Neuroblastoma
1624266
223702108
2008-07-05T10:05:02Z
DOI bot
6652755
Citation maintenance. Removed redundant parameters. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]].
{{DiseaseDisorder infobox |
Name = Neuroblastoma, NOS |
ICD10 = {{ICD10|C|74|9|c|73}}|
ICD9 = {{ICD9|194.0}} |
ICDO = {{ICDO|9500|3}} |
Image = Neuroblastoma rosettes.jpg |
Caption = microscopic view of a typical neuroblastoma with rosette formation |
OMIM = 256700 |
MedlinePlus = 001408 |
eMedicineSubj = med |
eMedicineTopic = 2836 |
eMedicine_mult = {{eMedicine2|ped|1570}} |
DiseasesDB = 8935 |
MeshID = D009447 |
}}
[[Image:Gray839.png|thumb|Sympathetic nervous system]]
'''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.<ref name="titleeMedicine - Neuroblastoma : Article by Norman J Lacayo, MD">{{cite web |url=http://www.emedicine.com/ped/topic1570.htm |title=eMedicine - Neuroblastoma : Article by Norman J Lacayo, MD |accessdate=2007-12-20 |format= |work=}}</ref> Close to 50 percent of neuroblastoma cases occur in children younger than two years old.<ref>Janet Sassi, [http://www.fordham.edu/campus_resources/public_affairs/inside_fordham/february_16_2007/in_focus_faculty_and/cellular_communicati_24950.asp "Cellular Communication: Unraveling the Secrets of Histone Proteins"], Fordham University, February 16, 2007</ref> It is a [[neuroendocrine tumor]], arising from any [[neural crest]] element of the [[sympathetic nervous system]] or SNS. A branch of the [[autonomic nervous system]], the SNS is a nerve network that carries messages from the brain throughout the body and is responsible for the [[fight-or-flight response]] and production of [[adrenaline]] or [[epinephrine]]. Its solid tumors, which take the form of a lump or mass, commonly begin in one of the [[adrenal gland]]s, though they can also develop in nerve tissues in the [[neck]], [[chest]], [[abdomen]], or [[pelvis]]. [[Esthesioneuroblastoma]], also known as olfactory neuroblastoma, is believed to arise from the [[olfactory epithelium]] and classification remains controversial. Since it is not a sympathetic nervous system malignancy it is a distinct clinical entity not to be confused with neuroblastoma.<ref name="titleeMedicine - Esthesioneuroblastoma : Article by Pavel Dulguerov, MD">{{cite web |url=http://www.emedicine.com/med/topic748.htm |title=eMedicine - Esthesioneuroblastoma : Article by Pavel Dulguerov, MD |accessdate=2007-12-15 |format= |work=}}</ref><ref>{{cite book
| last = Cheung
| first = Nai-Kong
| authorlink =
| title = Neuroblastoma
| publisher = [[Springer-Verlag]]
| series = p. 73
| year = 2005
| doi =
| isbn = 10 3-540-40841-X }}</ref>
The cause of neuroblastoma is unknown, though most physicians believe that it is an accidental cell growth that occurs during normal development of the adrenal glands.
Neuroblastoma is one of the rare human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely [[benign]] cellular appearance.
==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.<ref>Brodeur GM, Castleberry RP. Neuroblastoma. In: Pizzo PA, Poplack DG. Principles and practice of pediatric oncology, 3rd ed. 1997:761-797.</ref>
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,<ref name="pmid9149032">{{cite journal |author=Franks LM, Bollen A, Seeger RC, Stram DO, Matthay KK |title=Neuroblastoma in adults and adolescents: an indolent course with poor survival |journal=Cancer |volume=79 |issue=10 |pages=2028–35 |year=1997 |pmid=9149032 |doi=}}</ref> but only 10% of cases occur in people older than 5 years of age.<ref name="pmid17544628">{{cite journal |author=Howman-Giles R, Shaw PJ, Uren RF, Chung DK |title=Neuroblastoma and other neuroendocrine tumors |journal=Semin Nucl Med |volume=37 |issue=4 |pages=286–302 |year=2007 |pmid=17544628 |doi=10.1053/j.semnuclmed.2007.02.009 |url=http://linkinghub.elsevier.com/retrieve/pii/S0001-2998(07)00030-X}}</ref>
== Etiology ==
The [[etiology]] of neuroblastoma is not well understood. Several risk factors have been proposed and are the subject of ongoing research.
