UPDATED AUGUST 2015
1. GENERAL INFORMATION
Neuroblastoma (NBL) is a malignant tumour arising in the sympathetic nervous system; it originates from neuroectodermal cells of the primitive neural crest (Caron 2005; Brodeur 2006).
1.2 Incidence, epidemiology and risk factors
NBL is a very rare tumour; however it is the most frequent solid tumour in children aged <5 years. The occurrence of NBL is unusual in adolescents and adults (Gatta 2012). Ninety-five percent of all NBL occurs in children under 5 years of age. Actually, cases have been detected antenatally, during ultrasound examination, and some of these patients, together with the ones diagnosed in the first days of life, have been observed to undergo spontaneous regression (De Bernardi 2009).
In European children (0-14 years), according to the RARECAREnet project (period of diagnosis 2000-2007), the annual incidence rate was 6 cases per million (RARECAREnet). In Europe (EU28), almost 500 new cases of NBL were diagnosed in 2013. The occurrence was about 13% more frequent in boys than girls (RARECAREnet). Incidence was highest in Southern Europe; age-adjusted rates per million was 2.0 for all ages. Incidence slightly, but significantly, increased during the period 1995-2007 from 1.2 to 1.4 (RARECAREnet). In the previous period (1978-1997) the increase was more marked, mostly due to an increase in infants (Spix 2006).
Prognosis is very good for infants, while it is not satisfying in older children. Five-year survival in children diagnosed between 2000-2007 was 91% in infants, 59% in children aged 1-4 years, 52% in children 5-9 years, and 56% in patients aged 10-14 years. Survival dropped steeply after the first year from diagnosis, so there was a large gap between 1-year and 3-year survival.
For all cases, survival reduced from 87% at 1 year after diagnosis to 70% at 3 year (RARECAREnet), but the decrease was more marked in children (Gatta 2014). Between 1999 and 2007, 5-year survival (age-adjusted) rose only in European Regions (Northern, Southern, and Eastern) that had a low survival in the period 1999-2001. Overall, in Europe no progress has been reported (Gatta 2014). Five-year survival remained low in Eastern Countries (62%) and reached the highest value in Northern Countries (80%): the large outcome disparity across European Countries still persists.
Based on very few cases (59 cases), 5-year survival in adolescents and adults for NBL and ganglioneuroblastoma was the lowest: 48% and 40%, in 15-24-year patients and 25-64-year patients, respectively (RARECAREnet). The clinical course of NBL in adults seems modestly influenced by therapy; the outcome is poorer at all stages (Sorrentino 2014).
About 12,000 persons were estimated being alive in Europe (EU27) at the beginning of 2008 with a diagnosis of malignant NBL or ganglioneuroblastoma (Gatta 2014), of whom 14% and 29% were diagnosed within 2 and 5 years since prevalence date, respectively. The difference (15%) between these two proportions represents people diagnosed within 2 and 5 years since the index date, whose treatment was presumably completed, but under active clinical follow-up. Thirty-eight percent of all prevalent cases survived more than 15 years after diagnosis (slightly less than 4,600 cases at the beginning of 2008) and are considered cured from their cancer.
1.5 Risk factors
Due to the rarity of NBL, epidemiological studies are a challenge. However, a body of literature has begun to emerge, suggesting that certain exposures are more common in NBL patients (Heck 2009). The early age at diagnosis of the disease suggests that prenatal exposures might play an important role.
It is well establish that foetal exposure to alcohol causes disruption of normal neuronal development. Several studies (Heck 2009) showed evidence of an increasing risk of disease with use of alcohol during pregnancy with odds ratios (OR) ranging between 1.2 and 12.0. Interestingly, a German population-based study found an important association with maternal alcohol consumption during pregnancy (7 glasses/week: odds ratio 5.2; 95%Cl 1.3-20.6) only for unfavourable advanced stages of NBL (Schüz 2001).
There is a little evidence to support a casual association between maternal tobacco use in pregnancy and NBL (Heck 2009).
Several studies investigated potential link between parental occupational pre-conceptional and prenatal exposures and NBL risk in offspring. A multi-centre case-control study (Olshan 1999) found an increased risk for parental occupations with electromagnetic field and pesticide exposure; the risk estimates were relatively large (between 6 and 2). The same group of researchers also identified a significant risk for non-volatile and volatile hydrocarbons (OR: 1.5) and specifically diesel fuels, lacquer thinner and turpentine, and also wood dusts and solders (De Roos 2001).
Two studies showed a strong association between the use of oral contraceptives or other sex hormones in early pregnancy. The German study (Schüz 2001) reported a fourfold risk increase for NBL among children diagnosed at early stage (1 or 2). A second study (Michalek 1996) reported a strong and significant association between fertility hormones (OR: 10.4); the estimation of the risk was based on 5 cases of NBL and 1 control.
The use of diuretics or other pills to treat water retention in pregnancy was investigated in few studies: their ORs varying between 5.8 and 1.2, all significant (Heck 2009). A positive significant association was also found with medications containing codeine during pregnancy or lactation (OR: 3.4) (Cook 2004).
Several studies observed a protective effect for childhood allergies and family history of asthma, ORs ranging between 0.2 and 0.9, three of them statistically significant (Heck 2009).
Protective effect was reported with maternal vitamin intake during pregnancy (ORs ranging between 0.5 and 0.7) (Heck 2009). An ecologic investigation showed a decline in rates of NBL in Ontario after the 1997 implementation of a folic acid fortification programme for Canadian cereal grains (French 2003). This finding is important given the established relationship between folate intake and neuronal cell development in utero. Actually, a concurrent decline of neural tube defects incidence was reported, suggesting that data are not affected by the ecological bias.
There are several studies investigating the relationship with low birth weight. Unfortunately, few of them control by gestational age. The risks (OR) ranged between 1.2 and 2.1, for the studies that adjusted for gestational age or term births (Heck 2009; Johnson 2008).
2. PATHOLOGY AND BIOLOGY
The term “neuroblastoma” is usually used inaccurately to encompass the entire family of peripheral neuroblastic tumours, which derive from neuroectodermal embryonic cells (Shimada 1999).
The family of peripheral neuroblastic tumours actually includes several tumours which have different cellular composition and degrees of differentiation.
These tumours can be classified as:
- Neuroblastoma: which consists of immature neuroblastic cells, with a limited stromal Schwannian component. Subtypes are: undifferentiated, poorly differentiated, or differentiated.
- Ganglioneuroblastoma, nodular: which consists of a prevalent or predominant Schwannian stromal component and of a macroscopic nodular component of neuroblastic cells that are stroma-poor
- Ganglioneuroblastoma intermixed: consists of a prevalent Schwannian stromal component (>50%) and of a component of microscopic neuroblastoma cell aggregates intermixed with the stroma.
- Ganglioneuroma: consists of a predominant Schwannian stromal component with completely differentiated ganglion cells (“mature ganglioneuroma”) or incompletely differentiated ganglion cells (“maturing ganglioneuroma”).
2.1.1 International Neuroblastoma Pathological Classification
The International Neuroblastoma Pathological Classification (INPC) distinguishes between different categories of neuroblastoma and defines the prognostic impact of each category. For neuroblastoma and ganglioneuroblastoma nodular, age and two microscopic features, mitosis karyorrhexis index (MKI) and grade of differentiation, have to be considered as standard (Table 1 and Figure 1) (Shimada 1999; Umehara 2000; Teshiba 2014).
Table 1. Prognostic groups according to the I.N.C.P.
|Ganglioneuroma mature: Favourable histology|
|Ganglioneuroma maturing: Favourable histology|
|Neuroblastoma: Favourable histology||<18 months:
Neuroblastoma poorly differentiated
differentiating with low MKI (<2%) or intermidiate MKI (>2% and <4%)
|Between 18 months and 5 years:
Neuroblastoma differentiating with low MKI
|Neuroblastoma: Unfavourable histology||<18 months:
Neuroblastomas with high MKI (>4%)
|Between 18 months and 5 years:
Neuroblastoma undifferentiated or poorly differentiated, any MKI
Neuroblastoma differentiating with intermediate or high MKI
Neuroblastoma, all histotypes
|Ganglioneuroblastoma: Favourable histology||Ganglioneuroblastoma with nodule(s) of neuroblastoma with favourable hostology|
|Ganglioneuroblastoma: Unfavourable histology||Ganglioneuroblastoma with nodule(s) of neuroblastoma with unfavourable hostology|
Figure 1. Mitosis karyorrhexis index (MKI). (Source: Shimada 1999)
2.1.2 Recommendations for tumour sampling
Correct handling of the tumour tissue is crucial, since there can be heterogeneity at both the histological and genetic level, and each has important prognostic implications. In all cases, for either tumour resection or biopsies, material from different areas of the tumour must be taken for histological and molecular-genetic/biological examination. For this reason, the SIOP (International Society of Paediatric Oncology) – Europe Neuroblastoma Group has developed a series of recommendations for tumour sampling as detailed below, on a type C basis (Beiske 2009).
