Protein S antibody as an adjunct therapy for hemophilia B.

ABSTRACT: Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation factor IX (FIX). Approximately 60% of pediatric patients with HB possess a severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy through the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant protein S (PS) inhibits activated FIX (FIXa). PS ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercially obtained plasma and plasma from pediatric patients with HB. We included 11 pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of the FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Furthermore, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB.

Children's Oncology Group's 2023 blueprint for research: Diversity and health disparities.

The Children's Oncology Group (COG) Diversity and Health Disparities Committee's (DHDC's) mission is to guarantee the highest standard of care for children and adolescents and young adults (AYA) with cancer regardless of ethnic, racial, gender, or socioeconomic background. We strive to identify and address issues of disparity within the existing scientific structure of COG and to support research across COG to improve survival by ensuring equitable access to COG-sponsored clinical trials. We are committed to advance COG-led research identifying mechanistic drivers of disparities and, concurrently, evaluating interventions to alleviate disparities in the COG trial setting. As trials identify the most promising therapies, diverse representation is critical to ensure that findings are relevant to everyone. Factors impacting clinical trial participation among vulnerable populations are complex, consisting of barriers at societal, systems, and individual levels. Recent efforts by investigators within DHDC demonstrated that trial-embedded collection of family-reported sociodemographic data and social determinants of health (SDoH) is feasible and acceptable in the context of COG. Diversity in the pediatric oncology workforce is essential and one potential approach to improving representation on clinical trials. To support and retain diverse oncology providers and researchers, a Minority Young Investigator Award (MYIA) was created to facilitate opportunities for graduating trainees and YIs with an interest in childhood cancer disparities research within COG. Although there are challenges to achieve the DHDC's priorities, only through collaboration and support for this work we will be able to elucidate mechanisms underlying inferior survival outcomes for historically marginalized children and AYA, and more importantly, implement interventional investigation to improve outcomes.

Autoimmune Myelofibrosis in a 12-Year-old Male With Monosomy 7, Systemic Lupus Erythematous and Lupus Nephritis: A Case Report and Review of the Literature.

Complete or partial loss of chromosome 7 is a common and well-known cytogenetic abnormality associated with preleukemic myelodysplasia and myeloid leukemia but not with autoimmune myelofibrosis. Detection of this molecular change represents poor prognosis. When malignant transformation occurs, the condition tends to be chemotherapy-resistant requiring haematopoietic stem cell transplantation (HSCT) to obtain a cure. Disappearance after immunosuppressive therapy has been documented in children with hematological disorders but not in association with cyclophosphamide and systemic lupus erythematous.We present the interesting case of a 12-year-old male with monosomy 7, systemic lupus erythematous, and lupus nephritis with the resolution of the monosomy 7 and autoimmune myelofibrosis after treatment with cyclophosphamide, along with a review of the literature.

Evaluation for Bleeding Disorders in Suspected Child Abuse.

Bruising or bleeding in a child can raise the concern for child abuse. Assessing whether the findings are the result of trauma and/or whether the child has a bleeding disorder is critical. Many bleeding disorders are rare, and not every child with bruising/bleeding that may raise a concern for abuse requires an evaluation for bleeding disorders. However, in some instances, bleeding disorders can present in a manner similar to child abuse. Bleeding disorders cannot be ruled out solely on the basis of patient and family history, no matter how extensive. The history and clinical evaluation can be used to determine the necessity of an evaluation for a possible bleeding disorder, and prevalence and known clinical presentations of individual bleeding disorders can be used to guide the extent of laboratory testing. This clinical report provides guidance to pediatricians and other clinicians regarding the evaluation for bleeding disorders when child abuse is suspected.

Multisystem Inflammatory Syndrome in a Pediatric Patient With Sickle Cell Disease and COVID-19: A Case Report.

To this day, there are limited data about the effects and management of coronavirus disease infection in pediatric patients with sickle cell disease. We present the management and successful clinical course of an 8-year-old female with homozygous sickle cell disease (SS) and severe acute chest syndrome secondary to coronavirus disease 2019 infection, complicated by cortical vein thrombosis.

In Vitro Lymphocyte Functions in Undernourished Children With Sickle Cell Anemia.

