Introduction Endothelial injury is a major contributor to morbidity and mortality in pediatric patients undergoing hematopoietic cell transplantation (HCT). It appears as sinusoidal obstruction syndrome (SOS) or transplant-associated thrombotic microangiopathy (TMA), among other conditions. Composite indices like the Endothelial Activation and Stress Index (EASIX) and its modified version (m-EASIX) may serve as accessible biomarkers for early identification. However, their utility in pediatric populations is unestablished. We aimed to explore whether EASIX and m-EASIX can help identify endothelial complications in this setting. Methods We conducted a prospective, single-center observational cohort study of 31 children and young adults undergoing HCT. Serial measurements of EASIX and m-EASIX scores, based on standard laboratory parameters, were collected at baseline and at multiple post-HCT time points (Days 0, 7, 14, 21, 28, and 100). Results Within 100 days after HCT, SOS and/or TMA developed in six patients. At Day 21, EASIX and m-EASIX scores were significantly higher in children with endothelial complications than in controls. The m-EASIX score also showed predictive value at Day 14. Receiver operating characteristic analysis showed discrimination at Day 21 for both scores (AUCs of 0.807 for EASIX and 0.865 for m-EASIX). Changes from baseline to Day 21 further improved accuracy, with thresholds achieving high sensitivity for screening patients at increased risk of SOS and/or TMA. The Day 21 landmark is most relevant for identifying patients at risk of later-onset or persistent endothelial injury, which remains clinically significant. Conclusions Our findings suggest that EASIX and m-EASIX may serve as practical and dynamic biomarkers for detecting endothelial injury in pediatric HCT recipients. The observation that Day 21 scores and their changes from baseline correlate with later complications highlights a potential window for risk stratification. However, these results should be interpreted cautiously, given the single-center design and limited sample size. Further research is needed to confirm whether these indices can reliably guide clinical decisions across diverse settings. Exploring their use in populations where reduced-intensity conditioning (RIC) and alternative donors are standard could provide important insights. Multicenter studies will be essential to validate these preliminary observations and refine biomarker-based strategies for post-HCT care.

Gancao decoction ameliorated senecionine-induced Hepatic Sinusoidal Obstruction Syndrome in mice by inhibiting NET formation and senecionine bioactivation in liver.

Children with non-malignant hematological disorders (NMHD) often require numerous red blood cell transfusions prior to hematopoietic stem cell transplant (HSCT), leading to iron overload. Ferritin and liver iron concentration (LIC) are used to estimate the degree of iron overload to determine eligibility for HSCT, but neither marker has been definitively associated with poorer HSCT outcomes in pediatric cohorts. We conducted a multicenter retrospective cohort study using PEDSnet to examine the association between elevated pre-HSCT ferritin and LIC and HSCT outcomes, and to evaluate iron reduction therapy post-transplant. 580 patients with a pre-HSCT ferritin and 260 patients with a pre-HSCT LIC were studied. Patients with high pre-HSCT ferritin >2500 ng/mL had decreased 3-year overall survival (adjusted HR 2.31, 1.06-5.04). A sensitivity analysis demonstrated this trend only in patients with severe aplastic anemia (SAA). Elevated ferritin was associated with a markedly increased risk of bacteremia after HSCT in patients with SAA (HR 3.33, 1.72 - 6.44). Elevated pre-HSCT LIC >5 mg Fe/g dry weight was not associated with decreased survival, bacteremia, graft failure, or veno-occlusive disease (VOD). VOD was assessed only in patients undergoing busulfan-based transplant. Post-transplant, 63% of patients in the multicenter analysis had an elevated ferritin, while 68% had an elevated LIC. Chelation and phlebotomy were equally effective in reducing post-HSCT iron. These results challenge the use of LIC as the gold standard for iron-related risk stratification in HSCT. Further research into peri-HSCT iron management is necessary in an era of expanding availability of HSCT for NMHD.

