Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Oral sirolimus for the treatment of juvenile xanthogranuloma: Report of two pediatric cases.

Juvenile xanthogranuloma (JXG) with extensive cutaneous or visceral organ involvement is often associated with high morbidity and treatment commonly involves surgical excision, radiotherapy, systemic steroids, or chemotherapy. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is an oral antitumor and immunosuppressive therapy used to treat various neoplastic disorders, including histiocytic disorders. We report two pediatric cases of JXG successfully treated with oral sirolimus monotherapy, and postulate that sirolimus may induce rapid disease resolution and long-term remission for patients with both skin-limited and multisystemic JXG. Our findings warrant further investigation of the relationship between the mTOR pathway and JXG.

Mycophenolate Mofetil Use in Pediatric Immune Thrombocytopenia Refractory to First-line Therapy: a Single-center Experience.

Most children treated for immune thrombocytopenia remit during the first year following diagnosis. For the ∼40% who develop persistent or chronic disease, second-line treatment options include immunomodulation and thrombomimetic agents. While immunomodulators target the underlying mechanism, prolonged immunosuppression may increase the risk of infection. We report the use of the reversible immunomodulating agent mycophenolate mofetil (MMF) in 16 pediatric patients with immune thrombocytopenia refractory to first-line treatment. Using escalating doses up to 2400 mg/m 2 /d, MMF treatment resulted in a 73% response rate. Adverse events were mostly mild and tolerable. Complete responders have been successfully tapered off MMF with sustained responses.

Pediatric Peritoneal Epithelial Malignant Mesothelioma Case Report.

We present a 14-year-old boy with peritoneal epithelial malignant mesothelioma (PEMM). While pathology is required to make this diagnosis, radiology plays a crucial role throughout the clinical course of this disease. The key imaging characteristics of peritoneal mesothelioma have been previously well-described in the adult population, but there are rare reports in the pediatric population. This pediatric report highlights the multidimensional use of imaging in this disease, from the initial evaluation to therapeutic supplementation and subsequent follow-up.

Severe Coronavirus Disease 2019 Infection in an Adolescent Patient After Hematopoietic Stem Cell Transplantation.

Infection with the severe acute respiratory syndrome coronavirus 2 causes severe acute lung injury in approximately 5% of infected adults, but few reports have been made of severe pediatric disease. We present an adolescent patient who contracted severe acute respiratory syndrome coronavirus 2 one week after a paternal haplo-identical hematopoietic stem cell transplant, with development of severe hyperferritinemic acute lung injury and macrophage activation-like syndrome. We present her case and a comparison of her laboratory data with those of a cohort of pediatric patients with coronavirus disease 2019 without severe disease.

The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) can be familial or secondary, which is often triggered by infection or malignancy. HLH therapy includes dexamethasone and etoposide. However, therapy is associated with significant morbidity and mortality. Anakinra, a recombinant interleukin-1 receptor antagonist, has been reported to treat macrophage activation syndrome (MAS), rheumatic sHLH. We report our experience with anakinra to treat patients with nonrheumatic secondary HLH (sHLH). PROCEDURE: Six children were diagnosed with HLH from December 2014 to August 2016 and were treated with subcutaneous anakinra (6-10 mg/kg/day divided over four doses) with or without dexamethasone (10 mg/m2 /day). Therapy was either escalated or weaned based on clinical and laboratory response. RESULTS: Five of six patients were treated with anakinra and dexamethasone, and one with anakinra alone due to active cytomegalovirus (CMV) pneumonitis. The median age of diagnosis was 1.8 years (range 0.8-14.9 years). No pathogenic mutations associated with HLH were identified, but three of six possessed genetic variants of unknown significance. Infectious triggers were identified for four patients and two patients had malignancies. The average treatment duration was 8 weeks with 3.5-5.5 years of follow up. No patient needed escalation of therapy to include etoposide. All patients achieved remission. Anakinra was well tolerated without significant adverse effects. CONCLUSION: Initial treatment with anakinra (with or without dexamethasone) is a feasible treatment alternative for patients with secondary HLH and may allow for avoidance of etoposide. We recommend early initiation of anakinra when HLH is suspected. A broader investigation of the use of anakinra as a first-line agent for HLH is ongoing.

A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.

Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.

Health supervision for people with Bloom syndrome.

Bloom Syndrome (BSyn) is an autosomal recessive disorder that causes growth deficiency, endocrine abnormalities, photosensitive skin rash, immune abnormalities, and predisposition to early-onset cancer. The available treatments for BSyn are symptomatic, and early identification of complications has the potential to improve outcomes. To accomplish this, standardized recommendations for health supervision are needed for early diagnosis and treatment. The purpose of this report is to use information from the BSyn Registry, published literature, and expertise from clinicians and researchers with experience in BSyn to develop recommendations for diagnosis, screening, and treatment of the clinical manifestations in people with BSyn. These health supervision recommendations can be incorporated into the routine clinical care of people with BSyn and can be revised as more knowledge is gained regarding their clinical utility.

