Optical Genome Mapping in Pediatric Hematologic Malignancies: High Diagnostic Yield and Unique Insights Across Leukemia Subtypes.

In the rapidly evolving field of hematology, the diagnosis of leukemias and lymphomas poses major challenges, despite significant genetic advancements. Although established diagnostic methods comprise a multidisciplinary approach and are considered gold standard, in some cases they fall short in conclusively identifying hematological neoplasms. In this context, the current SIRIUS study (NCT05046444) delves into the potential of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to bridge diagnostic gaps. By analyzing 106 patients with an unclear diagnosis or clinical condition following gold standard diagnostics, our study demonstrates that WGS and WTS can uncover a broader range of somatic alterations, including rare single-nucleotide variants (SNVs), small copy number variations (CNVs), and aberrant gene expression patterns not detected by conventional diagnostics. WGS and WTS provided additional diagnostic insights in 25% of cases, suggesting their value not only in enhancing diagnostic accuracy but also in contributing to more informed prognostic assessments and personalized treatment strategies. Therefore, our study underscores the importance of integrating WGS and WTS into the diagnostic toolbox for hematological neoplasms. This approach promises not only to improve patient outcomes but also to do so in a manner that is both financially sustainable and ethically sound.

Multiple myeloma (MM) is a plasma cell dyscrasia sustained by the clonal proliferation of plasma cells within the bone marrow. MM represents the second most common hematologic neoplasm and, despite the continuous effort to overcome this disease, it remains an uncurable disease. Throughout the recent years, novel therapeutic targets have been investigated, leading to the development of novel treatments for MM patients. In the last ten years, the interest for the long non-coding RNA NEAT1 has significantly grown within the field of cancer, including MM. In this review we offer a panoramic view of the role of NEAT1 in MM, with a focus on its possible role as both biomarker and therapeutic target.

BackgroundCoronary artery bypass grafting (CABG) in patients with concurrent coronary artery disease (CAD) and hematological neoplasms presents unique challenges due to immunosuppression, hematologic dysfunction, and coagulopathy. This study aimed to assess the safety and feasibility of CABG in this population and to evaluate factors influencing prognosis.MethodsThis retrospective study included 41 patients with CAD and hematological neoplasms who underwent CABG between 2018 and 2023. Hematological neoplasms were classified into seven categories, and patients were stratified by hematological disease status: stable, disease-free, or progressive. Key perioperative outcomes, graft patency, and survival data were analyzed. Cox regression models identified independent predictors of prognosis.ResultsOf the 41 patients, 28 (68.3%) were stable, 10 (24.4%) were disease-free, and 3 (7.3%) were progressive. The median preoperative platelet count was 143 × 109/L, with 8 patients presenting counts <50 × 109/L requiring preoperative platelet transfusions. Postoperative transfusion rates for packed red blood cells (PRBCs), fresh frozen plasma (FFP) and platelets were 51.2%, 39.0%, and 12.2%, respectively. The median operation time was 210 min, with 87.8% undergoing off-pump CABG. Graft patency at discharge was 92.3%. Major infections occurred in 4.9% of patients, and 9 (22%) deaths were recorded during follow-up, 8 due to hematological progression and 1 due to myocardial infarction. Cox regression identified preoperative blood cell levels as independent predictors of survival (p < 0.05), while CABG-related factors showed no significant association (p > 0.05).ConclusionsCABG can be performed safely in most patients with stable hematological neoplasms, with no perioperative mortality, providing an opportunity for further hematological treatments. Preoperative blood cell levels significantly influence prognosis, underscoring the importance of multidisciplinary management. Larger studies are needed to validate these findings and refine treatment strategies.

