Neuroblastoma progress on many fronts: the Neuroblastoma Research Symposium

Neuroblastoma (NBL) is a pediatric tumor of infancy derived from precursor cells of the sympathetic nervous system. Clinicians and researchers in developmental biology and genetics recently met to facilitate meaningful crosstalk and to discuss considerable progress made in the clinical treatment and basic biology of NBL. For instance, discoveries in familial NBL have identified genetic aberrations in Phox2b and Alk that predispose to NBL, while advances in epigenetics and MYCN regulation have also offered insight into NBL pathogenesis and future treatment. Moreover, novel therapeutic avenues are also being explored, including targeted immunotherapies, and innovative radiotherapeutic and chemotherapeutic approaches. This multi-disciplinary meeting was convened to aid the transfer of new biological findings into the clinic and to use clinical advances to inform the basic biological understanding of this devastating disease.     

Gangliosides promote platelet adhesion and facilitate neuroblastoma cell adhesion under dynamic conditions simulating blood flow

BACKGROUND: Aberrant gangliosides are produced and shed by some tumors into the extracellular milieu. Their concentration is related to disease progression in children with neuroblastoma and in experimental models. The mechanism for this tumor promoting effect is not known. PURPOSE: Here, we investigated the effect of gangliosides on platelet and tumor cell adhesion under shear forces simulating venous and arterial flow. RESULTS: High shear force increased platelet adhesion 2.5-fold compared to low force. Pre-incubation of platelets with gangliosides increased adhesion at low shear to a level comparable to high shear alone. The addition of gangliosides to platelets perfused at high shear did not further increase adhesion. LAN1 neuroblastoma cells are adherent to collagen in static assays. No effect of either shear or gangliosides was observed on cell adhesion under dynamic conditions. However, when perfused in the presence of platelets, an increase in binding of tumor cells was observed at both shear forces compared to cells alone. CONCLUSIONS: These results demonstrate that shear and gangliosides increase dynamic platelet adhesion to collagen. In addition, platelets facilitate tumor cell binding. Therefore, by acting as a mediator of platelet activation, gangliosides may promote blood borne metastasis by increasing platelet binding to the vessel wall and in turn facilitate tumor cell arrest in circulation.     

Cabozantinib for relapsed neuroblastoma: Single institution case series

Relapsed high‐risk neuroblastoma has few effective therapies currently available or in development. Cabozantinib is an Food and Drug Administration approved multitargeted tyrosine kinase inhibitor for select adult malignancies with preclinical data suggesting efficacy against neuroblastoma. A safe and tolerable dose has been identified for children, but its efficacy remains unknown. We describe four children with relapsed metastatic neuroblastoma treated with cabozantinib. All four patients had extended disease control (two complete responsesfor >12 months, 2 stable disease >6 months) with manageable predictable toxicities requiring dose reduction in two patients. We discuss the potential for the use of cabozantinib in neuroblastoma.     

Fetal and neonatal neuroblastoma: retrospective review of 271 cases

Neuroblastoma is the foremost malignant neoplasm of the fetus and neonate. The tumor is unique because of its distinctive biologic behavior and many different clinical manifestations. The purpose of this review is to focus on the fetus and neonate to determine the various ways perinatal neuroblastomas differ clinically and morphologically and in their treatment from those found in the older child to show that some forms of the tumor have a better outcome than others. The report attempts to evaluate the influence of site, histology, stage, biologic markers, and treatment on survival.     

Rapid and accurate determination of MYCN copy number and 1p deletion in neuroblastoma by quantitative PCR

MYCN amplification and 1p36 deletion are adverse prognostic factors in neuroblastoma, and rapid accurate determination of MYCN amplification is essential for risk stratification. MYCN copy number and 1p36 deletion status were determined by fluorescence in situ hybridization (FISH) and real time PCR in a diagnostic pathology laboratory setting on 35 consecutive patients with neuroblastoma. The PCR technique was technically successful in all cases and results were generally available within 24 hr of biopsy. There was no discordance between FISH and PCR results. Real time PCR is a reliable, accurate, and simple technique that can be applied to small neuroblastoma biopsies allowing rapid diagnosis.     

Neuroblastoma in a pair of identical twins

Hereditary neuroblastoma in a pair of identical twins is reported. In one of the twins the tumor occurred in fetal life and caused death of the twin before birth; in the other one, the tumor occurred at two months of life as IV-S neuroblastoma in the liver with primary tumor undetected. The unusual clinical course of the latter case is described: twice there was tumor regression, but in spite of treatment, fatal uncontrolled growth occurred. The family history, characterized by neoplasms of dissimilar cell types but without additional cases of neuroblastoma, is also detailed.     

Progression‐free survival of two cases of high‐risk neuroblastoma with refractory/relapsed disease following surgery alone

Outcome for the vast majority of high‐risk neuroblastoma patients with refractory or relapsed disease is dismal. We report two high‐risk patients who remain progression‐free for more than 113 and 18 months following the diagnosis of refractory/relapsed disease who were treated with surgery alone. Complete resolution of a refractory thoracic mass and relapsed liver nodules was observed in one patient. The refractory/relapsed disease in the second patient has remained stable. In both cases, the tumor showed histologic evidence of neuroblastoma maturation. These cases demonstrate that refractory/relapsed neuroblastoma is clinically heterogeneous and highlight the need for better biomarkers to optimize patient care. Pediatr Blood Cancer 2013; 60: 512–514. © 2012 Wiley Periodicals, Inc.     

