Neuroblastoma

Neuroblastoma, NOS
Classification and external resources

microscopic view of a typical neuroblastoma with rosette formation
ICD-10 C74.9
ICD-9 194.0
ICD-O: M9500/3
OMIM 256700
DiseasesDB 8935
MedlinePlus 001408
eMedicine med/2836 ped/1570
MeSH D009447

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 new cases per year in the US.[1] Close to 50 percent of neuroblastoma cases occur in children younger than two years old.[2] It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system or SNS. It most frequently originates in one of the adrenal glands, but can also develop in nerve tissues in the neck, chest, abdomen, or pelvis.

Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.[3]

A disease exhibiting extreme heterogeneity, neuroblastoma is stratified into three risk categories: low, intermediate, and high risk. Low-risk disease is most common in infants and highly treatable with observation only or surgery, whereas high-risk disease is difficult to treat even with the most intensive multi-modal therapies available.[4]

Note: Esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium and its classification remains controversial. However, since it is not a sympathetic nervous system malignancy it is a distinct clinical entity and is not to be confused with neuroblastoma.[5][6]

Contents

Signs and symptoms

The first symptoms of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:[7]

Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases.[8]

The most common location for neuroblastoma to originate (i.e. the primary tumor) is on the adrenal glands. This occurs in 40% of localized tumors and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, no primary tumor can be discerned.[9]

Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), Horner's syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome[10] and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).[11]

Cause

The etiology of neuroblastoma is not well understood. Certain cases however do run in families and have been linked to genetics. Familial neuroblastoma is caused by a very rare germline mutation in the anaplastic lymphoma kinase (ALK) gene.[12]

Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors; however, results have been inconclusive.[13]

Other studies have examined possible links with atopy and exposure to infection early in life,[14] use of hormones and fertility drugs,[15] and maternal use of hair dye.[16][17]

Diagnosis

MRI showing orbital and skull vault metastatic NB in 2 year old

The diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests.

Serology

In about 90% of cases of neuroblastoma, elevated levels of catecholamines or its metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).[18]

Imaging

Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid."[19] The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-ionated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.[20]

Histology

microscopic view of stroma-rich ganglioneuroblastoma

On microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (Homer-Wright pseudo-rosettes) may be seen.[21] A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma, Ewing's sarcoma, lymphoma and Wilms' tumor. In February 2007, Althea Technologies announced the development of a molecular diagnostic capable of clearly differentiating various types of childhood cancers, developed in cooperation with the U.S. National Cancer Institute (NCI).[22]

Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to stroma-rich ganglioneuroblastoma with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (MKI). This pathology classification system describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC, also called Shimada system) which was established in 1999 and revised in 2003.[23]

Staging

The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:[24][25][26]

Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12-18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12-18 month old children without N-myc (also commonly referred to as MYCN) amplification to intermediate risk category.[27]

The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):

The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk.[28][29]

Treatment

When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy[30] with anti-GD2 monoclonal antibody therapy).

Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity.[31] These criteria include the age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulates microRNAs[32]), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk.[33] (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)[34]

The therapies for these different risk categories are very different.

With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70%-90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time.[38] The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009 an early analysis of a Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group randomized to received ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling on the trial will receive the antibody therapy.[39]

Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.

Prognosis

Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory.[40][41] Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.[42]

Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease.[43][44] An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.[45][46] These results were confirmed in a National Cancer Institute publication released July 2009 comparing outcomes of neuroblastoma survivors to siblings. The study reported that survivors are more likely than siblings to develop chronic neurological, sensory, endocrine, and musculoskeletal complications and less likely to be married or have a high income job.[47]

Cytogenetic profiles

Based on a series of 493 neuroblastoma samples, it has been reported that overall genomic pattern, as tested by array-based karyotyping, is a predictor of outcome in neuroblastoma:[48]

Earlier publications categorized neuroblastomas into three major subtypes based on cytogenetic profiles:[49]

Virtual karyotyping can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma.[50] ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.

Epidemiology

Neuroblastoma comprises 6-10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.[51]

The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults,[52] but only 10% of cases occur in people older than 5 years of age.[19] A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.[53]

History

Rudolf Virchow: the first to describe an abdominal tumor in a child as a "glioma"

In 1864 German physician Rudolf Virchow was the first to describe an abdominal tumor in a child as a "glioma". The characteristics of tumors from the sympathetic nervous system and the adrenal medulla when than noted in 1891 by German pathologist Felix Marchand.[54] [55] In 1901 the distinctive presentation of stage 4S in infants (liver but no bone metastases) was described by William Pepper. In 1910 James Homer Wright understood the tumor to originate from primitive neural cells, and named it neuroblastoma. He also noted the circular clumps of cells in bone marrow samples which are now termed "Homer-Wright pseudorosettes."[56]