Due to characteristic early onset many studies have focussed on parental factors around [[fertilisation|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 inconsistent.<ref>Olshan, AF, Bunin, GR (2000) Epidemiology of Neuroblastoma. In: Brodeur, GM, Sawada, T, Tsuchida, Y, Voute, PA eds. , Neuroblastoma, Elsevier, Amsterdam, pp 33-39. ISBN 044450222X [http://us.elsevierhealth.com/product.jsp?isbn=9780444502223]</ref>
Other studies have examined possible links with [[atopy]] and exposure to [[infection]] early in life,<ref>Menegaux F,''et al''. [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15105177 "Day Care, Childhood Infections and Risk of Neuroblastoma"], Am J Epidemiol 2004; 159:843-851,</ref> use of hormones and fertility drugs,<ref name="Olshan et al 1999">Olshan AF,''et al'' [http://aje.oxfordjournals.org/cgi/content/abstract/150/9/930 "Hormone and Fertility Drug Use and the Risk of Neuroblastoma: A Report from the Children's Cancer Group and the Pediatric Oncology Group"], Am J Epidemiol 1999;150:930-8.</ref> and maternal use of hair dye.<ref name="McCall EE,''et al'' 2005">,McCall EE,''et al''. [http://www.springerlink.com/content/n3645430v710npu2/ "Maternal hair dye use and risk of neuroblastoma in offspring"], Cancer Causes and Control 2005; 16,6:743-8</ref>
==Diagnosis==
[[Image:Neuroblastoma mets.JPG|thumb|MRI showing orbital and skull vault metastatic NB in 2 year old]]
[[Image:Neuroblastoma-mets-on-MIBG-scan-003.jpg|thumb|MIBG showing metastatic NB (salivary glands, liver, and bladder concentrate MIBG)]]
The first [[symptom]]s of neuroblastoma are often vague and may include [[Fatigue (medical)|fatigue]], [[loss of appetite]], and [[fever]]. Later symptoms depend on tumor locations:<ref name="titleNeuroblastoma in children : Cancerbackup">{{cite web |url=http://www.cancerbackup.org.uk/cancertype/childrenscancers/typesofchildrenscancers/neuroblastoma#9216 |title=Neuroblastoma in children : Cancerbackup |accessdate=2008-01-01 |format= |work=}}</ref>
* In the [[abdomen]], a tumor may cause a [[swollen belly]] and [[constipation]].
* A tumor in the [[chest]] may cause [[breathing problems]].
* Tumors pressing on the [[spinal cord]] cause a feeling of [[weakness]].
* Bone lesions in the legs and hips often cause bone pain and limping.
* A tumor in the [[head]] may cause the eyes to start to swell outwards and turn black due to the pressure from behind.
Often because symptoms are so unclear, 50 to 60% of all neuroblastomas have already spread ([[metastasis|metastasized]]) to other parts of the body by the time a diagnosis is made.<ref name="titleNeuroblastoma: Pediatric Cancers: Merck Manual Professional">{{cite web |url=http://www.merck.com/mmpe/sec19/ch285/ch285b.html |title=Neuroblastoma: Pediatric Cancers: Merck Manual Professional |accessdate=2008-01-01 |format= |work=}}</ref>
The diagnosis is usually confirmed by a [[anatomical pathology|surgical pathologist]], taking into account the clinical presentation, microscopic findings, and other laboratory tests. On microscopy, the tumor cells are typically described as small, round and blue, and [[Rosette (design)|rosette]] patterns ([[James Homer Wright|Homer-Wright]] pseudo-rosettes) may be seen.<ref name="pmid11844067">{{cite journal |author=Miura K, Mineta H, Yokota N, Tsutsui Y |title=Olfactory neuroblastoma with epithelial and endocrine differentiation transformed into ganglioneuroma after chemoradiotherapy |journal=Pathol. Int. |volume=51 |issue=12 |pages=942–7 |year=2001 |pmid=11844067 |doi= 10.1046/j.1440-1827.2001.01300.x|url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1320-5463&date=2001&volume=51&issue=12&spage=942}}</ref> 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).<ref> [http://www.genengnews.com/news/bnitem.aspx?name=13129903 "Althea Technologies Announces the Development of a Diagnostic Capable of Differentiating Multiple Forms of Childhood Cancer"], press release, February 20, 2007</ref>
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).<ref name="pmid16732582">{{cite journal |author=Strenger V, Kerbl R, Dornbusch HJ, ''et al'' |title=Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients |journal=Pediatr Blood Cancer |volume=48 |issue=5 |pages=504–9 |year=2007 |pmid=16732582 |doi=10.1002/pbc.20888}}</ref>