22.214.171.124 Macroscopic description and sampling
Specimens should be delivered to the pathology laboratory unfixed, unexamined and, if possible, with an indication of the anatomical orientation.
SURGICAL RESECTION (complete, with minimal residual disease or incomplete) from localised neuroblastic tumours stage 1, 2 and 3.
The unfixed specimen should be orientated and measured (AxBxC).
The specimen should then be halved along the major axis. When possible, a photograph of the cut surface should be taken. The cut surface should be carefully examined: special attention should be paid to nodular/haemorrhagic areas in otherwise homogeneous, pinkish or white-yellowish tumours.
At least one (better two) fresh sample(s) of about 1cm3 should be taken from the tumour for biological investigation, with special attention to areas of different macroscopic appearance. If nodule/s are present, they should be sampled separately. (Figure 2).
Figure 2. Nodule sampling. (Source: Beiske 2009)
Each sample should be identified with a letter (i.e., A, B, C, etc), snap frozen in liquid nitrogen or at -70C, and adequately “centralised”, that is transported to the national reference laboratory in a BioCase, which will preserve the sample according to international guidelines. The samples will then be processed appropriately and touch preparations made for FISH (N-myc and Chromosome 1p) analysis, for molecular biology (DNA index, LMPA), and immunocytochemistry. For diagnostic purposes, the margins should be inked and the neoplasm fixed in 10% formalin. For sampling purposes, a 4mm-thick central section of the tumour should be examined in toto (if possible, after mapping the surface in order to identify the position of the single sample), plus about 1 sample per cm of the maximum diameter of the residual tumour mass (Figure 3).
Figure 3. Sampling process. (Source: Beiske 2009)
BIOPSY: open (preferred) or needle biopsies or fine-needle aspiration form stage-3, -4, and -4s neuroblastic tumours.
When dealing with biopsy specimens, the main concern is reaching a diagnosis. The material should therefore be subdivided into at least two parts: i.e. sample A for diagnosis and the definition of cellular composition, and sample B for touch preparations and molecular biology investigations (DNA content, N-myc, Chromosome 1p, MLPA, etc.) Any residual material will be utilized for immunocytochemistry and biobanking.
Alternatively, the whole sample, especially if there is only one small biopsy, may be sent to the central or National laboratory, frozen in liquid nitrogen, or preserved in RNA-Later or Allprotect Tissue Reagent (QIAGEN).
When needle biopsy is indicated instead of an open surgery procedure, the same general principles must be applied to the handling of the material. Currently, no data are available to indicate the minimum volume of tissue required to enable the INPC classification to be applied. This implies that, when dealing with needle biopsies containing less than 5,000 tumour cells, the INPC prognostic categorization is not applicable. The INPC is not applicable to fine-needle aspiration samples.
126.96.36.199 Histological report
Histological report of untreated tumours: It is recommended that untreated peripheral neuroblastic tumours should be classified on the basis of the macro/microscopic features of the tumour (INPC Classification) and assigned to the Favourable or Unfavourable Prognosis group on the basis of both age on diagnosis and INPC Classification.
Histological report of pre-treated tumours: The histological report should specify:
- the percentage of residual viable tumour (together with a description of its different components);
- the percentage of post-treatment changes and their description;
- the state of the inked surgical margins;
- all the other structures present in the surgical specimen must be described (e.g. lymph-nodes, adrenal gland, ganglia, etc.): involvement of vital tumour or regressive changes must be specified for each structure.
188.8.131.52 Bone marrow assessment
Both on diagnosis and throughout treatment, each patient >1yr of age will undergo bone marrow evaluation by means of two (bilateral) bone marrow trephine biopsies. Each of these should be kept in B5 fixative for 2 hours and then transferred to 70% alcohol. The specimens or, alternatively, 1 H&E plus 10 unstained slides, can be sent to a central National Centre.
2.2.1 MYCN oncogene in neuroblastoma
Gene amplification of homologous sequence of MYC gene was discovered in 1983 in human neuroblastoma cells lines by Schwab and colleagues (Schwab 1983) and called MYCN. Afterwards MYCN was found amplified in at least 20% of neuroblastoma with a greater prevalence in patients with stage 4 disease (Tonini 1997). MYCN oncogene amplification plays a crucial role in the tumour aggressiveness and several studies show that MYCN amplification promotes tumour growth and tumour progression. A significant correlation between MYCN amplification and poor prognosis has been demonstrated in patients with localised tumours (Canete 2009; De Bernardi 2008; De Bernardi 2009). Furthermore, high-risk patients with disseminated tumour showing MYCN amplification have a faster progression compared with those that do not have MYCN amplification. Since 1995, when the Localised Neuroblastoma European Study Group 1 (LNESG1) was licensed, the evaluation of MYCN gene status in neuroblastoma is a mandatory procedure in the International Trials (Tonini 1997; Ambros 2003; De Bernardi 2008).
2.2.2 Genomics abnormalities
Neuroblastoma cells show several chromosomal abnormalities. Neuroblastoma genome-wide analysis by microarray has demonstrated a complex picture of chromosomal abnormalities in both localised and disseminated tumours. Localised tumours have several numerical aberrations, whereas disseminated tumours have both numerical and structural chromosome abnormalities (Figure 4) (Coco 2012; Stigliani 2012; Schleiermacher 2012; Oberthuer 2015).
Figure 4. Most frequent chromosome aberrations (deletion [del]; imbalance [imb]; amplification [ampl], and gain) observed in tumour of patients with metastatic stage 4 neuroblastoma.
The discovery of structural (or segmental) chromosome abnormalities in neuroblastoma is very important because these aberrations have been found to be associated with a poor prognosis. Pangenomic tumour analysis has been introduced in the Low-Intermediate Neuroblastoma European Study (LINES) in order to provide a better evaluation of the risk for patients with localised tumour. Many laboratories performing molecular diagnosis of neuroblastoma evaluate chromosome abnormalities by Multiplex Ligand-dependent Probe Amplification (MLPA) or by array Comparative Genomic Hybridisation (arrayCGH). Pangenomic tumour analysis helps to identify segmental chromosomes so that tumours are classified as S0, S1, S2, S3, S4, and S5 according to the number of segmental aberrations found in the tumour cells. The chromosome segmental classification as reported in the diagnostic analysis of patient included in the LINES protocol (Schleiermacher 2010). The SIOP Europe Neuroblastoma Biology Committee indicated the guidelines to perform genomics profile in neuroblastoma (Ambros 2011). It is interesting to note that, although chromosome 1p deletion is one of the most frequent aberrations in neuroblastoma, its role is less important of MYCN gene amplification. Chromosome 17q gain is largely observed in neuroblastoma while chromosome 11q loss is less frequent, but is an important lesion in those tumours without MYCN amplification. Indeed, chromosome 11q loss has been employed in the New International Staging and Risk Stratification of Neuroblastoma as a negative predictor factor of patients under 18 months of age with localised or metastatic tumours (Ambros 2009; Bagatell 2009; Cohn 2009; Monclair 2009).
2.2.3 The evolution of nanotechnology and the sequencing of neuroblastoma genome
The array CGH is able to identify gene deletion, gene rearrangement, and gene amplification by a resolution of 1 kb, but it is not able to discovery mutation of one nucleotide that can dramatically change the function of the related protein. The next generation sequencing (NGS) performed by advanced nanotechnological instruments is able to sequence the whole genome of neuroblastoma cells (Figure 5).
Figure 5. Development of technologies for cancer molecular analysis.
The scheme shows how technologies has been developed starting from the evaluation of single gene (MYCN oncogene amplification by Southern blot analysis) to the study of whole genome by NGS technique. Between these two extreme there are:
- interphase fluorescent in situ hybridization (FISH) for MYCN gene;
- loss of heterozygosis;
- PCR for allelic loss valuation for chromosome 1 and others chromosome regions;
- array CGH for chromosome abnormalities detection;
- microarray for gene expression signature evaluation.
