fusion genes in acute leukemias: genetic characterization of rare cases.

Introduction: Alterations of the gene (9q34) are recurrent in acute leukemias. Rearrangements of chromosomal band 9q34 targeting this locus can be karyotypically distinct, for example t(6;9)(p22;q34)/, or cryptic, in which case no visible change of 9q34 is seen by chromosome banding.

Methods: We examined 9 cases of acute leukemia with rearrangement by array Comparative Genomic Hybridization (aCGH), reverse-transcription polymerase chain reaction (RT-PCR), and cycle sequencing/Sanger sequencing to detect which fusion genes had been generated.

Intensifying treatment in PET-positive multiple myeloma patients after upfront autologous stem cell transplantation.

F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET) positivity after first-line treatment with autologous stem cell transplantation (ASCT) in multiple myeloma is strongly correlated with reduced progression-free and overall survival. However, PET-positive patients who achieve PET negativity after treatment seem to have comparable outcomes to patients who were PET negative at diagnosis. Hence, giving PET-positive patients additional treatment may improve their outcome.

Extracorporeal Photopheresis as Graft-versus-Host Disease Prophylaxis: A Randomized Controlled Trial.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole curative option for many patients diagnosed with hematologic malignancies. A major obstacle is graft-versus-host disease (GVHD), causing significant morbidity and mortality. Extracorporeal photopheresis (ECP) is an increasingly applied treatment for GVHD, owing in part to its favorable safety profile.

Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases.

Background: In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce.

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

Background: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear.

Methods: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98).

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice.

Thymectomy in Juvenile Myasthenia Gravis Is Safe Regarding Long Term Immunological Effects.

Thymectomy is an established treatment in adult MG and also recommended for the treatment of post-pubertal onset juvenile MG. Whether the youngest children should be thymectomized is still debated. Signs of premature aging of the immune system have been shown in studies on early perioperative thymectomy in children with congenital heart defect.

Therapy-induced Deletion in 11q23 Leading to Fusion of With and Development of B Lineage Acute Lymphoplastic Leukemia in a Child Treated for Acute Myeloid Leukemia Caused by t(9;11)(p21;q23)/.

Background/aim: Fusion of histone-lysine N-methyltransferase 2A gene (KMT2A) with the Rho guanine nucleotide exchange factor 12 gene (ARHGEF12), both located in 11q23, was reported in some leukemic patients. We report a KMT2A-ARHGEF12 fusion occurring during treatment of a pediatric acute myeloid leukemia (AML) with topoisomerase II inhibitors leading to a secondary acute lymphoblastic leukemia (ALL).

Materials And Methods: Multiple genetic analyses were performed on bone marrow cells of a girl initially diagnosed with AML.

Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.

PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR.

Partial Response to Sorafenib in a Child With a Myeloid/Lymphoid Neoplasm, Eosinophilia, and a ZMYM2-FLT3 Fusion.

Dysregulated tyrosine kinases in myeloid/lymphoid neoplasms with eosinophilia are rare, but do occur in children. To increase awareness of this diagnosis, we present a child who was diagnosed after a 3-year disease history. The patient was initially treated according to a T-cell lymphoblastic lymphoma protocol, but genetic analyses at recurrence revealed microdeletions resulting in an in-frame fusion of ZMYM2 and FLT3.

Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency.

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With parental consent, 21 000 newborns were TREC-tested in the pilot.

Correction: Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

T-cell acute lymphoblastic leukemia in patients 1-45 years treated with the pediatric NOPHO ALL2008 protocol.

The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) < 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD > 0.

Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.

Introduction: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

Materials And Methods: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score.

Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study.

Objective: Acute Epstein-Barr virus (EBV) infection is a known trigger of both acute and chronic fatigue. The aim of this study was to investigate associations to fatigue in adolescents with EBV infection during the initial stage and six months after, as well as in healthy controls.

Methods: 200 adolescents (12-20 years old) with EBV infection were assessed as soon as possible after the onset of symptoms (EBV) and six months later (EBV, 5 drop-outs).

Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later.

Aim: Acute Epstein-Barr virus (EBV) infection is a trigger of prolonged fatigue. This study investigated baseline predictors of physical activity six months after an acute EBV infection.

Methods: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively.

Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol.

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.

Introduction: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection.

Materials And Methods: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively.

Data on circulating leukocyte subpopulations and inflammatory proteins in children with familial hypercholesterolemia and healthy children.

The data in this relies on a previous publication: "Altered leukocyte distribution under hypercholesterolemia: a cross-sectional study in children with familial hypercholesterolemia" (Christensen et al. 2016) [1]. In the present paper, whole blood leukocyte distribution and plasma inflammatory proteins were measured for association with cholesterol concentration and CRP in children with familial hypercholesterolemia (FH) and healthy children.

Altered leukocyte distribution under hypercholesterolemia: A cross-sectional study in children with familial hypercholesterolemia.

Background And Aims: Children with familial hypercholesterolemia (FH) have elevated LDL cholesterol from the first year of life, and represent a model of early-stage atherosclerosis. Data suggest that adults with FH have alterations in circulating monocyte subpopulations towards a more pro-inflammatory phenotype, but it is not known whether FH children have similar perturbations. In addition, there are no data on the distribution of lymphocyte subpopulations in FH children.

A potential founder variant in in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.

Background: Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected.

Methods And Results: The four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies.

Targeting Integrin α4β7 in Steroid-Refractory Intestinal Graft-versus-Host Disease.

Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin α4β7, in 6 patients.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

A Cross-Sectional Study of the Prevalence of Gastrointestinal Symptoms and Pathology in Patients With Common Variable Immunodeficiency.

Objectives: The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation.

Methods: In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163).

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls.