Beckwith–Wiedemann syndrome (BWS) is a genetic syndrome associated with overgrowth and cancer predisposition, including predisposition to Wilms tumor (WT). Patients with BWS and BWS spectrum are ...screened from birth to age 7 years for BWS‐associated cancers. However, in some cases a BWS‐associated cancer may be the first recognized manifestation of the syndrome. We describe 12 patients diagnosed with BWS after presenting with a WT. We discuss the features of BWS in these patients and hypothesize that earlier detection of BWS by attention to its subtler manifestations could lead to earlier detection of children at risk for associated malignancies.
Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life‐saving, these ...therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.
Cancer genomic studies that rely on analysis of biopsies from primary tumors may not fully identify the molecular events associated with tumor progression. We hypothesized that characterizing the ...transcriptome during tumor progression in the TH-MYCN transgenic model would identify oncogenic drivers that would be targetable therapeutically. We quantified expression of 32,381 murine genes in nine hyperplastic ganglia harvested at three time points and four tumor cohorts of progressively larger size in mice homozygous for the TH-MYCN transgene. We found 93 genes that showed a linearly increasing or decreasing pattern of expression from the preneoplastic ganglia to end stage tumors. Cross-species integration identified 24 genes that were highly expressed in human MYCN-amplified neuroblastomas. The genes prioritized were not exclusively driven by increasing Myc transactivation or proliferative rate. We prioritized three targets centromere-associated protein E (Cenpe), Gpr49, and inosine monophosphate dehydrogenase type II with previously determined roles in cancer. Using siRNA knockdown in human neuroblastoma cell lines, we further prioritized CENPE due to inhibition of cellular proliferation. Targeting CENPE with the small molecular inhibitor GSK923295 showed inhibition of in vitro proliferation of 19 neuroblastoma cell lines (median IC(50), 41 nmol/L; range, 27-266 nmol/L) and delayed tumor growth in three xenograft models (P values ranged from P < 0.0001 to P = 0.018). We provide preclinical validation that serial transcriptome analysis of a transgenic mouse model followed by cross-species integration is a useful method to identify therapeutic targets and identify CENPE as a novel therapeutic candidate in neuroblastoma.
Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by aggressive local invasion and a syndrome of platelet trapping known as Kasabach-Merritt phenomenon that, through ...deposition of platelet derived growth factors, may perpetuate the growth of the tumor. Although many cases of KHE are successfully treated with local control or low-intensity chemotherapy, some cases are often refractory even to aggressive treatment. Herein, we describe a patient with a refractory, recurrent KHE despite multiple attempts at local control and intensive chemotherapy, that ultimately was successfully treated with rationally designed and low-intensity combination therapy of sirolimus and aspirin.
Hemophagocytic lymphohistiocytosis is a rare, life-threatening complication of Epstein Barr virus (EBV) infection. Current treatments are directed at reducing virus-induced immune dysregulation. ...Addition of agents that eliminate EBV-infected B cells may improve therapeutic efficacy. On the basis of the observations that the anti-CD-20 monoclonal antibody rituximab reduces disease burden in individuals with EBV-associated lymphoproliferative disorders, we treated a patient with severe EBV-hemophagocytic lymphohistiocytosis using a combination of rituximab and chemotherapy. This patient demonstrated a rapid clinical response and an 18-fold reduction in EBV viral load within 24 hours of receiving rituximab. He remains free of disease 8 months after completing treatment.
Ectopic production of β-human chorionic gonadotropin (β-hCG) by nontrophoblastic tumors has been reported but mostly in carcinomas. We report a case of an adolescent female patient with a epithelioid ...osteosarcoma that was discovered to secrete β-hCG after routine pregnancy testing. Immunohistochemical staining of her primary tumor biopsy demonstrated immunoreactivity for β-hCG. Levels of serum β-hCG were monitored throughout her therapy and demonstrated normalization with effective systemic therapy and local control. She remains disease free 6 months off therapy, with undetectable hormone levels. A review of the available literature on β-hCG production by sarcomas is also presented.
Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types ...of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene
are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in
are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of
in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels.
The most common mutation in cystic fibrosis, Delta F508, results in a cystic fibrosis transmembrane conductance regulator (CFTR) protein that is retained in the endoplasmic reticulum (ER). Retention ...is dependent upon chaperone proteins, many of which require Ca(++) for optimal activity. Interfering with chaperone activity by depleting ER Ca(++) stores might allow functional Delta F508-CFTR to reach the cell surface. We exposed several cystic fibrosis cell lines to the ER Ca(++) pump inhibitor thapsigargin and evaluated surface expression of Delta F508-CFTR. Treatment released ER-retained Delta F508-CFTR to the plasma membrane, where it functioned effectively as a Cl(-) channel. Treatment with aerosolized calcium-pump inhibitors reversed the nasal epithelial potential defect observed in a mouse model of Delta F508-CFTR expression. Thus, ER calcium-pump inhibitors represent a potential target for correcting the cystic fibrosis defect.
This is a report of an 11-year-old, prepubertal boy with acute-onset urinary urgency and frequency, obsessions and compulsions related to urination, severe mood lability, inattention, impulsivity, ...hyperactivity, and intermittent periods of immobilization. Fever, cough, otitis, and sinusitis preceded neuropsychiatric symptoms. Antistreptolysin O and DNAse B antibody titers were elevated, and magnetic resonance imaging revealed bilateral diffuse caudate nuclei swelling. Plasmapheresis resulted in significant and rapid clinical improvement of obsessive-compulsive disorder symptoms and a simultaneous decrease in basal ganglia swelling, consistent with an immune-mediated pathophysiological process involving group A beta-hemolytic streptococci. Hyperactivity, impulsivity, and inattention improved with lorazepam, suggesting that the attention-deficit/hyperactivity disorder symptoms could be manifestations of catatonia.
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