Hepatic sinusoidal obstruction syndrome (HSOS) is a disease characterized by damage to hepatic sinusoidal endothelial cells (HSECs). This research investigates the role and regulatory pathway of PU box-binding protein (PU.1) in the progression of HSOS. We established an in vivo HSOS model through peritoneal administration of monocrotaline (MCT). Primary murine HSECs were isolated and treated with various concentrations of MCT to establish an in vitro HSOS model. PU.1 knockdown was achieved using lentiviral shRNA constructs, and its impact on oxidative stress, PTBP1 expression, β-catenin mRNA stability, and Wnt/β-catenin signaling was evaluated through kits, RT-qPCR, and western blot. Dual-luciferase and chromatin immunoprecipitation assays were conducted to assess the interaction between PU.1 and the PTBP1 promoter. The molecular association between PTBP1 and β-catenin mRNA was confirmed through RNA pull-down and RIP assays. PU.1 was upregulated in MCT-induced HSOS, contributing to elevated oxidative stress and activation of the Wnt/β-catenin pathway. PU.1 directly enhanced PTBP1 transcription, which stabilized β-catenin mRNA and sustained Wnt/β-catenin signaling. PU.1 knockdown alleviated oxidative stress, reduced liver damage, and disrupted the PTBP1-β-catenin interaction, leading to Wnt/β-catenin activity inhibition. Overexpression of PTBP1 reversed the protective effects of PU.1 knockdown, reinstating oxidative stress and reactivating Wnt/β-catenin signaling. PU.1 facilitated HSOS pathogenesis by promoting the transcriptional activity of PTBP1 and activating the Wnt/β-catenin pathway. Targeting PU.1 can serve as a promising therapeutic strategy for reducing oxidative stress and liver damage in HSOS.

Our goal was to identify new environmental or genetic causes in heritable pulmonary arterial hypertension (HPAH) families outside the 18 known diagnostics PAH genes. PAH gene panel sequencing was performed for 47 HPAH families which revealed pathogenic variants in 39 families. Five of the remaining families agreed to whole exome sequencing and to fill in a drug and toxin exposure questionnaire. In Family 1 and 2, mother and daughter with HPAH carried a likely pathogenic variant in the CYBA gene and a variant of uncertain significance in the FKBP1A gene, respectively, following ACMG guidelines. In Family 3, we detected a likely pathogenic variant in the PTGR2 gene. These genes could play part in PAH pathogenesis but further functional analyses are required to corroborate these findings. In the remaining two families, we could not identify any plausible genetic cause. However, a father and son with PAH reported exposure to trichloroethylene, asbestos and tramadol in Family 4. In Family 5, two brothers with pulmonary veno-occlusive disease showed occupational toxin exposure. Thus, our findings indicate that not only a genetic predisposition but also environmental triggers should be investigated for HPAH patients.

We present the case of an 83-year-old woman with a long-standing history of rheumatoid arthritis (RA) who was found collapsed at home. The patient presented with cardiopulmonary arrest and could not be resuscitated. A postmortem examination was performed to determine the cause of death. Postmortem computed tomography (CT) ruled out intracranial hemorrhage but revealed diffuse bilateral pulmonary consolidations and signs of bronchial obstruction. The autopsy revealed severe pulmonary edema and marked right ventricular hypertrophy. Microscopic examination of the lungs demonstrated characteristic features of pulmonary veno-occlusive disease (PVOD), including widespread fibrous intimal thickening and occlusion of small pulmonary veins and venules. Notably, there was no evidence of RA-associated interstitial lung disease (ILD). The direct cause of death was identified as pulmonary edema secondary to PVOD. This case highlights that PVOD can occur in patients with RA as a distinct pathological entity, independent of ILD. This finding is significant as it contrasts with previous reports where PVOD was associated with ILD. Therefore, clinicians should consider PVOD in the differential diagnosis of RA patients who present with unexplained pulmonary hypertension or progressive dyspnea, even in the absence of interstitial lung disease.

Epigenetic modifications, particularly DNA methylation, are strongly associated with chronological age across mammalian species. This study developed cheetah-specific epigenetic clocks from methylation profiles generated from cheetah blood and liver samples tested on the HorvathMammalMethylChip40 Illumina Array. The resulting age clock used 52 CpG sites and predicted age across blood and liver samples (r = 0.97 and MAE = 0.86). When applied to a test set of blood collected from live cheetahs, the clock provided accurate predictions for adult individuals (age > 3 years) but was less precise at and around age of sexual maturity. A second clock, incorporating cheetah, lion, and tiger profiles, used 46 CpG sites and predicted age across these feline species (r = 0.94 and MAE = 1.16). Additionally, a sex clock using 67 CpG sites accurately predicted sex in all test samples. To explore the potential of methylation as a biomarker beyond age and sex, we conducted a differential methylation analysis to investigate disease-related methylation patterns in cheetahs diagnosed with hepatic sinusoidal obstruction syndrome (SOS). This analysis identified 4,377 CpG sites with significant differences between SOS-positive and SOS-negative cheetahs (adjusted p-value < 0.05). These findings advance the development of epigenetic clocks for precise age and sex prediction in cheetahs and related species and establish a foundation for leveraging methylation biomarkers to investigate diseases in wildlife conservation efforts.