West Nile virus (WNV) is the leading mosquito-borne infection in the US, causing West Nile fever or West Nile neuroinvasive disease (WNND) with substantial morbidity and mortality. Contemporary analyses are needed to identify at-risk populations and to target interventions. To assess risk factors associated with WNND and mortality among adults with WNV infection using a national cohort from federated data. This retrospective cohort study of deidentified electronic medical record data from the TriNetX research network from January 2013 to December 2024 included patients from 65 health care organizations from across the US. Data were accessed from March 28 to April 30, 2025. Demographic characteristics (age, sex, race, and ethnicity), comorbidities (hematologic malignant neoplasms, heart disease, diabetes, HIV infection, chronic kidney disease [CKD], liver disease, hypertension, alcohol-related disorders, cerebrovascular disease [CEVD], chronic obstructive pulmonary disease, asthma, multiple sclerosis, dementia, rheumatoid arthritis, and organ transplant), and medications (immune suppressants, antineoplastics). Primary outcomes were WNND development and all-cause mortality (at 30 days, 90 days, and overall). Among the initial cohort of 3064 patients with a diagnosis of WNV infection (per the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes), those with demographic data included 1249 (53%) who were consistent with West Nile fever (624 females [50%]; mean [SD] age, 55 [17] years) and 1127 (47%) who were consistent with WNND (691 males [61%]; mean [SD] age, 59 [17] years). Risk factors associated with WNND included age (adjusted hazard ratio [AHR], 1.10 [95% CI, 1.06-1.15] per decade), male sex (AHR, 1.29 [95% CI, 1.15-1.45]), CKD (AHR, 1.21 [95% CI, 1.00-1.45]), CEVD (AHR, 1.22 [95% CI, 1.03-1.45]), hematologic malignant neoplasms (AHR, 1.38 [95% CI, 1.09-1.76]), immune suppressant use (AHR, 1.43 [95% CI, 1.11-1.83]), hypertension (AHR, 1.18 [95% CI, 1.04-1.34]), alcohol-related disorders (AHR, 1.54 [95% CI, 1.20-1.97]), and multiple sclerosis (AHR, 2.34 [95% CI, 1.62-3.37]). Significant risk factors associated with mortality were WNND (AHR, 2.49 [95% CI, 1.37-4.52] for 30-day mortality), age (AHR, 1.32 [95% CI, 1.07-1.60] per decade), CKD (AHR, 2.08 [95% CI, 1.01-3.93]), and CEVD (AHR, 2.00 [95% CI, 1.14-3.50]). In this cohort study of patients with WNV infection, multiple comorbidities were identified as risk factors associated with WNND; and patients who developed WNND had increased mortality risk. Targeted prevention strategies and countermeasures for high-risk individuals may substantially reduce morbidity and mortality.

Onco-hypertension recognizes well-controlled blood pressure as a favorable prognostic factor for survival in patients with hypertension and solid tumors, including hematologic neoplasms. However, it remains unknown whether continuous use of hydralazine-an antihypertensive agent (AHA) with notable anti-neoplastic activity-is associated with a lower risk of hematologic neoplasms compared to other AHAs. Utilizing Taiwan's National Health Insurance Research Database, we conducted a 16-year follow-up study (2000-2015) involving 375,107 patients with hypertension treated with an AHA for ≥180 days. The patients with hypertension were divided into two groups based on hydralazine prescription duration: an exposure group (hydralazine ≥180 days; n = 59,786) and a reference group (hydralazine <180 days; n = 239,144) after 1:4 matching for sex, age, and index date with the exposure group. Both groups were well-matched, with a mean age of approximately 60.8 years and 52.19% male. We assess the association between hydralazine use and the risk of hematologic neoplasms using Kaplan-Meier analysis and multivariable Cox proportional hazards regression, with models adjusted for concomitant medications possessing potential anti-neoplastic properties. The 16-year cumulative incidence of hematologic neoplasms was lower in the exposure group (105.58 per 100,000 person-years) than in the reference group (160.33). Accounting for death as competing risk, the exposure group exhibited an adjusted subdistribution hazard ratio (adjusted sHR) of 0.789 (95% confidence interval [0.667,0.913]; P < .001) for hematologic neoplasms compared to the reference group. Subgroup analyses demonstrated that the association with a lower risk was strongest in the longest prescription duration category. For example, for patients with prescription durations of ≥668 days, the adjusted sHR was 0.448 (95% CI [0.366,0.555]; P < .001) for other malignant neoplasms of lymphoid and histiocytic tissue, 0.552 (95% CI [0.453,0.683]; P < .001) for multiple myeloma and immunoproliferative neoplasms, and 0.555 (95% CI [0.457,0.689]; P < .001) for myeloid leukemia. The main limitation was the potential for residual confounding due to the unavailability of lifestyle and laboratory data in the administrative database. In this study, we observed that long-term hydralazine use in patients with hypertension was associated with a lower, duration-dependent risk of hematologic neoplasms. These findings warrant prospective studies to confirm this association and its potential clinical implications.