Background: Children with sickle cell disease (SCD) often suffer from growth deficits and impaired immunity. However, the association between mild to moderate malnutrition and in vitro lymphocyte function has not been well studied. The goal of this study was to investigate the effects of undernutrition on lymphocyte functions in children with SCD. Methods: Weight; height; plasma concentrations of albumin (Alb), prealbumin (PA), transferrin (Tf), retinol-binding protein (RBP), α1-acid glycoprotein (AGP), C-reactive protein (CRP), and ceruloplasmin (Cp); and lymphocyte proliferation and interleukin (IL)-2 in phytohemagglutinin-treated blood lymphocytes were measured in 90 children with SCD (59 SS, 4 Sß°, 27 SC hemoglobin genotypes). Results: The mean age of the children included in the analysis was 7.65 years. Four of the 90 children had weight and height below the fifth percentile. A higher percentage of children with HbSS/HbSß° (61.4%) than of those with HbSC (44%) had ≥2 plasma protein concentrations below normal (Alb <35 g/L, PA <160 mg/L, Tf <2.0 g/L, and RBP ≤20 mg/L). Mean anthropometric measurements, hemoglobin, and hematocrit were lower in children with HbSS/HbSß° than in those with HbSC (P<0.05). Lymphocyte proliferation was reduced by 20% to 27% in children with HbSS/HbSß° with undernutrition plus inflammation (AGP >1 g/L, CRP >5 mg/L, Cp >600 mg/L) compared to children with neither. Regardless of inflammatory status, lymphocyte proliferation was reduced by 29% to 49% in children with HbSS/HbSß° and undernutrition defined by PA or Alb plus RBP (P<0.05) compared to those with RBP within normal range. Neither undernutrition nor inflammation reduced lymphocyte proliferation in children with HbSC. Mean IL-2 activity was reduced by undernutrition, defined as PA <160 mg/L, in both groups. PA, RBP, and hemoglobin concentrations positively correlated with in vitro lymphocyte functions (P<0.05). Conclusion: Undernutrition altered in vitro lymphocyte function in children with the HbSS/HbSß° genotypes. Dietary supplements may improve the altered functions in these children.

Impact of Hurricane Katrina on healthcare delivery for New Orleans patients, 2005-2014.

BACKGROUND AND OBJECTIVES: Hematology/oncology patients have special health needs. To identify barriers to care, we surveyed patients/parents at Children's Hospital of New Orleans 1 year after Hurricane Katrina. We then implemented a "Hurricane Action Plan"-identification of families' evacuation plans at each hurricane season's onset; of hospital(s) and pharmacies in the intended evacuation area; updating roadmaps/treatment plans; giving information to families requiring hematology/oncology services in evacuation areas. Administration of a second survey was initiated 7 years post Katrina to assess the efficacy of the "Hurricane Action Plan." METHODS: Both surveys were conducted on random patients attending Children's Hospital. Survey #1 was performed in 2006, while survey #2 was conducted in 2013-2014. RESULTS: Eighty-nine percent of 124 families left New Orleans during Hurricane Katrina; only 50% had an evacuation plan. Twenty-five percent of families had difficulty physically accessing care; others (13%) could not find a hematology/oncology provider for follow-up and had difficulty reaching their primary provider or making appointments. An additional 25 percent did not have access to medical records. There was no access to mental health services. Eighty- two patients/representatives were surveyed in 2013/2014; 72% of families were evacuated during subsequent hurricane seasons with 78% of families having an evacuation plan. Thirty-six percent of patients had a roadmap/treatment plan with them; 71% had a 2-week medication supply. Ninety-two percent found information given to them by providers helpful. CONCLUSIONS: Interventions instituted to allow greater access to care by our hematology/oncology patients after Hurricane Katrina resulted in better preparedness, easier acquisition of information, and possibly better continuity of care.

Level of knowledge, emotional impact and perception about the role of nursing professionals concerning palliative sedation.