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."<ref name="pmid17544628">{{cite journal |author=Howman-Giles R, Shaw PJ, Uren RF, Chung DK |title=Neuroblastoma and other neuroendocrine tumors |journal=Semin Nucl Med |volume=37 |issue=4 |pages=286–302 |year=2007 |pmid=17544628 |doi=10.1053/j.semnuclmed.2007.02.009 |url=http://linkinghub.elsevier.com/retrieve/pii/S0001-2998(07)00030-X}}</ref> 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.<ref name="pmid15653652">{{cite journal |author=Pashankar F,O’Dorisio M, Menda Y |title=MIBG and somatostatin receptor analogs in children: current concepts on diagnostic and therapeutic use |journal=Journal of Nuclear Medicine |volume=46 |issue=1 (suppl) |pages=55S–61S |year=2005 |pmid=15653652 |doi= |url=http://jnm.snmjournals.org/cgi/content/full/46/1_suppl/55S}}</ref>
=== Histology ===
[[Image:Neuroblastoma.jpg|thumb|microscopic view of stroma-rich ganglioneuroblastoma]]
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 differentiating 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.<ref name="pmid14601099">{{cite journal |author=Peuchmaur M, d'Amore ES, Joshi VV, ''et al'' |title=Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular |journal=Cancer |volume=98 |issue=10 |pages=2274–81 |year=2003 |pmid=14601099 |doi=10.1002/cncr.11773}}</ref>
=== Stage and risk assignment ===
The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:<ref name="titleNeuroblastoma Treatment - National Cancer Institute">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/page3#Section_185 |title=Neuroblastoma Treatment - National Cancer Institute |accessdate=2007-12-15 |format= |work=}}</ref><ref name="pmid3199170">{{cite journal |author=Brodeur GM, Seeger RC, Barrett A, ''et al'' |title=International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma |journal=J. Clin. Oncol. |volume=6 |issue=12 |pages=1874–81 |year=1988 |pmid=3199170 |doi= |url=http://www.jco.org/cgi/pmidlookup?view=long&pmid=3199170}}</ref><ref name="pmid8336186">{{cite journal |author=Brodeur GM, Pritchard J, Berthold F, ''et al'' |title=Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment |journal=J. Clin. Oncol. |volume=11 |issue=8 |pages=1466–77 |year=1993 |pmid=8336186 |doi= |url=http://www.jco.org/cgi/pmidlookup?view=long&pmid=8336186}}</ref>
*Stage 1: Localized tumor confined to the area of origin.
*Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.
*Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.
*Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.
*Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.
*Stage 4S: Age <1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).
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 MYCN amplification to intermediate risk category.<ref name="pmid16116154">{{cite journal |author=Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O'Leary M, Gerbing RB, Matthay KK |title=Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study |journal=J Clin Oncol |volume=23 |issue=27 |pages=6474–80 |year=2005 |pmid=16116154 |doi= 10.1200/JCO.2005.05.183|url=http://jco.ascopubs.org/cgi/content/full/23/27/6474}}</ref>
The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):
*Stage L1: Localized disease without image-defined risk factors.
*Stage L2: Localized disease with image-defined risk factors.
*Stage M: Metastatic disease.
*Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.
The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, [[MYCN]] amplification, unbalanced 11q aberration, and [[ploidy]] into four pre-treatment risk groups: low, intermediate, high, and ultra-high risk.<ref name="pmid17586306">{{cite journal |author=Maris JM, Hogarty MD, Bagatell R, Cohn SL |title=Neuroblastoma |journal=Lancet |volume=369 |issue=9579 |pages=2106–20 |year=2007 |pmid=17586306 |doi=10.1016/S0140-6736(07)60983-0 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60983-0}}</ref><ref name="pmid">{{cite journal |author=Cohn SL, London WB, Monclair T, Matthay KK, Ambros PF, Pearson AD, for the INRG Working Group |title=Update on the development of the international neuroblastoma risk group (INRG) classification schema |journal=Journal of Clinical Oncology 2007 ASCO Annual Meeting Proceedings Part 1 |volume=25 |issue=18S |pages= |year=2007|doi= |url=http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=30945 |format=abstract}}</ref>
== 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, and Germany since the 1980s.<ref name="pmid11932470">{{cite journal |author=Woods WG, Gao RN, Shuster JJ, ''et al'' |title=Screening of infants and mortality due to neuroblastoma |journal=N. Engl. J. Med. |volume=346 |issue=14 |pages=1041–6 |year=2002 |pmid=11932470 |doi=10.1056/NEJMoa012387 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11932470&promo=ONFLNS19}}</ref><ref name="pmid12880955">{{cite journal |author=Schilling FH, Spix C, Berthold F, ''et al'' |title=Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany |journal=Cancer Lett. |volume=197 |issue=1-2 |pages=19–28 |year=2003 |pmid=12880955 |doi= 10.1016/S0304-3835(03)00077-6|url=http://linkinghub.elsevier.com/retrieve/pii/S0304383503000776}}</ref> 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.<ref name="pmid15128908">{{cite journal |author=Tsubono Y, Hisamichi S |title=A halt to neuroblastoma screening in Japan |journal=N. Engl. J. Med. |volume=350 |issue=19 |pages=2010–1 |year=2004 |pmid=15128908 |doi=10.1056/NEJM200405063501922}}</ref><ref name="titleNeuroblastoma Screening - National Cancer Institute">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfessional/page3 |title=Neuroblastoma Screening - National Cancer Institute |accessdate=2007-12-15 |format= |work=}}</ref>