BackgroundOnco-hypertension recognizes well-controlled blood pressure as a favorable prognostic factor for survival in patients with hypertension and solid tumors, including hematologic neoplasms. However, it remains unknown whether continuous use of hydralazine—an antihypertensive agent (AHA) with notable anti-neoplastic activity—is associated with a lower risk of hematologic neoplasms compared to other AHAs.Method and findingsUtilizing Taiwan’s National Health Insurance Research Database, we conducted a 16-year follow-up study (2000–2015) involving 375,107 patients with hypertension treated with an AHA for ≥180 days. The patients with hypertension were divided into two groups based on hydralazine prescription duration: an exposure group (hydralazine ≥180 days; n = 59,786) and a reference group (hydralazine <180 days; n = 239,144) after 1:4 matching for sex, age, and index date with the exposure group. Both groups were well-matched, with a mean age of approximately 60.8 years and 52.19% male. We assess the association between hydralazine use and the risk of hematologic neoplasms using Kaplan–Meier analysis and multivariable Cox proportional hazards regression, with models adjusted for concomitant medications possessing potential anti-neoplastic properties. The 16-year cumulative incidence of hematologic neoplasms was lower in the exposure group (105.58 per 100,000 person-years) than in the reference group (160.33). Accounting for death as competing risk, the exposure group exhibited an adjusted subdistribution hazard ratio (adjusted sHR) of 0.789 (95% confidence interval [0.667,0.913]; P < .001) for hematologic neoplasms compared to the reference group. Subgroup analyses demonstrated that the association with a lower risk was strongest in the longest prescription duration category. For example, for patients with prescription durations of ≥668 days, the adjusted sHR was 0.448 (95% CI [0.366,0.555]; P < .001) for other malignant neoplasms of lymphoid and histiocytic tissue, 0.552 (95% CI [0.453,0.683]; P < .001) for multiple myeloma and immunoproliferative neoplasms, and 0.555 (95% CI [0.457,0.689]; P < .001) for myeloid leukemia. The main limitation was the potential for residual confounding due to the unavailability of lifestyle and laboratory data in the administrative database.ConclusionsIn this study, we observed that long-term hydralazine use in patients with hypertension was associated with a lower, duration-dependent risk of hematologic neoplasms. These findings warrant prospective studies to confirm this association and its potential clinical implications.

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common hematological neoplasm in adults globally and in Colombia, but there are limited data on its local economic impact. This study analyzed the relationship between clinical variables and healthcare resource utilization of patients with DLBCL in a Colombian health maintenance organization.MethodsThis analytical observational study included patients with histopathologically confirmed DLBCL treated at the Luis Carlos Sarmiento Angulo Cancer Treatment and Research Center (CTIC) between July 2022 and September 2025. We reported an interim analysis with a data cut-off in July 2024. Clinical data from CTIC’s institutional registry were merged with the information provided by the administrative database, covering healthcare resource use and costs for drugs, procedures, and medical supplies. A multivariate linear regression estimated the effect of prognosis (revised International Prognostic Index [R-IPI] score) on total costs, adjusting for confounding (e.g., sex, comorbidities, and history of neoplasm).ResultsSixty-two patients were included (mean 66 years [standard deviation 14]; 58% men). R-IPI scores at baseline indicated that 34 percent were at high-intermediate risk, 21 percent had low and low-intermediate risk, and 23 percent were at high risk. R-IPI scores at baseline showed that 17.7 percent patients had very good prognosis, while 24.2 and 41.9 percent had good or poor prognosis, respectively (16.1% missing). The R-CHOP chemotherapy regimen was the most common first-line (1L) treatment (73%), and fifteen percent of patients had disease progression. The total 1L treatment cost was COP1,386,178,104 (USD320,500) per patient. Thirteen patients received second-line (2L) treatment, costing COP3,203,033,513 (USD740,577) per patient. Regression analysis showed that patients with poor prognosis, per R-IPI score, incurred 8.9 times higher costs than those with very good R-IPI scores.ConclusionsOur study showed the association between clinical variables and the cost of treatment in patients with DLBCL. Regression analysis indicated that higher R-IPI scores and advanced disease stages significantly increased costs. The cost per patient for 2L treatment was 2.3 times higher than for 1L treatment, highlighting the importance of timely detection and treatment.