AIMS AND OBJECTIVES: To explore aspects related to the fulfilment of the role of nurses in palliative sedation. BACKGROUND: Palliative sedation demands knowledge and a proper attitude for maintaining comfort, preserving dignity and contributing to a peaceful death. In some developed countries, nurses have a well-established role in palliative sedation. However, studies on their role and its fulfilment are limited, particularly in the developing world. DESIGN: An exploratory, mixed, qualitative and quantitative study was conducted. A self-administered questionnaire was used to examine the level of knowledge of palliative sedation and the level of confidence in skills and knowledge about palliative sedation. Also, focus groups were conducted to explore the emotional impact and the perceived role of nurses. METHODS: Forty-one nurses from three advanced-care hospitals with palliative care units in Colombia completed the questionnaire. Also, four focus groups were conducted with 22 participants selected from the first phase. RESULTS: A high level of knowledge regarding palliative sedation was found, but the level of confidence in skills was higher than the confidence in knowledge. The participants expressed their belief that their knowledge was derived from experience but believed that it was not enough to fulfil their role with confidence. A negative emotional impact about the patients' condition was found. For some, it served as motivation to provide better care. For others, it was difficult to face, especially when assisting children. They also expressed satisfaction and gratification about providing relief from suffering through sedation. CONCLUSIONS: The role of nursing is essential in palliative sedation. Although the nurses' knowledge is adequate, it primarily derives from experience and not from formal training, which impacts on their perceived confidence and their distress. RELEVANCE TO CLINICAL PRACTICE: Formal training for the optimal fulfilling of the nursing role in palliative sedation is crucial to provide better end-of-life care, particularly in developing countries.

Access to hematopoietic stem cell transplant for patients with sickle cell anemia.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for patients with phenotypically severe sickle cell anemia, and survival rates following matched-sibling HSCT are very high. However, despite cure rates much higher than HSCT for malignant diseases, the field has been slow to adopt this treatment modality for sickle cell anemia. This article explores some of the social forces that may contribute to this dichotomy.

Pediatric Pulmonary Embolism: Diagnostic and Management Challenges.

A rare case of massive pulmonary embolism is presented in an oligosymptomatic teenager with predisposing factors. Computed tomography pulmonary angiography supported by three-dimensional reconstruction was diagnostic. The embolus qualified as massive by conventional anatomical guidelines, but as low risk by more recent functional criteria. Functional assessment has complemented morphologic assessment for risk stratification in adult patients. Such evidence is scarce in pediatrics. The patient underwent surgical embolectomy, followed by prophylactic anticoagulation, without further events. Diagnostic and management challenges are discussed.

Multimodal management of a pediatric cervical yolk sac tumor.

Even though vaginal bleeding is an unusual clinical presentation in infants and young children, thorough evaluation by the pediatric urologist requires the recognition and knowledge of less-common conditions, including malignancy. Extragonadal germ cell tumors are rare in children aged <15 years, representing approximately 1% of all cancers. Because of the close collaboration between pediatric oncologists and pediatric urologists, a multidisciplinary approach to the management and treatment of these tumors includes chemotherapy and surgical resection, aiming for fertility preservation when possible. We present a 10-month-old infant with a cervical or uterine germ cell tumor and the challenges found during her treatment.

A facile, branched DNA assay to quantitatively measure glucocorticoid receptor auto-regulation in T-cell acute lymphoblastic leukemia.

Glucocorticoid (GC) steroid hormones are used to treat acute lymphoblastic leukemia (ALL) because of their pro-apoptotic effects in hematopoietic cells. However, not all leukemia cells are sensitive to GC, and no assay to stratify patients is available. In the GC-sensitive T-cell ALL cell line CEM-C7, auto-up-regulation of RNA transcripts for the glucocorticoid receptor (GR) correlates with increased apoptotic response. This study aimed to determine if a facile assay of GR transcript levels might be promising for stratifying ALL patients into hormone-sensitive and hormone-resistant populations. The GR transcript profiles of various lymphoid cell lines and 4 bone marrow samples from patients with T-cell ALL were analyzed using both an optimized branched DNA (bDNA) assay and a real-time quantitative reverse transcription-polymerase chain reaction assay. There were significant correlations between both assay platforms when measuring total GR (exon 5/6) transcripts in various cell lines and patient samples, but not for a probe set that detects a specific, low abundance GR transcript (exon 1A3). Our results suggest that the bDNA platform is reproducible and precise when measuring total GR transcripts and, with further development, may ultimately offer a simple clinical assay to aid in the prediction of GC-sensitivity in ALL patients.

Experimental field test of spatial variation in rodent predation of nuts relative to distance and seed density.

The spatial context in which seed predation occurs may modify the spatial structure of recruitment generated by seed dispersal. The Janzen-Connell (J-C) model predicts that granivores will exert greater pressure on the parent plant or at those sites where the density of dispersed seeds is higher. We have investigated how the probability of post-dispersal survival of Juglans australis varies with nut density across a hierarchy of spatial scales. We experimentally evaluated the survival of 3,120 nuts at three spatial scales: meso-scale (

Characterization of S-glutathionyl hemoglobin in homozygous sickle cell disease.