<ref>Darshak Sanghavi, [http://www.slate.com/id/2154563/ "Screen Alert: How an Ounce of RX Prevention can Cause a Pound of Hurt"], ''Slate'' magazine, November 28, 2006</ref>
==Treatment==
=== Current ===
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]]<ref name="pmid18081947">{{cite journal |author=Johnson E, Dean SM, Sondel PM |title=Antibody-based immunotherapy in high-risk neuroblastoma |journal=[[Expert Rev Mol Med]] |volume=9 |issue=34 |pages=1–21 |year=2007 |pmid=18081947 |doi=10.1017/S1462399407000518 |url=http://journals.cambridge.org/abstract_S1462399407000518 |format=abstract}}</ref> 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.<ref>Neuroblastoma: biological insights into a clinical enigma. Brodeur GM. Nature Reviews Cancer. 2003 Mar;3(3):203-16. PMID 12612655</ref> These criteria include the age of the patient, extent of disease spread, microscopic appearance, and several other biological features, most importantly [[MYCN]] [[oncogene]] amplification (MYCN regulates [[microRNA]]s<ref name="pmid17943719">{{cite journal |author=Schulte JH, Horn S, Otto T, ''et al'' |title=MYCN regulates oncogenic MicroRNAs in neuroblastoma |journal=Int. J. Cancer |volume=122 |issue=3 |pages=699–704 |year=2008 |pmid=17943719 |doi=10.1002/ijc.23153}}</ref>), 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.<ref name="titleTranslating Neuroblastoma Genomics to the Clinic - J. Maris presentation ASCO 2007">{{cite web |url=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=, |title=Translating Neuroblastoma Genomics to the Clinic - J. Maris presentation ASCO 2007 |accessdate=2008-01-13 |format= |work=}}</ref> (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.)<ref name="pmid17897457">{{cite journal |author=Gisselsson D, Lundberg G, Ora I, Höglund M |title=Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas |journal=J Carcinog |volume=6 |issue= |pages=15 |year=2007 |pmid=17897457 |doi=10.1186/1477-3163-6-15}}</ref>
The therapy for these different risk categories is very different.
* ''Low risk'' patients can frequently be [[Watchful waiting|observed without any treatment at all]] or cured with surgery alone.<ref name="titleNeuroblastoma Treatment - National Cancer Institute">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/Patient/page5 |title=Neuroblastoma Treatment - National Cancer Institute |accessdate=2008-02-02 |format= |work=}}</ref>
* ''Intermediate risk'' patients are treated with surgery and [[chemotherapy]].<ref name="pmid9988866">{{cite journal |author=Haase GM, Perez C, Atkinson JB |title=Current aspects of biology, risk assessment, and treatment of neuroblastoma |journal=Semin Surg Oncol |volume=16 |issue=2 |pages=91–104 |year=1999 |pmid=9988866 |doi= |url=}}</ref>
* ''High risk'' neuroblastoma is treated with intensive chemotherapy, [[surgery]], [[radiation therapy]], [[bone marrow]] / [[Hematopoietic stem cell transplantation]]<ref name="pmid18037943">{{cite journal |author=Fish JD, Grupp SA |title=Stem cell transplantation for neuroblastoma |journal=Bone Marrow Transplant |volume= 41|issue= |pages= 159|year=2007 |pmid=18037943 |doi=10.1038/sj.bmt.1705929}}</ref> and biological-based therapy with 13-''cis''-retinoic acid ([[isotretinoin]] or Accutane).<ref name="pmid10519894">{{cite journal |author=Matthay KK, Villablanca JG, Seeger RC, ''et al'' |title=Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group |journal=N. Engl. J. Med. |volume=341 |issue=16 |pages=1165–73 |year=1999 |pmid=10519894 |doi= 10.1056/NEJM199910143411601|url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10519894&promo=ONFLNS19}}</ref>
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 results in cures only about 30% of the time.<ref name="titleNeuroblastoma Treatment - National Cancer Institute (2)">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/page3#Section_17 |title=Neuroblastoma Treatment - National Cancer Institute |accessdate=2007-12-15 |format= |work=}}</ref>
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.