Malignant histiocytoses are rare histiocytic neoplasms that exhibit aggressive clinical and histopathological features. One of these entities, Langerhans cell sarcomas (LCS), shares some histopathological features with Langerhans cell histiocytosis but is distinguished by its overtly malignant cytologic features. The literature on LCS is mostly limited to short reports and a few reviews, while a complete revision of its nosology is lacking. This study aims to fill this gap in the knowledge on LCS, explore potential prognostic factors, and propose a clinical subclassification for better patient stratification, which could guide future treatment investigations. A systematic review of the literature was conducted following PRISMA guidelines. From each included patient, a complete set of clinical and pathological features was collected. Descriptive and association statistics, as well as survival analysis, were performed using R Studio. A cohort of 88 patients was analyzed, the majority being adult males with multisystem pictures often involving skin and lymph nodes. pERK pathway gene mutations were reported in around half. Overall prognosis was poor, even though the association with another hematological neoplasm displayed a significant negative prognostic impact (p = 0.0017). Moreover, in primary cases, a significant difference was observed dividing patients into single system vs multisystem (p = 0.012). Despite treatment modalities being highly heterogeneous, statistical analyses provided insights into the relevance of treating patients according to disease spread (e.g., treating localized masses with surgery alone leads to frequent complete remission, p = 0.0002). This study provides an extensive analysis of LCS nosology and prognostic factors, underscoring the importance of distinguishing LCS from LCH and other histiocytoses, as well as adopting a unified system to define disease spread and guide therapeutic management.

Juvenile myelomonocytic leukemia (JMML) is a rare and distinctive hematologic neoplasm affecting infants and younger children. Hyperactivation of the RAS signaling pathway is a central initiating event in JMML, which also delineates its various genetic and clinical subtypes. While a small percentage of children may achieve spontaneous clinical remission, allogeneic hematopoietic cell transplantation (HCT) remains the only possible cure for most JMML patients. In this article, we reviewed the indications of HCT in JMML. Other myeloproliferative diseases, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are extremely rare in pediatrics and are briefly discussed.

Background/Objectives: Accurate detection of all classes of genomic structural variants (SVs), including chromosomal rearrangements and copy number alterations (CNAs), is essential for the diagnosis and classification of hematologic neoplasms. Conventional cytogenetic methods currently serve as routine clinical tools for detecting SVs. However, each commonly used cytogenetic test has specific limitations, and sequential application of these different tests may delay timely diagnosis and treatment. Methods: In this study, we evaluated the feasibility and utility of genomic proximity mapping (GPM), a novel high-throughput chromosome conformation capture (Hi-C)-based next-generation sequencing (NGS) method, to identify chromosomal and genetic aberrations in hematologic neoplasms in the clinical setting. GPM was performed on 18 cases of hematologic neoplasms (fresh/frozen cells or formalin-fixed paraffin-embedded tissue), and concordance with other methodologies was assessed, including karyotyping, FISH, RT-PCR, chromosomal microarray analysis (CMA), and/or RNA sequencing. Results: GPM reliably detected balanced and unbalanced chromosomal rearrangements, including chimeric gene fusions and gene juxtapositions, with 95.2% concordance with previously applied methods in cases with >10% tumor burden. Additionally, GPM can detect CNAs and copy-neutral loss of heterozygosity (cnLOH) simultaneously in a single assay. Furthermore, detection of genomic rearrangements not identified by other methods improved the accuracy of disease classification. Conclusions: These findings demonstrate that GPM is a powerful method for identifying clinically actionable variants in hematologic neoplasms, overcoming some limitations of current cytogenetic technologies and improving the diagnostic accuracy and classification in challenging cases.

