Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice.

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model.

Infantile leukemia-What factors determine its distinct biological nature? Clinicopathological study of 78 cases.

Introduction: Infantile leukemia encompasses a heterogeneous group which needs stratifying for treatment selection.

Methods: We collected 78 cases of infantile leukemia and retrospectively analyzed their clinicopathological data.

Results: Infantile leukemia featured a ratio of acute myeloid leukemia (AML) to B-lymphoblastic leukemia (B-ALL) of 1:2, with a better survival for AML than B-ALL (median survival 36 vs 24 months).

Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS.

Objectives: Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients.

Analysis of clinicopathological and cytogenetic differences between B-lymphoblastic lymphoma and B-lymphoblastic leukemia in childhood.

Although considered the same disease by 2016 WHO Classification, B-ALL and B-LBL show different clinicobiologic behavior, with B-ALL manifesting as disseminated disease and B-LBL as a localized mass. Distinction between the two is based on an arbitrary cutoff of 25% bone marrow involvement. We reviewed clinical, immunophenotypic, and cytogenetic data in B-lymphoblastic neoplasms of childhood to explain the differences.

Comprehensive analysis of genomic alterations detected by next-generation sequencing-based tissue and circulating tumor DNA assays in Chinese patients with non-small cell lung cancer.

While tumor genotyping is the standard treatment for patients with non-small cell lung cancer (NSCLC), spatial and temporal tumor heterogeneity and insufficient specimens can lead to limitations in the use of tissue-based sequencing. Circulating tumor DNA (ctDNA) fully encompasses tumor-specific sequence alterations and offers an alternative to tissue sample biopsies. However, few studies have evaluated whether the frequency of multiple genomic alterations observed following ctDNA sequencing is similar to that observed following tissue sequencing in NSCLC.

A Review of Neuropathological Features of Familial and Adult Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a hematological disorder that can be due to genetic (primary HLH) causes or excessive activation of the immune system in association with infection, malignancy, rheumatologic disorders, or immune suppression (secondary HLH). Hemophagocytic lymphohistiocytosis remains an under-recognized condition among neuropathologists, especially the secondary forms, where it may be diagnosed only at brain biopsy or autopsy due to confounding comorbidities. The CNS is frequently affected, but neuropathological features are underappreciated.

Castleman disease in pediatrics: Insights on presentation, treatment, and outcomes from a two-site retrospective cohort study.

Background: Castleman disease (CD) is an uncommon lymphoproliferative disorder that is rare in pediatric populations; the literature describing this population is sparse. We sought to describe pediatric CD, including unicentric CD (UCD) and human herpes virus-8 (HHV8)-negative multicentric CD (MCD), in a multi-institutional cohort.

Methods: We retrospectively reviewed 24 patients, aged 0 to 26 years at diagnosis, who were diagnosed with CD between January 1, 2005, and May 16, 2017, at two tertiary children's hospitals.

Primary Nonanaplastic Peripheral Natural Killer/T-Cell Lymphoma in Pediatric Patients-An Unusual Distribution Pattern of Subtypes.

Peripheral NK/T-cell lymphoma (PNKTCL) represents a group of uncommon diagnoses for children in Western countries, and studies have often necessitated multiple institutions to assemble enough cases. We retrospectively analyzed 11 cases of nonanaplastic PNKTCL in children over 19 years at our institution with comparison to several published large multi-institutional studies. Patients included 9 males and 2 females of white (5), Native American (3), and Hispanic (3) background with 6 cases of extranodal NK/T-cell lymphoma, nasal type (EN-NKTL, 54.

Clinicopathologic and genetic spectrum of infantile B-lymphoblastic leukemia: a multi-institutional study.

Acute lymphoblastic leukemia (ALL) in infants <1-year-old is biologically different from ALL in older children. Although KMT2A rearrangement is the predominant genetic signature in infantile B-ALL, disease course is heterogenous, behaving more aggressively in younger infants. We investigated clinicopathological differences throughout the first year to understand the transition to pediatric B-ALL.

Vitamin K Deficiency Presenting in an Infant with an Anterior Mediastinal Mass: A Case Report and Review of the Literature.

We report a case of a 1-month-old infant with spontaneous thymic hemorrhage secondary to severe vitamin K deficiency. He was brought to medical attention due to scrotal bruising and during evaluation was noted to be tachypneic and hypoxemic. Chest X-ray revealed an enlarged cardiothymic silhouette, and a follow-up echocardiogram revealed a mass in the anterior mediastinum.

Distinct GATA1 Point Mutations in Monozygotic Twins With Down Syndrome and Transient Abnormal Myelopoiesis From a Triplet Pregnancy: A Case Report and Review of Literature.

Objectives: Down syndrome (DS)-associated transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL) in monozygotic twins is exceedingly rare and has not been well characterized.

Methods: We describe a unique case of monozygotic twins with simultaneous TAM from a triplet pregnancy at 34 weeks' gestation. Previously reported cases of TAM and DS-AMKL in monozygotic twins have been reviewed to compare with our cases.

Oct2 and Bob1 are sensitive and specific markers in lineage determination of B cell lymphomas with no expression of conventional B cell markers.

