British Journal of Haematology

Background: In 2026, the US Food and Drug Administration (FDA) identified uveitis as a potential signal of serious risk for the B-cell maturation antigen (BCMA) x CD3 bispecific antibodies teclistamab and elranatamab. Uveitis in this setting may reflect opportunistic infection or immune-mediated inflammation, which require opposite management. Methods: We analyzed FDA Adverse Event Reporting System (FAERS) reports from July 2020 to June 2026 (8,690,601 reports after deduplication) using a case-non-case design, calculating reporting odds ratios (RORs) and the information component for primary-suspect reports. Comparators were belantamab mafodotin, talquetamab and CD3 bispecific antibodies used outside myeloma. Every primary-suspect uveitis report (n = 76) was classified as infectious, probable immune-mediated (hereafter immune-mediated) or indeterminate by a physician blinded to a rule-based algorithm. Results: Uveitis was reported in 18 of 2,995 teclistamab and 29 of 1,691 elranatamab reports (ROR 4.10 [95% CI 2.58-6.52] and 11.85 [8.21-17.12]). Of these 47 cases, 20 were infectious (18 cytomegalovirus chorioretinitis; median onset 92 days), and infection-specified uveitis was disproportionately reported for both agents and for CD3 bispecific antibodies used outside myeloma. Thirteen were immune-mediated, arose early (median onset 4 days) and were co-reported with cytokine release syndrome in six; immune-mediated uveitis showed a signal only for elranatamab (8 cases; ROR 3.59, 1.79-7.18), not for teclistamab or any comparator. Six of the eight elranatamab cases originated from Japan. Agreement between physician and algorithm was 98.7%. Conclusions: The FDA uveitis signal appears to comprise a late infectious uveitis shared by most T-cell-redirecting bispecific antibodies examined and an early immune-mediated uveitis that showed a signal only with elranatamab. These hypothesis-generating findings support prompt ophthalmological assessment of new visual symptoms and exclusion of cytomegalovirus retinitis before corticosteroids are started.

Background: The clinical course of acute leukemias and related hematologic neoplasms is defined by aggressive clonal proliferation, severe hematopoietic disruption, and recurrent molecular alterations. Although serial bone marrow biopsies, multiparameter flow cytometry, and next-generation sequencing remain standard surveillance modalities, procedural invasiveness, high costs, and operational turnaround times limit their frequency. Minimally invasive, scalable biomarkers integrating routine hematologic indices, targeted gene expression, circulating oncoprotein levels, and patient compliance metrics may provide an accessible framework for dynamic monitoring. Methods: In this longitudinal cohort study of 66 patients across 272 serial encounters (discrete follow-up intervals: days 0, 14, 41, 71, and 78), we assessed the prognostic value of peripheral complete blood counts (white blood cell count [WBC], hemoglobin [Hb]), molecular indicators (FLT3, NPM1, and DNMT3A transcript levels; targeted soluble FLT3 quantification), and medication adherence. The primary clinical endpoint was longitudinal progression to critical deterioration or disease-related mortality. Generalized linear mixed-effects models (GLMM) with patient-specific random intercepts were constructed to account for intra-subject repeated measures. Predictors were standardized per 1-SD increment. Model performance was assessed via the Akaike Information Criterion (AIC) and the Concordance index (C-index). Results: Leukocyte expansion correlated inversely with hemoglobin concentration (r=-0.877, p<0.001), reflecting bone marrow infiltration and secondary erythroid suppression. Multivariable mixed-effects modeling confirmed that elevated WBC count (adjusted odds ratio [aOR] = 1.52 per 1-SD increase; 95% CI: 1.24-1.86; p<0.001) and reduced medication adherence (aOR = 0.58; 95% CI: 0.44-0.76; p<0.001) independently predicted adverse clinical transition. Integrating targeted molecular markers (FLT3 expression and soluble protein levels) with routine hematologic indices and adherence demonstrated superior calibration and discrimination over single-domain models ({Delta}AIC[&ge;]116; Harrells C-index = 0.81). Conclusions: Readily accessible peripheral hematologic indices, targeted molecular quantification, and medication adherence provide complementary prognostic information regarding disease activity. Integrating these low-burden parameters into clinical workflows offers an efficient, scalable paradigm for early risk stratification in hematologic malignancies.

