Gut diversity and the resistome as biomarkers of febrile neutropenia outcome in paediatric oncology patients undergoing hematopoietic stem cell transplantation.

The gut microbiota of paediatric oncology patients undergoing a conditioning regimen before hematopoietic stem cell transplantation is recently considered to play role in febrile neutropenia. Disruption of commensal microbiota and evolution of opportune pathogens community carrying a plethora of antibiotic-resistance genes play crucial role. However, the impact, predictive role and association of patient´s gut resistome in the course of the therapy is still to be elucidated. We analysed gut microbiota composition and resistome of 18 paediatric oncology patients undergoing hematopoietic stem cell transplantation, including 12 patients developing febrile neutropenia, hospitalized at The Bone Marrow Transplantation Unit of the National Institute of Children´s disease in Slovak Republic and healthy individuals (n = 14). Gut microbiome of stool samples obtained in 3 time points, before hematopoietic stem cell transplantation (n = 16), one week after hematopoietic stem cell transplantation (n = 16) and four weeks after hematopoietic stem cell transplantation (n = 14) was investigated using shotgun metagenome sequencing and bioinformatical analysis. We identified significant decrease in alpha-diversity and nine antibiotic-resistance genes msr(C), dfrG, erm(T), VanHAX, erm(B), aac(6)-aph(2), aph(3)-III, ant(6)-Ia and aac(6)-Ii, one week after hematopoietic stem cell transplantation associated with febrile neutropenia. Multidrug-resistant opportune pathogens of ESKAPE, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli found in the gut carried the significant subset of patient's resistome. Over 50% of patients treated with trimethoprim/sulfamethoxazole, piperacillin/tazobactam and amikacin carried antibiotic-resistance genes to applied treatment. The alpha diversity and the resistome of gut microbiota one week after hematopoietic stem cell transplantation is relevant predictor of febrile neutropenia outcome after hematopoietic stem cell transplantation. Furthermore, the interindividual diversity of multi-drug resistant opportunistic pathogens with variable portfolios of antibiotic-resistance genes indicates necessity of preventive, personalized approach.

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Hybrid solder joints: the effect of nanosized ZrO2 particles on morphology of as-reflowed and thermally aged Sn-3.5Ag solder joints.

The main number of current researches has been focused on the microstructure and mechanical properties of the Sn-based Sn-Ag-Cu-based solders, while various kinds of nanosized particles have been added. The synthesis and handling of ceramic nanosized powder are much easier than of metal nanoparticles. In addition, metal nanoparticles solved in solder joints during the soldering process or by thermal aging could behave as an alloying element similar to bulk metal additions, while ceramic nanoparticles retain their chemically inactive behavior in various thermal, thermo-mechanical, and electrical constraints. In some cases, the solved metal nanosized inclusions could increase the growth kinetics of the present intermetallic phases or even create new phases, which leads to more complexity in the predictions and simulations of chemical processes in the solder joints. Based on the assertions mentioned above, ceramic nanosized particles are industrially more favorable as reinforcing inclusions. On the other hand, there is no direct comparison in the literature between Sn-based Sn-Ag-Cu and Sn-Ag solder joints with similar ceramic nanoinclusions based on microstructural features and mechanical properties. In the present research, the Cu/flux + NPs/SAC/flux + NPs/Cu solder joints were produced with a nominal amount of 0.2 wt%, 0.5 wt%, and 1.0 wt% nanosized ZrO2 powder. The solder joints prepared via the above-described method are called in the literature as hybrid solder joints. The microstructure of the as-reflowed and thermally aged samples has been studied, especially at the interface solder/substrate. It has been shown that the minor additions of ZrO2 NPs lead to a decrease in the thickness of the Cu6Sn5 interfacial layer in the as-reflowed solder joints and a reduction in the growth kinetics of this layer, while the Cu3Sn interfacial IMC layer remains practically unaffected. Similar investigations were performed in our previous study but for both the hybrid and nanocomposite Sn-3.0Ag-0.5Cu solder joints. A comparative analysis of the impact of the ZrO2 nanoinclusions on the hybrid solder joints using Sn-3.5Ag and Sn-3.0Ag-0.5Cu has been performed.

Metal deposited nanoparticles as "bridge materials" for lead-free solder nanocomposites.