Successful treatment of progressive stage 4s hepatic neuroblastoma in a neonate with intra-arterial chemoembolization

Stage 4s neuroblastoma (NB) is a unique entity seen in infants less than 1 year of age, with metastatic disease confined to liver, skin, or bone marrow. Despite metastatic spread, stage 4s NB has a favorable outcome. An exception to this is seen in neonates who present with progressive enlargement of the liver with secondary respiratory compromise and liver failure. We describe a 4-week-old neonate who presented with 4s NB, with a rapidly enlarging liver, resulting in respiratory and hepatic failure, who had a rapid, sustained, and ongoing response to chemoembolization of the hepatic artery. This approach is feasible at this age, and may be effective in improving the outcome in this group of patients.     

A sequential treatment algorithm for infants with stage 4s neuroblastoma and massive hepatomegaly

Infants with 4s neuroblastoma (NB) and massive hepatomegaly have a guarded prognosis and mortality approaches 30%. We report on eight patients with 4s NB and massive hepatomegaly treated with multiple modalities. One patient had spontaneous tumor regression. Three patients had progressive disease and responded to chemotherapy. Four patients progressed despite intravenous chemotherapy, of whom two died, and two were salvaged with hepatic intra-arterial chemoembolization. Treatment of infants with stage 4s NB with massive hepatomegaly should be individualized based on disease course. A sequential approach with observation, intravenous chemotherapy, and intra-arterial chemoembolization, may improve the outcome of these infants.     

Congenital dumbbell neuroblastoma

A rare case of congenital dumbbell neuroblastoma with paraplegia and sphincter involvement is described. Magnetic resonance imaging (MRI) clearly demonstrated both intraspinal and right paravertebral tumors in a patient who showed signs of paraplegia of the lower extremities at birth. The patient was treated by laminectomy and intraspinal tumor excision followed by retroperitoneal tumor excision. Mild chemotherapy consisting of low-dose cyclophosphamide and vincristine was carried out postoperatively for 6 months. Radiation therapy was not employed. At 13 months of age the patient showed no evidence of residual or recurrent tumor, and the paralysis of the right lower extremity was greatly improved. Offprint requests to: S. Uemoto     

Congenital cervical neuroblastoma

Primary congenital cervical neuroblastomas are very rare. A history of upper aerodigestive compromise with Horner syndrome can be of value for the early diagnosis of this lesion. Congenital neuroblastomas usually have a favorable outcome. Like all the other clinically relevant groups of neuroblastomas, management should take into consideration the biological findings of each tumor, which predicts outcome than other clinical findings.     

Successful treatment of MYCN amplified, progressive stage 4S neuroblastoma in a neonate with hepatic artery embolization in addition to multimodality treatment

Stage 4S metastatic neuroblastoma (NB) has a favorable prognosis due to a high rate of spontaneous regression. Young infants risk lethal complications arising from hepatomegaly, which can develop rapidly despite treatment. MYCN oncogene amplification confers a significantly worse prognosis. We describe a 4-week-old neonate with MYCN-amplified stage 4S NB complicated by gross hepatomegaly causing rapidly progressive respiratory, hepatic, and renal failure. The child remains in remission 3 years after hepatic artery embolization, radiotherapy, standard, and high-dose chemotherapy. Embolization of the hepatic artery, with classical treatment, is feasible and safe at this age and may contribute substantially to the management of high-risk patients.     

Involvement of chromosomes 1 and 17 in a case of neuroblastoma

We report here the cytogenetic analysis of a neuroblastoma from a 6-month-old male. Both conventional GTG banded analysis and fluorescence in situ hybridization were performed. The tumour was found to have a der(17)t(1;17)(p34;q21).     

Urologic Outcomes of Pediatric Pelvic Neuroblastoma Presenting in Acute Urinary Retention

Purpose: To evaluate long-term urologic outcomes of patients with pelvic neuroblastoma (NB) presenting with urinary retention. Methods: Five cases of pelvic NB presenting with urinary retention were identified between 1971 and 2011. Clinical presentation, treatment, survival and long-term voiding outcomes were analyzed. Results: All five patients presented with acute urinary retention and pelvic outlet dysfunction including bladder perforation (20%), constipation (40%), or fecal incontinence (20%). The presenting age ranged from 7 days to 4 years with female to male ratio of 3:2. Two patients presented with bilateral hydronephrosis and three patients were stage 4 at presentation. All required debulking surgery, four patients required combined anterior and posterior approaches for tumor resection, with two patients requiring concurrent laminectomy. Adjuvant or neoadjuvant chemoradiation was used in four of five cases. Follow-up ranged from 2 to 41 years. Although the long-term oncological outcome is favorable, urologic outcomes of these patients ranged from normal bladder function to the need significant reconstructive procedures. Conclusion: Urologic outcomes are related to pelvic nerve and organ preservation during resection more than the severity of urinary symptoms at presentation.