Clonal hematopoiesis (CH) can predict treatment outcomes in solid cancers, but the prevalence and clinical impact of CH in previously untreated, aggressive large B-cell lymphomas (LBCL) remains poorly characterized. Moreover, CH may be detected in cell-free DNA (cfDNA)-based biomarker assays, but the longitudinal dynamics of CH mutations during and after immunochemotherapy in LBCL remain unknown. Hence, we characterized the spectrum of CH mutations in 247 patients with high-risk primary LBCL from three phase II clinical trials. We identified CH mutations in 23% of patients. Compared with healthy controls, TET2 mutations were enriched in peripheral blood (PB) samples of LBCL patients (P=0.01). CH clone size showed high concordance between PB and cfDNA (R2=0.59, P<0.0001) but was not associated with circulating tumor DNA (ctDNA) concentration (P-values 0.25-0.86). In contrast with prior reports in the context of recurrent lymphoma, CH mutation status was not associated with overall survival (OS) (P=0.78) or progression-free survival (PFS) (P=0.89) in our primary LBCL cohort. CH clones showed variable longitudinal dynamics during immunochemotherapy, with 18% of evaluable patients developing mutant CH clones, mostly with TP53/PPM1D mutations. Together, CH mutations can be readily detected in cfDNA of lymphoma patients, but they do not predict survival in primary high-risk LBCL.

BackgroundFebrile neutropenia requires rapid empirical antibiotic therapy, with regimen selection shaped by local prescribing practice and pathogen patterns. We described starting treatment, later drug changes, microbiological findings, and inpatient outcomes. MethodsThis ambispective cohort comprised 96 episodes from 90 patients admitted to a tertiary-level teaching hospital. Treatment and outcome analyses used each episode as the unit of observation. Recorded variables included the starting antibiotics, later regimen modification, microbiology, hospitalization length, invasive fungal infection (IFI) as captured in study records, and disposition. Comparisons based on escalation status were exploratory. ResultCefoperazone-sulbactam appeared in 62/96 initial regimens (64.6%), amikacin in 42 (43.8%), teicoplanin in 28 (29.2%), and meropenem in 14 (14.6%). Eighteen episodes (18.8%) required a change that broadened or substituted antibacterial therapy. Among 31 microbiologically documented infections, 22 (71.0%) yielded Gram-negative organisms and 9 (29.0%) were polymicrobial. Median length of admission was 18.5 days in the escalation group and 9 days in the remainder (p<0.001). Mortality was 27.8% (5/18) with escalation and 5.1% (4/78) without it (p=0.011), with nine inhospital deaths overall (9.4%). ConclusionAntibacterial management differed within this cohort, with treatment escalation required in 18 of 96 episodes. Gram-negative organisms comprised most microbiologically confirmed infections. Escalation marked a clinically complex course with prolonged hospitalization and greater observed mortality; the observational design does not establish comparative efficacy or causation.

Homozygosity for the HBB codon 8/9 (+G) frameshift (c.27dup (p.Ser10ValfsTer14)) causes transfusion-dependent {beta}-thalassaemia and is common in South Asia. Prime editing can reverse this insertion without double-strand breaks or donor DNA, but its efficiency depends on pegRNA design. We derived Sendai-reprogrammed iPSCs from a homozygous patient, optimised PEmax editing (spacer, pegRNA extension, secondary nick, MLH1dn) and compared patient, PEmax-treated and control iPSC-derived erythroid cells by flow cytometry, colony assays, RT-qPCR, western blotting and cation-exchange HPLC. Patient iPSCs had a normal 46,XY karyotype, expressed pluripotency markers, formed all three germ layers and were Sendai-free by passage 15. A PAM-disrupting spacer with a +68 nicking sgRNA gave the highest intended-edit frequency 8.4%; MLH1dn added little. PEmax-treated cultures matured and formed colonies more like control than patient cultures, restored HBB transcript (about 4-fold control iPSC-derived cells) and detectable {beta}-globin protein, and contained an HPLC fraction consistent with HbA ( undetectable in patient cells). Fetal haemoglobin (about 80%) and embryonic globin remained predominant. Prime editing corrects HBB c.27dupG in patient iPSCs and restores {beta}-globin expression, with partial restoration of adult haemoglobin in a fetal/embryonic-type erythroid background. Validation in additional donors, haematopoietic stem cells and in vivo is required.

