Long-term parental distress after pediatric hematopoietic stem cell transplantation for nonmalignant diseases

BackgroundSurvival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high-intensity treatment, knowledge about long-term parental impact is lacking.ProcedureThis cross-sectional study assessed parental distress and everyday problems in parents of patients 2 years and older after pediatric HSCT for a nonmalignant disease using Distress Thermometer for Parents (DT-P), and compared outcomes to matched Dutch parents of healthy children and Dutch parents of children with a chronic condition (CC).ResultsMedian follow-up was 5.3 years (interquartile range [IQR]: 2.9-8.6). Underlying diseases were inborn errors of immunity (N = 30), hemoglobinopathies (N = 13), and bone marrow failure (N = 27). Mothers of pediatric HSCT recipients (N = 70) reported comparable overall distress levels to mothers of healthy children, but experienced more distress related to parenting problems, specifically managing their child's emotions, discussing disease consequences, and fostering independence. Fathers of HSCT recipients (N = 45) reported higher overall distress levels and had more emotional distress compared to fathers of healthy children.ConclusionsOverall, parental distress and everyday problems of parents of HSCT recipients are comparable to those of parents of children with CC. However, there is ongoing parental burden, both emotional and in parenting, long-term after HSCT compared to parents of healthy children, and the type of burden differs between mothers and fathers. These results indicate that individualized parental supportive care should not remain restricted to the acute hospitalization phase, but also be actively offered during long-term follow-up after pediatric HSCT.Transplantation and immunomodulatio

Immunoglobulin G fragment crystallizable glycosylation after hematopoietic stem cell transplantation is dissimilar to donor profiles

Immunoglobulin G (IgG) fragment crystallizable (Fc) N-glycosylation has a large influence on the affinity of the antibody for binding to Fcγ-receptors (FcγRs) and C1q protein, thereby influencing immune effector functions. IgG Fc glycosylation is known to be partly regulated by genetics and partly by stimuli in the microenvironment of the B cell. Following allogeneic hematopoietic stem cell transplantation (HSCT), and in the presence of (almost) complete donor chimerism, IgG is expected to be produced by, and glycosylated in, B cells of donor origin. We investigated to what extent IgG glycosylation in patients after transplantation is determined by factors of the donor (genetics) or the recipient (environment). Using an IgG subclass-specific liquid chromatography-mass spectrometry method, we analyzed the plasma/serum IgG Fc glycosylation profiles of 34 pediatric patients pre-HSCT and at 6 and 12 months post-HSCT and compared these to the profiles of their donors and age-matched healthy controls. Patients treated for hematological malignancies as well as for non-malignant hematological diseases showed after transplantation a lower Fc galactosylation than their donors. Especially for the patients treated for leukemia, the post-HSCT Fc glycosylation profiles were more similar to the pre-HSCT recipient profiles than to profiles of the donors. Pre-HSCT, the leukemia patient group showed as distinctive feature a decrease in sialylation and in hybrid-type glycans as compared to healthy controls, which both normalized after transplantation. Our data suggest that IgG Fc glycosylation in children after HSCT does not directly mimic the donor profile, but is rather determined by persisting environmental factors of the host

118: Co-transplanation of haploidentical mesenchymal stem cells to overcome graft dysfunction associated with parental haploidentical CD34 postive selected peripheral stem cell grafts

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Combining mobilizing agents with busulfan to reduce chemotherapy-based conditioning for hematopoietic stem cell transplantation

In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient's diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Automating outcome analysis after stem cell transplantation: the YORT tool

Hematopoietic stem cell transplantation is a high-risk procedure. Auditing and yearly outcome reviews help keep optimal quality of care and come with increased survival, but also has significant recurring costs. When data has been entered in a standardized registry, outcome analyses can be automated, which reduces work and increases standardization of performed analyses. To achieve this, we created the Yearly Outcome Review Tool (YORT), an offline, graphical tool that gets data from a single center EBMT registry export, allows the user to define filters and groups, and performs standardized analyses for overall survival, event-free survival, engraftment, relapse rate and non-relapse mortality, complications including acute and chronic Graft vs Host Disease (GvHD), and data completeness. YORT allows users to export data as analyzed to allow you to check data and perform manual analyses. We show the use of this tool on a two-year single-center pediatric cohort, demonstrating how the results for both overall and event-free survival and engraftment can be visualized. The current work demonstrates that using registry data, standardized tools can be made to analyze this data, which allows users to perform outcome reviews for local and accreditation purposes graphically with minimal effort, and help perform detailed standardized analyses. The tool is extensible to be able to accommodate future changes in outcome review and center-specific extensions.Transplantation and immunomodulatio