Screening

Urine catecholamine level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, Austria and Germany since the 1980s.[57][58] Japan began screening six-month olds for neuroblastoma via analysis of the levels of homovanillic acid and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.[59][60] [61]

Research

New frontline treatments

Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%.[62] A study of 467 intermediate risk patients enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those patients with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.[63]

By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:

In addition to these phase III studies, research institutions such as Baylor College of Medicine/Texas Children's, St. Jude Children's Research Hospital (Memphis, Tennessee), and Memorial Sloan-Kettering Cancer Center in New York offer unique treatment protocols. Texas Children's used a novel induction regimen which included a method of giving chemotherapy called “chemo-switching” where cisplatin was given as high-dose pulse and etoposide was given at low-dose over several weeks for the first two cycles.[80] St Jude's recently finished (2007) testing a new up-front chemotherapy regimen in 23 children which included irinotecan and gefitinib with 16 months of maintenance chemotherapy after stem cell transplant with alternating oral 13-cis-retinoic acid and topotecan.[81] In December 2008 St Jude's opened a new trial using temsirolimus and irinotecan in induction.[82] Sloan-Kettering offers treatment that includes a mouse-derived monoclonal antibody, 3F8, used in protocols since the mid 1980s. This antibody is used for treating minimal residual disease or consolidation instead of stem cell transplant.[83]

Refractory and relapsed neuroblastoma

microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents

Some children (particularly in high-risk cases) do not respond completely to frontline treatment (with a complete response or very good partial response) and are labeled refractory. These children are removed from the frontline therapy (clinical trial) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to frontline therapy and achieve a remission, but later the disease recurs (relapse). These children are also eligible for new therapies being tested in clinical trials.

Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group.[84] Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.[85][86]

Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are studying targeted therapy, anti-angiogenesis agents, and new monoclonal antibodies such as hu14.18-IL2.

In 2008 the Phase IIa trial of Azedra opened. This uses the I-131 MIBG molecule radiolabeled using Molecular Insight's proprietary Ultratrace technology, which removes unnecessary nonradioactive molecules (or "cold contaminants").[87][88][89] A group of 15 children’s hospitals in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium coordinates the I-131 MIBG radiation therapy trials. The NANT consortium also offers trials using an oral powder formulation of fenretinide, intravenous fenretinide, bisphosphonate (Zometa) with other agents, and combining I-131 MIBG with chemotherapy.[90]

A Swedish study reported in 2007 that a common painkiller might inhibit the development of neuroblastoma and help make treatment of the disease more effective. Celecoxib, an analgesic, anti-inflammatory agent that inhibits the inflammatory enzyme Cox-2 which is required for neuroblastoma cells growth and proliferation. Clinical studies are now planned; research to date has been done only in animals and cell cultures.[91][92]

The protein p53 is believed to play a role in the development of resistance to chemotherapy.[93] A November 2009 study in mice shows that activating the tumor suppressor p53 with a new drug, nutlin-3, may slow tumor growth.[94]. In this study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and obstructs p53’s ability to trigger programmed cell death. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53.