=== Clinical trials for new treatments ===
Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%.<ref name="titleNeuroblastoma Committee - Current Focus of Research">{{cite web |url=http://www.curesearch.org/our_research/index_sub.aspx?id=1767 |title=Neuroblastoma Committee - Current Focus of Research |accessdate=2008-01-13 |format= |work=}}</ref> 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.<ref name="titleA phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma. - ASCO">{{cite web |url=http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=47&abstractID=30458 |title=A phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma. - ASCO |accessdate=2008-01-13 |format= |work=}}</ref>
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:
*1982-1985: European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized to melphalan autologous bone marrow transplant or no further therapy (no radiation therapy given to any). Transplant and no-transplant arms each had 65 patients, and recent long-term follow-up report revealed significantly better 5 year event-free survival for stage 4 over 1 year old in melphalan-transplant group versus no further treatment: 33% versus 17% respectively.<ref name="pmid15546135">{{cite journal |author=Pritchard J, Cotterill SJ, Germond SM, Imeson J, de Kraker J, Jones DR |title=High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group |journal=Pediatr Blood Cancer |volume=44 |issue=4 |pages=348–57 |year=2005 |pmid=15546135 |doi=10.1002/pbc.20219}}</ref>
*1990-1999: European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over 1 year old and revealed higher survival rate for rapid sequence induction (10-day cycle) versus standard induction (21-day cycle) with same total dose. Ten-year event free survival was 27% and 18% respectively with non-aggressive surgical approach, no radiotherapy, and melphalan-only autologous bone marrow or stem cell transplant for both groups.<ref name="pmid18308250">{{cite journal |author=Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D |title=High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial |journal=Lancet Oncol. |volume=9 |issue=3 |pages=247–256 |year=2008 |pmid=18308250 |doi=10.1016/S1470-2045(08)70069-X}}</ref>
*1991-1996: Phase III trial with two sequential randomizations for 379 high-risk NB patients was carried out by the Children's Cancer Group (CCG-3891) which demonstrated improved survival with myeloablative therapy (with total body irradiation) and 13-cis-retinoic acid (Accutane) with 50 patients in each of the four arms of the study.<ref name="titleTreatment of high-risk neuroblastoma with intensiv...[N Engl J Med. 1999] - PubMed Result">{{cite web |url=http://www.ncbi.nlm.nih.gov/pubmed/10519894 |title=Treatment of high-risk neuroblastoma with intensiv...[N Engl J Med. 1999] - PubMed Result |accessdate=2008-02-02 |format= |work=}}</ref>
*1996-2003: The German (GPOH) study NB97 compared outcomes of 295 high-risk NB patients randomized for stem cell transplant or consolidation chemotherapy. Results showed increased survival with transplant.<ref name="titleMyeloablative megatherapy with autologous stem-cel...[Lancet Oncol. 2005] - PubMed Result">{{cite web |url=http://www.ncbi.nlm.nih.gov/pubmed/16129365?dopt=Abstract++ |title=Myeloablative megatherapy with autologous stem-cel...[Lancet Oncol. 2005] - PubMed Result |accessdate=2008-02-02 |format= |work=}}</ref>
*2000-2006: The recent study (COG-A3973)<ref name="titleClinical Trials (PDQ�) - National Cancer Institute">{{cite web |url=http://www.cancer.gov/templates/view_clinicaltrials.aspx?version=healthprofessional&cdrid=67429+ |title=Clinical Trials (PDQ�) - National Cancer Institute |accessdate=2008-02-02 |format= |work=}}</ref> questioned the need for purged stem cells for CEM-LI (carboplatin, etoposide, melphalan, with local irradiation)<ref name="Autologous Stem Cell Transplantation for High-Risk Neuroblastoma">{{cite web |url=http://mmserver.cjp.com/gems/blood/ABMT.10.Villablanca.pdf |title=Autologous Stem Cell Transplantation for High-Risk Neuroblastoma |accessdate=2008-02-02 |format= |work=}}</ref> transplant, and accrued 486 patients. Purging stem cells was not found to improve survival<ref name="titleResponse and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Childrens Oncology Group (COG A3973) study. - ASCO">{{cite web |url=http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=31659 |title=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 |accessdate=2008-02-02 |format= |work=}}</ref>
*2000-2012: An additional study (COG-ANBL0032)<ref name="titleNational Cancer Institute - Clinical">{{cite web |url=http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=69018&version=HealthProfessional&protocolsearchid=2119048+ |title=Clinical Trials - National Cancer Institute |accessdate=2008-02-02 |format= |work=}}</ref> will determine if the antibody ch14.18 with [[interleukin 2]] and [[GMCSF]] (studied retrospectively in German GPOH NB90 and NB 97 at a lower dose and without [[cytokines]]<ref name="titleConsolidation 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">{{cite web |url=http://jco.ascopubs.org/cgi/content/full/22/17/3549 |title=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 |accessdate=2008-02-02 |format= |work=}}</ref>) improves survival, and will accrue a total of 423 patients.