An influence of carbon nanotubes and carbon nanospheres coated by Au-Pd and Pt on the microstructure of solder/copper joints at room temperature and after aging at sub-zero temperature. The carbon nanosized admixtures were mixed with ternary Sn3.0Ag0.5Cu matrix to prepare a composite solder. The microstructure of the solder joints between the nanocomposite solders and a copper substrate was studied by scanning electron microscopy. It was found that minor (0.05 wt. %) admixtures of both the carbon nanospheres and nanotubes increase the shear strength of the solder joints and reduce the growth rate of the intermetallic Cu6Sn5 layer, formed at the interface between solder and copper. This effect may be related to the adsorption of nanoinclusions on the grain surface during the solidification process. Comparative analysis suggests that exposure for 2 months at 253 K does not lead to deterioration of such an important mechanical characteristic of the solder joint as shear strength, indicating the possibility of using these nanocomposite solders in microelectronic equipment even at temperatures below 0 ℃.

High Diversity but Monodominance of Multidrug-Resistant Bacteria in Immunocompromised Pediatric Patients with Acute Lymphoblastic Leukemia Developing GVHD Are Not Associated with Changes in Gut Mycobiome.

Graft-versus-host disease (GvHD) is a severe complication after hematopoietic stem cell transplantation (HSCT). Our study focused on identifying multidrug-resistant (MDR) gut bacteria associated with GvHD-prone guts and association with gut microbiota (GM) diversity, bacteriome, and mycobiome composition in post-HSCT patients. We examined 11 pediatric patients with acute lymphoblastic leukemia (ALL), including six with GvHD, within three time points: seven days pre-HSCT, seven days post-, and 28 days post-HSCT. The gut microbiome and its resistome were investigated using metagenomic sequencing, taxonomically classified with Kraken2, and statistically evaluated for significance using appropriate tests. We observed an increase in the abundance of MDR bacteria, mainly Enterococcus faecium strains carrying msr(C), erm(T), aac(6')-li, dfrG, and ant(6)-la genes, in GvHD patients one week post-HSCT. Conversely, non-GvHD patients had more MDR beneficial bacteria pre-HSCT, promoting immunosurveillance, with resistance genes increasing one-month post-HSCT. MDR beneficial bacteria included the anti-inflammatory Bacteroides fragilis, Ruminococcus gnavus, and Turicibacter, while most MDR bacteria represented the dominant species of GM. Changes in the gut mycobiome were not associated with MDR bacterial monodominance or GvHD. Significant α-diversity decline (Shannon index) one week and one month post-HSCT in GvHD patients (p < 0.05) was accompanied by increased Pseudomonadota and decreased Bacteroidota post-HSCT. Our findings suggest that MDR commensal gut bacteria may preserve diversity and enhance immunosurveillance, potentially preventing GvHD in pediatric ALL patients undergoing HSCT. This observation has therapeutic implications.

Chemical-Dealloying-Derived PtPdPb-Based Multimetallic Nanoparticles: Dimethyl Ether Electrocatalysis and Fuel Cell Application.

In this work, we report a novel multimetallic nanoparticle catalyst composed of Pt, Pd, and Pb and its electrochemical activity toward dimethyl ether (DME) oxidation in liquid electrolyte and polymer electrolyte fuel cells. Chemical dealloying of the catalyst with the lowest platinum-group metal (PGM) content, Pt2PdPb2/C, was conducted using HNO3 to tune the catalyst activity. Comprehensive characterization of the chemical-dealloying-derived catalyst nanoparticles unambiguously showed that the acid treatment removed 50% Pb from the nanoparticles with an insignificant effect on the PGM metals and led to the formation of smaller-sized nanoparticles. Electrochemical studies showed that Pb dissolution led to structural changes in the original catalysts. Chemical-dealloying-derived catalyst nanoparticles made of multiple phases (Pt, Pt3Pb, PtPb) provided one of the highest PGM-normalized power densities of 118 mW mgPGM-1 in a single direct DME fuel cell operated at low anode catalyst loading (1 mgPGM cm-2) at 70 °C. A possible DME oxidation pathway for these multimetallic catalysts was proposed based on an online mass spectrometry study and the analysis of the reaction products.

The Importance of New EBMT Criteria on the Diagnosis of Veno-Occlusive Liver Disease in Children.

