Treatment of newly diagnosed severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.

Treatment of relapsed/refractory severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.

A chronic eyelid lesion in a child: multi-disciplinary approach to diagnosis, treatment and management of a highly atypical histiocytic lesion.

Malignant histiocytic neoplasm with histiocytic sarcoma phenotype is a rare malignant neoplasm, distinguished by malignant cells with phenotypic characteristics of mature tissue histiocytes. Histiocytic sarcoma typically presents as a primary malignancy, although can also present as a secondary malignancy, and is rarely seen in the pediatric population. Due to the rarity of this condition, diagnosis of histiocytic sarcoma is difficult and considered a diagnosis of exclusion. We describe a unique case of a chronic upper eyelid lesion with biopsy findings of a highly atypical histiocytic neoplasm initially concerning for histiocytic sarcoma; however, after integration of clinical findings, non-progressive and quiescent molecular profile, concluded to be an atypical juvenile xanthogranuloma in a child treated with excision and observation alone. This report highlights the importance of an integrated team approach to diagnosis of unusual histiocytic neoplasms.

Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium.

The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.

Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2.

Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome resulting from defective cytotoxicity. A previously healthy 3-month-old female presented with fever, irritability, abdominal distention, and tachypnea. She ultimately met all eight HLH-2004 diagnostic criteria, accompanied by elevated CXCL9. Initial empiric anti-inflammatory treatment included anakinra and IVIg, which stabilized ferritin and cytopenias. She had molecular and genetic confirmation of perforin deficiency and was started on dexamethasone and etoposide per HLH-94. She clinically improved, though CXCL9 and sIL-2Ra remained elevated. She was readmitted at week 8 for relapsed HLH without clear trigger and HLH-94 induction therapy was reinitiated. Her systemic HLH symptoms failed to respond and she soon developed symptomatic CNS HLH. She was incidentally found to have multifocal lung and kidney nodules, which were sterile and consisted largely of histiocytes and activated, oligoclonal CD8 T cells. The patient had a laboratory response to salvage therapy with alemtuzumab and emapalumab, but progressive neurologic decline led to withdrawal of care. This report highlights HLH foci manifest as pulmonary/renal nodules, demonstrates the utility of monitoring an array of HLH biomarkers, and suggests possible benefit of earlier salvage therapy.

Diagnosis and treatment of pediatric myelodysplastic syndromes: A survey of the North American Pediatric Aplastic Anemia Consortium.

BACKGROUND: Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic stem cell disorders that commonly progress to acute myeloid leukemia (AML). The diagnostics, prognostics, and treatment of adult MDS are established but do not directly translate to children and adolescents. Pediatric MDS is a rare disease, characterized by unique cytogenetics and histology compared with adult MDS, and often arises secondary to germline predisposition or cytotoxic exposures. Our objective was to highlight aspects of diagnosis/management that would benefit from further systematic review toward the development of clinical practice guidelines for pediatric MDS. PROCEDURE: The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is composed of collaborative institutions with a strong interest in pediatric bone marrow failure syndromes and hematologic malignancies. The NAPAAC MDS working group developed a national survey distributed to 35 NAPAAC institutions to assess data on (1) clinical presentation of pediatric MDS, (2) diagnostic evaluation, (3) criteria for diagnosis, (4) supportive care and treatment decisions, and (5) role of hematopoietic stem cell transplantation (HSCT). RESULTS: Twenty-eight of 35 institutions returned the survey. Most centers agreed on a common diagnostic workup, though there was considerable variation regarding the criteria for diagnosis. Although there was consensus on supportive care, treatment strategies, including the role of cytoreduction and HSCT, varied across centers surveyed. CONCLUSIONS: There is lack of national consensus on diagnosis and treatment of pediatric MDS. This survey identified key aspects of MDS management that will warrant systematic review toward the goal of developing national clinical practice guidelines for pediatric MDS.

Development of Electronic Chemotherapy Roadmaps for Pediatric Oncology Patients.

A chemotherapy roadmap is a summary of the chemotherapy plan for a pediatric oncology patient. Chemotherapy roadmaps exist as paper documents for most, if not all, pediatric oncology programs. Paper chemotherapy roadmaps are associated with risks that can negatively affect the safety of the chemotherapy process. This institution explored the feasibility of converting paper chemotherapy roadmaps into an electronic form. The pediatric information systems team developed an innovative computer application that can generate electronic chemotherapy roadmaps, and the pediatric oncology program established a novel workflow that can operationalize them. Electronic chemotherapy roadmaps have been produced for 36 treatment protocols, and 369 electronic chemotherapy roadmaps have been used for 352 pediatric oncology patients. They have functioned as designed and have not had any unintended effects. In the 5 years after their implementation, the average proportion of patient safety events involving paper or electronic chemotherapy roadmaps decreased by 78.7%. This report is the first to demonstrate the feasibility of creating and implementing electronic chemotherapy roadmaps. Continued expansion of the current library will be necessary to formally test the hypothesis that electronic chemotherapy roadmaps can decrease the risks associated with their paper counterparts and increase the safety of the chemotherapy process.