*2002-2008: SIOP (International Society of Paediatric Oncology) formed the European SIOP Neuroblastoma Group (ESIOP NB) in 1994 <ref name="SIOP Neuroblastoma Education Book">{{cite web |url=http://www.cure4kids.org/private/courses_documents/m_148/SIOP-2005-Education-Book.pdf |title=Neuroblastoma Education Book |accessdate=2008-02-02 |format= |work=}}</ref> and activated a phase III high-risk NB protocol in 2002 (SIOP-EUROPE-HR-NBL-1) <ref name="titleTrials - National Cancer Institute">{{cite web |url=http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=69191&version=HealthProfessional&protocolsearchid=4015135 |title=Clinical Trials (PDQ�) - National Cancer Institute |accessdate=2008-02-02 |format= |work=}}</ref> using “rapid” COJEC (8 cycles of chemotherapy given at 10-day intervals) followed by transplant randomization to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan) and then randomization to with or without ch14.18 antibody treatment. This study will evaluate the use of growth factors as well as compare transplant regimens, with or without ch14.18 antibody, and all patients receive retinoic acid. This trial will accrue 1000 patients (175 per year). There are eight arms to this study.
*2005-2010: The current German NB2004 <ref name="titleNB2004 - kinder krebs info . de">{{cite web |url=http://www.kinderkrebsinfo.de/e1664/e1676/e1758/e7720/index_ger.html+ |title=NB2004 - kinder krebs info . de |accessdate=2008-02-02 |format= |work=}}</ref> randomization will include MIBG therapy and randomize topotecan use in up-front therapy and will accrue a total of 642 for all risk groups (roughly half will be high-risk). After transplant, the high-risk protocol includes six months of cis-retinoic acid, a three month break, and another three months of retinoic acid.
*2007: The COG phase III ANBL0532 <ref name="titleNational Cancer Institute- Clinical trials">{{cite web |url=http://www.cancer.gov/clinicaltrials/COG-ANBL0532 |title=Clinical Trials (PDQ�) - National Cancer Institute |accessdate=2008-02-19 |format= |work=}}</ref> trial opened December 2007 for accrual of 495 and will compare single versus tandem transplants, and induction begins with two cycles of topotecan.<ref name="titleHigh-risk neuroblastoma treated with tandem autolo...[J Clin Oncol. 2006] - PubMed Result">{{cite web |url=http://www.ncbi.nlm.nih.gov/pubmed/16782928 |title=High-risk neuroblastoma treated with tandem autolo...[J Clin Oncol. 2006] - PubMed Result |accessdate=2008-02-02 |format= |work=}}</ref>
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 uses a novel induction regimen which includes a method of giving chemotherapy called “chemo-switching” where [[cisplatin]] is given as high-dose pulse and [[etoposide]] is given at low-dose over several weeks for the first two cycles.<ref name="titleTexas Childrens Cancer Center - Clinical Trials - PEPI: Protracted Etoposide In a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma">{{cite web |url=http://www.txccc.org/content.cfm?content_id=1475 |title=Texas Children's Cancer Center - Clinical Trials - PEPI: Protracted Etoposide In a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma |accessdate=2008-02-19 |format= |work=}}</ref> 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]].<ref name="titleNeuroblastoma Protocol 2005: Therapy for Children with Advanced Stage High-Risk Neuroblastoma">{{cite web |url=http://clinicaltrial.gov/ct2/show/NCT00135135?intr=%22Tazarotene%22&show_desc=Y#desc |title=Neuroblastoma Protocol 2005: Therapy for Children with Advanced Stage High-Risk Neuroblastoma |accessdate=2008-02-02 |format= |work=}}</ref> 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.<ref name="titleSloan-Kettering - Neuroblastoma: Our Clinical Trials">{{cite web |url=http://www.mskcc.org/mskcc/html/63090.cfm |title=Sloan-Kettering - Neuroblastoma: Our Clinical Trials |accessdate=2008-02-02 |format= |work=}}</ref>
=== Clinical trials for refractory and relapsed neuroblastoma ===
[[Image:BiggeggSH-SY5Y.jpg|thumb|microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents]]