BACKGROUND: Early recognition and specific therapy facilitate a favorable disease course in hepatic venous-occlusive disease (HVOD) following hematopoietic stem cell transplantation (HCT). Diagnostic and classification criteria, published by the European Society for Blood and Marrow Transplantation (EBMT), better account for clinical differences in disease presentation in pediatric populations. OBJECTIVES: To compare the course of HVOD in children before and after the implementation of new EBMT criteria. MATERIAL AND METHODS: The study retrospectively evaluates 26 HVODs in 179 children treated in a single HCT unit (Slovakia) comparing the period of 2014-2017 using the Baltimore and modified Seattle criteria with the period of 2018-2021, when new EBMT criteria were adopted. RESULTS: No difference in HVOD incidence (11.2% vs. 14.8%, p = 0.46) and in time of diagnosis post-HCT (15.6 days vs. 15.7 days, p = 0.75) was found. With EBMT criteria we observed more frequent anicteric disease at diagnosis (50% vs. 87.5%, p = 0.04), lower serum bilirubin at diagnosis (3.4 mg/dL vs. 1.23 mg/dL, p = 0.045), and non-significant trends of shorter defibrotide treatment (21.7 days vs. 15.6 days, p = 0.73), decreased mortality (30% vs. 6.2%, p = 0.10) and shorter hospitalization (73.1 days vs. 59.6 days, p = 0.54). CONCLUSIONS: Different time periods around the implementation of new criteria are evaluated, underling that pediatric EBMT criteria for post-transplant HVOD diagnosis appear more sensitive.

Ni Porous Preforms Compacted with Al2O3 Particles and Al Binding Agent.

This work presents an energy-efficient, cheap, and rapid production method of a metal-ceramic preform with open porosity suitable for liquid metal infiltration and filtration applications. It is based on cold isostatic pressing of a mixture of relatively hard Ni and Al2O3 powders with the addition of small amount of Al powders, acting as a binding agent. Open porosity is primarily controlled by Al2O3 particles partially separating Ni particles from mutual contacts. Cold isostatic pressed green compacts were subjected to thermal oxidation by heating in air to 600 °C, 700 °C, and 800 °C. The weight gain and open porosity of oxidized compacts were examined. The chemical composition and microstructure were analyzed by SEM-EDS and XRD techniques. The stability of preforms and the effect of thermal cycling on the open porosity were tested by thermal cycling in an inert Ar atmosphere in the temperature range up to 800 °C. It appeared that, in addition to NiO being an expected product of oxidation, Ni aluminides and spinel particles also played an important role in inter-particle bonding formation. Ni-NiO porous composites resist chemical corrosion and exhibit structural and chemical stability at higher temperatures and admixed Al2O3 particles do not deteriorate them. After subsequent infiltration with Al, it can offer a lower density than other materials, which could result in lower energy consumption, which is highly needed in industries such as the automotive industry.

Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study.

Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.

Gut Microbiome Suffers from Hematopoietic Stem Cell Transplantation in Childhood and Its Characteristics Are Positively Associated with Intra-Hospital Physical Exercise.

Gut microbiome impairment is a serious side effect of cancer treatment. The aim of this study was to identify the effects of hematopoietic stem cell transplantation (HSCT) treatment on gut microbiota composition in children with acute lymphoblastic leukemia (ALL). Fecal microbiotas were categorized using specific primers targeting the V1-V3 region of 16S rDNA in eligible pediatric ALL patients after HSCT (n = 16) and in healthy controls (Ctrl, n = 13). An intra-hospital exercise program was also organized for child patients during HSCT treatment. Significant differences in gut microbiota composition were observed between ALL HSCT and Ctrl with further negative effects. Plasma C-reactive protein correlated positively with the pathogenic bacteria Enterococcus spp. and negatively with beneficial bacteria Butyriccocus spp. or Akkermansia spp., respectively (rs = 0.511, p = 0.05; rs = -0.541, p = 0.04; rs = -0.738, p = 0.02). Bacterial alpha diversity correlated with the exercise training characteristics. Therefore, specific changes in the microbiota of children were associated with systemic inflammation or the ability to exercise physically during HSCT treatment.

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia.

Total-body irradiation (TBI) based conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT) is generally regarded as the gold-standard for children >4 years of age with acute lymphoblastic leukaemia (ALL). Retrospective studies in the 1990's suggested better survival with irradiation, confirmed in a small randomised, prospective study in the early 2000's. Most recently, this was reconfirmed by the early results of the large, randomised, international, phase III FORUM study published in 2020. But we know survivors will suffer a multitude of long-term sequelae after TBI, including second malignancies, neurocognitive, endocrine and cardiometabolic effects. The drive to avoid TBI directs us to continue optimising irradiation-free, myeloablative conditioning. In chemotherapy-based conditioning, the dominant myeloablative effect is provided by the alkylating agents, most commonly busulfan or treosulfan. Busulfan with cyclophosphamide is a long-established alternative to TBI-based conditioning in ALL patients. Substituting fludarabine for cyclophosphamide reduces toxicity, but may not be as effective, prompting the addition of a third agent, such as thiotepa, melphalan, and now clofarabine. For busulfan, it's wide pharmacokinetic (PK) variability and narrow therapeutic window is well-known, with widespread use of therapeutic drug monitoring (TDM) to individualise dosing and control the cumulative busulfan exposure. The development of first-dose selection algorithms has helped achieve early, accurate busulfan levels within the targeted therapeutic window. In the future, predictive genetic variants, associated with differing busulfan exposures and toxicities, could be employed to further tailor individualised busulfan-based conditioning for ALL patients. Treosulfan-based conditioning leads to comparable outcomes to busulfan-based conditioning in paediatric ALL, without the need for TDM to date. Future PK evaluation and modelling may optimise therapy and improve outcome. More recently, the addition of clofarabine to busulfan/fludarabine has shown encouraging results when compared to TBI-based regimens. The combination shows activity in ALL as well as AML and deserves further evaluation. Like busulfan, optimization of chemotherapy conditioning may be enhanced by understanding not just the PK of clofarabine, fludarabine, treosulfan and other agents, but also the pharmacodynamics and pharmacogenetics, ideally in the context of a single disease such as ALL.

