Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas.

Background: Patients with relapsed pediatric sarcomas have a poor outcome and are in need of novel effective therapies.

Methods: We retrospectively reviewed the records of patients at Children's Healthcare of Atlanta who were treated with gemcitabine (675 mg/m(2)) intravenously (IV) on Day 1 and Day 8, and docetaxel (75 mg/m(2)) IV on Day 8, repeated every 3 weeks.

Results: Nineteen patients with a median age of 11 years were treated from 2006-2010 and received 123 total courses.

Prevalence of malignancies among U.S. male patients with haemophilia: a review of the Haemophilia Surveillance System.

The prevalence of malignancies in US male patients with haemophilia, with or without concomitant viral infections, remains unknown. To estimate the prevalence of malignancy in US male patients with haemophilia. We investigated the prevalence of malignancies among male patients with haemophilia using data from a six-state haemophilia surveillance project.

Gab adapter proteins as therapeutic targets for hematologic disease.

The Grb-2 associated binder (Gab) family of scaffolding/adaptor/docking proteins is a group of three molecules with significant roles in cytokine receptor signaling. Gabs possess structural motifs for phosphorylation-dependent receptor recruitment, Grb2 binding, and activation of downstream signaling pathways through p85 and SHP-2. In addition, Gabs participate in hematopoiesis and regulation of immune response which can be aberrantly activated in cancer and inflammation.

Hedgehog Pathway in Pediatric Cancers: They're Not Just for Brain Tumors Anymore.

The Hedgehog (HH) pathway regulates fundamental processes in embryonic development, including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. In the vertebrate pathway, Sonic hedgehog (SHH) binds to Patched1 (PTCH1), which relieves its inhibition of Smoothened (SMO), allowing the GLI family of transcription factors to translocate to the nucleus and activate HH target genes such as GLI1, GLI2, PTCH1, CYCLIN D1, BCL-2, and MYCN. The HH pathway is also an active participant in tumorigenesis.

Nonhuman primate transplant models finally evolve: detailed immunogenetic analysis creates new models and strengthens the old.

Nonhuman primate (NHP) models play a critical role in the translation of novel therapies for transplantation to the clinic. However, although MHC disparity significantly affects the outcome of transplantation, until recently, experiments using NHP models were performed without the ability to rigorously control the degree of MHC disparity in transplant cohorts. In this review, we discuss several key technical breakthroughs in the field, which have finally enabled detailed immunogenetic data to be incorporated into NHP transplantation studies.

Grb2-associated binding (Gab) proteins in hematopoietic and immune cell biology.

Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved. Since the discovery of these proteins, there has been an extensive amount of work done to better understand Gab functional roles in multiple signaling pathways, typically acting as a downstream effectors of receptor-tyrosine kinase (RTK)-triggered signal transduction. In addition to their participation in hematopoiesis, Gabs play important roles in regulation of immune response and in also in cancer cell signaling.

Implementation of a pediatric trauma massive transfusion protocol: one institution's experience.

Background: Massive transfusion protocols (MTPs) with fixed ratios of blood products may improve outcomes in coagulopathic adult trauma patients. However, there is a paucity of data on transfusion support protocols for pediatric trauma patients, whose mechanisms of injury may differ from those seen in adults. We hypothesized that an MTP would improve outcomes in children, through a balanced blood product resuscitation.

Coagulopathy is prevalent and associated with adverse outcomes in transfused pediatric trauma patients.

Objective: To evaluate coagulopathy in pediatric trauma patients on presentation to the emergency department, and to quantify the relationship with mortality.

Study Design: Pediatric trauma patients requiring a blood transfusion (red blood cells, fresh frozen plasma, platelets, or cryoprecipitate) within 24 hours of arrival were included. Coagulation values on emergency department arrival were analyzed, as were clinical details and outcome.

Crosstalk between MYCN and MDM2-p53 signal pathways regulates tumor cell growth and apoptosis in neuroblastoma.

Previous studies show that the MYCN and MDM2-p53 signal pathways are mutually regulated: MYCN stimulates MDM2 and p53 transcription, whereas MDM2 stabilizes MYCN mRNA and induces its translation. Herein, we report that the interaction between MDM2 and MYCN plays a critical role in MYCN-amplified neuroblastoma tumor cell growth and survival. Distinct from the known role that MDM2 has in regulating tumor promotion in non-MYCN-amplified neuroblastoma, in which MDM2 inhibits p53, we found that MDM2 stimulated tumor growth in MYCN-amplified neuroblastoma in a p53-independent manner.