Among patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL), those who failed to respond to CD19-directed immunotherapies, there are limited options available pre-HSCT. This study aimed to evaluate the efficacy and safety of Inotuzumab ozogamicin (InO) as the definitive treatment pre-HSCT in patients with R/R B-cell B-ALL. Sixteen patients were enrolled, ten of whom failed treatment with prior CD19-directed immunotherapies, and two of whom relapsed after first HSCT. All patients achieved morphologic complete remission; 13 patients achieved negative measurable residual disease after InO. After bridging to HSCT, the 1-year probabilities of leukemia-free survival and overall survival were 66.5% and 80.8%. One patient developed sinusoidal obstruction syndrome post-HSCT. The prognosis for patients with R/R B-ALL, particularly those who do not respond to prior immunotherapies, is very poor. InO serves as an effective and safe bridging therapy prior to HSCT.

Tranexamic acid to prevent bleeding in patients with hematologic malignancies and hypoproliferative thrombocytopenia: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

Introduction Severe combined immunodeficiencies (SCIDs) lead to early death from overwhelming infection, usually in the first year of life. Haploidentical transplantation should be considered when there are no matched related donors for its immediate donor availability and when any delays may lead to catastrophic results. Method Retrospective study including patients with SCID receiving their first hematopoietic cell transplantation (HCT) using a haploidentical donor in 6 Latin American transplant centers. Results At a median age of 9.3 months, 52 SCID patients were transplanted between 04/2011 and 06/2024. Bone marrow was the stem cell source in 86% and the father was the donor in 76% of all transplants. A total of 49 patients received a conditioning regimen, the majority being busulfan-based (81%). The 1-year and 2-year overall survival (OS) were 70% and 64.2%, respectively. At 100 days, cumulative incidence (CI) of acute graft versus host disease (GVHD) was 19.2% and, at 2 years, CI of chronic GVHD was 8.3%. The CI of CMV reactivation was 35.4% at a median of 25 days after transplant. Severe hepatic sinusoidal obstruction syndrome (SOS) was observed in one quarter of the cases (27%), all in the busulfan group. Twenty-one patients died, with 8 very early deaths (before day +28), seven due to infection and one due to SOS. In the conditioned group, there were 4 graft failures (1 primary and 3 secondary), 2 successfully rescued with a second procedure, and 2 deaths related to CMV infection. Mixed chimerism was frequent (46%) and led to an inability to stay off intravenous immunoglobulin (IGIV) after transplant in 30% of patients. One patient was later found to be FOXN1 mutated, currently expecting a thymus transplantation. Conclusions Haploidentical transplants are feasible and, considering the late diagnosis and active infection on admission, our OS was good. Earlier diagnosis through newborn screening and intensive infection prevention/treatment may allow for better outcomes in the future.

Abstract Gastrointestinal bleeding is relatively common in children. While most patients present with mild bleeding, gastric antral vascular ectasia (GAVE) is a rare but potentially life‐threatening cause. GAVE is typically associated with chronic conditions and more common in adults. The incidence, diagnosis, and management of GAVE in the pediatric population have not been established. We present two cases of GAVE with severe and chronic gastrointestinal bleeding. The first patient, a 7‐year‐old with chronic granulomatous disease who had melena and anemia following hematopoietic stem cell transplantation (HSCT). Endoscopic intervention with argon plasma coagulation (APC) was successful in achieving hemostasis. The second patient, an 18‐year‐old with veno‐occlusive disease (VOD), developed GAVE as a result of portal hypertension. Endoscopic intervention with APC successfully controlled the bleeding in this patient as well. These cases highlight the challenges associated with diagnosing and managing GAVE in children.