Up-to-date, more than 500 neuroblastomas have been sequenced and the data are stored in public databases (Eleveld 2015). NGS allows us to identify the damaging mutation at level of single base of DNA and then to predict the damage made by the protein. It is interesting to note that the average number of mutation per tumour is quite low (about 12/tumour) (Pugh 2013; Molenaar 2012). We foresee that in the next future tumour of each patient will undergo to the NGS analysis. The sequencing of tumour genome could give advantage for neuroblastoma patients, because the discovery of damaging mutations may give the possibility to adapt therapy for each patient with advanced neuroblastoma.
2.2.4 Gene expression abnormalities in neuroblastoma
In neuroblastoma, the expression of several genes is deregulated and drives the growth of tumour cells. In the last decade, the use of high-density oligonucleotides microarray has elucidated the gene expression profile of neuroblastoma. It is possible to screen more than 30,000 genes and to identify which genes are up- or down-regulated in the tumour. Several studies of gene expression profiles (GEP) of a large number of neuroblastoma generate the so called “gene signatures” that are associated with favourable or unfavourable tumour progression. In fact, the genomic era has introduced a new vision for evaluating the patient’s risk. In neuroblastoma, the first molecular marker strongly associated with a poor prognosis for patients with localised disease was MYCN gene amplification. However, since MYCN amplification is only found in about 20% of tumours, other additional markers are required to evaluate the risk of patient relapse. Vermeulen et al. generated a 59-gene signature able to predict the outcome in children with neuroblastoma, and Oberthuer et al. proposed a 144-gene signature that was highly performing to predict the patient’s outcome (Vermeulen 2009; Oberthuer 2015). However, unlike chromosome abnormalities, the gene signature has not been introduced in clinical trial as prognostic factor, yet. One of the reasons is that RNA is not available for all tumours; moreover, DNA is more stable than RNA and can circulate easily among different laboratories for double check analysis. So, the genomics profile is routinely used today to predict patient outcome in children with low or intermediate risk (Figure 6) (Wang 2006; Scaruffi 2007; Coco 2009; Tonini 2006; Tonini 2009).
Figure 6. Example of GEP microarray analysis of neuroblastoma.
The figure shows the heat-map with different colours: red high expressed genes; green: low expressed gene. In the bar the yellow and blue colour represent two groups of tumours with different GEP. More than 30,000 genes are screened in the microarray.
2.2.5 Genotype and phenotype
Neuroblastoma shows great clinical and biological heterogeneity. Neuroblastoma has small round undifferentiated cells without stroma, whereas ganglioneuroblastoma has large Schwannian stromal cells with very few or an absence of neuroblastic cells. Neuroblastic and Schwann stromal cells have different gene signatures (Coco 2005; Albino 2008). Genes highly expressed in neuroblastic cells are mainly those concerned with cell cycle control, transcription factor activity and regulation of gene transcription; whereas genes expressed in Schwann cells are those involved in cell differentiation, signal transduction and lipid metabolism pathway. Moreover, several reports indicate a complex cytokines cross-talk between stroma cells and neuroblastic cells, and a cross-talk that greatly influence the tumour growth (Del Grosso 2011).
2.2.6 Role of TRK, CD44 and ALK in neuroblastoma
A group of genes that are mostly involved in neuroblastoma belong to the TRK gene family. At least three genes, TRKA, TRKB and TRKC, have some role in neuroblastoma development (Brodeur 2009). TRKA is the receptor for nerve growth factor (NGF). TRKA is a member of the TRK family of tyrosine kinases regulating cell growth, differentiation and the programmed cell death of neurons in both the peripheral and central nervous systems. TRKA expression may be involved in the regulation of cell differentiation and also in the induction of programmed cell death of neural crest cells of sympathoadrenal lineage. In NB, the amount of NGF in the tumour microenvironment and the expression of TRKA receptors have a profound effect on cellular behaviour – tumour cells expressing TRKA undergo cell differentiation in the presence of NGF. Furthermore, it has been reported that TRKA expression is a crucial factor in the spontaneous regression of neuroblastoma; TRKA expression is associated with a favourable patient outcome and its expression is almost completely down regulated in tumours with MYCN amplification (Scaruffi 1999; Brodeur 2009).
CD44 is a cell surface protein expressed and secreted by several tissues. CD44 has been found widely expressed in ganglioneuroblastoma and in about 50% of undifferentiated neuroblastomas. In neuroblastoma CD44 expression strongly correlates with patients’ survival and lack of CD44 expression significantly correlates with a poor survival. An inverse association between CD44 expression and MYCN amplification has been observed.
ALK, the anaplastic lymphoma kinase gene, is a fused gene between nucleophosmin and a tyrosine kinase region observed in the t(2;5)(p23;q35) chromosome translocation of children with anaplastic large cell lymphoma. ALK is a large gene and belongs to the insulin-receptor superfamily. With inappropriate activity, ALK acts as an oncogene and can transform mammalian cell both in vitro and in vivo. ALK phosphorylation triggers signaling cascades of more than one metabolic pathway.
Recently, the ALK gene has been identified as the first neuroblastoma predisposing gene (Longo 2005; Longo 2007; Mossé 2008). In neuroblastoma cells, ALK is a tyrosin kinase receptor that became activated by point mutations in the tyrosin kinase domain. ALK gene is overexpressed in advanced neuroblastoma and in neuroblastoma Schwannian-stroma poor tumours (Passoni 2009). ALK activated receptor is a targetable receptor by small molecule inhibitors. Crizotinib, an ALK inhibitor has been employed in the therapy of non-small cell lung cancer, has been used in the therapy of neuroblastoma (Mossé 2013). However, other ALK inhibitors have been developed. One problem in the use of ALK inhibitor is the emerging ALK resistance cell clones and new therapeutic strategies should be applied to overcome this aspect (Bresler 2014).
2.2.7 Next future
The miRNA is a relatively new RNA family discovered in cancer and it regulates the expression of several genes. More than 1,000 miRNAs have been discovered so far. Some of them, such as the miR-17-5p-92 cluster and miR-34, are deregulated in neuroblastoma and they contribute to the aggressiveness of neuroblastoma (Stallings 2009). De Preter et al. (De Preter 2011) studied a large number of NB by miRNA expression and established a 25-miRNA signature that significantly predict high-risk patients’ survival. These results suggest that miRNAs regulate the NB cell activity improving their capacity to growth, but they can be used as novel prognostic marker to predict the patient outcome.
Another group of RNA, the long non-coding RNA (lncRNA), is emerging in the NB cell function. More than 35,000 lncRNAs have been identified. The lncRNAs are non-protein coding transcripts which lenght is more than 200 nucleotides; they can regulate gene expression by binding promoter gene region. The role of lncRNA in NB is still clarifying, although several studies have shown that some lncRNAs are involved in MYCN gene regulation (Liu 2014) and in tumour progression (Scaruffi 2009; Barnhill 2014).
One of the main problems that may impair the full genomics study of neuroblastoma tumour is the paucity of biological samples. Frequently, a small biopsy is available for tumour belonging to high-risk patients not allowing the complete analysis of genome profile or gene signature. This aspect could be overcome studying blood samples. In fact, it has been demonstrated that tumour cell and tumour DNA is circulating in the blood stream of patients with cancer. The exosomes that originate by direct budding of plasma membrane are part of the large family of extracellular vesicles (Minciacchi 2015). These vesicles carry proteins, nucleic acid, and lipids belonging to the tumour cells and can be extracted from the peripheral blood. Their content is a great font of information about tumour cells that cannot be removed by surgery. In the next future, the sequencing of DNA contented in the extracellular vesicles couldgive the genomic profiling of tumour cells. Recently, it has been reported that neuroblastoma cell lines secrete exosomes containing miRNA that have potential role in cancer progression (Haug 2015).
3.1 Clinical presentation
In two-thirds of cases NBL originates from the adrenal glands or the retroperitoneal paravertebral ganglia and presents as an abdominal mass with symptoms of compression of the abdominal viscera. In 20% of cases, NBL originates from the posterior mediastinal ganglia, sometimes presenting with severe respiratory symptoms. In the remaining cases it originates from the neck, where it appears as laterocervical mass or as Bernard-Horner syndrome, or from the pelvis. The most frequent metastatic sites, usually present at the time of diagnosis in the majority (~60%) of patients, are bone and bone marrow. Sometimes, the first signs and symptoms are related to the dissemination of the disease (anorexia, fever, pain, periorbital ecchimoses), and these are the symptoms that capture the attention of the patients and their doctors (Brodeur 2006). About 7% of patients present with signs and symptoms of spinal cord compression due to the infiltration of the intervertebral foramina; the effects of this compression are reversible in the majority of cases with timely diagnosis and treatment (De Bernardi 2014).