Topotecan with 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.<ref name="titleRecurrent neuroblastoma: Randomized treatment with topotecan + cyclophosphamide (T+C) vs. topotecan alone(T). A POG/CCG Intergroup Study -- Frantz et al. 22 (14 Supplement): 8512 -- ASCO Meeting Abstracts">{{cite web |url=http://meeting.ascopubs.org/cgi/content/abstract/22/14_suppl/8512 |title=Recurrent neuroblastoma: Randomized treatment with topotecan + cyclophosphamide (T+C) vs. topotecan alone(T). A POG/CCG Intergroup Study -- Frantz et al. 22 (14 Supplement): 8512 -- ASCO Meeting Abstracts |accessdate=2008-03-13 |format= |work=}}</ref> Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.<ref name="titleIrinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma -- Kushner et al. 24 (33): 5271 -- Journal of Clinical Oncology">{{cite web |url=http://jco.ascopubs.org/cgi/content/full/24/33/5271 |title=Irinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma -- Kushner et al. 24 (33): 5271 -- Journal of Clinical Oncology |accessdate=2008-03-13 |format= |work=}}</ref><ref name="titlePhase I study of oral irinotecan and temozolomide in children with relapsed high-risk neuroblastoma: A New Approach to Neuroblastoma Therapy (NANT) Consortium study -- Wagner et al. 25 (18 Supplement): 9567 -- ASCO Meeting Abstracts">{{cite web |url=http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9567 |title=Phase I study of oral irinotecan and temozolomide in children with relapsed high-risk neuroblastoma: A New Approach to Neuroblastoma Therapy (NANT) Consortium study -- Wagner et al. 25 (18 Supplement): 9567 -- ASCO Meeting Abstracts |accessdate=2008-03-13 |format= |work=}}</ref>
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 November 2006, DRAXIS Health received approval from the U.S. Food and Drug Administration (FDA) to run two clinical trials using radioactive [[Iobenguane]] I-131 Injection (I-131 MIBG) to treat high-risk neuroblastoma<ref>[http://acnp.snm.org/index.cfm?PageID=5717&RPID=63 "DRAXIS Radiopharmaceutical Unit Approved to Run 2 Clinical Trials to Treat Neuroblastoma"], DRAXIS Health Inc. press release, November 22, 2006</ref> and in May 2008 Molecular Insight Pharmaceuticals announced the opening of a Phase IIa trial of Azedra, the I-131 MIBG molecule radiolabeled using Molecular Insight's proprietary Ultratrace technology, which removes unnecessary nonradioactive molecules, effectively concentrating radiation in the neuroblastoma tumor cells.<ref name="urlMolecular Insight Pharmaceuticals, Inc. Initiates Phase 2a Azedra(TM) Clinical Trial in Neuroblastoma Patients">{{cite web |url=http://www.businesswire.com/portal/site/google/?ndmViewId=news_view&newsId=20080501005145&newsLang=en |title=Molecular Insight Pharmaceuticals, Inc. Initiates Phase 2a Azedra(TM) Clinical Trial in Neuroblastoma Patients |format= |work= |accessdate=}}</ref><ref name="urlMolecular Insight Pharmaceuticals : Azedra Trials">{{cite web |url=http://www.molecularinsight.com/phase2a.aspx |title=Molecular Insight Pharmaceuticals : Azedra Trials |format= |work= |accessdate=}}</ref> <ref name="urlIodine I 131 Metaiodobenzylguanidine and a Stem Cell Transplant in Treating Young Patients With Relapsed or Refractory High-Risk Neuroblastoma - Full Text View - ClinicalTrials.gov">{{cite web |url=http://clinicaltrials.gov/ct/show/NCT00659984 |title=Iodine I 131 Metaiodobenzylguanidine and a Stem Cell Transplant in Treating Young Patients With Relapsed or Refractory High-Risk Neuroblastoma - Full Text View - ClinicalTrials.gov |format= |work= |accessdate=}}</ref> These trials are coordinated by a group of 11 children’s hospitals and two universities in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium, and are continuations of earlier NANT studies. The NANT consortium is also currently offering trials using a [[tyrosine kinase]] inhibitor CEP-701 (lestaurtinib), new oral powder formulation of [[fenretinide]], [[intravenous]] fenretinide, and [[bisphosphonate]] (Zometa).<ref name="titleNANT Home Page">{{cite web |url=http://www.nant.org/ |title=NANT Home Page |accessdate=2008-02-02 |format= |work=}}</ref>
In February 2007, a study in Sweden reported that a common [[painkiller]], might inhibit the development of neuroblastoma and help make treatment of the disease more effective. [[Celecoxib]], an analgesic, anti-inflammatory substance that works by inhibiting the effect of the inflammatory enzyme, [[Cox-2]], and thus could affect neuroblastoma tumors, which depend on Cox-2 for their growth and proliferation. Clinical studies are now planned; research to date has been done only in animals and cell cultures.<ref>[http://www.medicalnewstoday.com/medicalnews.php?newsid=62564 "Painkiller Helps Against Child Cancer"], medicalnewstoday.com, February 8, 2007, accessed March 8, 2007 (source apparently is a press release from the Karolinska Institutet in Sweden)</ref><ref name="pmid17289900">{{cite journal |author=Ponthan F, Wickström M, Gleissman H, ''et al'' |title=Celecoxib prevents neuroblastoma tumor development and potentiates the effect of chemotherapeutic drugs in vitro and in vivo |journal=Clin. Cancer Res. |volume=13 |issue=3 |pages=1036–44 |year=2007 |pmid=17289900 |doi=10.1158/1078-0432.CCR-06-1908 |url=http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17289900}}</ref>