Systemic juvenile idiopathic arthritis (SJIA) is a chronic inflammatory disease characterized by systemic features and arthritis. Macrophage activation syndrome (MAS) is a severe complication of SJIA often involving the liver. MAS confined predominantly to the liver, causing severe hepatitis, has been increasingly recognized. When liver MAS is the primary manifestation, significant hepatic injury can occur, requiring differentiation from other forms of SJIA-related liver involvement, which may warrant distinct treatment approaches. This study examined liver pathology in SJIA-MAS patients and explored potential mechanisms. This retrospective case series analyzed data from four SJIA-MAS patients who presented with liver dysfunction and underwent core liver biopsies at Cincinnati Children's Hospital Medical Center (2019-2024). Four patients (age range 4 -15 years) had elevated transaminases, with one meeting MAS criteria and three diagnosed with subclinical MAS. Liver biopsies showed portal and sinusoidal inflammatory infiltrates of CD3+ CD8+ T cells and CD163+ macrophages, with extensive hepatocellular damage, including centrilobular parenchymal collapse, multifocal necrosis, and lymphocyte-mediated bile duct injury. One case revealed features of veno-occlusive disease (VOD), a novel finding. Elevated serum CXCL9 and rapid response to emapalumab (anti-IFNγ) in all patients suggested IFNγ-driven liver pathology. This study underscores the critical roles of CD8+ T cells, macrophages, and IFNγ in SJIA-MAS hepatitis. Future research should explore whether serum biomarkers of IFNγ activity can differentiate SJIA-MAS from other liver pathologies, such as drug-induced liver injury (methotrexate or anakinra-induced) and hepatic steatosis, to guide tailored therapies.

Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy have transformed the treatment of hematologic malignancies, with expanding applications in selected solid tumors and nonmalignant hematologic conditions, but are frequently complicated by kidney dysfunction. Acute and chronic kidney disease after HSCT are often multifactorial, with several unique causes such as capillary leak syndrome, sinusoidal obstruction syndrome, transplant-associated thrombotic microangiopathy, and post-transplant nephrotic syndrome playing important roles. Key drivers of CAR T-cell therapy-related kidney disease include sepsis, cytokine release syndrome, and tumor lysis syndrome. Understanding of these injury mechanisms is critical to optimizing prevention, early detection, and management of kidney complications in these populations, with the overall goals of improving kidney and overall outcomes.

Pulmonary veno-occlusive disease: Insights from animal models.

Introduction. Signs of pulmonary veno-occlusive disease (PVOD) may be found in patients with pulmonary arterial hypertension (PAH), particularly in systemic sclerosis (SSc)¹. This association (PVOD/PAH) remains poorly characterized in SSc. We aimed to compare the clinical, echocardiographic and hemodynamic profile of patients with SSc-PAH with and without a concomitant diagnosis of PVOD, and their potential response to vasodilators. Materials and Methods. We retrospectively analyzed 23 patients with SSc-PAH diagnosed by right heart catheterization, followed at our center between 2017 and 2023. Data collected at diagnosis and after 12 months included clinical, laboratory, functional and imaging parameters. Multidisciplinary assessment allowed the identification of cases with clinical and radiological features suggestive of PVOD/PAH¹. Patients were divided into two groups (PVOD/PAH and non-PVOD/PAH) and data were compared at baseline and 12-month follow-up. Results. Twenty-three patients with SSc-PAH were enrolled in the study, of whom 6 (26%) had signs of PVOD/PAH. At PAH diagnosis, PVOD/PAH patients had higher values of mean pulmonary arterial pressure compared to non-PVOD/PAH (47.5±5.3 vs. 36.7±8.8 mmHg, p=0.011), but similar pulmonary vascular resistance. Age, sex, cardiovascular risk factors, SSc features, echo findings as well as cardiac biomarker values were similar between the two groups (Table 1). At follow-up, most PVOD/PAH patients (67%) were on monotherapy with endothelin receptor antagonists (ERA), and 33% on dual therapy (ERA + phosphodiesterase inhibitors). Only one case of pulmonary edema was recorded. In the non-PVOD/PAH group, most patients (53%) were on dual vasodilator therapy. On echocardiography, PVOD/PAH patients showed higher tricuspid regurgitation velocity (4.10±0.68 vs. 3.07±0.91 m/s; p=0.035) and worse right ventricular function (FAC 25.6±8.4% vs. 33.9±6.8%; p=0.046). Changes in NT-proBNP levels from baseline differed between groups (p=0.012), showing a trend toward increase in PVOD/PAH (p=0.076) and reduction in non-PVOD/PAH (p=0.069). At 12 months, 5 hospitalizations for heart failure in each group, and a total of 5 deaths (2 PVOD/PAH and 3 non-PVOD/PAH) were recorded, with similar event-free survival (p=0.101). Conclusions. PVOD is frequently associated with PAH in SSc and does not seem to be associated with specific SSc features. Vasodilators, at least on monotherapy, should be considered in PVOD/PAH, as they seem to be well tolerated. Nevertheless, at follow-up these patients exhibit unfavorable laboratory and echo profiles compared to those with SSc-PAH alone, highlighting the importance of early referral for lung transplantation.