Alloimmunization to transfused HOD red blood cells is not increased in mice with sickle cell disease.

Background: Increased rates of red blood cell (RBC) alloimmunization in patients with sickle cell disease may be due to transfusion frequency, genetic predisposition, or immune dysregulation. To test the hypothesis that sickle cell pathophysiology influences RBC alloimmunization, we utilized two transgenic mouse models of sickle cell disease.

Study Design And Methods: Transgenic sickle mice, which express human α and β(S) globin, were transfused with fresh or 14-day-stored RBCs containing the HOD (hen egg lysozyme, ovalbumin, and human Duffy(b) ) antigen; some recipients were inflamed with poly(I : C) before transfusion.

Treatment of high-grade glioma in children and adolescents.

Pediatric high-grade gliomas (HGGs)--including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma--are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children.

AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group.

Background: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML.

Methods: AAML03P1 enrolled 350 children with previously untreated AML.

Transfusion of fresh murine red blood cells reverses adverse effects of older stored red blood cells.

Background: Although a subset of recent studies have suggested that red blood cell (RBC) storage length is associated with adverse patient outcomes, others have shown no such relationship. Adults may be transfused with RBC units of different storage lengths, and existing studies do not take into consideration that fresh RBCs may alter responses to concurrently transfused stored RBCs. To test this possibility, we utilized a murine model and investigated transfusion outcomes of fresh, stored, or fresh-plus-stored RBCs.

Enhanced biosynthesis of coagulation factor VIII through diminished engagement of the unfolded protein response.

Human and porcine coagulation factor VIII (fVIII) display a biosynthetic efficiency differential that is being exploited for the development of new protein and gene transfer-based therapies for hemophilia A. The cellular and/or molecular mechanism(s) responsible for this phenomenon have yet to be uncovered, although it has been temporally localized to post-translational biosynthetic steps. The unfolded protein response (UPR) is a cellular adaptation to structurally distinct (e.

Rapid clearance of transfused murine red blood cells is associated with recipient cytokine storm and enhanced alloimmunogenicity.

Background: Fourteen-day stored red blood cells (RBCs) containing an RBC-specific transgenic antigen (HOD) induce a recipient proinflammatory cytokine storm and are significantly more immunogenic compared to fresh RBCs. Given that recipient mice clear transfused stored RBCs more rapidly than fresh RBCs, we hypothesized that rapid RBC clearance was associated with adverse transfusion outcomes.

Study Design And Methods: HOD RBCs were treated by two distinct methods known to lead to rapid posttransfusion RBC clearance: phenylhydrazine or heat.

Tandem stem cell rescue as consolidation therapy for high-risk neuroblastoma.

Background: Despite aggressive treatment for high-risk neuroblastoma (NB), event-free survival (EFS) remains <40%. In single arm studies, intensifying therapy with high-dose chemotherapy and tandem autologous stem cell rescue (HDC/SCR) improved outcome. We retrospectively describe our institutional experience in using HDC/SCR for patients with high-risk NB, focusing on outcome and acute toxicities.

Global gene expression profiling of endothelium exposed to heme reveals an organ-specific induction of cytoprotective enzymes in sickle cell disease.

Background: Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion and ischemia reperfusion injury. These events cause endothelial dysfunction and vasculopathies in multiple systems. However, the lack of atherosclerotic lesions has led to the idea that there are adaptive mechanisms that protect the endothelium from major vascular insults in SCD patients.

Polycythemia in an infant secondary to granulocyte transfusions.

Granulocyte transfusions may be useful for neutropenic pediatric patients with refractory bacterial or fungal infections. Many potential adverse sequelae associated with granulocyte transfusions are well recognized, including febrile reactions, fluid overload, alloimmunization, and lung injury. Other potential adverse sequelae, however, are less well known.

Neurofibromatosis-2 and spinal cord ependymomas: Report of two cases and review of the literature.

Object: The incidence of ependymoma in patients with neurofibromatosis-2 (NF-2) is low and information regarding treatment and prognosis is lacking. We present two cases of cervicomedullary tumors in patients with NF-2 from our institution, and we provide a review of the literature in order to summarize the known clinical information about this rare occurrence.

Patients And Methods: Patient #1 had histological confirmation of ependymoma and was treated with subtotal resection followed by observation and has had no evidence of progression for 11 months.