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Raising money for a serious medical condition such as neuroblastoma is a good way to help the patient receive the necessary care while keeping the family together throughout the entire process.
Charleigh was only 21 months old when she was diagnosed with Stage IV neuroblastoma, and this caused her family to deal with a long list of medical bills.
When someone is dealing with a medical emergency, it is important for them to have access to emotional support. Neuroblastoma is a form of leukemia, and it is one of the most common types of cancer that infants and young children develop. Unfortunately, the initial symptoms of neuroblastoma can make it very difficult to reach a quick and accurate diagnosis.
Although a lot of research has been done on the topic, it is still unknown exactly what causes people to contract neuroblastoma. The vast majority of people with neuroblastoma are diagnosed due to a blood or urine test, but the mIBG scan is also used to verify the presence of the disease in 95 percent of all cases. Dealing with a serious medical condition can be very difficult for the patient and their family members, and this problem is exacerbated by medical bills. DonationTo understands that every penny counts when you are raising money for a medical emergency, so we enable all of our users to keep 100 percent of their online donations and avoid paying for additional credit card processing fees. A Tozzo Frios conta com uma vasta gama de produtos como: frios, laticA­nios, embutidos, enlatados, congelados e produtos a granel. References1.Ogita S, Tokiwa K, Majima S (1985) An evaluation of surgical treatment and chemotherapy of advanced neuroblastoma (stages III and IV) with special reference to proliferation kinetics of residual tumor. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser. Other Comparisons of Autologous BMT and Chemotherapy—Previous smaller studies comparing autologous marrow transplantation to chemotherapy had yielded conflicting results, with Pinkerton reporting the only randomized trial showing a significant improvement with autologous BMT.[32] This report included a total of only 65 patients, however. Overall, autologous BMT appears to be at least as effective as intensive chemotherapy and may provide an advantage in some extremely high-risk subgroups. Another ongoing phase I dose-escalation study of a non-TBI-containing myeloablative regimen has thus far shown event-free survival comparable to that seen in the previous 321P3 study (55% at 2 years from autologous BMT).
The most recently completed CCG trial in high-risk disease was designed to answer, in a prospective, randomized fashion, the relative importance of ablative therapy with purged autologous BMT vs intensive consolidation.
The outcome of this study, still blinded for analysis, will help determine the future role of myeloablative therapy, as well as the potential utility of differentiating agents, in high-risk neuroblastoma. The source and purity of the stem cells used for ablative therapy in neuroblastoma have been the focus of concern.
More recently, testing of peripheral blood stem-cell collections and bone marrow with PCR has confirmed the problem of contamination with tumor cells, even in CD34-selected preparations. Dose-intensive therapy, with or without stem-cell support, is rapidly approaching the limits of toxicity, both in terms of acute and late effects. Phase I and II studies of anti-GD2 antibodies have shown some modest antitumor efficacy in patients with relapsed neuroblastoma.[38,39] Both the murine monoclonal 3F8 and 14G2a (murine), the latter tested with IL-2 and with GM-CSF, have shown some tumor responses, as well as in vitro stimulation of antibody-dependent cellular cytotoxicity (ADCC). Targeted therapy using antibody or MIBG for the delivery of radiation in the form of iodine-131 has also been tested in clinical trials. Iodine-131-MIBG has been widely tested in Europe for refractory neuroblastoma and, more recently, for initial therapy in patients with regional disease. Differentiating agents are another approach for circumventing the undesirable effects of cytotoxic agents. Currently, various derivatives of retinoic acid are the differentiating compounds in clinical testing. Other retinoids currently in phase I investigation include all-trans-retinoic acid (ATRA [Vesanoid]) combined with interferon-alfa (Intron A, Roferon-A), 9-cis-retinoic acid, and fenretinide, another analog that causes growth arrest and apoptosis in vitro, even in cell lines shown to be resistant to trans-retinoic acid. Substantial advances are occurring in the elucidation of the molecular pathogenesis of neuroblastoma, as well as in the definition of clinical prognostic groups. Is complete surgical resection of stage 4 neuroblastoma a prerequisite for optimal survival or may >95A % tumour resection suffice? Numerous studies have shown that for optimal survival in localized International Neuroblastoma Staging System stage 1a€“3 neuroblastoma, complete tumour resection (CR, macroscopic total tumour removal) is usually mandatory. IntroductionOver the years, the contribution of surgery towards survival of International Neuroblastoma Staging System (INSS) stage 1, 2 and 3 patients has become apparent [1a€“6]. Surgery for neuroblastomaINSS and surgical terminologySince the INSS was introduced in 1988 a complete gross resection (CR), as distinct from incomplete resection (IC), is defined as the macroscopic total removal of all visible tumour and nearby abnormal lymph nodes.
