Amulya A. Nageswara Rao

Pleomorphic xanthoastrocytoma in children and adolescents.

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor occurring primarily in children and young adults. The superficial location of the tumor facilitates gross total resection (GTR) thus conferring a relatively favorable outcome with a reported 10‐year overall survival (OS) of 70%.

Rituximab for successful management of probable pediatric catastrophic antiphospholipid syndrome

Catastrophic antiphospholipid syndrome (CAPS) is a life‐threatening condition characterized by small‐vessel thrombi and a rapid onset of multiorgan system failure associated with systemic inflammatory response syndrome. Current treatment options include anticoagulants, corticosteroids, plasma exchange, and intravenous immunoglobulin, but these are not always effective. Rituximab, a chimeric anti‐CD20 monoclonal antibody, may help eliminate autoreactive B cells and thus limit the rapid inflammatory process involved in CAPS. We describe the use of rituximab in the successful initial management of a probable case of pediatric CAPS. Pediatr Blood Cancer 2009;52:536–538.

Biologically targeted therapeutics in pediatric brain tumors.

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale.

Cumulative cisplatin dose is not associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma treated with cisplatin based adjuvant chemotherapy: report from the Children's Oncology Group.

Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin‐containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with newly diagnosed average‐risk medulloblastoma.

Transient neonatal acquired von Willebrand syndrome due to transplacental transfer of maternal monoclonal antibodies

Although typically a disorder of adults, acquired von Willebrand syndrome (AVWS) is increasingly being recognized in the pediatric population in association with congenital cardiac diseases, certain neoplasia, and hypothyroidism. Transplacental transfer of maternal immunoglobulin G (IgG) antibodies as a cause of neonatal disorders in infants born to mothers with autoimmune conditions has been reported. We describe the diagnosis and peripartum clinical management of AVWS due to monoclonal gammopathy of undetermined significance (MGUS) and the first reported case of transient neonatal AVWS due to transplacental transfer of maternal IgG antibodies. Pediatr Blood Cancer 2009;53:655–657.

Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation.

Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy‐number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A‐PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%–60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A‐PXA (93%), BRAF V600E (87%), and wild‐type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses −22 (n = 11), −14 (n = 7), −13 (n = 5). Losses and copy‐neutral loss of heterozygosity were significantly more common in A‐PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy‐number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A‐PXA with areas of distinct low‐ and high‐grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy‐number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy‐number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

Bilateral temporal bone langerhans cell histiocytosis: radiologic pearls.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder with an unpredictable clinical course and highly varied clinical presentation ranging from single system to multisystem involvement. Although head and neck involvement is common in LCH, isolated bilateral temporal bone involvement is exceedingly rare. Furthermore, LCH is commonly misinterpreted as mastoiditis, otitis media and otitis externa, delaying diagnosis and appropriate therapeutic management. To improve detection and time to treatment, it is imperative to have LCH in the differential diagnosis for unusual presentations of the aforementioned infectious head and neck etiologies. Any lytic lesion of the temporal bone identified by radiology should raise suspicion for LCH. We hereby describe the radiologic findings of a case of bilateral temporal bone LCH, originally misdiagnosed as mastoiditis.

Neurotoxicity of Biologically Targeted Agents in Pediatric Cancer Trials

Biologically targeted agents offer the promise of delivering specific anticancer effects while limiting damage to healthy tissue, including the central and peripheral nervous systems. During the past 5-10 years, these agents were examined in preclinical and adult clinical trials, and are used with increasing frequency in children with cancer. This review evaluates current knowledge about neurotoxicity from biologically targeted anticancer agents, particularly those in pediatric clinical trials. For each drug, neurotoxicity data are reviewed in adult (particularly studies of brain tumors) and pediatric studies when available. Overall, these agents are well tolerated, with few serious neurotoxic effects. Data from younger patients are limited, and more neurotoxicity may occur in the pediatric population because these agents target pathways that control not only tumorigenesis but also neural maturation. Further investigation is needed into long-term neurologic effects, particularly in children.

Management of pediatric hepatocellular carcinoma: A multimodal approach

HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post‐transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post‐transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.

Neonatal renal vein thrombosis: Role of anticoagulation and thrombolysis—An institutional review

ABSTRACT Neonatal renal vein thrombosis (NRVT) is a rare thromboembolic complication in the neonatal period, and sequelae from renal dysfunction can cause significant morbidity. The authors retrospectively reviewed 10 patients with NRVT treated at their institution. The majority of the cohort were male (n = 9), preterm (n = 6), and had unilateral NRVT (n = 6). Six patients received thrombolysis and/or anticoagulation, and 4 patients received supportive care only. Two of the 6 patients treated with anticoagulation who had bilateral NRVT and anuria received thrombolysis with low-dose tissue plasminogen activator. Thrombolysis was not associated with any major adverse events, and both patients had marked improvement of renal function. Eight patients subsequently developed renal atrophy (3 received anticoagulation, 2 received thrombolysis with anticoagulation, and 3 received supportive care). Anticoagulation/thrombolysis did not appear to prevent renal atrophy. The role of thrombolysis needs to be further studied and considered in the setting of bilateral NRVT and acute renal failure.