S-glutathionyl hemoglobin is a proposed biomarker of oxidative stress but has not been measured in sickle cell disease patients. Unlike the S-glutathionyl adduct of normal adult hemoglobin, S-glutathionyl sickle hemoglobin (HbSSG) cannot be directly measured by capillary isoelectric focusing, because it coelutes with fetal hemoglobin (HbF). This suggests that HbF, measured in sickle cell patients with or without hydroxyurea therapy, might contain endogenous HbSSG. As S-glutathionyl hemoglobin can form during sample storage, HbSSG could falsely elevate HbF levels in stored samples. We measured HbSSG based on the quantitative difference in the heterogeneous HbF/HbSSG peak before and after hemolysates were treated with dithiothreitol. Paired t tests showed that dithiothreitol reduced HbF/HbSSG in blood from pediatric sickle cell patients (n=25, mean decrease+/-SD=1.0%+/-0.6, P<0.05) but not in normal infants (n=25). Higher HbF levels in hydroxyurea-treated patients (n=5) were not attributable to HbSSG. HbSSG increased significantly within 1 day in samples stored at -20 degrees C but was unchanged in samples stored 60 days at-70 degrees C. We conclude that blood from sickle cell patients contained up to 2.2% HbSSG, and that endogenous HbSSG is a minor interferent in the measurement of HbF in fresh blood but a major interferent in improperly stored samples.

Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.

Pediatric Hodgkin's and non-Hodgkin's lymphomas: a retrospective analysis at the Children's Hospital of New Orleans.

Lymphomas constitute 10-12% of childhood cancers and are the third most common childhood malignancy. A retrospective analysis of thirty-six patients from the tumor registry of Children's Hospital of New Orleans was conducted during the period from 1995-2000. Patients were divided based on patient and tumor characteristics with recurrence and survival data compared to the Surveillance, Epidemiology and End Results (SEER) data of the National Cancer Institute. There were 18 patients (51%) with Non-Hodgkin's Lymphoma (NHL) and 17 (49%) with Hodgkin's disease (HD). Our sample had a similar distribution compared to the national population cohort except for different gender distribution in our HD patients. Also, most of our patients (63%) presented with advanced disease (Stages III and IV). Seventeen percent had recurrence of disease and 80% achieved remission, of which two patients developed secondary leukemia. Overall mortality was 17%. The survival in patients with HD was 94% which is comparable if not slightly superior to the national data. In patients with NHL, survival was 72% which was marginally lower than the national results (80%), most likely due to more advanced disease. Increased awareness in the pediatric community of the signs and symptoms of childhood lymphoma should result in earlier diagnosis and improved survival.

Gamma/delta T-cell lymphoma as a recurrent complication after transplantation.

We present a case of gamma-delta (gammadelta) T-cell lymphoma as a recurrent event in a pediatric liver transplant recipient. Liver transplantation was performed during infancy in an 18-month-old black girl because of cryptogenic cirrhosis. The patient received immunosuppression with cyclosporine and prednisone. Five years after transplantation, the patient was found to have a gammadelta T-cell lymphoma located in retroperitoneal nodes. She received chemotherapy and did well, remaining disease-free for 6 years. She remained only on prednisone for prevention of graft rejection, but was noted to have a non-tender skin nodule that upon biopsy proved to be again a gammadelta T-cell lymphoma. However, comparison of tissue from both tumors revealed that the second occurrence of this malignancy was a de novo event, differing from the first by immunophenotypic and immunohistochemical characteristics, and TCR rearrangement. The patient continues to do well, without evidence of disease recurrence, after being treated again with chemotherapy. A summary of the literature is presented and comparison of our case is made.

Acute perforative appendicitis during preoperative chemotherapy for Wilms tumor.

Infectious complications are not uncommon in children undergoing treatment for cancer. Abdominal pain, especially right lower quadrant pain secondary to appendiceal and cecal inflammation, is a major concern in immunocompromised hosts and a potential source of sepsis. The authors report the case of a child who developed acute perforative appendicitis requiring appendectomy while on preoperative chemotherapy for Wilms tumor, stage IV, favorable histology. Problems related to diagnosis and management of acute abdominal pain and infection in an immunocompromised child with an abdominal mass are discussed along with a review of the literature.