Pillar 3-Pre-processed web server log file dataset of the banking institution.

The dataset presented in this article represents the pre-processed web server log file of the commercial bank. The source of data is the web server of the bank and keeps access of web users starting the year 2009 till 2012. It contains accesses to the bank website during and after the financial crisis. Unnecessary data saved by the web server was removed to keep the focus only on the textual content of the website. Many variables were added to the original log file to make the analysis workable. To keep the privacy of website users, sensitive information in the log file were anonymized. The dataset offers a way to understand the behavior of stakeholders during and after the crisis and how they comply with the Basel regulations. The behavior of users can be modeled using the multinomial logit model, which is in detail described in the research article [1] related to this data article.

Methodology of stakeholders' behaviour modelling based on time.

The methods presented in this article were created to model and describe the behaviour of the web users of a bank institution web portal. The source dataset is represented by a log file of the commercial bank web server. The analysis is oriented on examining the behaviour of visitors over an extended period (2009-2012). The years 2009-2010 represent the years of the financial crisis, and the years 2011-2012 represent the years after the financial crisis. The following method describes the sequence of steps necessary to pre-process the raw log file and model the web user behaviour using the multinomial logit model. The introduced methods can be used also for other domains in the case of appropriate data preparation.•Data preparation- data cleaning, user/session identification, path completion, variables determination;•Data analysis- model definition, parameters estimation, logits estimation, probabilities estimation;•Results evaluation- comparison of empirical and theoretical values in term of counts, probabilities and logits.

What Is the Role of HSCT in Philadelphia-Chromosome-Positive and Philadelphia-Chromosome-Like ALL in the Tyrosine Kinase Inhibitor Era?

Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph+) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph+ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph+ ALL and Ph-like ALL less clear. The prognosis of patients with Ph+ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph+ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.

DUX4r, ZNF384r and PAX5-P80R mutated B-cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch.

Recently, we described B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with early switch to the monocytic lineage and loss of the B-cell immunophenotype, including CD19 expression. Thus far, the genetic background has remained unknown. Among 726 children consecutively diagnosed with BCP-ALL, 8% patients experienced switch detectable by flow cytometry (FC). Using exome and RNA sequencing, switch was found to positively correlate with three different genetic subtypes: PAX5-P80R mutation (5 cases with switch out of 5), rearranged DUX4 (DUX4r; 30 cases of 41) and rearranged ZNF384 (ZNF384r; 4 cases of 10). Expression profiles or phenotypic patterns correlated with genotypes, but within each genotype they could not identify cases who subsequently switched. If switching was not taken into account, the B-cell-oriented FC assessment underestimated the minimal residual disease level. For patients with PAX5-P80R, a discordance between FC-determined and PCR-determined MRD was found on day 15, resulting from a rapid loss of the B-cell phenotype. Discordance on day 33 was observed in all the DUX4r, PAX5-P80R and ZNF384r subtypes. Importantly, despite the substantial phenotypic changes, possibly even challenging the appropriateness of BCP-ALL therapy, the monocytic switch was not associated with a higher incidence of relapse and poorer prognosis in patients undergoing standard ALL treatment.

ABO incompatibile graft management in pediatric transplantation.

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG.

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13 ± 2% and 17 ± 4% (p = NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60 ± 2% vs. 42 ± 5%, p < 0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9 ± 1% vs. 23 ± 4%, p < 0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.

Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome.

PURPOSE: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies. EXPERIMENTAL DESIGN: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency. RESULTS: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10-5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); P < 0.0001]. CONCLUSIONS: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

PURPOSE: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.