Quantitative measurement of fetal hemoglobin (HbF) using high-performance liquid chromatography (HPLC) is standard but expensive and widely unavailable in low-income settings. The newer Gazelle method, which employs single-use alkaline electrophoresis cartridges, provides a portable and relatively inexpensive potential alternative. In the current study, we tested 3055 venous blood samples collected from 1780 children with sickle cell anemia who were enrolled into the H-PRIME trial by both Gazelle and the Bio-Rad D-10 HPLC instrument, before and during hydroxyurea treatment. Data reinterpretation was required to quantify accurately high HbF values derived using the D-10. Mean (standard deviation) baseline HbF values by HPLC and Gazelle (N=2042) were 11.4% (SD 5.9%) versus 16.3% (SD 7.5%), respectively, while mean on-treatment HbF values (N=1013) were 18.9% (SD 9.0%) versus 25.4% (SD 11.5%), respectively. While overall agreement was good (Lins concordance 0.76, 95% CI 0.75-0.78), HbF values derived using Gazelle were modestly higher than HPLC values (Bland-Altman agreement mean +5.4%, 95%CI -2.4% to +13.2%), with the difference between measures increasing at higher HbF percentages. With strong concordance and more easily interpretable HbF values, Gazelle represents an attractive and inexpensive alternative to HPLC for HbF quantification in the low-income settings where most patients with sickle cell anemia live.

Sickle cell disease (SCD) results from homozygosity or compound heterozygosity for a single point mutation in the beta hemoglobin gene. Despite carrying the same underlying causal mutation, patients exhibit highly heterogeneous clinical outcomes. Acute chest syndrome (ACS) is one of the leading causes of mortality in SCD. In this study, we aimed to identify genetic variants associated with ACS occurrence and recurrence (>5 episodes) in two SCD cohorts (OMG-SCD and Walk-PHaSST) of predominantly African ancestry and characterize their downstream molecular consequences. Although none of the SNPs reached the genome-wide threshold in the occurrence meta-analysis, we identified 40 independent genetic loci with p <10-5. However, the recurrence GWAS in OMG-SCD, which compared individuals with no prior history of ACS to individuals with a history of >5 episodes, identified one genome-wide significant locus along with 38 other independent loci with p <10-5. Survival analysis suggested lower survival probability among young ACS recurrence cases compared to controls or occurrence cases. Furthermore, molecular QTL analysis of ACS recurrence identified 42 SNP-protein and eight SNP-metabolite associations with p <10-3. Pathway and enrichment analysis identified secretory, platelet/hemostatic, and complement-mediated pathways, confirming the complex and heterogeneous pathophysiology of ACS. This study highlights the importance of a well-defined phenotype for identification of risk loci and elucidates the complex interplay of hemolytic, inflammatory, and cellular organization pathways that warrants further evaluation through large-scale multi-omic studies of SCD patients. Ultimately, the more extreme phenotype of ACS recurrence may be a more informative phenotype for analysis, risk prediction, and therapeutic targeting.

Venetoclax and azacitidine (ven-aza) is a standard of care therapy for newly diagnosed acute myeloid leukemia (AML) patients unfit to receive intensive therapy, and may also be appropriate for certain fit patients. Models predicting response to ven-aza currently focus predominantly on genetics. Here, we present two multimodal fusion models: a custom ResNet-34-based model and a pathology foundation model fine-tuned for bone marrow smear (BMS) images that combine clinical and genetic variables with whole slide images. Training on 193 newly diagnosed AML patients who received ven-aza, we obtained an area-under-the-receiver-operating-characteristic (AUROC) of 0.79 and 0.82 for the ResNet-based and fine-tuned foundation models in a heldout test set, and 0.76 and 0.73 in an external validation set, predicting best response to this therapy. Sensitivity analysis showed that fusing image data with clinical and genetic variables outperformed training on either modality alone. In univariable and multivariable analyses, image-based classification was an independent predictive marker, second only in effect size to IDH1/2 mutation status, outperforming other genetic alterations. Image-based explainability showed high model attention on myeloblasts, suggesting previously unrecognized cell-specific patterns associated with response. Our findings suggest BMS images complement genetic biomarkers to refine outcome prediction in ven-aza treatment and incentivize AI-supported outcome prediction, including bone marrow morphology.

Cytosolic phospholipase A2 (cPLA2), encoded by PLA2G4A plays a crucial role in platelet activation through thromboxane A2 biosynthesis. Defects in this pathway can lead to bleeding disorders; however, the precise role of cPLA2 in Glanzmann thrombasthenia (GT) or GT-like syndromes remains poorly understood. The current study emerged from a fortuitous discovery of novel PLA2G4A variants, p.Asp455Val (D455V) and p.Glu119Lys (E119K), among 3 GT patients from two unrelated families in south India. We envisaged a hypothesis to identify a hitherto unknown role of cPLA2 that could be attributed to GT-like bleeding symptoms in these patients. An extensive computational workflow, including variant classification, conservation analysis, stability prediction, molecular docking, molecular dynamics simulations, principal component analysis, and binding free energy (MMPBSA) calculations, were employed to assess mutation-induced alterations in the cPLA2 protein. The current findings depicted that both variants affected conformational dynamics, ligand recognition patterns, and local interaction networks, without causing any drastic global structural destabilization. In particular, the D455V partially disrupted the catalytic domain, potentially reducing substrate (PAPC) stabilization and hampering interactions with catalytic products. Likewise, the E119K variant partially affected the C2 domain, potentially altered electrostatic interactions and enhanced regional flexibility, which may compromise product (AA) stabilization. Further analyses revealed mutation-induced changes in collective motions, protein-ligand interactions, solvent accessibility, and secondary structural elements. Overall, our findings promote the hypothesis that both E119K and D455V variants may partially alter phospholipid-associated interactions, and cPLA2-mediated downstream signaling. Moreover, this study underscores cPLA2 as a potential modifier of platelet function and bleeding severity.