INSS stage 1a€“3The important role of radical surgery in the treatment of localized stage 1a€“3 neuroblastoma is nowadays widely acknowledged [1a€“6] and will not be further addressed in this review.INSS stage 4Several reports aimed at determining the optimal level of surgery in stage 4 patients have been published. In the 4th column, the survival of patients undergoing the intended level of surgery is compared to patients undergoing all less extensive surgery. CR versus GTRIn most studies either CR or GTR was compared to patients undergoing all less extensive surgery. DiscussionThe optimal extent of surgery in INSS stage 4 patients is still a matter of debate. Survival of children >12 months of age with stage 4 neuroblastoma during two 10-year periods.
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Figure 1: Frequency of amino-acid-changing somatic mutations in neuroblastoma correlates with age, stage and survival. Figure 2: Chromothripsis is frequent in neuroblastoma and is associated with a poor prognosis. Figure 4: Neuroblastoma with genomic defects in neuritogenesis genes cluster in high-risk tumours. Neuroblastoma have a highly variable clinical outcome, with an excellent prognosis for stage 1 and 2 tumours, but a poor outcome for high-stage tumours.
Full genome paired-end sequencing allowed us to identify structural variants specifically perturbing single genes (see Methods and Supplementary Fig. The X-chromosome-encoded ATRX gene was affected by structural variants in five tumours (Fig. We conclude that alterations with significant frequencies (PTPRD and ODZ genes) affect transmembrane receptors that function in neuronal growth cone guidance and maintenance. Fortunately, you can use a donation website to make it easy for people to contribute to the cause, and DonationTo has a proven history of providing the perfect platform for medical crowdfunding campaigns.
Unfortunately, Charleigh is still undergoing extensive medical treatments, including chemotherapy, and she has also been going through facial radiation treatment in an attempt to prevent the tumors behind her eyes from stealing her eyesight. Fortunately, DonationTo makes it easy for people to leave a comment after they make a donation. In fact, the first few symptoms that a patient with neuroblastoma will exhibit are so vague and commonplace that many parents will fail to recognize that their child has a serious medical condition.
Only two percent of patients have specific gene mutations within their family, and there is no conclusive evidence that ties the other 98 percent of cases together. The stage that is assigned to the different levels of neuroblastoma indicates how far the disease has progressed, and this makes it easier to determine the patient’s prognosis.
Fortunately, you can easily turn to a donation website such as DonationTo in order to launch a medical crowdfunding campaign.
When you combine these perks with the support that your family will receive from the comments that are left on your page, it becomes easy to see why DonationTo is the preferred crowdfunding resource of such a large and diverse group of people.
Venha conhecer nossa loja pessoalmente ou acesse a pA?gina de produtos e confira alguns dos nossos itens.
Several prospective and retrospective studies have provided conflicting conclusions regarding the benefit of combining aggressive chemotherapy with complete surgical resection.
These patients continue to respond poorly even to very dose-intensive therapy, although incremental advances have certainly been made over the past decade. All three studies treated patients with five to six cycles of induction chemotherapy consisting of cisplatin (Platinol), doxorubicin, cyclophosphamide, and etoposide (VePesid). With a median follow-up of 5 years, the event-free survival at 5 years from the time of autologous BMT for 147 patients is 37%.
However, a definitive conclusion cannot be made until the results of a recently completed CCG randomized prospective trial comparing outcomes among unselected high-risk patients from the time of diagnosis become available. This phase I study has further verified the earlier suggestion from Kushner and co-workers[28] that higher-dose local irradiation to tumor sites may prevent primary site relapse, a common problem in previous CCG protocols.