The most important signs and symptoms at diagnosis are opsoclonus and ataxia, related to the presence of anti-cerebellar autoantibodies; this presentation is generally associated with a favourable outcome. However, approximately one third of patients have severe psycho-motor sequelae despite the use of immunosuppressive agents (Krug 2010). Another rare presentation of the disease is associated with watery diarrhoea due to a paraneoplastic production of vasoactive intestinal peptide (Brodeur 2009).
3.2 Diagnostic criteria
For accurate diagnosis and staging the following examinations as suggested by the International Neuroblastoma Staging System (INSS) are required (Brodeur 1993; Monclair 2009):
- CT or MR of the site of the primary, to evaluate the extension of the primary disease;
- histological evaluation in the site of the primary or metastatic sites;
- bone marrow aspirate and biopsy in 2 different sites to evaluate whether a marrow infiltration is present. Imunocytochemical or molecular biology techniques to detect bone marrow infiltration may be performed but these are considered investigative (Viprey 2008; Beiske 2009);
- meta-iodo-benzyl-guanidine (I-MIBG) scintigraphy, to evaluate the site of primary and to detect metastatic sites. This technique is also very important to evaluate the response to the treatment in metastatic sites (Brisse 2011);
- CT of the bones which have been shown to be positive with MIBG scan, in children less than 1 year old;
- levels of the urinary catecholamine metabolites (homovanillic and vanilmandelic acids);
- additional evaluations are ferritin level, serum LDH, neuron-specific enolase (NSE).
The stage of the disease, which, together with MYCN status and age is largely used to define prognosis and to design the treatment programmes, is based on the study of local and distant extension and on the resecability of the disease in nonmetastatic cases (Table 2) (Brodeur 1993). The system universally used in the past two decades, called International Neuroblastoma Staging System (INSS), was based on the judgment of resectability by the surgeon at the time of diagnosis, on a type C basis (Table 2) (Brodeur 1993).
Table 2. International Neuroblastoma Staging System (INSS)
|Stage I||Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive).|
|Stage IIA||Localised tumour with incomplete gross excision;
representative ipsilateral non-adherent lymph nodes negative for tumour microscopically.
|Stage IIB||Localised tumour with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumour.
Enlarged contralateral lymph nodes must be negative microscopically.
|Stage III||Unresectable unilateral tumour, infiltrating across the midline,* with or without regional lymph node involvement;
localised unilateral tumour with contralateral regional lymph node involvement;
midline tumour with bilateral extension by infiltration or lymph node involvement.
|Stage IV||Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver and/or other organs(except as defined for Stage IVS).|
|Stage IVS||Localised primary tumour (as defined for Stage 1, 2A or 2B), with dissemination limited to liver, skin, and/or bone marrow** (limited to infants <1 year of age)|
* The midline is defined as the vertebral column. Tumours originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.† Marrow involvement in Stage 4S should be minimal, i.e. less than 10% nucleated cells on bone marrow biopsy or quantitative assessment of nucleated cells on marrow aspirate. More extensive marrow involvement should be considered Stage 4. The MIBG scan should be negative in the marrow for Stage 4S.
|**Multi-focal primary tumours (e.g. bilateral adrenal primary tumours) should be staged according to the greatest extent of disease, as defined above, and be followed by a subscript “M” (e.g. Stage 3M).|
The International Neuroblastoma Risk Group (INRG) classification system was developed in 2009 to facilitate the comparison of risk-based clinical trials conducted in different areas of the world by defining homogenous pretreatment patient cohorts. This system defines in a more homogeneous way reproducible risk groups, and radiological criteria at diagnosis have been adopted as risk factors for surgery, on a type C basis (Table 3) (Cecchetto 2005; Monclair 2009).
Table 3. Image-defined risk factors (IDRFs) in neuroblastic tumours
|Ipsilateral tumour extension within two body compartments|
|Neck||Tumour encasing carotid and/or vertebral artery and/or internal jugular vein|
|Tumour extending to base of the skull|
|Tumour compressing the trachea|
|Cervico-thoracic junction||Tumour encasing brachial plexus roots|
|Tumour encasing subclavian vessels and/or vertebral and/or carotid artery|
|Tumour compressing the trachea|
|Thorax||Tumour encasing the aorta and/or major branches|
|Tumour compressing the trachea and/or principal bronchi|
|Lower mediastinal tumour, infiltrating the costo-vertebral junction between T9 and T12|
|Thoraco-abdominal||Tumour encasing the aorta and/or the vena cava|
|Abdomen/pelvis||Tumour infiltrating the porta hepatis and/or the hepatoduodenal ligament|
|Tumour encasing branches of the superior mesenteric artery and the mesentery root|
|Tumour encasing the origin of celiac axis and/or of the superior mesenteric artery|
|Tumour invading one or both renal pedicles|
|Tumour encasing the aorta and/or the vena cava|
|Tumour encasing the iliac vessels|
|Pelvic tumour across the sciatic nerve|
|Intraspinal tumour extension whatever the location provided that:
more than one third of the spinal canal in the axial plane is invaded
the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal
|Infiltration of adjacent organs/structures:
Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery
|Conditions to be recorded, but not considered IDRFs||Multifocal primary tumours;
Pleural effusion, with or without malignant cells;
Ascites, with or without malignant cells.
These criteria are based on the relation of the tumour to the adjacent structures and vasculature and predict severe surgical complications; they are the basis for the new International Neuroblastoma Risk Group Staging System (INRGSS) (Table 4).
Table 4. International Neuroblastoma Risk Group Staging System (INRGSS)
|Stage L1||Radiological risk factors absent: Localised tumour not involving vital structures as defined by the list of image-defined risk factors, and confined to one body compartment|
|Stage L2||Locoregional tumour with presence of one or more image-defined risk factors|
|Stage M||Distant metastatic disease (except stage MS)|
|Stage MS||Metastatic disease in children younger than 18 months with metastases confined to skin, liver and/or bone marrow (bone marrow involvement should be limited to <10% of total nucleated cells on smears or biopsy)|
Several international groups have developed a model of risk stratification to facilitate the delivery of risk-adapted treatments (Maris 2005; Maris 2010; Cohn 2009). Different biological features were added to the different clinical characteristics, and nowadays the most important prognostic factors include age, stage and N-MYC amplification. These parameters define at least 2 different patterns of disease. The first one is NBL which arises in the first months of life: some patients show a spontaneous regression of the disease or have excellent survival with minimal treatment, provided the tumour is not N-MYC amplified (Fritsch 2004; De Bernardi 2009; Brodeur 2014).
By contrast, an unfavourable outcome is expected for children with N-MYC amplified tumours or metastatic tumours and age > 18 months at diagnosis (De Bernardi 2003; Canete 2009; Caron 2005). Between these two extreme groups there is a less defined group with commensurately “intermediate” characteristics. Additional prognostic markers, such as histopathological classification, tumour ploidy, chromosomal anomalies including 1q-, 17gain, ploidy could help in better defining the prognosis and consequently enable physicians to tailor different treatment strategies to individuals in this subgroup of patients.
NBL in adolescents and adults is very rare, and in these patients the disease has a different clinical outcome. Absence of metastatic disease is the most frequent clinical presentation at onset, often accompanied by an absence of N-MYC amplification. However, despite a relatively inactive disease, multiple local relapses or metastatic disease may occur which give rise to an unfavourable prognosis (Conte 2006; Podda 2010; Mossé 2014).
The International Neuroblastoma Risk Group (INRG) Task force has developed a classification system, called the International Neuroblastoma Risk Group Consensus Pretreatment Classification Schema to establish a consensus approach for pretreatment risk stratification, on a type C basis (Cohn 2009) (Table 5).
Table 5. International Neuroblastoma Risk Group Consensus Pretreatment Classification Scheme.