== Post-treatment prognosis and late-effects ==
Neuroblastoma frequently recurs in high-risk cases. 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.<ref name="pmid16395684">{{cite journal |author=Ceschel S, Casotto V, Valsecchi MG, Tamaro P, Jankovic M, Hanau G, Fossati F, Pillon M, Rondelli R, Sandri A, Silvestri D, Haupt R, Cuttini M |title=Survival after relapse in children with solid tumors: a follow-up study from the Italian off-therapy registry |journal=Pediatr Blood Cancer |volume=47 |issue=5 |pages=560–6 |year=2006 |pmid=16395684 |doi= 10.1002/pbc.20726|url=http://www.ncbi.nlm.nih.gov/pubmed/16395684?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum}}</ref>
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.<ref name="pmid17974716">{{cite journal |author=Gurney JG, Tersak JM, Ness KK, Landier W, Matthay KK, Schmidt ML |title=Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group |journal=Pediatrics |volume=120 |issue=5 |pages=e1229–36 |year=2007 |pmid=17974716 |doi=10.1542/peds.2007-0178}}</ref><ref name="pmid17724446">{{cite journal |author=Trahair TN, Vowels MR, Johnston K, Cohn RJ, Russell SJ, Neville KA, Carroll S, Marshall GM |title=Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation |journal=Bone Marrow Transplant |volume=40 |issue=8 |pages=741–6 |year=2007 |pmid=17724446 |doi= 10.1038/sj.bmt.1705809|url=http://www.ncbi.nlm.nih.gov/pubmed/17724446?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum}}</ref> 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.<ref>[http://www.ajc.com/health/content/shared-auto/healthnews/-bon/602068.html "Childhood Cancer Survivors Face Increased Sarcoma Risk"], HealthDay News, February 21, 2007</ref><ref>Oeffinger et al., [http://content.nejm.org/cgi/content/abstract/355/15/1572 "Chronic Health Conditions in Adult Survivors of Childhood Cancer"], New England Journal of Medicine, October 12, 2006</ref>
The protein [[p53 (protein)|p53]] is believed to play a role in the development of resistance to chemotherapy.<ref name="pmid17974978">{{cite journal |author=Xue C, Haber M, Flemming C, ''et al'' |title=p53 determines multidrug sensitivity of childhood neuroblastoma |journal=Cancer Res. |volume=67 |issue=21 |pages=10351–60 |year=2007 |pmid=17974978 |doi=10.1158/0008-5472.CAN-06-4345 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17974978}}</ref>
==References==
{{Reflist|2}}
==External links==
*{{DMOZ|Health/Conditions_and_Diseases/Cancer/Brain_and_CNS/Neuroblastoma/}}
*[http://www.cancer.gov/cancertopics/types/neuroblastoma/ Overview] at [[National Cancer Institute]]
*[http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_neuroblastoma_31.asp?rnav=cri Overview] at [[American Cancer Society]]
*{{Chorus|00869}}
*[http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional Treatment] at [[National Cancer Institute]]
*[http://www.nbhope.org/NBConference2005_32.aspx VIDEOS - Neuroblastoma topics] at [http://www.nbhope.org/NBConference2005_32.aspx Neuroblastoma Conference Chicago 2005]
*[http://www.cncf-childcancer.org/cs/blogs/neuroblastoma_conference_videos_2007/default.aspx VIDEOS - Neuroblastoma topics] at [http://www.cncf-childcancer.org/cs/blogs/neuroblastoma_conference_videos_2007/default.aspx Neuroblastoma Conference Chicago 2007]
*[http://www.mskcc.org/mskcc/html/2868.cfm Overview] at [[Memorial Sloan-Kettering Cancer Center]]
*[http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=neuroblastoma&srch_type=any&labels=&details=-1&no_filter=-1&plane_id=&capt_id=&filter_m=&filter_o=&acr_pre=&filter_p=&acr_post=#top Medical Image Database] at [[Uniformed Services University of the Health Sciences]]
*[http://videos.med.wisc.edu/videoInfo.php?videoid=248 VIDEO - Neuroblastoma], Jeannie Yang, MD, gives an overview at the Department of Surgery Grand Rounds (2007) at [[University of Wisconsin]]
{{Nervous tissue tumors}}
[[Category:Types of cancer]]
{{Link FA|pl}}
[[de:Neuroblastom]]
[[fr:Neuroblastome]]
[[it:Neuroblastoma]]
[[ja:神経芽細胞腫]]
[[pl:Nerwiak płodowy]]
[[pt:Neuroblastoma]]
[[fi:Neuroblastooma]]