Current and future studies will examine repetitive stem-cell transplants, more intensive induction therapies, and the use of alternative stem-cell sources. Immunocytology techniques have shown that as many as 70% of patients have bone marrow tumor at diagnosis and 50% have circulating tumor cells in peripheral blood. This has been inferred from studies showing the development of tumor cell lines from harvested bone marrow and by reports of miliary lung metastases following autologous BMT,[35] and has been demonstrated more definitively by the gene-marking studies of Rill and co-workers.[36] In these gene-marking studies, autologous unpurged but histologically tumor-free marrow was transfected with the neomycin resistance gene and then reinfused into patients, some of whom subsequently relapsed with neuroblastoma tumors expressing the marker. The significance of such low-level contamination is still undetermined but will be examined in future studies. Novel approaches that are more tumor-specific and less toxic are required to make further progress in metastatic neuroblastoma. Cheung and co-workers have documented responses to iodine-131-3F8 among patients with refractory neuroblastoma,[41] and are currently conducting a study in which newly diagnosed patients are receiving iodine-131-3F8 in ablative doses followed by bone marrow rescue, with further treatment with cold antibody post-transplant. We have conducted a phase I dose escalation trial of iodine-131-MIBG at the University of California (San Francisco) and have determined the maximal non-marrow-ablative dose and the maximal practical ablative dose with stem-cell rescue.[42] In 30 patients, we observed a 37% response rate and no significant toxicity other than hematologic effects. For many years, laboratory studies have shown the capacity for either spontaneous or induced differentiation and growth arrest of neuroblastoma cell lines in culture.
In addition, modest but significant improvements in the treatment of metastatic disease have been achieved by increasing dose intensity with the use of hematopoietic support.
Suzuki T, Yokota J, Mugishima H, et al: Frequent loss of heterozygosity on chromosome 14q in neuroblastoma.
Plantaz D, Mohapatra G, Matthay KK, et al: Gain of the chromosome 17 is the most frequent abnormality detected in neuroblastoma by CGH.
Seeger RC, Brodeur GM, Sather H, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. Crabbe DCG, Peters J, Seeger RC: Rapid detection of MYCN gene amplification in neuroblastomas using the polymerase chain reaction. Suzuki T, Bogenmann E, Shimada H, et al: Lack of high affinity nerve growth factor receptors in aggressive neuroblastomas. Hiyama E, Hiyama K, Yokoyama T, et al: Correlating telomerase activity levels with human neuroblastoma outcomes.
Shimada H, Stram DO, Chatten J, et al: Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis.
Matthay KK, Sather HN, Seeger RC, et al: Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. Matthay K, Seeger R, Haase G, et al: Treatment and outcome for stage III neuroblastoma based on prospective biologic staging. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Moss TJ, Reynolds CP, Sather HN, et al: Prognostic value of immunocytologic detection of bone marrow metastases in neuroblastoma. Cheung NKV, Heller G: Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. Kushner BH, O’Reilly RJ, Mandell LR, et al: Myeloablative combination chemotherapy without total body irradiation for neuroblastoma. Matthay KK, Seeger RC, Reynolds CP, et al: Allogeneic vs autologous purged bone marrow transplantation for neuroblastoma. Philip T, Zucker JM, Bernard JL, et al: Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: Is cure possible in a small subgroup? Schuster JJ, Cantor AB, McWilliams N, et al: The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma.
Rill DR, Santana VM, Roberts M, et al: Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Reynolds CP, Seeger RC, Vo DD, et al: Model system for removing neuroblastoma cells from bone marrow using monoclonal antibodies and magnetic immunobeads. Matthay KK, Desantes K, Hasegawa B, et al: Phase I dose escalation of 131I-metaiodo-benzylguanidine (MIBG) with autologous bone marrow support in refractory neuroblastoma.
Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. Reynolds CP, Kane DJ, Einhorn PA, et al: Response of neuroblastoma to retinoic acid in vitro and in vivo. Since tumours in these stages are still localized, it is comprehensible that this approach may lead to optimal survival.
This was compared with the following set of search terms: Neuroblastoma AND (surgery OR surgical OR resection OR excision) AND (stage IV OR stage 4 OR high-risk) AND (survival OR mortality).


The presence or absence of residual microscopic tumour is not counted in the terms of complete gross resection [7]. Because this may have resulted in the inclusion of patients with substantial tumour remnants, bias may occur. Since tumours in this stage are no longer localized, some have postulated that local control by complete resection may not be necessary for optimal survival and less extensive surgery (GTR) may suffice. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1.
The inner ring represents the copy number variations (red, gain; green, loss) based on coverage of the tumour and lymphocyte genomes.
The dots indicate summed coverage for bins of 1,000 base pairs of the tumour genome, normalized to the coverage in corresponding normal tissue. ALK mutations were found in 6% of the tumours, in accordance with frequencies established in large neuroblastoma tumour series (Supplementary Table 4)2, 3, 4, 5.
