Allogeneic Hematopoietic Stem Cell Transplantation in Immunodeficiency-Centromeric Instability-Facial Dysmorphism (ICF) Syndrome: an EBMT/ESID Inborn Errors Working Party Study.

Immunodeficiency-Centromeric instability-Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients.

Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells.

Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients who lack a suitable bone marrow donor, but developing such therapy for RAG1/2 has proven challenging.

Case report: Persistent hypogammaglobulinemia and mixed chimerism after HLA class-II disparate-hematopoietic stem cell transplant.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient's hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor.

Clinical phenotype of FOXP1 syndrome: parent-reported medical signs and symptoms in 40 individuals.

Background: The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications.

Methods: Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay.

Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect.

In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon.

Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study.

Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear.

Treosulfan-induced myalgia in pediatric hematopoietic stem cell transplantation identified by an electronic health record text mining tool.

Treosulfan is increasingly used as myeloablative agent in conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). In our pediatric HSCT program, myalgia was regularly observed after treosulfan-based conditioning, which is a relatively unknown side effect. Using a natural language processing and text-mining tool (CDC), we investigated whether treosulfan compared with busulfan was associated with an increased risk of myalgia.

Taking a Rational Approach to a Reported Antibiotic Allergy.

Up to 10% of hospitalized patients have an antibiotic allergy label in their medical file, most frequently concerning penicillins. However, the vast majority of reported allergies to antibiotics does not represent a "true" allergy but are due to drug intolerance, idiosyncratic reactions or symptoms of the concurrent infectious disease. Since antibiotic allergy labels result in deviation from first-choice antimicrobial therapy, tackling the issue of incorrect antibiotic allergy labelling, already at young age, is a core element of antibiotic stewardship.

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.

Seasonal Human Coronavirus Respiratory Tract Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT).

Methods: This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019.

Results: We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes.

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively.

Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID.

Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized to ensure optimal expression.

B Cell Reconstitution and Influencing Factors After Hematopoietic Stem Cell Transplantation in Children.

B cell reconstitution after hematopoietic stem cell transplantation (HSCT) is variable and influenced by different patient, donor, and treatment related factors. In this review we describe B cell reconstitution after pediatric allogeneic HST, including the kinetics of reconstitution of the different B cell subsets and the development of the B cell repertoire, and discuss the influencing factors. Observational studies show important roles for stem cell source, conditioning regimen, and graft vs.

Dynamics of the Gut Microbiota in Children Receiving Selective or Total Gut Decontamination Treatment during Hematopoietic Stem Cell Transplantation.

Bloodstream infections and graft-versus-host disease are common complications after hematopoietic stem cell transplantation (HSCT) procedures, associated with the gut microbiota that acts as a reservoir for opportunistic pathogens. Selective gut decontamination (SGD) and total gut decontamination (TGD) during HSCT have been associated with a decreased risk of developing these complications after transplantation. However, because studies have shown conflicting results, the use of these treatments remains subject of debate.

Expression of CCL21 in Ewing sarcoma shows an inverse correlation with metastases and is a candidate target for immunotherapy.

Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy.

CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients.

Purpose: Ewing sarcoma (EWS) is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. Our goal was to identify novel predictive biomarkers for these patients, focusing on chemokines, specifically genes involved in the CXCR4-pathway because of their established role in metastasis and tumour growth.

Characterization of human mesenchymal stem cells from ewing sarcoma patients. Pathogenetic implications.

Background: Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin.

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

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.

Histone deacetylase inhibitors enhance expression of NKG2D ligands in Ewing sarcoma and sensitize for natural killer cell-mediated cytolysis.

Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity.

Intact interferon signaling in peripheral blood leukocytes of high-grade osteosarcoma patients.

High-grade osteosarcoma has a poor prognosis with an overall survival rate of about 60 percent. The recently closed European and American Osteosarcoma Study Group (EURAMOS)-1 trial investigates the efficacy of adjuvant chemotherapy with or without interferon-α. It is however unknown whether the interferon-signaling pathways in immune cells of osteosarcoma patients are functional.