Prohibitins (PHBs) are predominantly located at the inner mitochondrial membrane, displaying significant roles in tumor progression, invasion, and apoptotic resistance, often overexpressed in primary tumors. Importantly, we developed a synthetic molecule, fluorizoline, that induces apoptosis by selectively targeting PHBs in various cancer cell lines and primary samples from different hematological neoplasms. Fluorizoline induces apoptosis by activating the pro-apoptotic branch of the integrated stress response (ISR) pathway in HeLa and HAP1 cells, specifically via the ATF4-CHOP-NOXA axis. We identified compensatory mechanisms for four ISR-related kinases, with HRI emerging as the primary kinase responsible for the activation of the ISR and apoptosis induction, implicating mitochondrial stress in ISR activation. Here, we investigate the mitochondrial stress response signaling pathway responsible for activating HRI after targeting PHBs either by fluorizoline treatment or by PHBs downregulation in HeLa and HAP1 cancer cell lines. In this study, we describe how PHBs regulate the localization of the mitochondrial stress sensor DELE1, leading to ISR activation and apoptosis induction in HeLa and HAP1 cells. Our findings demonstrate that DELE1 promotes ISR activation upon fluorizoline treatment and PHBs downregulation. Although fluorizoline treatment activates the cleavage of long DELE1 (L-DELE1) to its cleaved form (S-DELE1), OMA1 was found to be dispensable for activating the ISR upon fluorizoline treatment. Furthermore, our findings indicate a potential impairment of the mitochondrial protein import machinery upon targeting PHBs, as the import of other mitochondrial proteins beyond DELE1 is also disrupted. These findings reveal a previously unknown physiological role of PHBs in preserving the mitochondrial protein import pre-sequence pathway, possibly due to the interaction between PHBs and DNAJC19. This novel insight underscores the potential of targeting PHBs, such as with fluorizoline, to overwhelm mitochondrial stress in cancer.

Venous thromboembolism (VTE) is associated with increased mortality and morbidity in patients with cancer. Existing risk prediction models are typically validated within individual sites, a fragmented approach that limits clinical adoption. To validate the electronic health record cancer-associated thrombosis (EHR-CAT) score compared with the benchmark Khorana score in a contemporary cohort of patients with cancer across the nation, before and after treatment, excluding those at high risk of bleeding. This prognostic study included patients in a nationwide longitudinal EHR database from January 2018 to December 2023 with follow-up continuing to April 2025. Patients with newly diagnosed, invasive, solid, or hematologic malignant neoplasms (defined using validated International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] algorithms) receiving systemic therapy (defined using the first antineoplastic medication) were included. Those with recent history of acute VTE diagnosis or anticoagulant prescription were excluded. Demographics, risk model variables, and common anticoagulant trial exclusion criteria (as a proxy for identifying people at high risk of bleeding) were extracted on or before index therapy initiation date. Incident VTE and bleeding outcomes at 6 months were defined using validated ICD-10-CM algorithms. A total of 732 594 patients (median [IQR] age, 65.0 [56.9-73.0] years; 425 124 female [58.0%]; 25 634 Asian [3.5%], 94 269 Black [12.9%], 48 266 Hispanic [6.6%], 583 047 White [76.9%]) with active cancer receiving systemic therapy between 2018 and 2023 from 184 health systems were identified. With a median (IQR) follow-up of 676 (340-1151) days, the incidence of 6-month VTE, bleeding, and mortality was 4.7% (34 499 patients), 3.7% (26 993 patients), and 8.4% (60 239 patients), respectively. Bleeding risk was higher in the 26.0% of patients (190 413) meeting anticoagulant trial exclusion criteria (7.2% vs 2.4%; hazard ratio, 2.5 [95% CI, 2.5-2.5]). The EHR-CAT score stratified patients into discriminative risk groups (C statistic, 0.70-0.71) both before and after exclusion for bleeding risk. When compared with the benchmark Khorana score (C statistic, 0.63), EHR-CAT reclassified 20% of patients into revised categories with improved prediction accuracy. Furthermore, EHR-CAT had consistent calibration in subgroups by age, sex, race, ethnicity, and individual health system sites. This prognostic study of the EHR-CAT risk score demonstrated the external validity and feasibility of using readily available structured EHR data to estimate VTE risk in patients with cancer.