Racial and ethnic disparities in treatment and survival of pediatric sarcoma.

BACKGROUND: Childhood sarcomas are rare and require complex interdisciplinary care including surgery, chemotherapy, and radiation. The goal of this study was to determine if racial or ethnic disparities exist for pediatric sarcoma patients in the United States. METHODS: The United States' National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 diagnosed with primary sarcomas from 1973 to 2012. Patients were considered by race and ethnicity. Survival curves were computed using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 11,502 patients were included in this study. When stratified by race, non-Hispanic black and Hispanic patients were significantly more likely to present with advanced stage disease than white patients. White patients were more likely to receive radiation therapy than black and Hispanic patients (P = 0.01). There was no significant difference between patients who underwent surgery (P = 0.21). Overall survival was better for white patients than black or Hispanic ones. Despite the overall 5-year survival improvement during the study period (56.2%-70.3%), survival disparities between race and ethnicity have grown. CONCLUSIONS: Racial and ethnic disparities do exist with respect to stage, treatment, and survival of these rare tumors. Black and Hispanic patients are presenting at more advanced stage and have overall worse survival. This survival disparity has widened over the past 4 decades.

Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children's Oncology Group Study.

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. ß-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

Chest wall Ewing sarcoma: a population-based analysis.

BACKGROUND: The globally low incidence of pediatric chest wall Ewing sarcoma (CWES) has limited prior studies of this disease to mostly small, single-institution reviews. Our objective was to assess incidence, demographics, treatment patterns, and long-term survival of this disease through a population-based analysis. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 y diagnosed with CWES from 1973 to 2011. Patients were grouped by decade to assess changes in treatment patterns and outcomes. The effects of clinical, demographic, and treatment variables on overall survival (OS) were assessed by the computation of Kaplan-Meier curves and the log-rank test, with Cox proportional hazard regression used for multivariable analysis. RESULTS: A total of 193 pediatric patients with histologically confirmed CWES were identified. The disease was more common in men (61%), whites (92%), and 11- to 17-y olds (49%). It was metastatic at presentation in 37% of patients. When grouped approximately by decade, 10-y OS improved progressively from 38% in 1973-1979 to 65% in 2000-2011 (P = 0.033). The use of radiation decreased from 84% in the earliest period to 40% in the most recent, whereas the proportion of patients receiving surgery increased from 75% to 85%. When controlling for covariates in multivariable analysis, male patients were found to have a higher mortality than female patients (hazard ratio: 2.4; confidence interval: 1.4, 4.4; P = 0.0028). CONCLUSIONS: This population-based analysis of CWES demonstrated an impressive trend of improving OS, with increasing use of surgery and decreasing use of radiation therapy. Our study demonstrated a gender difference in survival of CWES, with females having a better prognosis. The presence of metastatic disease is a very important prognostic factor for this illness.

Esophageal carcinoma in children and adolescents.

BACKGROUND: Esophageal cancer is rare in children and is limited to isolated case reports. We describe 2 cases of esophageal carcinoma (1 case each of squamous cell carcinoma and adenocarcinoma) and present literature review of esophageal carcinoma in childhood. OBSERVATIONS: Both of our patients had common symptoms of progressive dysphagia and significant weight loss at presentation. We were unable to identify any specific predisposing factors for either adenocarcinoma (caustic ingestion, reflux disease, Barrett esophagus) or squamous cell carcinoma (caustic ingestion, inherited bone marrow failure syndromes). Both patients responded poorly to chemotherapy and died of progressive disease. CONCLUSIONS: On account of the rarity of esophageal carcinoma in this age group, there are no management guidelines for the pediatric oncologist. There is a strong need for collaborative efforts between adult and pediatric oncologists to establish cooperative diagnostic and therapeutic protocols for successful management of rare pediatric tumors like esophageal carcinoma.

Reversible posterior leukoencephalopathy syndrome in a child treated with bevacizumab.

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Hypertension is a well-recognized, common side effect of VEGF blocking agents. The reversible posterior leukoencephalopathy syndrome (RPLS) has been described as a rare but serious consequence of bevacizumab administration. We present a case of a 6-year-old child with refractory hepatoblastoma who developed hypertensive crisis, seizures and MRI changes consistent with RPLS while receiving bevacizumab with gemcitabine and oxaliplatin. Findings completely resolved without neurologic sequelae with stringent blood-pressure control. Better understanding of risk for RPLS, prompt recognition and aggressive management will be required as bevacizumab gains wider use in pediatrics.