6.1 General data
The clinical behavior of NBL ranges from spontaneous maturation to inexorable progression despite multimodal intensive therapy (Mueller 2009). This variability in the behaviour is attributable to molecular differences in the tumour. The high-risk clinical prognostic factors (age >18 months and advanced stage) are closely associated with unfavourable biologic risk factors, including unfavourable histopathology, MYCN amplification, loss of heterozygosity of 1p and 11q, or other chromosome deletions. The 5-year event-free survival (EFS) rate for high-risk neuroblastoma is <50%, including patients with metastatic neuroblastoma with ages >18 months, and patients with locoregional or metastatic neuroblastoma with MYCN gene amplification (Cohn 2009). The best outcome (on a type 2 level of evidence) reported for high-risk neuroblastoma was achieved with intensive combination induction chemotherapy and surgery, followed by myeloablative therapy plus hematopoietic stem cell rescue, and then differentiation therapy with maintenance therapy with isotretinoin alternated with an immunological approach including anti-disialoganglioside 2 (anti-GD2) in combination with cytokines (GM-CSF, IL-2) (Yu 2010).
Surgery plays a key role both for diagnosis and treatment. The objectives of surgery are to define the diagnosis, to acquire tumour tissue for biological studies, and to resect the tumour with minimal morbidity. When the anatomical characteristics (site, dimensions, relationship with the surrounding structures, presence of a pseudo-capsule) indicate that a surgical resection is feasible, surgery is the treatment of choice for patients presenting with localised disease, on a type 3 level of evidence (Strother 2012; Monclair 2015). Radiological criteria for a safe resection were established by an international panel of surgeons and radiologists who identified surgical risk factors by CT or MRI (Cecchetto 2005). When surgical risk factors are present, pre-surgical chemotherapy is mandatory in order to obtain a tumour shrinkage, on a type C basis. Since neuroblastoma has an elevated trophism for lymphatic vessels and lymph node infiltration, it is important to perform a surgical exploration of the loco-regional lymph nodes, especially in abdominal and pelvic localisations. For the paravertebral localisations with infiltration of the rachideal channel through intervertebral foramina, laminectomy is indicated only in selected cases with neurological symptoms. In fact, chemotherapy can lead to a rapid decrease of the tumour volume and the magnitude of the spinal cord compression, on a type 3 level of evidence (De Bernardi 2005; De Bernardi 2014).
By contrast to its pivotal role in localised disease, surgery occupies a somewhat controversial role in metastatic disease (Caron 2005; Wolden 2000; Simon 2013). However, considering the high incidence of local relapses, the actual indication in the majority of treatment protocols is the resection of the primary tumour after the induction of remission in the metastases, on a type R basis (La Quaglia 2004; Matthay 2009).
Chemotherapy has an important role in treating neuroblastoma, since the majority of patients present with metastatic disease or locally advanced disease at diagnosis, and therefore require systemic treatment. Alkylating agents (cyclophosphamide, ifophosphamide, busulfan, melphalan), platinum analogues (cis-platinum and carboplatinum), vincristine, epipodophyllotoxins (VP16, VM26), and anthracyclines (doxorubicin) have a well-known established activity and efficacy in NBL, and are considered as standard options (Peinemann 2015a). In the last years other agents, such as topotecan, irinotecan or temozolomide have been demonstrated to be effective on a type 3 level of evidence), and further investigative combinations including those drugs are ongoing in phase II studies (Garaventa 2003; Wagner 2009; Park 2013; Di Giannatale 2014).
NBL is a radiosensitive tumour, and tumoricidal doses are in the range 15 – 32 Gy (with fractional radiation doses ranging from 150cGy to 400cGy) depending on site, volume and age of the patient. The role of external beam radiotherapy is under continuous refinement, depending on the identification of risk factors that can limit its use in low-risk patients. The lack of randomized trials addressing the contribution of radiotherapy hampers proper evaluation of the impact of this treatment modality on clinical outcome. However, the more recent trend is towards the use of radiotherapy in combination with or without surgery for treatment at the site of the primary tumour in patients with MYCN amplified tumours, or in stage 4 disease, or in stage 3 disease with unfavourable biological or histological prognostic factors, on a type 3 level of evidence (Haas-Kogan 2003; Matthay 2009; Gatcombe 2009; Laprie 2004; Park 2009; Gaze 2013). Furthermore, external beam radiation therapy is largely and successfully used as palliative care on painful sites in patients with end-stage neuroblastoma, on a type C basis (Brodeur 2006) .
Another radiological approach is the use of radio-metabolic therapy with I-131 carried by benzylguanidin, a noradrenalin (epinephrine) analogue which is incorporated in the neurosecretory granules of neuroblastoma cells. Dosimetry problems, together with the non-homogeneous uptake of the I-MIBG in the tumour due to heterogeneity in its composition, and toxicity have limited the use of this treatment approach in selected Centres. Some groups used radio-metabolic therapy as first-line treatment, but long-term results are not favourable; other approaches that include radiometabolic therapy with I-MIBG in the conditioning phase before haemopoietic stem cell transplantation or as consolidation treatment are under investigation (Mastrangelo 2001; Garaventa 1999; Matthay 2009; Wilson 2014; Yanik 2015).
6.2 Treatment strategy
Treatment is currently determined by 3 parameters: stage, age and biological characteristics of the disease, on type C basis (Brodeur 2006; Cohn 2009; Park 2013).
Patients less than 18 months old (infants) at diagnosis have a significantly better outcome than older children, and some infants undergo a spontaneous remission of the disease (especially those with congenital adrenal tumours and those with stage 4S disease) (Brodeur 2014). For these reasons, in selected newborns or infants with diagnosed neuroblastic tumours it may be appropriate to adopt a regimen of close clinical and radiological surveillance progressing to surgery only after several months observation, when spontaneous regression of the tumour has not occurred, on a type 3 level of evidence. When systemic treatment is necessary, it has been shown that excellent results can be achieved with treatment programmes that are less intensive than those used in older children, on a type 3 level of evidence (Rubie 2011).
The status of N-MYC in the tumour is an accepted criterion for defining treatment risk: when N-MYC in the tumour is amplified, intensive investigative treatment programmes are standard regardless of the stage and age of the patient, on a type C basis (Cohn 2009; Yu 2010; Park 2013). For the different ongoing cooperative trials other parameters may be more important -, such as INPC classification, 1p deletion and other chromosomal abnormalities, which should be considered still investigational (Defferrari 2015).
6.2.1 Treatment for non-metastatic, resectable disease
In all cases where risk factors as defined by the criteria in section 4 are absent, surgical resection can be effective, on a type 3 level of evidence. If the biochemical investigations report the absence of MYCN amplification, surgical resection has a high chance of cure; 5-yrs event-free survival being >95% for completely resected tumours and > 85 % in incompletely resected tumours (De Bernardi 2008; Strother 2012). Rarely, patients have localised stage 2 disease and N-MYC amplification, in which case the patient has to be treated with chemo- and radio-therapy, on a type 3 level of evidence.
6.2.2 Treatment for locally advanced, unresectable disease
Since the complete resection of the tumour is the principal objective, surgery should not be undertaken before cytoreductive chemotherapy has been given in patients with a high, or unfavourable, surgical risk, on a type 3 level of evidence.
Planned presurgical chemotherapy, may be based on a variety of combinations of cyclophosphamide, doxorubicin, vincristine, platinum derivatives and etoposide. The intent of chemotherapy, which is given preoperatively for around 4 months, is to obtain tumour shrinkage, in order to carry out a complete resection with minimal risks of morbidity (Modak 2009; Baker 2010; Kohler 2013). In cases of incomplete resection, the feasibility of administering radiotherapy at 21-30 Gy, should be considered depending on patient age and site of residual disease. However, the contribution of such radiotherapy to disease control is not yet well established, on a type C basis (Caron 2005; Kohler 2013).
6.2.3 Treatment for advanced disease or N-MYC amplified disease
The prognosis for children with metastatic disease is poor – with the exception of infants without MYCN amplification (De Bernardi 2009; Garaventa 2014). The 5year-overall survival is around 30% (Maris 2010).
In this setting, the most recent international cooperative ongoing studies have employed highly intensive treatments including intense multi-agent chemotherapy as the predominant treatment. The challenge is to maintain remission, since more than half of patients with high-risk disease develop systemic disease recurrence with or without a relapse at the primary tumour site (Brodeur 2006; Maris 2007). Therapy failures are mostly attributed to the development of resistance to chemotherapy and minimal residual disease is considered an important cause of recurrence (Viprey 2014; van Wezel 2015). The combination of different agents has resulted in an objective response rate more than 70%; however the percentage of long term survivors remains unsatisfactory (Pearson 2008; De Bernardi 2003; Luksch 2005; Maris 2007; Park 2013). The trial conducted between 1991 and 1996 by the Children Oncology Group provided the cornerstone for treatment design for the majority of stage II or III studies around the world, and consisted of remission induction with intensive chemotherapy, local treatment at the site of the primary tumour with surgery and/or radiotherapy, myeloablative treatment with autologous haemopoietic stem cell rescue, and maintenance therapy with 13cis retinoic acid (Matthay 2009). The subsequent trial of the Children Oncology Group demonstrated a contribution to the 3-year event free survival of immunotherapy with a anti-disialoganglioside2 monoclonal antibody in combination with cytokines monoclonal antibody in remission after multimodality treatment (Yu 2010). The ongoing investigative trials are exploring the efficacy of new investigational combinations of drugs in the induction phase, or new programmes with single or double autologous transplantation or allogeneic transplantation in the consolidation phase, new maintenance schema for the remission phase, and combining immunotherapy with treatment with 13-cis-retinoic acid (Peinemann 2015a; Peinemann 2015b; Yalçin 2013; Willems 2014; Mossé 2013; Louis 2011; Matthay 2012; Kanold 2012; Sun 2015).