Background Immune checkpoint blockade (ICB) has become the standard of treatment for metastatic melanoma (MM). However, patients with melanoma brain metastases (MBM) are often excluded from clinical trials. Here we analyse patients within the real-world OxCITE cohort receiving ICB treatment for metastatic melanoma, with a focus on MBM, aiming to discern outcomes, prognostic factors and peripheral biomarkers. Methods Patients eligible for ICB treatment were recruited prospectively. Demographic, clinical and radiological data were collected from electronic patient records. Plasma samples were collected prior to the first cycle of treatment for plasma proteomic analysis. Results 307 patients were included, 81 of whom had MBM on commencing ICB. No difference in overall survival between patients with and without brain metastases was noted on multivariable analysis (HR=1.1, 95% CI 0.73-1.6, p=0.68), whereas hepatic metastases were associated with increased risk of death (HR 1.7, 95% CI 1.2-2.4, p=0.0019). Within the MBM group, steroid treatment (HR=2.5, 95% CI 1.3-5.0, p=0.006) was associated with poor OS, whilst treatment with single agent ICB (HR=1.9, 95% CI 0.86-3.9, p=0.11), symptomatic first presentation of MBM (HR=1.5, 95% CI 0.76-2.8, p=0.25) and anti-seizure drug treatment (HR=1.74, 95% CI 0.89-3.4, p=0.10) were not. Amongst all patients carriage of a BRAF mutation was associated with increased risk of MBM (OR 2.49, 95% CI 1.4-4.4, p=0.0007), and increased propensity to new brain metastases on ICB treatment (OR 2.5, 95% CI 1.1-5.9, p=0.036). Analysis of blood and plasma samples demonstrated that patients with MBM have altered haematological profiles, with raised NLR and increased plasma glial fibrillary acidic protein levels, reinforcing the distinct systemic features of MBM. Conclusions In this real-world cohort of patients receiving ICB for metastatic melanoma, the presence of MBM did not associate with worse OS. Conversely, baseline corticosteroid use was adversely prognostic. Intriguingly, plasma GFAP was significantly elevated in patients with MBM and correlated with the burden of intracranial disease, highlighting a potential role for GFAP as a candidate biomarker for MBM in high-risk surveillance. Our observations indicate the adversely prognostic weight historically attached to M1d disease is no longer applicable in the ICB era.

Purpose: How sarcoma subtypes engage telomerase versus alternative lengthening of telomeres (ALT), and with what consequence, is incompletely defined. Methods: We analyzed 11,792 patients with sarcoma sequenced across 19 centers in AACR Project GENIE v20.0. Telomerase activation was defined as TERT promoter mutation, amplification, or rearrangement, and ATRX/DAXX inactivation served as the ALT proxy, each assessed only where the assay interrogated the locus. Findings were tested for TERT expression in The Cancer Genome Atlas (TCGA), for overall survival (OS) in MSK-IMPACT 50K, and for replication in an independent Foundation Medicine cohort. Mendelian randomization (MR) in FinnGen tested germline telomere length. Results: Telomerase activation (8.8%) and ATRX/DAXX loss (8.0%) were mutually exclusive across subtypes (odds ratio [OR], 0.52; 95% CI, 0.29 to 0.92) and segregated by histology. In MDM2-amplified dedifferentiated liposarcoma (DDLPS), telomerase was activated through TERT amplification (17.2%) or rearrangement (2.7%), never promoter mutation (0/261), and never with ATRX/DAXX loss (0/49; P = .011). TERT-amplified tumors expressed TERT (TCGA; P = .002), and amplification was largely focal. Telomere maintenance alterations were present in 28.0% of DDLPS versus 8.7% of well-differentiated liposarcoma (P < .001) and predicted shorter OS in DDLPS (hazard ratio, 2.04; 95% CI, 1.23 to 3.39; P = .005). ATRX/DAXX loss was more frequent in uterine than extrauterine leiomyosarcoma in GENIE (adjusted OR, 1.96) and in the independent cohort (OR, 1.95; both P < .001). Genetically longer telomeres were associated with liposarcoma (OR per SD, 4.10; 95% CI, 2.15 to 7.81). Conclusion: Sarcoma telomere maintenance is histology-specific and mutually exclusive. In liposarcoma it is acquired at dedifferentiation through focal TERT amplification or ALT and identifies DDLPS with inferior survival.