Description of the clinical cases: the cases of two common hematological neoplasms are presented, a diffuse large B cell lymphoma (DLBCL) and a recurrence of acute myeloblastic leukemia (AML), but with an extremely rare initial clinical presentation such as penile involvement. the treatment consisted of chemotherapy, and in the case of LAM also adding radiotherapy, without requiring surgery in its management. Relevance: a review of the bibliography of the cases published up to date was carried out, finding only 20 published cases of DLBCL of the penis and 5 cases of extramedullary involvement of AML in the penis. Clinical implications: knowledge of penile lesion due to blood neoplasms is important because they have high response to medical treatment and the possibility of avoiding radical or mutilating interventions. Conclusions: the biopsy of a penile lesion should be performed in all cases before considering local treatment.

Lymphoid leukemia is a hematologic neoplasm characterized by the replacement of normal hematopoietic tissue by malignant clones, leading to cytopenias and diverse clinical manifestations. This study aimed to compare the acute (ALL) and chronic (CLL) forms of lymphoid leukemia through an integrative literature review. Searches were conducted in PubMed, SciELO, and LILACS databases, using the descriptors Lymphoid leukemia AND acute AND chronic, between 2020 and 2025, including articles in Portuguese and with free access. From 716 initially identified studies, only five met the inclusion criteria and were analyzed. Results indicated that ALL has an aggressive clinical course, characterized by rapid expansion of immature lymphoblasts, leading to sudden and severe manifestations such as anemia, thrombocytopenia, and extramedullary infiltration. In contrast, CLL evolves indolently, with predominance of mature B lymphocytes, but may acquire secondary alterations, such as 13q14 deletion and TP53 mutations, associated with therapeutic resistance and worse prognosis. It is concluded that differentiating between ALL and CLL is essential for early diagnosis, prognosis definition, and therapeutic decision-making, reinforcing the importance of integrating clinical, immunophenotypic, and genetic parameters.

BackgroundWaldenström’s macroglobulinemia (WM) is a rare hematologic neoplasm characterized by an indolent clinical course. However, a significant proportion of patients undergo histological transformation to aggressive diffuse large B-cell lymphoma (DLBCL). Long-term population-based data on the transformation and survival are scarce. Based on the Surveillance, Epidemiology, and End Results (SEER) database, we performed this study to estimate the risk of transformation and outcomes of patients with WM.Methods8191 patients with WM were retrieved from the SEER database. Competing risk methods were employed to evaluate the cumulative incidences and putative risk factors for transformation. Survival outcomes were analyzed using Kaplan-Meier and Cox proportional hazards regression.ResultsThe cumulative incidence rates for transformation at 5 and 10 years were 1.0% (95% CI, 0.8%–1.3%) and 1.9% (95% CI, 1.5%–2.2%), respectively. A substantial increase in total mortality was related to the time-dependent transformation (HR, 4.21 [95% CI, 3.36–5.26]; P < 0.001). Patients who presented with transformation > 24 months after WM diagnosis had a longer overall survival (OS) than those who experienced transformation within 24 months (5-year rate, 81.9% [95% CI, 74.7%–89.9%] v 42.7% [95% CI, 26.4%–69.2%]; P < 0.001). The OS was shorter for patients with DLBCL transformed from WM than for those with matched de novo DLBCL (5-year rate, 28.0% [95% CI, 20.5%–38.1%] v 49.5% [95% CI, 41.2%–59.4%]; P = 0.001).ConclusionsHistological transformation to DLBCL was associated with significantly increased mortality in patients with WM, and the survival outcomes substantially worse than matched de novo DLBCL cases.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03946-6.

Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints.