In addition gene ontology analysis of the 1,041 genes showed significant enrichment of GTPase-regulating genes. We we also make it easy to hit your fundraising goal by enabling you to avoid paying extra credit fees, and you will be able to keep 100 percent of the online donations that you receive. In order to help the family pay for medical bills and travel expenses, they launched a medical crowdfunding campaign via DonationTo.
These words of support are a great comfort to a family that is going through a difficult time, and they can also help keep everyone unified throughout the crowdfunding process.
These initial symptoms include loss of appetite, joint pain, fever and fatigue, but a neuroblastoma patient may eventually start dealing with breathing problems, constipation, a swollen stomach, physical weakness that makes it difficult to stand, walk or crawl, swelling and bruising around the eyes, anemia and painful leg and hip bone lesions. Researchers have focused their attention on high risk factors that happen during gestation and early life such as the mother drinking alcohol and smoking, but no study has been able to prove that these elements are a factor in the disease. For example, a Stage I diagnosis indicates that the tumor is localized and has not spread past the area of origin. After all, it is much easier for people to make donations online, and you will also be able to keep you entire family in the loop by posting regular updates to your fundraising page. We analyzed our experience to evaluate the effect of complete surgical resection of the primary tumor on survival when disseminated disease has been controlled by chemotherapy. After undergoing surgery for local control and receiving irradiation to residual disease sites, patients received ablative chemotherapy and total-body irradiation (TBI) with BMT or were continued on four-drug induction chemotherapy for a total of 13 cycles. By the end of five to seven courses of chemotherapy, 159 patients were event-free; 67 of these patients went on to receive autologous BMT, while 74 continued chemotherapy for a total of 1 year. However, the relapse rate for patients transplanted after first disease progression has continued to be high; the current event-free survival rate at 2 years post-transplantation is only 15%.
A second randomization, done at the end of chemotherapy consolidation or autologous BMT, assigned patients to receive or not to receive 6 months of 13-cis-retinoic acid (isotretinoin [Accutane]). This review shows substantial survival benefit in studies reporting on stage 4 patients undergoing CR, but also in studies reporting on patients undergoing GTR. In contrast, the optimal level of surgery in stage 4 (disseminated) tumours is subject of discussion.
Because complete gross excision is often difficult to obtain, some authors added the term near-complete excision [8]. Only four studies we found explicitly compared survival after CR to survival after GTR (Table 2a, 5th column). In ten of the 20 studies included in this review, the authors eventually seem in favour of GTR, while the other ten articles advocate CR as the procedure of choice, clearly depicting the present lack of consensus (Table 2a, b, 6th column). Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2, 3, 4, 5. The lines traversing the ring indicate inter- and intrachromosomal rearrangements identified by discordant mate pairs from paired-end reads.
Rac and Rho small GTPases cycle between an inactive GDP-bound and active GTP-bound conformation, transducing signals from a wide variety of membrane receptors.
Low-stage tumours are marked by numeric changes of chromosomal copy numbers, whereas high-stage tumours typically show structural chromosomal defects resulting in, for example, hemizygous deletions of the chromosomal regions 1p36 or 11q and gain of 17q (refs 1, 10–12). Three tumours carried mutations in TIAM1, a known regulator of cytoskeleton organization and neuritogenesis15. We detected a total of 451 genes harbouring structural variants (306 genes without the events on chromothripsis chromosomes, Supplementary Tables 5 and 6). Alterations in GEFs for Rac and GAPs for Rho significantly deviate from a random distribution, implicating inhibition of Rac1 and activation of RhoA in impairing neuritogenesis in neuroblastoma (Fig.
As an added bonus, DonationTo will help keep the entire family connected throughout the process by providing a crowdfunding platform that makes it simple to share updates, photos, videos and comments with all of your supporters. Providing supporters with an easy way to make online donations helped the family raise more than $2,000td in a very short period of time, and this will help relieve some of the financial stress that Charleigh’s medical condition has placed on her parents.
After all, it is very difficult to keep everyone in the loop individually when something serious is happening, but you can easily utilize your DonationTo page as a resource for spreading the word quickly to a large group of people. Patients who have a low or intermediate risk will have at least a 70 percent chance of surviving, but high risk patients will be given a 30 percent long-term survival rate. Because of this, patients who have Stage I have a very high survival rate, especially if they are older than 18 months.
We retrospectively reviewed the medical records of 44 consecutive children with neuroblastoma treated between 1990 and 2000. The relative risk of an event after autologous BMT was only 58% of that with chemotherapy (P = .01). In vitro and some in vivo studies have reported this differentiating agent to have efficacy against neuroblastoma.