Background: Stroke risk is increased in cancer patients, but variations by stroke type, cancer characteristics, and treatment timing remain incompletely characterized. We investigated stroke incidence after cancer diagnosis and temporal patterns of ischemic stroke around treatments. Methods: We conducted a retrospective multicenter cohort study using linked cancer registry and administrative data from 68 cancer hospitals in Osaka, Japan. Patients diagnosed between 2019 and 2022 were followed for up to 1 year. In diagnosis-based analyses, standardized incidence ratios (SIRs) compared stroke incidence with the general population. In treatment-based analyses, ischemic stroke incidence rates and adjusted incidence rate ratios (IRRs) were estimated from 14 days before through 365 days after cancer treatments (surgery, chemotherapy, or radiotherapy). Results: Among 190,471 patients, 1660 strokes occurred: 1296 (78.0%) ischemic strokes, 315 (19.0%) intracerebral hemorrhages, and 49 (3.0%) subarachnoid hemorrhages. In diagnosis-based analyses, the overall stroke SIR was 2.13 (95% CI, 2.03?2.24), with a 1.01% 1-year cumulative incidence. SIRs were 2.37 (95% CI, 2.24?2.50), 1.72 (95% CI, 1.53?1.92), and 1.22 (95% CI, 0.91?1.62) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. SIRs peaked immediately after diagnosis and declined thereafter. Excess risk persisted through 180 days for ischemic stroke, 30 days for intracerebral hemorrhage, and 7 days for subarachnoid hemorrhage. In treatment-based analyses, ischemic stroke incidence increased transiently around treatments. After surgery, the adjusted IRR peaked during days 0?7 (12.27 [95% CI, 8.50?17.71]) and remained elevated through days 31?90 versus days 181?365. A postoperative increase was observed even in early-stage disease. For chemotherapy, incidence was relatively high before treatment initiation. Conclusions: Stroke risk after cancer diagnosis varied by stroke type, cancer characteristics, and time since diagnosis. Ischemic stroke incidence increased transiently around cancer treatment, including an early postoperative increase in patients with early-stage disease. These findings identify periods and patient groups that may warrant heightened clinical vigilance.

Purpose: Metastatic pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine malignancies with limited systemic treatment options. Although inhibition of vascular endothelial growth factor (VEGF) signaling has demonstrated clinical benefit in metastatic PPGL, prospective data evaluating selective VEGF receptor inhibition remain limited. Axitinib is a potent and selective inhibitor of VEGFR-1, -2, and -3 with established activity in several solid tumors. We evaluated the efficacy and safety of axitinib in patients with progressive metastatic PPGL. Methods: Patients with progressive metastatic or unresectable PPGL were enrolled in a prospective, open-label, single-arm, phase II study (NCT03839498). Eligible patients had measurable disease according to RECIST version 1.1 and no prior treatment with a tyrosine kinase inhibitor. Axitinib was administered orally at an initial dose of 5 mg twice daily with protocol-defined dose modifications based on tolerability. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: Nineteen patients were enrolled, and 17 received study treatment. A confirmed partial response was achieved in 35.3% of treated patients. Median progression-free survival was 7.9 months (95% CI, 6.1-16.8 months), median duration of response was 7.4 months, median duration of treatment was 9.5 months, and median overall survival was 29 months. Hypertension, the most common treatment-related adverse event, occurring in 79% of patients, was effectively managed with antihypertensive therapy and dose modification. Other common treatment-related adverse events included fatigue, diarrhea, oral mucositis, and palmar-plantar erythrodysesthesia. No patient permanently discontinued treatment because of treatment-related toxicity. Conclusions: In patients with progressive metastatic PPGL, single-agent axitinib demonstrated clinically meaningful antitumor activity with a manageable safety profile. The observed efficacy compares favorably with sunitinib in this rare disease. The ability to maintain treatment despite predictable VEGF-associated toxicities suggests that axitinib represents a viable therapeutic option for patients with metastatic PPGL.