Aims: Rare cases of B cell lymphomas do not express conventional B cell markers (CD20, CD79a and PAX5), and these types of lymphomas include anaplastic lymphoma kinase (ALK)-positive large B cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma and the solid variant of primary effusion lymphoma, extracavitary human herpesvirus 8 (HHV8)-positive large B cell lymphoma. Establishing accurate diagnoses of these B cell lymphomas can be challenging, and often requires a large panel of immunohistochemical stains, molecular assays and cytogenetic studies. B cell-specific transcription factors, Oct2 and Bob1, have been shown to be expressed consistently in most, if not all, B cell lymphomas, and therefore we investigated the utility of Oct2 and Bob1 immunohistochemistry in lineage determination of the aforementioned B cell lymphomas.

Heterogeneity of Abnormal RUNX1 Leading to Clinicopathologic Variations in Childhood B-Lymphoblastic Leukemia.

Objectives: Abnormalities of the RUNX1 gene in childhood B-acute lymphoblastic leukemia (B-ALL) are manifested by ETV6-RUNX1 or RUNX1 amplification. A detailed comparison between the two regarding clinicopathologic features with genetic analysis has not been performed previously. This parallel study assessed how different RUNX1 abnormalities affect the clinicopathology of B-ALL.

Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.

Hb Grand Junction (HBB: c.348_349delinsG; p.His117IlefsX42): a new hyperunstable hemoglobin variant.

Hyperunstable hemoglobinopathy (HUH) [dominantly inherited β-thalassemia (β-thal)] is a relatively rare form of congenital hemolytic anemia in which mutations occur in the genes encoding for α and β chains, or both chains of the hemoglobin (Hb) molecule. We describe two Hispanic adolescents with a new unstable Hb variant (HBB: c.348_349delinsG; p.

Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples.

Dual ALK and MYC rearrangements leading to an aggressive variant of anaplastic large cell lymphoma.

Anaplastic lymphoma kinase (ALK) and MYC are oncogenes often dysregulated in pediatric lymphomas. NPM-ALK/t(2;5)(p23;q35) is a genetic hallmark of ALK anaplastic large cell lymphoma (ALCL). MYC gene translocations are frequently detected in high-grade B-cell lymphomas.

Moderate aplastic anemia in children: preliminary outcomes for treatment versus observation from a single-institutional experience.

Introduction: Because of the variety of definitions used to describe moderate aplastic anemia (MAA), we review our institutional experience period with patients who met a proposed set of criteria for this disorder. On an exploratory basis, we sought to evaluate the influence of treatment with immunosuppressive therapy (IST) versus observation on long-term outcomes.

Materials And Methods: Records from 1999 to 2010 were screened for patients who met the criteria for MAA: (1) bone marrow cellularity of 20% to 50%; (2) cytopenias in at least 1 cell line (absolute neutrophil count<1000/µL, hemoglobin<9 g/dL, platelet count<100,000/µL); (3) mean corpuscular volume ≥90; (4) persistence >6 months; and (5) negative Fanconi studies.

Toddlers with anasarca and severe anemia: a lesson in preventive medicine.

Two toddlers presented to their primary medical providers with anasarca and severe anemia. Laboratory evaluation revealed iron deficiency along with hypoproteinemia and hypoalbuminemia. Both children were diagnosed with iron deficiency anemia and were suspected to have an associated protein-losing enteropathy.

Proteomic analyses of human plasma: Venus versus Mars.

Background: Plasma is vital for the resuscitation of injured patients and to restore necessary procoagulants, especially Factors (F)II, FV, FVII, FX, and FXIII; however, female plasma has been implicated in the majority of transfusion-related acute lung injury (TRALI) cases and male-only plasma transfusion regimens have significantly decreased the incidence of TRALI. Little is known about the human plasma proteome, and no comparisons have been made between male and female plasma; therefore, we hypothesize that there are significant differences between plasma from male and female donors.

Study Design And Methods: Five units of fresh-frozen plasma each were collected from nulliparous female donors and male donors, and the proteome was analyzed by depleting the 14 most common proteins by immunoaffinity columns followed by protein separation by one dimension gel electrophoresis, tryptic digestion of the proteins, analysis of the peptides by liquid chromatography-tandem mass spectrometry, and identification employing human protein sequence databases.

Activated platelets in heparinized shed blood: the "second hit" of acute lung injury in trauma/hemorrhagic shock models.

The return of heparinized shed blood (SB) in trauma/hemorrhagic shock (T/HS) models remains controversial because of potential anti-inflammatory properties. Although ubiquitous as an anticoagulant, heparin is ineffective on cellular coagulation as an antithrombotic agent. Therefore, we hypothesized that returning heparinized SB would paradoxically enhance acute lung injury (ALI) after T/HS because of the infusion of activated platelets.

A two-event in vitro model of acute chest syndrome: the role of secretory phospholipase A2 and neutrophils.

Background: Acute chest syndrome (ACS) in sickle cell disease is associated with elevation of secretory phospholipase A(2) (sPLA(2) ). We hypothesize that sPLA(2) cleaves membrane lipids from sickled red blood cells (RBCs) causing PMN-mediated endothelial cell injury (ECI) as the second event in a two-event model.

Methods: Whole blood was collected from children when in steady state or daily during admissions for vaso-occlusive pain (VOC) or ACS.

Primary high-grade B-cell lymphoma of the breast with concurrent IGH-BCL2 and MYC-IGL translocations in an adolescent patient.

BCL2 and MYC are oncogenes often deregulated in lymphomas. Concurrent IGH-BCL2 and MYC translocations result in a highly aggressive behavior of these tumors. Both primary breast lymphoma and lymphoma with concurrent BCL2-IGH and MYC translocations are rare and are primarily seen in adult patients.