited tumor growth and triggered an immune reaction characterized by the highest scores for adaptive immune response, cytokines/chemokines and receptors, cytotoxic cells, dendritic cells, NK CD56dim cells, and neutrophils (NanoString Immunology Panel).

Conclusions: Taken together, these results demonstrate a novel role for BCV in lymphoma therapy and suggest potential for combination with checkpoint immunotherapy.

Background: Psychoactive substance use (PSU) and cancer are frequently observed comorbidities that have reciprocal influences and shared behavioral traits of the affected patients. While, e.g., nicotine and alcohol are major carcinogens in the etiology of lung and head and neck cancers, little is known about a shared overarching genetic architecture of PSU and cancer that may predispose individuals to both illnesses.

Methods: Large-scale genome-wide association study (GWAS) summary data revealed shared genetic architecture between cancer and PSU, including alcohol use dependence (AlcUD) and nicotine use dependence (NicUD). Genetic correlations between PSU and cancer were assessed by linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Mendelian randomization (MR) analysis was additionally employed to explore causal associations between PSU and cancer. Moreover, phenome-wide association study (PheWAS) and drug target analysis were utilized to evaluate the safety and therapeutic value of pleiotropic hub genes.

Results: GWAS-based cross-referencing of PSU and cancer identified 34 shared trait pairs with significant genetic correlations and a total of 97 pleiotropic genomic risk loci. Affected loci mapped to genes expressed in the brain cerebellum (n = 109) and included cross-trait pleiotropic hub genes (n = 21). MR analysis further identified causal effects of AlcUD and NicUD on cancer risk. After exclusion of genes at high risk of side effects upon inhibition in a PheWAS, cholinergic receptor nicotinic alpha 2 (CHRNA2), histamine receptor H3 (HRH3), and protein tyrosine kinase 6 (PTK6) were identified as potentially druggable targets.

Conclusions: In summary, we identified a shared genetic architecture comprising pleiotropic cerebellar hub genes linking PSU-cancer trait pairs and described potential interventional drugs.

Background: Precision medicine for Alzheimer's disease (AD) requires the development of a robust management framework grounded in individualized disease staging systems. To date, only a limited number of studies have supplemented the existing AD staging systems.

Methods: This retrospective study included 7491 MRI examinations from five independent cohorts. We used a novel pseudo-healthy synthesis method to capture individualized brain atrophy patterns. An individualized brain atrophy score (BAS) was computed from the 30 regions with the most severe brain atrophy and used to stratify participants into distinct disease stages. The Jenks natural breaks optimization method was used to determine an optimal number of disease stages based on the individual BAS.

Results: BAS exhibited a strong biological basis and revealed a synergistic relationship among biomarker-based staging systems. Four stages were delineated based on the BAS for participants with MCI and clinically diagnosed AD. Stage I showed a slight cognitive decline with only mild hippocampal atrophy evident. Stage II showed mild cognitive decline and mild brain atrophy and shrinkage, extending to the temporal and parietal lobes. Stage III showed moderate cognitive decline and more severe brain atrophy in the temporal lobe, amygdala, hippocampus, parietal lobe, and frontal lobe. Stage IV showed severe mental impairment and diffuse atrophy across the whole brain. The disease stages are associated with dementia severity and abnormalities in AD biomarkers, such as cerebrospinal fluid (CSF) Aβ_1-42, CSF total tau, CSF p-tau₁₈₁, and cognitive scores. Furthermore, those MCI participants at higher disease stages at baseline have a higher risk of progressing to clinically diagnosed AD dementia even under the A/T-negative status.

Conclusions: The individualized staging system can accurately assess disease severity, enabling risk stratification at ultra-early pathological stages and facilitating precise AD management.

Background: Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-physical activity interaction analysis.

Methods: Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants).

Results: Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive] = 0.85; 95% CI = 0.81-0.90). The two-step EDGE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and physical activity for CRC risk (p-interaction = 2.6 × 10^-8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95% CI = 0.75-0.85), but no significant physical activity-CRC associations among CT or TT carriers. When physical activity was modeled as quartiles, the 1-d.f. test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between physical activity and CRC (p-interaction = 3.5 × 10^-8). Stratification at this locus showed that an increase in physical activity (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95% CI = 0.72-0.82).

Conclusions: In summary, we identified two genetic variants that modified the association between physical activity and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be involved in the protective association between physical activity and colorectal carcinogenesis.

Background: Hypertension (HTN) has been linked to changes in DNA methylation. However, longitudinal epigenome-wide analyses are still limited.

Methods: We analyzed data from the KORA F4 and FF4 studies, conducted approximately 7 years apart. The dataset included 2614 participants, each with DNA methylation measured at least once. Leucocyte DNA methylation was profiled using the Illumina 450 k and EPIC arrays. Linear mixed-effects models were employed to identify associations between methylation sites and HTN status, systolic (SBP) and diastolic blood pressure (DBP). Interaction terms with follow-up time captured longitudinal methylation trajectories. We further examined CpG sites related to reversed, persistent, or progressive HTN and assessed their correlations with gene expression.

Results: One CpG site was associated with SBP and four with DBP, all representing novel loci, including RILP (cg08625564) and SVIL (cg15298791). Differential annual methylation changes were observed for 2, 23, and 12 CpG sites by HTN status, SBP, and DBP, respectively, highlighting genes such as RHPN2, CLDND1, ZNF69, and FKBP1B. Twenty CpG sites were associated with persistent HTN, including PLCB2 and MPPE1. In whole blood, 22 significant CpG-transcript pairs were detected, involving 14 CpG sites and 19 gene transcripts.

Conclusions: This longitudinal epigenome-wide study identified novel CpG sites associated with blood pressure and persistent HTN. We observed differential DNA methylation trajectories over time linked to HTN, SBP, and DBP, with several changes correlating with gene expression, suggesting functional relevance. These findings underscore the dynamic role of DNA methylation in blood pressure regulation and provide new insights into epigenetic mechanisms of HTN.

Background: Cancer stem cells (CSCs) play a crucial role in breast cancer (BRCA) progression and lymph node metastasis. This study aimed to elucidate how CSCs reshape the immune microenvironment during metastatic dissemination, with a particular focus on macrophage and T-cell regulation.

Methods: A mouse orthotopic BRCA model was established to obtain primary tumor (BRCA_PT) and lymph node metastatic (BRCA_LNMT) tissues. Single-cell RNA sequencing and spatial transcriptomics were used to characterize cellular heterogeneity, marker genes, and intercellular communication. TCGA-BRCA data were analyzed for differential expression, functional enrichment, and immune cell infiltration. In vitro, 4T1-S CSCs were used to assess self-renewal, migration/invasion, ISG15-mediated signaling, and interactions with macrophages and T cells. ELISA, western blotting, sphere formation, colony formation, CCK-8, Transwell, luciferase reporter assays, and ChIP were performed. In vivo, subcutaneous and orthotopic mouse models were used to evaluate the effect of ISG15 on tumor growth and lymph node metastasis.

Results: Bioinformatic analyses revealed an elevated proportion of CSCs in BRCA_LNMT, where CSCs likely induced M2 macrophage polarization through TAM-mediated communication. ISG15 was highly expressed in metastatic tumors and associated with M2 polarization and reduced T-cell activation. In vitro, ISG15 enhanced CSC self-renewal and invasiveness, promoted IL-10-mediated M2 polarization, and upregulated PD-L1 via JAK-STAT signaling to suppress T-cell activity. In vivo, ISG15 silencing significantly inhibited tumor growth and lymph node metastasis.

Conclusion: ISG15 in BRCA CSCs promotes lymph node metastasis by driving M2 macrophage polarization and suppressing T-cell activation, highlighting a critical role for ISG15-mediated immunomodulation and a potential therapeutic target.