Background: Relapse remains the principal cause of treatment failure in pediatric acute leukemia. Clinically validated minimal residual disease (MRD) assays - multiparameter flow cytometry, immunoglobulin/T-cell-receptor rearrangement sequencing, and targeted next-generation sequencing panels -- are highly sensitive but read out predefined features and do not reconstruct clonal architecture or link a cell's genotype to its functional state. We systematically reviewed what single-cell sequencing has revealed about clonal evolution, chemoresistance, the immune microenvironment, and post-therapeutic immune dynamics in this disease. Methods: This review followed PRISMA 2020. PubMed/MEDLINE, the Cochrane Library, and Google Scholar were searched to September 2026 for primary studies applying single-cell DNA, RNA, chromatin-accessibility, surface-protein, or immune-repertoire sequencing to pediatric acute leukemia samples or pediatric-derived models. Risk of bias in non-randomized studies was assessed with ROBINS-I. Because designs, platforms, and outcomes were heterogeneous, findings were synthesized narratively by biologic theme without meta-analysis, following the SWiM guideline. Results: Of 63 records identified, 10 studies were included (published 2016-2026; 6-159 patients or samples per study; up to ~700,000 cells profiled). Single-cell DNA sequencing traced minor NOTCH1-mutant diagnostic subclones into PTEN- or TP53-mutant relapse clones that bulk sequencing missed. Rare dormant, label-retaining cells and developmental-state-dependent drug sensitivity defined chemoresistant compartments. Remodeling of the bone marrow immune microenvironment identified patients with adverse outcome among those classified as MRD-low, and pre-infusion CAR T-cell type 2 functionality and post-transplant cytotoxic memory CD8+ T-cell subsets were associated with durable remission. Of the seven studies assessed with ROBINS-I, four were at moderate and three at serious overall risk of bias, driven chiefly by small, selected cohorts. Conclusions: Single-cell sequencing yields mechanistic insight that complements, rather than replaces, clinically validated MRD assays, and nominates candidate biomarkers for risk stratification, treatment selection, cell-therapy manufacturing, and post-transplant monitoring. The evidence remains preliminary; adequately powered, prospective, and harmonized studies are required before clinical adoption.

Background: CADASIL caused by cysteine-altering NOTCH3 variants, the most frequent hereditary cerebral small vessel disease worldwide, is characterized by marked phenotypic variability. Mutation location within the EGFr domains of the NOTCH3 receptor has emerged as a key determinant of this variability. We investigated phenotypic variability and potential modifiers of CADASIL expression by comparing individuals harbouring the same pathogenic NOTCH3 variant across distinct recruitment settings in three European countries. Methods: We compared clinical features, MRI markers, and cardiovascular risk factors among individuals harbouring the p.Arg1231Cys NOTCH3 mutation across three distinct recruitment settings: a multigenerational founder population from Cilento, Italy (CILCAD), a population-based cohort from the UK Biobank (UKB), and a clinically referred cohort from a national referral centre in Lariboisiere Hospital, Paris, France (LRB). In addition, CILCAD carriers were compared with NON-Carriers from the same population. The NOTCH3 locus was finally analysed to define the shared haplotype in CILCAD and explore potential genetic contributions to phenotypic variability. Findings: By comparing populations from three European countries, this study showed marked context-dependent phenotypic variability associated with the sole pathogenic p.Arg1231Cys NOTCH3 variant. In CILCAD, a multigenerational founder population, the haplotype carrying the NOTCH3 mutation also predisposes to decreased LDL levels, resulting in an unusually low LDL cholesterol profile in this sample. Strikingly, these very low LDL levels were associated with a higher likelihood of stroke. Interpretation: In European carriers of NOTCH3 p.Arg1231Cys, factors beyond mutation location, including genetic background, may substantially shape disease expression, while exceptionally low LDL levels could paradoxically be associated with greater disease severity.