Hitomi X-ray studies of Giant Radio Pulses from the Crab pulsar.

To search for giant X-ray pulses correlated with the giant radio pulses (GRPs) from the Crab pulsar, we performed a simultaneous observation of the Crab pulsar with the X-ray satellite Hitomi in the 2 - 300 keV band and the Kashima NICT radio observatory in the 1.4 - 1.7 GHz band with a net exposure of about 2 ks on 25 March 2016, just before the loss of the Hitomi mission. The timing performance of the Hitomi instruments was confirmed to meet the timing requirement and about 1,000 and 100 GRPs were simultaneously observed at the main and inter-pulse phases, respectively, and we found no apparent correlation between the giant radio pulses and the X-ray emission in either the main or inter-pulse phases. All variations are within the 2 sigma fluctuations of the X-ray fluxes at the pulse peaks, and the 3 sigma upper limits of variations of main- or inter-pulse GRPs are 22% or 80% of the peak flux in a 0.20 phase width, respectively, in the 2 - 300 keV band. The values become 25% or 110% for main or inter-pulse GRPs, respectively, when the phase width is restricted into the 0.03 phase. Among the upper limits from the Hitomi satellite, those in the 4.5-10 keV and the 70-300 keV are obtained for the first time, and those in other bands are consistent with previous reports. Numerically, the upper limits of main- and inter-pulse GRPs in the 0.20 phase width are about (2.4 and 9.3) ×10-11 erg cm-2, respectively. No significant variability in pulse profiles implies that the GRPs originated from a local place within the magnetosphere and the number of photon-emitting particles temporally increases. However, the results do not statistically rule out variations correlated with the GRPs, because the possible X-ray enhancement may appear due to a > 0.02% brightening of the pulse-peak flux under such conditions.

A uniform metal distribution in the intergalactic medium of the Perseus cluster of galaxies.

Most of the metals (elements heavier than helium) produced by stars in the member galaxies of clusters currently reside within the hot, X-ray-emitting intra-cluster gas. Observations of X-ray line emission from this intergalactic medium have suggested a relatively small cluster-to-cluster scatter outside the cluster centres and enrichment with iron out to large radii, leading to the idea that the metal enrichment occurred early in the history of the Universe. Models with early enrichment predict a uniform metal distribution at large radii in clusters, whereas those with late-time enrichment are expected to introduce significant spatial variations of the metallicity. To discriminate clearly between these competing models, it is essential to test for potential inhomogeneities by measuring the abundances out to large radii along multiple directions in clusters, which has not hitherto been done. Here we report a remarkably uniform iron abundance, as a function of radius and azimuth, that is statistically consistent with a constant value of ZFe = 0.306 ± 0.012 in solar units out to the edge of the nearby Perseus cluster. This homogeneous distribution requires that most of the metal enrichment of the intergalactic medium occurred before the cluster formed, probably more than ten billion years ago, during the period of maximal star formation and black hole activity.

Baryons at the edge of the X-ray-brightest galaxy cluster.

Studies of the diffuse x-ray-emitting gas in galaxy clusters have provided powerful constraints on cosmological parameters and insights into plasma astrophysics. However, measurements of the faint cluster outskirts have become possible only recently. Using data from the Suzaku x-ray telescope, we determined an accurate, spatially resolved census of the gas, metals, and dark matter out to the edge of the Perseus Cluster. Contrary to previous results, our measurements of the cluster baryon fraction are consistent with the expected universal value at half of the virial radius. The apparent baryon fraction exceeds the cosmic mean at larger radii, suggesting a clumpy distribution of the gas, which is important for understanding the ongoing growth of clusters from the surrounding cosmic web.

Copy number gains in EGFR and copy number losses in PTEN are common events in osteosarcoma tumors.