Predicting patient death after allogeneic stem cell transplantation for inborn errors using machine learning (PREPAD): a European society for blood and marrow transplantation inborn errors working party study

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many inborn errors of immunity, metabolism, and hematopoiesis. No predictive models are available for these disorders. We created a machine learning model using XGBoost to predict survival after HSCT using European Society for Blood and Marrow Transplant registry data of 10,888 patients who underwent HSCT for inborn errors between 2006 and 2018, and compared it to a simple linear Cox model, an elastic net Cox model, and a random forest model. The XGBoost model had a cross-validated area under the curve value of .73 at 1 year, which was significantly superior to the other models, and it accurately predicted for countries excluded while training. It predicted close to 0% and >30% mortality more often than other models at 1 year, while maintaining good calibration. The 5-year survival was 94.7% in the 25% of patients at lowest risk and 62.3% in the 25% at highest risk. Within disease and donor subgroups, XGBoost outperformed the best univariate predictor. We visualized the effect of the main predictors-diagnosis, performance score, patient age and donor type-using the SHAP ML explainer and developed a stand-alone application, which can predict using the model and visualize predictions. The risk of mortality after HSCT for inborn errors can be accurately predicted using an explainable machine learning model. This exceeds the performance of models described in the literature. Doing so can help detect deviations from expected survival and improve risk stratification in trials.(c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Transplantation and immunomodulatio

Late effects in pediatric allogeneic hematopoietic stem cell transplantation for nonmalignant diseases: proxy- and patient-reported outcomes

Survival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and treatment of infections and graft-versus-host disease. Insight into the long-term patient-reported outcomes (PROs) after pediatric HSCT for nonmalignant disease is lacking but essential for optimal shared decision making, counseling, and quality of care. The purpose of this research was to determine long-term patient-reported outcomes in allogeneic pediatric HSCT for nonmalignant diseases and to compare these results with Dutch reference data. This single-center cohort study evaluated PROs (PedsQL 4.0, PROMIS item banks), self- or proxy-reported, among patients at >= 2 years after pediatric allogeneic HSCT for nonmalignant disease. Mean scores were compared with those of the Dutch general population. Of 171 eligible patients, 119 participated, for a 70% response rate. The median patient age was 15.8 years (range, 2 to 49 years), and the median duration of follow-up was 8.7 years (range, 2 to 34 years). Indications for HSCT included inborn errors of immunity (n = 41), hemoglobinopathies (n = 37), and bone marrow failure (n = 41). Compared with reference data, significantly lower scores were found in adolescents (age 13 to 17 years) on the Total, Physical Health, and School Functioning PedsQL subscales. Significantly more Sleep Disturbance was reported in children (age 8 to 18 years). On the other hand, significantly better scores were seen on PROMIS Fatigue (age 5 to 7 years) and Pain Interference (age 8 to 18 years) and, in adults (age 19 to 30 years), on Depressive Symptoms and Sleep Disturbance. This study showed better or comparable very long-term PROs in patients after pediatric HSCT for nonmalignant diseases compared with the reference population. Children and adolescents seem to be the most affected, indicating the need for supportive care to prevent impaired quality of life and, more importantly, to amplify their long-term well-being. (c) 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Metabolic health: pathophysiological trajectories and therap

Clinical features, treatment, and outcome of pediatric steroid refractory acute graft-versus-host disease: a multicenter study

Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a severe complication in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to assess clinical course and outcomes of pediatric SR-aGvHD. We performed a retrospective nationwide multicenter cohort study in the Netherlands. All patients aged 0 to 18 years who underwent transplantation between 2010 and 2020 with SR-aGvHD were included. For each patient, weeldy clinical aGvHD grade and stage, immunosuppressive treatment and clinical outcomes were collected. The primary study endpoint was the clinical course of SR-aGvHD over time. As a secondary outcome, factors influencing overall survival and SR-aGvHD remission were identified using a multistate Cox model. 20% of transplanted children developed grade II-IV aGvHD, of which 51% (n = 81) was SR-aGvHD. In these patients, second-line therapy was started at a median of 8 days after initial aGvHD-diagnosis. Forty-nine percent of SR-aGvHD patients received 3 or more lines of therapy. One year after start of second-line therapy, 34 patients (42%) were alive and in remission of aGvHD, 14 patients (17%) had persistent GvHD, and 33 patients (41%) had died. SR-aGvHD remission rate was lower in cord blood graft recipients than in bone marrow (BM) or peripheral blood stem cell (PBSC) recipients (hazard ratio [HR] = 0.51, 0.27-0.94, P = .031). Older age was associated with higher mortality (HR = 2.62, 1.04-6.60, P = .04, fourth quartile [aged 13.9-17.9] versus first quartile [aged 0.175-3.01]). In BM/PBSC recipients older age was also associated with lower remission rates (HR = 0.9, 0.83-0.96, P = .004). Underlying diagnosis, donor matching or choice of second-line therapy were not associated with outcome. Respiratory insufficiency caused by pulmonary GvHD was a prominent cause of death (26% of deceased). Our study demonstrates that SR-aGvHD confers a high mortality risk in pediatric HSCT. Older age and use of CB grafts are associated with an unfavorable outcome. Multicenter studies investigating novel treatment strategies to prevent pediatric SR-aGvHD and inclusion of children in ongoing trials, together with timely initiation of second-line interventions are pivotal to further reduce GvHD-related mortality. (C) 2022 The American Society for Transplantation and Cellular Therapy.Transplantation and immunomodulatio