References

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  2. ↑ Janet Sassi, "Cellular Communication: Unraveling the Secrets of Histone Proteins", Fordham University, February 16, 2007
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  27. ↑ Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O'Leary M, Gerbing RB, Matthay KK (2005). "Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study". J Clin Oncol 23 (27): 6474–80. doi:10.1200/JCO.2005.05.183. PMID 16116154. http://jco.ascopubs.org/cgi/content/full/23/27/6474. 
  28. ↑ Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007). "Neuroblastoma". Lancet 369 (9579): 2106–20. doi:10.1016/S0140-6736(07)60983-0. PMID 17586306. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60983-0. 
  29. ↑ Cohn SL, London WB, Monclair T, Matthay KK, Ambros PF, Pearson AD, for the INRG Working Group (2007). "Update on the development of the international neuroblastoma risk group (INRG) classification schema" (abstract). Journal of Clinical Oncology 2007 ASCO Annual Meeting Proceedings Part 1 25 (18S). http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=30945. 
  30. ↑ Johnson E, Dean SM, Sondel PM (2007). "Antibody-based immunotherapy in high-risk neuroblastoma" (abstract). Expert Rev Mol Med 9 (34): 1–21. doi:10.1017/S1462399407000518. PMID 18081947. http://journals.cambridge.org/abstract_S1462399407000518. 
  31. ↑ Neuroblastoma: biological insights into a clinical enigma. Brodeur GM. Nature Reviews Cancer. 2003 Mar;3(3):203-16. PMID 12612655
  32. ↑ Schulte JH, Horn S, Otto T, et al. (2008). "MYCN regulates oncogenic MicroRNAs in neuroblastoma". Int. J. Cancer 122 (3): 699–704. doi:10.1002/ijc.23153. PMID 17943719. 
  33. ↑ "Translating Neuroblastoma Genomics to the Clinic - J. Maris presentation ASCO 2007". http://media.asco.org/player/default.aspx?LectureID=317&conferenceFolder=vm2007&SessionFolder=01028&slideonly=yes&TrackID=N929&LectureTitle=Translating%20Neuroblastoma%20Genomics%20to%20the%20Clinic&Key=vm_47_10_222_317&SpeakerName=%3b%20Chair%3a%20John%20M.%20Maris%2c%20MD&mediaURL=%2fmedia&ServerName=media.asco.org&max=28&ext=jpg&useASX=false&playtype=&playtype=&playtype=,. Retrieved 2008-01-13. 
  34. ↑ Gisselsson D, Lundberg G, Ora I, Höglund M (2007). "Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas". J Carcinog 6: 15. doi:10.1186/1477-3163-6-15. PMID 17897457. 
  35. ↑ Haase GM, Perez C, Atkinson JB (1999). "Current aspects of biology, risk assessment, and treatment of neuroblastoma". Semin Surg Oncol 16 (2): 91–104. doi:10.1002/(SICI)1098-2388(199903)16:2<91::AID-SSU3>3.0.CO;2-1. PMID 9988866. 
  36. ↑ Fish JD, Grupp SA (2007). "Stem cell transplantation for neuroblastoma". Bone Marrow Transplant 41 (2): 159. doi:10.1038/sj.bmt.1705929. PMID 18037943. 
  37. ↑ Matthay KK, Villablanca JG, Seeger RC, et al. (1999). "Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group". N. Engl. J. Med. 341 (16): 1165–73. doi:10.1056/NEJM199910143411601. PMID 10519894. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10519894&promo=ONFLNS19. 
  38. ↑ "Neuroblastoma Treatment - National Cancer Institute". http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/page3#Section_17. Retrieved 2008-07-30. 
  39. ↑ "A phase III randomized trial of the chimeric anti-GD2 antibody ch14.18 with GM-CSF and IL2 as immunotherapy following dose intensive chemotherapy for high-risk neuroblastoma: Children’s Oncology Group (COG) study ANBL0032". http://www.abstract.asco.org/AbstView_65_35748.html. 
  40. ↑ "Reduction From Seven to Five Cycles of Intensive Induction Chemotherapy in Children With High-Risk Neuroblastoma -- Kushner et al. 22 (24): 4888 -- Journal of Clinical Oncology". http://jco.ascopubs.org/cgi/content/full/22/24/4888. 
  41. ↑ 41.0 41.1 "Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children's Oncology Group (COG A3973) study. - ASCO". http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=31659. Retrieved 2008-02-02. 
  42. ↑ Ceschel S, Casotto V, Valsecchi MG, et al. (Oct 2006). "Survival after relapse in children with solid tumors: a follow-up study from the Italian off-therapy registry". Pediatr Blood Cancer 47 (5): 560–6. doi:10.1002/pbc.20726. PMID 16395684. 
  43. ↑ Gurney JG, Tersak JM, Ness KK, Landier W, Matthay KK, Schmidt ML (2007). "Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group". Pediatrics 120 (5): e1229–36. doi:10.1542/peds.2007-0178. PMID 17974716. 
  44. ↑ Trahair TN, Vowels MR, Johnston K, Cohn RJ, Russell SJ, Neville KA, Carroll S, Marshall GM (2007). "Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation". Bone Marrow Transplant 40 (8): 741–6. doi:10.1038/sj.bmt.1705809. PMID 17724446. 
  45. ↑ "Childhood Cancer Survivors Face Increased Sarcoma Risk", HealthDay News, February 21, 2007
  46. ↑ Oeffinger et al., "Chronic Health Conditions in Adult Survivors of Childhood Cancer", New England Journal of Medicine, October 12, 2006