Although chimeric antigen receptor (CAR)-redirected T lymphocytes have achieved unprecedented clinical responses in hematologic neoplasms, their role in solid tumors still needs to be improved. To overcome current limitations, we rationally designed a next-generation CAR-T cell construct incorporating autonomous costimulatory signaling pathways that operate independently of tumor antigen engagement, thus faithfully emulating physiological T cell activation paradigms. We screened seven costimulatory receptors from the TNF receptor superfamily and identified that CD30 is the most effective enhancer of CAR-T cell function. Subsequent structural analysis revealed that the intracellular domain (ICD) of CD30 is primarily responsible for its costimulatory activity. Our data showed that these CAR-T cells co-expressing CD30 ICD have stronger proliferation ability and cytokine secretion function. The results of in vitro experiments showed that CD30 signaling improved the cytotoxicity of CAR-T cells and reduced the expression of exhaustion-related markers. In mouse models of orthotopic renal cancer, lung metastasis, and hematologic malignancies, these CAR-T cells showed better expansion capability and superior antitumor activity. Sequencing results suggest that CD30 signaling may enhance the function of CAR-T cells by increasing the activation of the nuclear factor κB (NF-κB) pathway. Further mechanistic experiments confirmed that the NF-κB pathway is significantly activated in CAIX.CD30(ICD) CAR-T cells compared to CAIX CAR-T cells. Reversal experiments demonstrated that NF-κB pathway inhibitors can reverse the effector function of CAIX.CD30(ICD) CAR-T cells, while CAIX-IKKβ CAR-T cells with self-activated NF-κB pathway also exhibit significant functional advantages. By integrating autonomous costimulatory signaling, we demonstrated improved CAR-T cell persistence, proliferation, and antitumor activity across multiple preclinical models, highlighting the therapeutic potential of this approach for both hematologic malignancies and solid tumors.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12943-025-02446-z.

When the World Health Organization (WHO) declared the global COVID-19 pandemic, it was recognised that patients with haematological cancers would be more susceptible to severe disease. Set within a UK population of ~4 million (https://hmrn.org/), all patients diagnosed with haematological neoplasms 2005-2019 who were alive on 1 January 2020 were followed up until March 2023. For comparative purposes, a similar age- and sex-matched general population cohort was also constructed. COVID-19 deaths were classified using ICD-10 codes and a multiple cause of death analysis was undertaken using a competing risk approach. Deaths of 486/18 883 haematology patients were attributed to COVID-19, yielding a cumulative incidence of 2.59% (95% confidence interval [CI]: 2.37-2.82) that was significantly higher than that of the general population (1.65; 95% CI: 1.58-1.72). In both cohorts, risks were higher in men, older people and those with co-morbidities. Within the patient cohort, excess mortality was largely concentrated in those suffering from more indolent conditions. Patients with the premalignancy MBL suffered from the highest excess mortality in the early phase of the pandemic when, unlike patients with malignancies, they were not advised to shield. Effects of shielding were evident and a clear vaccination benefit was demonstrated, with the exception of CLL and MCL; findings that warrant consideration in relation to other viruses.

In this study, we systematically compared early Al18F-FAPI-04 imaging performed at 15 and 30 minutes post-injection in patients with various types of cancer to determine whether an early imaging scan can fulfil the criteria for clinical diagnosis. The cohort comprised 101 patients with various cancer diagnoses who underwent Al18F-FAPI-04 PET/CT imaging at two time points: 15 and 30 minutes post-injection. Tracer uptake was assessed using SUVmax, SUVmean and TBR. In total, 560 lesions were detected among 101 patients (solid tumors: 466; hematologic neoplasms: 94), all of which were identified at both imaging time points. Between 15 and 30 minutes post-injection, the SUVmean of various organs decreased rapidly (the average ΔSUVmean for the brain, liver, and blood pool was -0.04, -0.07, and -0.21, respectively; P < 0.001). At the per-patient level, there was no significant difference in the SUVmax of tumor lesions. On a per-lesion basis, SUVmax remained largely consistent, showing no statistically significant variation. However, a higher TBR at 30 minutes was observed in liver cancer (4.14 vs. 4.54; P < 0.001), lymphoma (4.75 vs. 4.88; P = 0.043), and most metastatic tumor lesions. Al18F-FAPI-04 PET/CT imaging demonstrated remarkably stable tumor and background uptake with consistently high TBR. Both the tumor detection rate and lesion uptake were comparable at 15 and 30 minutes post-injection. Therefore, performing a FAPI-04 scan as early as 15 minutes post-injection appears feasible. Al18F-FAPI-04 PET/CT enables early imaging, significantly reducing patient waiting times.