BACKGROUND: Severe influenza pneumonia with secondary bacterial infection is complicated by progressive pulmonary thrombus exacerbation, a key contributor to respiratory failure, yet anticoagulant therapies show limited efficacy and bleeding risks. Although platelet-monocyte crosstalk initiates thrombosis, whether and how it drives thrombus exacerbation via procoagulant platelets and monocyte efferocytosis remains unclear. METHODS: Clinical samples, mouse models, and isolated platelets challenged with influenza A virus followed by methicillin-resistant Staphylococcus aureus (MRSA) were analyzed. Procoagulant platelet, platelet programmed cell death and monocyte efferocytosis were assessed, and pharmacological inhibition, platelet depletion and systemic/platelet-specific Gsdmd knockout were used. Platelet proteomics and exogenous C1qa supplementation identified C1qa as a key mediator. RESULTS: We showed that elevated procoagulant platelet-driven thrombus exacerbation, rather than initial thrombus formation, was a critical driver of disease progression in influenza pneumonia with secondary bacterial infection, whereas influenza alone caused milder illness. Procoagulant platelet formation was induced via MLKL-mediated necroptosis and GSDMD-mediated pyroptosis. These platelets exacerbated pulmonary thrombosis and lung injury by inhibiting monocyte efferocytosis via complement C1qa. Platelet depletion reduced monocyte efferocytosis and worsened pneumonia, while pharmacological inhibition or platelet-specific Gsdmd knockout decreased procoagulant platelet levels, restored monocyte efferocytosis, and alleviated thrombotic and pulmonary injury. Mechanistically, C1qa impaired efferocytosis both by directly suppressing monocyte function and by reducing the proportion of reparative (M2-like) monocytes. Clinical relevance was confirmed by detection of MLKL/GSDMD-dependent procoagulant platelets and reduced efferocytosis receptor levels on monocytes in bronchoalveolar lavage fluid from severe pneumonia patients. CONCLUSIONS: Necroptosis/pyroptosis-driven procoagulant platelets exacerbate pulmonary thrombosis by suppressing monocyte efferocytosis in a C1qa-dependent manner. These findings extend platelet-monocyte crosstalk from thrombus initiation to thrombus exacerbation, identifying modulation of the interaction between procoagulant platelets and monocyte efferocytosis as a potential therapeutic strategy for thrombus-exacerbating diseases, especially in subpopulations of patients with severe pneumonia and progressive pulmonary thrombosis.

Background Evidence on {beta}-thalassaemia carrier prevalence is fragmented across heterogeneous surveys and national summaries, leaving within-country variation and geographic concentration of carriers poorly resolved. This study characterises {beta}-thalassaemia carrier prevalence and carrier populations at high spatial resolution and identifies where additional data would most improve geographic coverage. Methods Using carrier-prevalence records curated through ITHANET, a global haemoglobinopathy resource, Bayesian geostatistical modelling generated high-resolution predictions across 25 countries. Predictions were integrated with population data to estimate national and subnational carrier numbers. Prediction uncertainty and gaps in existing survey coverage informed prioritisation of healthcare sites for additional surveys. Findings Predicted prevalence varied markedly within countries, and highest-prevalence areas did not coincide with the largest carrier populations. National mean prevalence was highest in Cyprus (12.99%), whereas India, China, and Pakistan had the largest carrier populations, together accounting for 81.21% of estimated carriers. Random five-fold cross-validation favoured a model capturing broad geographic patterns and location-specific variation. Predictive performance deteriorated when geographically clustered records were withheld together, indicating reduced reliability across larger gaps in geographic sampling and the need for additional data from poorly characterised areas. Survey prioritisation identified 183 healthcare sites across 17 countries for future carrier-prevalence surveys. Interpretation By distinguishing areas of high carrier prevalence, large carrier populations, and evidence gaps, this updatable framework provides a subnational evidence base to inform {beta}-thalassaemia prevention planning and guide future data collection, screening, and genetic counselling.

Background: Epigenetic deregulation is a defining feature of leukemia, and DNA methylation and chromatin accessibility profiles encode the cell of origin, lineage and clinical behaviour of the disease. Artificial intelligence (AI) and machine learning (ML) can extract predictive patterns from these high-dimensional data, but the published models have not been systematically appraised. We systematically reviewed AI models built on epigenomic data in leukemia for diagnosis, prognosis, relapse and treatment-response prediction, and measurable residual disease (MRD) detection. Methods: This review followed PRISMA 2020 and the SWiM guideline. PubMed was searched on 7 October 2026 with three structured queries, supplemented by a broader PubMed query, citation searching and web searching. Eligible studies were peer-reviewed primary studies that applied an ML or deep-learning algorithm to DNA methylation, chromatin-accessibility or histone-modification data from human leukemia samples and reported a quantitative diagnostic, prognostic, response or MRD outcome. Risk of bias and applicability were assessed with PROBAST, informed by PROBAST+AI. Owing to heterogeneity, results were synthesized narratively and in structured tables, without meta-analysis. Results: Of 68 unique database records and 32 reports from other sources, 30 studies (2010-2026; 22 since 2020) were included: 16 in acute myeloid leukemia, 4 in acute lymphoblastic leukemia, 2 spanning acute leukemia lineages, 3 in juvenile myelomonocytic leukemia and 5 in chronic lymphocytic leukemia; 10 were pediatric. DNA methylation was the input in 28 studies and chromatin accessibility in 2; no eligible study modelled histone marks. Tree ensembles (n = 9) and support vector machines (n = 5) were the most frequent algorithms. Diagnostic classifiers reported accuracy, concordance or F1 scores of 0.87-1.00, and two classifiers were applied to nanopore sequencing data, one returning acute leukemia subtype calls within about 2 hours. Prognostic epigenomic scores were associated with survival (reported hazard ratios 2.36-10.82), but discrimination fell on transport to independent cohorts (C-index 0.677 internally vs 0.529 in one external cohort). Fifteen studies validated models on an external epigenomic cohort, one prospectively. Overall risk of bias was high in 21 studies, unclear in 8 and low in 1, driven by the analysis domain (small samples, absent calibration, possible data leakage). Calibration was reported in 3 studies and code was available for 11. Conclusions: Epigenomic AI models classify leukemia subtypes with high reported accuracy and can deliver same-day diagnoses, and methylation-based scores add prognostic information. However, the evidence is dominated by retrospective, high-risk-of-bias development studies with limited external validation and almost no prospective or impact evaluation. Prospective, multi-center validation with calibrated, transparently reported models is required before clinical adoption.