  47. ↑ "Long-term Outcomes in Survivors of Neuroblastoma: A Report From the Childhood Cancer Survivor Study -- Laverdière et al., 10.1093/jnci/djp230 -- JNCI Journal of the National Cancer Institute". http://jnci.oxfordjournals.org/cgi/content/abstract/djp230. 
  48. ↑ Janoueix-Lerosey I, Schleiermacher G, Michels E, et al. (March 2009). "Overall genomic pattern is a predictor of outcome in neuroblastoma". J. Clin. Oncol. 27 (7): 1026–33. doi:10.1200/JCO.2008.16.0630. PMID 19171713. http://www.jco.org/cgi/pmidlookup?view=long&pmid=19171713. 
  49. ↑ Michels, E; Vandesompele, J; Hoebeeck, J; Menten, B; De Preter, K; Laureys, G; Van Roy, N; Speleman, F. Genome wide measurement of DNA copy number changes in neuroblastoma: dissecting amplicons and mapping losses, gains and breakpoints. Cytogenet Genome Res. 2006;115:273–282. doi: 10.1159/000095924. [PubMed]
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  53. ↑ Ladenstein R, Pötschger U, Hartman O, et al. (June 2008). "28 years of high-dose therapy and SCT for neuroblastoma in Europe: lessons from more than 4000 procedures". Bone Marrow Transplant. 41 Suppl 2: S118–27. doi:10.1038/bmt.2008.69. PMID 18545256. 
  54. ↑ Cheung, Nai-Kong (2005). Neuroblastoma. p. 63. Springer-Verlag. ISBN 10 3-540-40841-X. 
  55. ↑ "In Situ Neuroblastomas: a Contribution to the Natural History of Neural Crest Tumors". http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1949785&pageindex=1. 
  56. ↑ Rothenberg AB, Berdon WE, D'Angio GJ, Yamashiro DJ, Cowles RA (February 2009). "Neuroblastoma-remembering the three physicians who described it a century ago: James Homer Wright, William Pepper, and Robert Hutchison". Pediatr Radiol 39 (2): 155–60. doi:10.1007/s00247-008-1062-z. PMID 19034443. 
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  58. ↑ Schilling FH, Spix C, Berthold F, et al. (2003). "Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany". Cancer Lett. 197 (1-2): 19–28. doi:10.1016/S0304-3835(03)00077-6. PMID 12880955. http://linkinghub.elsevier.com/retrieve/pii/S0304383503000776. 
  59. ↑ Tsubono Y, Hisamichi S (2004). "A halt to neuroblastoma screening in Japan". N. Engl. J. Med. 350 (19): 2010–1. doi:10.1056/NEJM200405063501922. PMID 15128908. 
  60. ↑ "Neuroblastoma Screening - National Cancer Institute". http://www.cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfessional/page3. Retrieved 2008-07-30. 
  61. ↑ Darshak Sanghavi, "Screen Alert: How an Ounce of RX Prevention can Cause a Pound of Hurt", Slate magazine, November 28, 2006
  62. ↑ "Neuroblastoma Committee - Current Focus of Research". http://www.curesearch.org/our_research/index_sub.aspx?id=1767. Retrieved 2008-01-13. 
  63. ↑ "A phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma -- Baker et al. 25 (18 Supplement): 9504 -- ASCO Meeting Abstracts". http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9504. 
  64. ↑ Pritchard J, Cotterill SJ, Germond SM, Imeson J, de Kraker J, Jones DR (2005). "High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group". Pediatr Blood Cancer 44 (4): 348–57. doi:10.1002/pbc.20219. PMID 15546135. 
  65. ↑ Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D (2008). "High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial". Lancet Oncol. 9 (3): 247–256. doi:10.1016/S1470-2045(08)70069-X. PMID 18308250. 
  66. ↑ Matthay KK, Villablanca JG, Seeger RC, et al. (Oct 1999). "Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group". N. Engl. J. Med. 341 (16): 1165–73. doi:10.1056/NEJM199910143411601. PMID 10519894. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10519894&promo=ONFLNS19. 
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  70. ↑ "Autologous Stem Cell Transplantation for High-Risk Neuroblastoma". http://mmserver.cjp.com/gems/blood/ABMT.10.Villablanca.pdf. Retrieved 2008-02-02. 
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  72. ↑ "Consolidation Treatment With Chimeric Anti-GD2-Antibody ch14.18 in Children Older Than 1 Year With Metastatic Neuroblastoma -- Simon et al. 22 (17): 3549 -- Journal of Clinical Oncology". http://jco.ascopubs.org/cgi/content/full/22/17/3549. Retrieved 2008-02-02. 
  73. ↑ "NCI Cancer Bulletin for May 19, 2009 - National Cancer Institute". http://www.cancer.gov/ncicancerbulletin/051909/page2. 
  74. ↑ "Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma - Full Text View - ClinicalTrials.gov". http://clinicaltrials.gov/ct2/show/NCT01041638. 
  75. ↑ "Neuroblastoma Education Book". http://www.cure4kids.org/private/courses_documents/m_148/SIOP-2005-Education-Book.pdf. Retrieved 2008-02-02. 
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  77. ↑ "Observation, Combination Chemotherapy, Radiation Therapy, and/or Autologous Stem Cell Transplant in Treating Young Patients With Neuroblastoma - Full Text View - ClinicalTrials.gov". http://clinicaltrials.gov/ct2/show/NCT00410631. 
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