Relapse generally appears within 2 years after the end of the treatment in patients with metastatic disease or after surgery in patients with localised disease. Any signs or symptoms indicative of the presence of further local or metastatic disease should be evaluated with physical examination, urinary catecholamine levels, complete blood count and radiological evaluation of the site of primary tumour (echographic or X-ray, depending on the site of occurrence). Assessments should be carried out every 3 months for the first year, every 4 months in the second year and thereafter every 6 months up to the fifth year post treatment. In patients with stage 4 disease, relapse usually involves metastatic sites, therefore an MIBG scan and bone marrow evaluation should be performed every six months in the first 2 years of follow-up, on a type C basis (Brodeur 2006). Different prospecting studies addressing the significance of minimal residual disease (MRD) as assessed by immunocytochemistry or RT-PCR in bone marrow, peripheral blood and apheretic product, were conducted. The results suggest a possible role of MRD in predicting the outcome, but confirmatory studies are necessary. For this reason, these evaluations are still investigational and should only be conducted within the setting of a clinical trial (Viprey 2014; van Wezel 2015).
8. LATE SEQUELAE
Late relapses after 5 years are rare but not exceptional. For this reason, the late onset of symptoms has to be carefully evaluated. Furthermore, since the very intensive treatment employed for patients with metastatic disease is toxic, a long-term clinical follow-up programme for those patients is desirable. Such regimens have to be carefully designed, considering their impact on of the patients’ fertility, hormonal activity (especially thyroid function), and organ function, especially renal and cardiac function (Flandin 2006; Brodeur 2006; Laverdière 2009). For long-term survivors, the high risk of secondary tumours has to be taken into account, especially for those patients who received total-body irradiation, radiometabolic therapy, or myeloablative therapy with alkylating agents or high-dose epipodophyllotoxins (Garaventa 1999; Brodeur 2006; Martin 2014).
Albino D, Scaruffi P, Moretti S, Coco S, Truini M, Di Cristofano C et al. Identification of low intratumoral gene expression heterogeneity in neuroblastic tumors by genome-wide expression analysis and game theory. Cancer 2008; 113(6): 1412-22. [Medline]
Ambros IM, Benard J, Boavida M, Bown N, Caron H, Combaret V et al. Quality assessment of genetic markers used for therapy stratification. J Clin Oncol 2003; 21(11): 2077-84. [Medline]
Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A et al. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 2009; 100(9): 1471-82. [Medline]
Ambros IM, Brunner B, Aigner G, Bedwell C, Beiske K, Bénard J et al. A multilocus technique for risk evaluation of patients with neuroblastoma. Clin Cancer Res 2011; 17(4): 792-804. [Medline]
Bagatell R, Beck-Popovic M, London WB, Zhang Y, Pearson AD, Matthay KK et al. Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 2009; 27(3): 365-70. [Medline]
Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 2010; 363(14): 1313-23. [Medline]
Barnhill LM, Williams RT, Cohen O, Kim Y, Batova A, Mielke JA et al. High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma. Cancer Res 2014; 74(14): 3753-63. [Medline]
Beiske K, Burchill SA, Cheung IY, Hiyama E, Seeger RC, Cohn SL et al. Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Br J Cancer 2009; 100(10): 1627-37. [Medline]
Bourdeaut F, de Carli E, Timsit S, Coze C, Chastagner P, Sarnacki S et al. VIP hypersecretion as primary or secondary syndrome in neuroblastoma: A retrospective study by the Société Française des Cancers de l’Enfant (SFCE). Pediatr Blood Cancer 2009; 52(5): 585-90. [Medline]
Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 2014; 26(5): 682-94. [Medline]
Brisse HJ, McCarville MB, Granata C, Krug KB, Wootton-Gorges SL, Kanegawa K et al. Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project. Radiology 2011; 261(1): 243-57. [Medline]
Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11(8): 1466-77. [Medline]
Brodeur GM, Maris JM. Neuroblastoma. In: Principles and practice of pediatric oncology, Pizzo DA, Poplack DG editors. 5th ed. Philadelphia, PA, Lippincott, Williams &Wilkins, 2006; pp. 933-70.
Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer R, Varela CR et al. Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 2009; 15(10): 3244-50. [Medline]
Brodeur GM, Bagatell R. Mechanisms of neuroblastoma regression. Nat Rev Clin Oncol 2014; 11(12): 704-13. [Medline]
Canete A, Gerrard M, Rubie H, Castel V, Di CA, Munzer C et al. Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 2009; 27(7): 1014-9. [Medline]
Caron HN, Pearson AD. Neuroblastoma. In: Voute PA, Barrett A, Stevens MCG, Caron HN (eds). Cancer in children. 5th ed. Oxford, Oxford University Press, 2005; pp. 337-52.
Cecchetto G, Mosseri V, De Bernardi B, Helardot P, Monclair T, Costa E et al. Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 2005; 23(33): 8483-9. [Medline]
Coco S, Defferrari R, Scaruffi P, Cavazzana A, Di Cristofano C, Longo L et al. Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells. J Pathol 2005; 207(3): 346-57. [Medline]
Coco S, Tonini GP, Stigliani S, Scaruffi P. Genome and transcriptome analysis of neuroblastoma advanced diagnosis from innovative therapies. Curr Pharm Des 2009; 15(4): 448-55. [Medline]
Coco S, Theissen J, Scaruffi P, Stigliani S, Moretti S, Oberthuer A et al. Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma. Int J Cancer 2012; 131(7): 1591-600. [Medline]
Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 2009; 27(2): 289-97. [Medline]
Conte M, Parodi S, De Bernardi B, Milanaccio C, Mazzocco K, Angelini P et al. Neuroblastoma in adolescents: the Italian experience. Cancer 2006; 106(6): 1409-17. [Medline]
Cook MN, Olshan AF, Guess HA, Savitz DA, Poole C, Blatt J et al. Maternal medication use and neuroblastoma in offspring. Am J Epidemiol 2004; 159(8): 721-31. [Medline]
De Bernardi B, Nicolas B, Boni L, Indolfi P, Carli M, Cordero di Montezemolo L et al. Disseminated neuroblastoma in children older than one year at diagnosis: comparable results with three consecutive high-dose protocols adopted by the Italian Co-Operative Group for Neuroblastoma. J Clin Oncol 2003; 21(8): 1592-601. [Medline]
De Bernardi B, Balwierz W, Bejent J, Cohn SL, Garrè ML, Iehara T et al. Epidural compression in neuroblastoma: Diagnostic and therapeutic aspects. Cancer Lett 2005; 228(1-2): 283-99. [Medline]
De Bernardi B, Mosseri V, Rubie H, Castel V, Foot A, Ladenstein R et al. Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group. Br J Cancer 2008; 99(7): 1027-33. [Medline]
De Bernardi B, Gerrard M, Boni L, Rubie H, Canete A, Di Cataldo A et al. Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 2009; 27(7): 1034-40. [Medline]
De Bernardi B, Quaglietta L, Haupt R, Castellano A, Tirtei E, Luksch R et al. Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience. Pediatr Blood Cancer 2014; 61(8): 1369-75. [Medline]
De Preter K, Mestdagh P, Vermeulen J, Zeka F, Naranjo A, Bray I et al. miRNA expression profiling enables risk stratification in archived and fresh neuroblastoma tumor samples. Clin Cancer Res 2011; 17(24): 7684-92. [Medline]
De Roos AJ, Olshan AF, Teschke K, Poole C, Savitz DA, Blatt J et al. Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring. Am J Epidemiol 2001; 154(2): 106-14. [Medline]
Defferrari R, Mazzocco K, Ambros IM, Ambros PF, Bedwell C, Beiske K et al. Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification. Br J Cancer 2015; 112(2): 290-5. [Medline]
Del Grosso F, Coco S, Scaruffi P, Stigliani S, Valdora F, Benelli R et al. Role of CXCL13-CXCR5 crosstalk between malignant neuroblastoma cells and Schwannian stromal cells in neuroblastic tumors. Mol Cancer Res 2011; 9(7): 815-23. [Medline]