Modeling influencing factors in B-cell reconstitution after hematopoietic stem cell transplantation in children

Reduced total and memory B-cell numbers in peripheral blood long term after hematopoietic stem cell transplantation (HSCT) are associated with an increased incidence of infections and immune complications. Using novel modelling strategies, baseline factors influencing B-cell reconstitution can be comprehensively studied. This study aims to investigate the numerical total and memory B-cell reconstitution in children and the association with baseline determinants 0.5-2 years after allogeneic HSCT. Eligible for inclusion were children transplanted in our center between 2004-2017 who received a first HSCT for malignant or non-malignant disorders. The continuous absolute counts of total and memory B-cells were evaluated as outcome measure. Exploratory analysis at one year was done to identify possible determinants. Linear mixed effect modelling was used to analyze the association of these determinants with total and memory B-cell reconstitution 0.5-2 years after HSCT. In a cohort of 223 evaluable patients analyzed at 1-year after HSCT donor age, stem cell source, donor type, recipient age and conditioning were identified as significant determinants for total and memory B-cell numbers. Multivariable analysis revealed that both donor and recipient age were inversely correlated with the size of total and memory B-cell reconstitution. In contrast, no correlation was found with stem cell source, donor type and conditioning. Making use of linear mixed modelling both stem cell donor and recipient age were identified as independent determinants of total and memory B-cell reconstitution 0.5-2 years after HSCT.Development and application of statistical models for medical scientific researc

The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease

UNLABELLED BACKGROUND Chemokine receptor CXCR4, together with its ligand CXCL12, plays critical roles in cancer progression, including growth, metastasis and angiogenesis. Ewing sarcoma is a sarcoma with poor prognosis despite current therapies, particularly for patients with advanced-stage disease. Lungs and bone (marrow), organs of predilection for (primary/metastatic) Ewing sarcoma, represent predominant CXCL12 sources. METHODS To gain insight into the role of the CXCR4-CXCL12 axis in Ewing sarcoma, CXCR4, CXCL12 and hypoxia-inducible factor-1α protein expression was studied in therapy-naïve and metastatic tumors by immunohistochemistry. CXCR4 function was assessed in vitro, by flow cytometry and proliferation/ cell viability assays, in the presence of recombinant CXCL12 and/or CXCR4-antagonist AMD3100 or under hypoxic conditions. RESULTS Whereas CXCR4 was predominantly expressed by tumor cells, CXCL12 was observed in both tumor and stromal areas. Survival analysis revealed an (expression level-dependent) negative impact of CXCR4 expression (p < 0.04). A role for the CXCR4-CXCL12 axis in Ewing sarcoma growth was suggested by our observations that i) CXCR4 expression correlated positively with tumor volume at diagnosis (p = 0.013), ii) CXCL12 was present within the microenvironment of virtually all cases, iii) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines, which could be abrogated by AMD3100. CXCR4 expression was not correlated with occurrence of metastatic disease. Also, therapy-naïve tumors demonstrated higher CXCR4 expression as compared to metastases (p = 0.027). Evaluation of in vivo hypoxia-inducible factor-1α expression and culture of cells under hypoxic conditions revealed no role for hypoxia in CXCR4 expression. CONCLUSIONS Together, our results imply a crucial role for the CXCR4-CXCL12 axis in auto- and/or paracrine growth stimulation. Integration of CXCR4-targeting strategies into first- and/or second-line treatment regimens may represent a promising treatment option for Ewing sarcoma.Molecular tumour pathology - and tumour genetic