Neuroblastoma

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they...

Amplification of the human N-MYC proto-oncogene is frequently seen either in extrachromosomal double minutes or in homogeneously staining regions of aggressively growing neuroblastomas. N-MYC maps to chromosome 2 band p23-24, but homogeneously staining regions have never been observed at this band, suggesting transposition of N-MYC during amplification. Previous studies had suggested that in cells with amplified N-MYC the chromosomes 2 appear to be unaltered and to carry one apparently normal copy of N-MYC each. In contrast, the contribution of N-MYC to tumors which lack amplification has been unclear. We here show, by fluorescence in situ hybridization, that N-MYC is occasionally duplicated at its resident site in neuroblastoma cell lines previously thought to have a single copy gene. Additionally, we detected duplication in a neuroblastoma cell line carrying amplification. Our results raise the possibility that duplication may, in some neuroblastomas, either be a prelude to amplif...

Supraglottic stenosis/collapse is an uncommon condition. It can be difficult to detect and may be a cause of failed decannulation following tracheostomy. We present a novel technique to correct supraglottic stenosis/collapse. We performed a retrospective analysis of the records of patients in whom attempts at decannulation had failed at our center between 2003 and 2007. A subgroup with supraglottic stenosis/collapse with posterior displacement of the base of the epiglottis was identified. Our epiglottic repositioning procedure was performed in these patients. Through an external incision, the epiglottis was divided above the anterior commissure and attached to the superior border of the thyroid cartilage. Eight decannulation failures out of 36 attempted decannulations were identified. Three of these 8 cases involved supraglottic stenosis/collapse due to posterior displacement of the base of the epiglottis. Correction of the supraglottic stenosis/collapse led to successful decannulat...

Paclitaxel is an antimicrotubule agent that induces mitotic block and apoptosis. We show for the first time that paclitaxel acts directly on mitochondria isolated from human cancer cells. In isolated yeast mitochondria, paclitaxel (15 μm) induced an 18% increase in the ...

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real--time PK.Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m(2) Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m(2); n = 1) or grade 4 thrombocytopenia (470 mg/m(2); n = 2). Most common treatment-related adverse events (AE)...

Summary: We report a case of a hypothalamic chiasmatic ganglioglioma in a 21-year-old woman who presented with hyperprolactinemia and developed visual field defects. This circumscribed cystic lesion with an enhancing mural nod- ule was radiologically indistinguishable from a pilocytic as- trocytoma. Although rare, gangliogliomas should be in- cluded in the differential diagnosis of lesions occurring in this area of the brain. Gangliogliomas, although relatively rare, are the most frequently occurring mixed glioneuronal tu- mors of the CNS (1). Their incidence ranges from 0.4% to 1.3% of all brain tumors, but they are more common in the pediatric group, with an incidence of 7.6% (2, 3). Patients usually present with sei- zures (2). The temporal lobes are the most common site, but gangliogliomas can occur anywhere in the central neuraxis, including the brain stem and spi- nal cord (1). We report a case of a ganglioglioma arising in the hypothalamic chiasmatic region and its MR imaging...

Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa's nootropic action are not understood. In this study, we used deep sequencing (RNA-Seq) to identify the transcriptome changes upon Bacopa treatment on SH-SY5Y human neuroblastoma cells. We identified several genes whose expression levels were regulated by Bacopa. Biostatistical analysis of the RNA-Seq data identified biological pathways and molecular functions that were regulated by Bacopa, including regulation of mRNA translation and transmembrane transport, responses to oxidative stress and protein misfolding. Pathway analysis using the Ingenuity platform suggested that Bacopa may protect against brain damage and improve brain development. These newly identified molecular and cellular determinants may contribute to the nootropic...

Neuroblastoma is the most frequent tumor observed in the newborn. The aim of this study was to review clinical features, treatment and outcome of newborns diagnosed with a localized neuroblastoma.

POPULATION AND METHODS:
Data from 52 cases treated according to the NBL 90 and 94 protocols between 1990 and 1999 in 18 French centers of pediatric oncology were analyzed.

RESULTS:
The median age at diagnosis was 12 days (range 0-28) with antenatal detection in 14 patients (27%). Tumor location was abdominal in 40 patients (adrenal in 20 of the 40), thoracic in eight, pelvic in three, and cervical in one. N-myc amplification was observed in one out of 40 evaluable cases. The size of the primary tumor was less than 5 cm in 25 cases, between 5 and 10 cm in 25 and more than 10 cm in two. Dumbbell tumor was observed in seven, of whom five had neurological deficit. One child died from hemorrhage after fine needle biopsy during diagnostic procedure. Primary surgical resection was attempted in 37 infants, of whom two died of surgery related complications and three had nephrectomy. Tumor was deemed as unresectable in 14 patients, and primary chemotherapy was given followed by surgical excision in 12. One of them died a few days after the beginning of chemotherapy. As a whole, continuous complete remission was achieved in 48 children, four of them after relapse. Overall survival was 92% with a median follow-up of 46 months (0-113 months).

CONCLUSION:
The excellent prognosis of localized NB in neonates needs very restrictive surgical indications, with well-established anatomic and imaging criteria. Indeed, chemotherapy based on weight and managed by expert teams should allow to perform surgical excision in safer conditions for unresectable tumors.

WILMA WASCO*t4, KEITH BUPP*§, MARGARET MAGENDANTZ*, JAMES F. GUSELLAt, RUDOLPH E. TANZIt, AND FRANK SOLOMON* *Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and tMolecular ...

Neuroblastoma is the most common extracranial solid tumor in childhood in high-income countries (HIC), where consistent treatment approaches based on clinical and tumor biological risk stratification have steadily improved outcomes. However, in low- and middle- income countries (LMIC), suboptimal diagnosis, risk stratification, and treatment may occur due to limited resources and unavailable infrastructure. The clinical practice guidelines outlined in this manuscript are based on current published evidence and expert opinions. Standard risk stratification and treatment explicitly adapted to graduated resource settings can improve outcomes for children with neuroblastoma by reducing preventable toxic death and relapse. Pediatr Blood Cancer © 2015 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

B-myb gene is expressed in neuroblastoma cells and down-regulated during differentiation. We used B-myb-transfected LAN-5 cells, which constitutively express high level of B-myb, to detect changes at phenotypic and morphological levels in basal and differentiation conditions. Our results demonstrate that the overexpression of B-myb markedly affects the cytoskeletal composition, the pattern of neurotransmitter enzymes and the extracellular matrix expression. In general, B-myb transfected neuroblastoma cells show a broad potentiality without a direction toward a specific neuroectodermal differentiation pathway. On the other hand, we confirm inhibition of the neuronal differentiation upon retinoic acid (RA) treatment of B-myb transfected cells. Furthermore, the ultrastructural analyses are supportive of a change in the metabolism in B-myb transfected cell treated with RA. Our data suggest that B-myb expression is compatible with an early phase of differentiation of neuroectodermal cells, but must be down-regulated for the completion of the differentiative programme.