Di Giannatale A, Dias-Gastellier N, Devos A, Mc Hugh K, Boubaker A, Courbon F et al. Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study. Eur J Cancer 2014; 50(1): 170-7. [Medline]
Eleveld TF, Oldridge DA, Bernard V, Koster J, Daage LC, Diskin SJ et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 2015. [Epub ahead of print]. [Medline]
Flandin I, Hartmann O, Michon J, Pinkerton R, Coze C, Stephan JL et al. Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology. Int J Radiat Oncol Biol Phys 2006; 64(5): 1424-31. [Medline]
French AE, Grant R, Weitzman S, Ray JG, Vermeulen MJ, Sung L et al. Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol Ther 2003; 74(3): 288-94. [Medline]
Fritsch P, Kerbl R, Lackner H, Urban C. “Wait and see” strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening. Pediatr Blood Cancer 2004; 43(6): 679-82. [Medline]
Garaventa A, Bellagamba O, Lo Piccolo MS, Milanaccio C, Lanino E, Bertolazzi L et al. 131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients. Br J Cancer 1999; 81(8): 1378-84. [Medline]
Garaventa A, Luksch R, Biasotti S, Severi G, Pizzitola MR, Viscardi E et al. A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Cancer 2003; 98(11): 2488-94. [Medline]
Garaventa A. High risk neuroblastoma: small steps towards cure. Pediatr Blood Cancer 2014; 61(6): 964-5. [Medline]
Gatcombe HG, Marcus RB Jr, Katzenstein HM, Tighiouart M, Esiashvili N. Excellent local control from radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 2009; 74(5): 1549-54. [Medline]
Gatta G, Ferrari A, Stiller CA, Pastore G, Bisogno G, Trama A et al. Embryonal cancers in Europe. Eur J Cancer 2012; 48(10): 1425-33. [Medline]
Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J et al. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5 – a population-based study. Lancet Oncol 2014; 15(1): 35-47. [Medline]
Gaze MN, Boterberg T, Dieckmann K, Hörmann M, Gains JE, Sullivan KP et al. Results of a quality assurance review of external beam radiation therapy in the International Society of Paediatric Oncology (Europe) Neuroblastoma Group’s High-risk Neuroblastoma Trial: a SIOPEN study. Int J Radiat Oncol Biol Phys 2013; 85(1): 170-4. [Medline]
Haas-Kogan DA, Swift PS, Selch M, Haase GM, Seeger RC, Gerbing RB et al. Impact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study. Int J Radiat Oncol Biol Phys 2003; 56(1): 28-39. [Medline]
Haug BH, Hald ØH, Utnes P, Roth SA, Løkke C, Flægstad T et al. Exosome-like Extracellular Vesicles from MYCN-amplified Neuroblastoma Cells Contain Oncogenic miRNAs. Anticancer Res 2015; 35(5): 2521-30. [Medline]
Heck JE, Ritz B, Hung RJ, Hashibe M, Boffetta P. The epidemiology of neuroblastoma: a review. Paediatr Perinat Epidemiol 2009; 23(2): 125-43. [Medline]
Johnson KJ, Puumala SE, Soler JT, Spector LG. Perinatal characteristics and risk of neuroblastoma. Int J Cancer 2008; 123(5): 1166-72. [Medline]
Kanold J, Paillard C, Tchirkov A, Lang P, Kelly A, Halle P et al. NK cell immunotherapy for high-risk neuroblastoma relapse after haploidentical HSCT. Pediatr Blood Cancer 2012; 59(4): 739-42. [Medline]
Kohler JA, Rubie H, Castel V, Beiske K, Holmes K, Gambini C et al. Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study. Eur J Cancer 2013; 49(17): 3671-9. [Medline]
Krug P, Schleiermacher G, Michon J, Valteau-Couanet D, Brisse H, Peuchmaur M et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol 2010; 14(5): 400-9. [Medline]
La Quaglia MP, Kushner BH, Su W, Heller G, Kramer K, Abramson S et al. The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 2004; 39(3): 412-7. [Medline]
Laprie A, Michon J, Hartmann O, Munzer C, Leclair MD, Coze C et al. High-dose chemotherapy followed by locoregional irradiation improves the outcome of patients with international neuroblastoma staging system Stage II and III neuroblastoma with MYCN amplification. Cancer 2004; 101(5): 1081-9. [Medline]
Laverdière C, Liu Q, Yasui Y, Nathan PC, Gurney JG, Stovall M et al. Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009; 101(16): 1131-40. [Medline]
Liu PY, Erriquez D, Marshall GM, Tee AE, Polly P, Wong M et al. Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression. J Natl Cancer Inst 2014; 106(7): pii: dju113. [Medline]
Longo L, Tonini GP, Ceccherini I, Perri P. Oligogenic inheritance in neuroblastoma. Cancer Lett 2005; 228(1-2): 65-9. [Medline]
Longo L, Panza E, Schena F, Seri M, Devoto M, Romeo G et al. Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p. Hum Hered 2007; 63(3-4): 205-11. [Medline]
Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011; 118(23): 6050-6. [Medline]
Luksch R, Podda M, Gandola L, Polastri D, Piva L, Castellani R et al. Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment. Br J Cancer 2005; 92(11): 1984-8. [Medline]
Maris JM. The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr 2005; 17(1): 7-13. [Medline]
Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet 2007; 369(9579): 2106-20. [Medline]
Maris JM. Recent advances in neuroblastoma. N Engl J Med 2010; 362(23): 2202-11. [Medline]
Martin A, Schneiderman J, Helenowski IB, Morgan E, Dilley K, Danner-Koptik K et al. Secondary malignant neoplasms after high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma. Pediatr Blood Cancer 2014; 61(8): 1350-6. [Medline]
Mastrangelo S, Tornesello A, Diociaiuti L, Pession A, Prete A, Rufini V et al. Treatment of advanced neuroblastoma: feasibility and therapeutic potential of a novel approach combining 131-I-MIBG and multiple drug chemotherapy. Br J Cancer 2001; 84(4): 460-4. [Medline]
Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol 2009; 27(7): 1007-13. [Medline]
Matthay KK, George RE, Yu AL. Promising therapeutic targets in neuroblastoma. Clin Cancer Res 2012; 18(10): 2740-53. [Medline]
Michalek AM, Buck GM, Nasca PC, Freedman AN, Baptiste MS, Mahoney MC. Gravid health status, medication use, and risk of neuroblastoma. Am J Epidemiol 1996; 143(10): 996-1001. [Medline]
Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol 2015; 40: 41-51. [Medline]
Modak S, Kushner BH, LaQuaglia MP, Kramer K, Cheung NK. Management and outcome of stage 3 neuroblastoma. Eur J Cancer 2009; 45(1): 90-8. [Medline]
Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 2012; 483(7391): 589-93. [Medline]
Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 2009; 27(2): 298-303. [Medline]
Monclair T, Mosseri V, Cecchetto G, De Bernardi B, Michon J, Holmes K. Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group. Pediatr Blood Cancer 2015; 62(9): 1536-42. [Medline]
Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 2008; 455(7215): 930-5. [Medline]
Mossé YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol 2013; 14(6): 472-80. [Medline]
Mossé YP, Deyell RJ, Berthold F, Nagakawara A, Ambros PF, Monclair T et al. Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer 2014; 61(4): 627-35. [Medline]
Mueller S, Matthay KK. Neuroblastoma: biology and staging. Curr Oncol Rep 2009; 11(6): 431-8. [Medline]
Oberthuer A, Juraeva D, Hero B, Volland R, Sterz C, Schmidt R et al. Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers. Clin Cancer Res 2015; 21(8): 1904-15. [Medline]
Olshan AF, De Roos AJ, Teschke K, Neglia JP, Stram DO, Pollock BH et al. Neuroblastoma and parental occupation. Cancer Causes Control 1999; 10(6): 539-49. [Medline]
Olshan AF, Smith JC, Bondy ML, Neglia JP, Pollock BH. Maternal vitamin use and reduced risk of neuroblastoma. Epidemiology 2002; 13(5): 575-80. [Medline]
Park JR, Villablanca JG, London WB, Gerbing RB, Haas-Kogan D, Adkins ES et al. Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2009; 52(1): 44-50. [Medline]
Park JR, Bagatell R, London WB, Maris JM, Cohn SL, Mattay KK et al. Children’s Oncology Group’s 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer 2013; 60(6): 985-93. [Medline]