Aims: Mature, contractile vascular smooth muscle cells (vSMC) in muscular blood vessels can de-differentiate into synthetic vSMC, while human pluripotent stem cells (hPSC) differentiate into proliferating, fetal-like vSMC that can be induced to form contractile vSMC. Given the complicated embryonic origins and conflicting views on vSMC heterogeneity, our aim was to establish how closely hPSC-vSMC of a known germ layer lineage and defined phenotype are representative of vSMC obtained from aorta (AoSMC). Methods and Results: We generated paraxial mesoderm (PM)-derived synthetic and contractile vSMC from hPSC lines and performed phenotypic and mechanical comparisons with AoSMC. Synthetic hPSC-vSMC and cultured AoSMC are proliferative, sensitive to contact inhibition and exhibit phenotype switching. Contractile hPSC-vSMC are non-proliferative, capable of phenotype switching and have elevated levels of contractile proteins (CNN1, TAGLN, ACTA2). These contractile proteins also displayed density-dependent, cell-to-cell heterogeneity in both AoSMC and hPSC-vSMC. Single-cell traction force measurements on micropost array detectors (mPADs) yielded comparable forces per micropost in the nN range across cell types. Quantitative 3D force measurements on humanized smooth muscle cell microtissues (SMTs) developed similar forces per cell. Larger forces were generated by MEKi-treated hPSC-vSMC and AoSMC versus controls. Conclusions: We have systematically studied the properties of hPSC-vSMC and performed comprehensive phenotypic and mechanical comparisons with AoSMC. These results demonstrate that synthetic hPSC-vSMC generated in vitro and cultured AoSMC derived from tissues are comparable and mechanically similar, but results with hPSC-vSMC are more reproducible.

Purpose Tarlatamab, a bispecific T-cell engager, has generated favorable response and survival outcomes in relapsed small cell lung cancer (SCLC). Factors influencing tarlatamab-associated treatment outcomes and toxicity have yet to be established. We performed a multivariate analysis to identify biomarkers associated with cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) and integrated these variables into a novel risk stratification tool to identify patients at high risk of clinically significant toxicity. Patients and Methods Logistic and ordinal regression analyses evaluated the predictive value of variables contributing to the presence and severity, respectively, of CRS and ICANS in 115 patients with ES-SCLC receiving tarlatamab. Selected variables were then tuned using 5-fold cross-validation and incorporated into novel elastic net-based prediction models. Results Rates of observed CRS, ICANS, and dysgeusia were 46%, 28%, and 47%, respectively. ORR (overall response rate) and DCR (disease control rate) were 44% and 58.2%, while 6-month PFS (progression free survival) and OS (overall survival) rates were 30.4% and 54.9%, respectively. Excluding patients on tarlatamab <30 days, presence of dysgeusia was associated with a lower rate of disease progression (HR 0.44, p=0.00691) and death (HR 0.34, p=0.0145). The presence of, increased size and number of extracranial metastases as well as elevated baseline LDH were significantly associated with increased likelihood of CRS. Increased ECOG performance status, increased volume of brain metastases, development of CRS, and elevated baseline LDH were all associated with increased risk of developing ICANS. Our cross-validated risk model successfully predicted CRS grade [&ge;]2 and ICANS events with 90.9% and 75% sensitivity, respectively. Conclusions This exploratory analysis identified several predictive biomarkers of toxicity that successfully stratified low and high-risk populations as part of an internally validated novel risk scoring tool.