BACKGROUND: Osteosarcoma cell lines and tumors have been shown to express epidermal growth factor receptor (EGFR) and harbor amplifications at the EGFR locus. In this study, the authors further analyzed the genomic features of EGFR in osteosarcoma tumors and investigated whether they correlate with phosphatase and tensin homolog (PTEN) expression and copy number status. METHODS: EGFR and PTEN expression was assessed by immunohistochemistry (n = 28), and copy number alterations at the EGFR and PTEN loci were surveyed using Affymetrix (Santa Clara, Calif) 50K single nucleotide polymorphism (SNP) arrays (n = 31) and fluorescence in situ hybridization (FISH) (n = 27). The EGFR tyrosine kinase domain was sequenced to survey for activating mutations (n = 34). In addition, EGFRvIII expression was assessed using reverse transcriptase polymerase chain reaction (n = 24). Results were correlated with available clinical information on 59 patients, with a median age of 14.1 years (range, 5-23 years) and median follow-up of 4.4 years. RESULTS: EGFR expression was detected in the majority of osteosarcoma tumors surveyed (23 of 28; 82%). SNP arrays revealed evidence of frequent copy number gains at 7p11.2 and losses at 10q23.21. A sizeable subset (16 of 27 cases; 59%) showed gains at the EGFR locus using FISH (amplification in 4 of 27 [15%] and balanced chromosome 7 polysomy in 12 of 27 [44%]), and 12 cases showed deletions at the PTEN locus (biallelic deletions in 4 of 27 [15%] and monoallelic deletion in 9 of 27 [33%]). No activating mutations in the EGFR tyrosine kinase domain, EGFRvIII expression, or association with clinical findings were detected. CONCLUSIONS: EGFR expression and genomic gains at the EGFR locus are prevalent in osteosarcoma tumors, which also commonly harbor deletions at the PTEN locus.

Evidence-based referral results in significantly reduced mortality after congenital heart surgery.

OBJECTIVE: Significant interinstitutional variation in mortality after congenital heart surgery has been demonstrated. Noting an association between reduced mortality and higher volume, a center with a small annual case volume began in August 1998 to selectively refer to high-volume surgical centers based on published or "apparent" low mortality rates for specific cardiac lesions. This study was undertaken to evaluate the effect of evidence-based referral in this practice. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort comparison over a 10-year period for a small Midwestern pediatric cardiology practice. The institutional database was retrospectively reviewed for children (<18 years) undergoing surgery from August 1992 to July 2002. Data were divided into 3 time periods (August 1992 to July 1995, period 1; August 1995 to July 1998, period 2; and August 1998 to July 2002, period 3). Hospital discharge abstract data from 5 states (California, Illinois, Massachusetts, Pennsylvania, and Washington) in 1992, 1996, and 1998 provided contemporaneous benchmarks. Risk adjustment was performed using the Risk Adjustment in Congenital Heart Surgery-1 method. Risk category, age at surgery, prematurity, and major noncardiac structural anomaly were entered into a multivariate logistic regression model to compare in-hospital mortality adjusting for case-mix differences. RESULTS: A total of 514 congenital heart surgical cases were identified from August 1992 to July 2002; 507 cases (98.6%) were assigned to a risk category and analyzed further. Unadjusted in-hospital mortality rates were 9.3% in period 1, 5.9% in period 2, and 1.3% in period 3. Unadjusted mortality rates for cases from benchmark data were 6.4% in 1992, 4.8% in 1996, and 3.7% in 1998. Risk adjusted mortality was comparable to the benchmark data in periods 1 and 2, but superior outcomes (odds ratio = 0.24) were demonstrated in period 3. CONCLUSIONS: Evidence-based referrals from a small-volume pediatric cardiac center to large-volume institutions resulted in a reduction in mortality after congenital heart surgery.

Cosmological constraints from Chandra observations of galaxy clusters.

Chandra observations of rich, relaxed galaxy clusters allow the properties of the X-ray gas and the total gravitating mass to be determined precisely. Here, we present results for a sample of the most X-ray luminous, dynamically relaxed clusters known. We show that the Chandra data and independent gravitational lensing studies provide consistent answers on the mass distributions in the clusters. The mass profiles exhibit a form in good agreement with the predictions from numerical simulations. Combining Chandra results on the X-ray gas mass fractions in the clusters with independent measurements of the Hubble constant and the mean baryonic matter density in the Universe, we obtain a tight constraint on the mean total matter density of the Universe, Omega(m), and an interesting constraint on the cosmological constant, Omega(Lambda). We also describe the 'virial relations' linking the masses, X-ray temperatures and luminosities of galaxy clusters. These relations provide a key step in linking the observed number density and spatial distribution of clusters to the predictions from cosmological models. The Chandra data confirm the presence of a systematic offset of ca. 40% between the normalization of the observed mass-temperature relation and the predictions from standard simulations. This finding leads to a significant revision of the best-fit value of sigma(8) inferred from the observed temperature and luminosity functions of clusters.