Passoni L, Longo L, Collini P, Coluccia AM, Bozzi F, Podda M. Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients. Cancer Res 2009; 69(18): 7338-46. [Medline]
Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol 2008; 9(3): 247-56. [Medline]
Peinemann F, Tushabe DA, van Dalen EC, Berthold F. Rapid COJEC versus standard induction therapies for high-risk neuroblastoma. Cochrane Database Syst Rev 2015a; 5: CD010774. [Medline]
Peinemann F, van Dalen EC, Tushabe DA, Berthold F. Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2015b; 1: CD010685. [Medline]
Podda MG, Luksch R, Polastri D, Gandola L, Piva L, Collini P et al. Neuroblastoma in patients over 12 years old: a 20-year experience at the Istituto Nazionale Tumori of Milan. Tumori 2010; 96(5): 684-9. [Medline]
Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 2013; 45(3): 279-84. [Medline]
RARECAREnet Project. Avaialble at: http://www.rarecarenet.eu/rarecarenet/
Riley RD, Heney D, Jones DR, Sutton AJ, Lambert PC, Abrams KR et al. A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res 2004; 10(1 Pt 1): 4-12. [Medline]
Rubie H, De Bernardi B, Gerrard M, Canete A, Ladenstein R, Couturier J et al. Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 2011; 29(4): 449-55. [Medline]
Scaruffi P, Cusano R, Dagnino M, Tonini GP. Detection of DNA polymorphisms and point mutations of high-affinity nerve growth factor receptor (TrkA) in human neuroblastoma. Int J Oncol 1999; 14(5): 935-8. [Medline]
Scaruffi P, Parodi S, Mazzocco K, Defferrari R, Fontana V, Bonassi S et al. Detection of MYCN amplification and chromosome 1p36 loss in neuroblastoma by cDNA microarray comparative genomic hybridization. Mol Diagn 2004; 8(2): 93-100. [Medline]
Scaruffi P, Coco S, Cifuentes F, Albino D, Nair M, Defferrari R et al. Identification and characterization of DNA imbalances in neuroblastoma by high-resolution oligonucleotide array comparative genomic hybridization. Cancer Genet Cytogenet 2007; 177(1): 20-9. [Medline]
Scaruffi P, Stigliani S, Moretti S, Coco S, De Vecchi C, Valdora F et al. Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma. BMC Cancer 2009; 9: 441. [Medline]
Schleiermacher G, Mosseri V, London WB, Maris JM, Brodeur GM, Attiyeh E et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer 2012; 107(8): 1418-22. [Medline]
Schüz J, Kaletsch U, Meinert R, Kaatsch P, Spix C, Michaelis J. Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany. J Clin Epidemiol 2001; 54(7): 702-9. [Medline]
Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 1983; 305(5931): 245-8. [Medline]
Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B et al. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 1999; 86(2): 364-72. [Medline]
Simon T, Häberle B, Hero B, von Schweinitz D, Berthold F. Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 2013; 31(6): 752-8. [Medline]
Sorrentino S, Gigliotti AR, Sementa AR, Morsellino V, Conte M, Erminio G et al. Neuroblastoma in the adult: the Italian experience with 21 patients. J Pediatr Hematol Oncol 2014; 36(8): e499-505. [Medline]
Spix C, Pastore G, Sankila R, Stiller CA, Steliarova-Foucher E. Neuroblastoma incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42(13): 2081-91. [Medline]
Stallings RL. MicroRNA involvement in the pathogenesis of neuroblastoma: potential for microRNA mediated therapeutics. Curr Pharm Des 2009; 15(4): 456-62. [Medline]
Stigliani S, Coco S, Moretti S, Oberthuer A, Fischer M, Theissen J et al. High genomic instability predicts survival in metastatic high-risk neuroblastoma. Neoplasia 2012; 14(9): 823-32. [Medline]
Strother DR, London WB, Schmidt ML, Brodeur GM, Shimada H, Thorner P et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol 2012; 30(15): 1842-8. [Medline]
Sun J, Huye LE, Lapteva N, Mamonkin M, Hiregange M, Ballard B et al. Early transduction produces highly functional chimeric antigen receptor-modified virus-specific T-cells with central memory markers: a Production Assistant for Cell Therapy (PACT) translational application. J Immunother Cancer 2015; 3: 5. [Medline]
Teshiba R, Kawano S, Wang LL, He L, Naranjo A, London WB et al. Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children’s Oncology Group. Pediatr Dev Pathol 2014; 17(6): 441-9. [Medline]
Tonini GP, Boni L, Pession A, Rogers D, Iolascon A, Basso G et al. MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol 1997; 15(1): 85-93. [Medline]
Tonini GP, Pistoia V. Molecularly guided therapy of neuroblastoma: a review of different approaches. Curr Pharm Des 2006; 12(18): 2303-17. [Medline]
Tonini GP. Treatment of neuroblastoma: from cellular to molecular therapy. Curr Pharm Des 2009; 15(4): 422-3. [Medline]
Umehara S, Nakagawa A, Matthay KK, Lukens JN, Seeger RC, Stram DO et al. Histopathology defines prognostic subsets of ganglioneuroblastoma, nodular. Cancer 2000; 89(5): 1150-61. [Medline]
van Wezel EM, Stutterheim J, Vree F, Zappeij-Kannegieter L, Decarolis B, Hero B et al. Minimal residual disease detection in autologous stem cell grafts from patients with high risk neuroblastoma. Pediatr Blood Cancer 2015; 62(8): 1368-73. [Medline]
Vermeulen J, De Preter K, Naranjo A, Vercruysse L, Van Roy N, Hellemans J et al. Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. Lancet Oncol 2009; 10(7): 663-71. [Medline]
Viprey VF, Lastowska MA, Corrias MV, Swerts K, Jackson MS, Burchill SA. Minimal disease monitoring by QRT-PCR: guidelines for identification and systematic validation of molecular markers prior to evaluation in prospective clinical trials. J Pathol 2008; 216(2): 245-52. [Medline]
Viprey VF, Gregory WM, Corrias MV, Tchirkov A, Swerts K, Vicha A et al. Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study. J Clin Oncol 2014; 32(10): 1074-83. [Medline]
Wagner LM, Villablanca JG, Stewart CF, Crews KR, Groshen S, Reynolds CP et al. Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. J Clin Oncol 2009; 27(8): 1290-6. [Medline]
Wang Q, Diskin S, Rappaport E, Attiyeh E, Mosse Y, Shue D et al. Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number. Cancer Res 2006; 66(12): 6050-62. [Medline]
Willems L, Waer M, Billiau AD. The graft-versus-neuroblastoma effect of allogeneic hematopoietic stem cell transplantation, a review of clinical and experimental evidence and a perspective on mechanisms. Pediatr Blood Cancer 2014; 61(12): 2151-7. [Medline]
Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MN. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer 2014; 50(4): 801-15. [Medline]
Wolden SL, Gollamudi SV, Kushner BH, LaQuaglia M, Kramer K, Rosen N et al. Local control with multimodality therapy for stage 4 neuroblastoma. Int J Radiat Oncol Biol Phys 2000; 46(4): 969-74. [Medline]
Yalçin B, Kremer LC, Caron HN, van Dalen EC. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev 2013; 8: CD006301. [Medline]
Yanik GA, Villablanca JG, Maris JM, Weiss B, Groshen S, Marachelian A et al. 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant 2015; 21(4): 673-81. [Medline]
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010; 363(14): 1324-34. [Medline]
Dr. Maria Rita Castellani (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
Dr. Paola Collini (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
Dr. Bruno De Bernardi (Reviewer)
Istituto G. Gaslini – Genoa, Italy
Dr. Claudio Gambini (Author)
Istituto G. Gaslini – Genoa, Italy
Dr. Lorenza Gandola (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
Dr. Alberto Garaventa (Author)
Istituto G. Gaslini – Genoa, Italy
Dr. Roberto Luksch (Editor and Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
Dr. Davide Biasoni (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
Dr. Marta Podda (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
Dr. Angela Sementa (Author)
Istituto G. Gaslini – Genoa, Italy
Dr. Gian Paolo Tonini (Author)
Neuroblastoma Laboratory, Pediatric Research Institute, Padua, Italy