PurposeComplications such as graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome, and infections compromise the success of allogeneic hematopoietic stem cell transplantation (HSCT) as a treatment modality for malignant or genetic diseases. Identification of beneficial non-human leukocyte antigens (HLA), such as cytokines, is one approach to reduce the rate of unintended events. This study investigated the association between single-nucleotide polymorphisms (SNPs) of the gene of the proinflammatory cytokine interleukin-1 (IL-1) and treatment outcomes after allogeneic HSCT in a pediatric population.MethodsIn our single-center study, we retrospectively analyzed a cohort of 270 children and their respective donors. They underwent allogeneic HSCT for the first time, and their conditioning regimen was myeloablative in all cases. We used polymerase chain reaction to genotype the SNPs of IL-1α rs1800587 (C > T), IL-1β rs16944 (C > T), and IL-1β rs1143627 (C > T). The outcome measures included overall survival (OS), event-free survival (EFS), relapse rate (RR), transplant-related mortality (TRM), and the occurrence of acute or chronic GVHD.ResultsThe distribution of IL-1α rs1800587 genotype was as follows: we observed the CC genotype in 124 of 256 recipients (48.4%) and 132 of 270 donors (48.9%). We detected the CT genotype in 115 patients (44.9%) and 114 donors (42.2%) and found the homozygous TT genotype in 17 children (6.6%) and 24 of their donors (8.9%). The distribution of the SNP IL-1α rs1800587 is in Hardy-Weinberg equilibrium. The incidence of moderate or severe acute GVHD was significantly decreased in recipients receiving a donor transplant with the TT genotype (4% (TT) versus 25% (CC/CT); p = 0.028). We found no significant SNP IL-1α rs1800587 (C > T) associations for chronic GVHD, RR, TRM, EFS, and OS. For the other genotypes analyzed, IL-1β rs11644 (C > T) and IL-1β rs1143627 (C > T), we also found no significant associations for acute and chronic GVHD, RR, TRM, EFS, and OS, neither in donors nor in recipients. The results of the multivariate analysis revealed a hazard ratio of 0.17 (confidence interval 0.0229-1.27), and a trend that IL-1α rs1800587 could be an independent risk factor for acute GVHD (p = 0.084).ConclusionOur study identified the donor IL-1α rs1800587 CC/CT genotype as a possible genetic risk factor for developing moderate to severe acute GVHD (grade II - IV) in pediatric patients who underwent allogeneic HSCT. Once confirmed in further studies, these results may influence the donor selection and prophylaxis to decrease the risk of acute GVHD in children.

Pulmonary arterial hypertension (PAH) is a rare and incurable disease characterized by progressive narrowing of pulmonary arteries (PA), resulting in right ventricular (RV) hypertrophy, RV failure, and eventually death. Orai1 inhibition has emerged as promising therapeutic approach to mitigate PAH. In this study, we investigated the efficacy of a clinically applicable selective Orai1 inhibitor, CM5480, and its effects when combined with standard PAH therapies in a preclinical PAH model. In male and female monocrotaline PAH-rats, CM5480 monotherapy improved hemodynamics, PA, and RV remodeling, as confirmed by RV catheterization, echocardiography, histology, and unbiased RNA-Seq. Standard PAH therapies, ambrisentan or sildenafil, achieved modest improvements in experimental PAH. In contrast, combination therapies with CM5480 yielded significantly greater benefits in reducing PA remodeling and improving cardiac function compared with monotherapies. Furthermore, in vitro experiments showed that Orai1 knockdown reduced pulmonary endothelial cell dysfunction in PAH and that the Orai1 pathway is independent of standard PAH-targeted pathways in PA smooth muscle cells (PASMCs). Finally, we found enhanced Orai1 expression/function in PASMCs and pulmonary vein SMCs from patients with pulmonary veno-occlusive disease. These findings suggest that Orai1 inhibition represents a potentially novel and complementary therapeutic strategy for PAH by acting at pulmonary vascular and RV levels.

Integrated multi-omics study identifies ursolic acid as a novel therapeutic agent targeting the TNF-α/TAK1/IKKβ/NF-κB axis in hepatic sinusoidal obstruction syndrome

A novel prognostic model for predicting mortality in adults with sickle cell disease and severe sinusoidal obstruction syndrome

A real-world multi-institution experience of standard vs alternative dosing of inotuzumab ozogamicin for Relapsed/Refractory pediatric B-cell acute lymphoblastic leukemia