Due to the metastatic nature of this stage some experts postulate that local control by means of complete resection may not improve survivala€”or may even be detrimentala€”and less extensive surgery, combined with other therapies, may suffice. Boxes include 50% of data and error bars indicate extremes with a maximum of two times the box size.
In a parallel study we sequenced four primary neuroblastoma tumours as well as cell lines derived from these tumours and their metastases.
The structural variants often consisted of deletions of one or a few exons, inversions or translocations deleting part of a gene. 4a).From these findings we propose that defects in neuritogenesis-regulating genes form an important category of tumour-driving events in neuroblastoma. Sadly, this young girl still has deal with extensive treatments, so the family is continuing to update the fundraising page in hopes of receiving additional financial support. Additionally, you can post updates whenever you would like, and this can include photos and videos. Therefore, it is important to take your child to the doctor immediately if they begin to exhibit the symptoms of neuroblastoma.
We found only four studies that explicitly compared survival between patients undergoing either CR or GTR. In publications focussing on this matter, survival following a certain level of excision is usually compared with survival following all less radical surgery, often including biopsies. The latter search strategy provided a wider palette of publications, encompassing the publications retrieved with the former search strategy, and was used in this review.We found 172 articles. All samples had a minimal tumour content of 80% as determined by immunohistochemical analysis.
One tumour showed an intrachromosomal rearrangement activating FOXR1 transcription (Supplementary Fig.
ATRX is a chromatin remodelling protein involved in exchange of H3.3 in GC-rich repeats and mutations of this gene are associated with X-linked mental retardation20.
Taking the time to make these updates will help encourage your supporters to make a second donation, and it will enable out-of-state family members to feel like they can make an important difference. Two of these studies showed favourable results for patients treated with CR, while the other two did not show differences in survival. The title and abstracts were thoroughly screened and papers focussing on the influence of the extent of surgery on survival in stage 4 neuroblastoma were selected and studied in detail. This multitude of surgical terms was recently discussed by Kubota [11] and is summarized in Table 1. The other two studies showed no differences in survival following CR or GTR.Studies favouring CRBased on a series of 36 operated patients Le Tourneau et al.
In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma6. Genomes were sequenced at an average coverage of 50 and an average fully called genome fraction of 96.6% (Supplementary Table 2). Exon mRNA profiles of part of the sequenced series showed that the three samples included with ATRX structural variations had the lowest ATRX mRNA expression of all samples and showed a specific collapse of the signal in the deleted regions, illustrating the inactivating nature of the ATRX defects (Fig.
The survival rate was compared based on the timing (primary versus delayed until chemotherapy had been given) and results of surgery (complete tumor resection, microscopic residual disease, and gross residual disease). It seems more logical to compare a true radical resection with a narrowly irradical resection, a situation resembling the actual situation in the OR more closely.
Only manuscripts that explicitly described the degree of surgical resection were considered eligible. Still, the possibility that this means that CR may be advantageous over GTR has to be acknowledged.
The optimal cut-off level for the categories was determined by Kaplan scanning (see Supplementary Information and Methods).
Compared to the HG18 reference genome we obtained an average of 3,347,592 single-nucleotide variants (SNVs) per genome, in accordance with reported frequencies of interpersonal variants.
Together with the lack of recurrent mutations, our data indicate that neuroblastoma carry few early somatic tumour-driving mutations with amino-acid-changing consequences.Analysis of the paired-end clones with discordant ends can be used to identify candidate structural rearrangements, which together with sequence coverage data can identify somatic structural variants (SVs). The authors stress that metastatic control is more important than the level of surgery and is probably essential for optimal survival [12]. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7, 8, 9.
The significance (log-rank test) was corrected for the multiple testing (Bonferroni correction). Comparison of tumour versus lymphocyte coverage generated ultra-high-resolution comparative genomic hybridization (CGH)-like profiles (Supplementary Fig.
1e), which extends the well-established relationship between tumour stage and structural chromosomal defects in neuroblastoma10, 11, 12. 3b).ODZ3 and PTPRD were also hit by structural variations in five tumours each (Supplementary Fig. In the CSR group, 1-, 2-, 3-, and 5-year survival rates were 88%, 77%, 77%, and 65%, respectively, vs.
Haase reported a significant survival and disease free survival benefit 3 years after CR compared to less extensive surgery, but survival percentages were not separately mentioned in this manuscript [13]. Of the four publications that explicitly make a comparison between CR and GTR [9, 14, 17, 26] a significant survival benefit (for CR) was shown in one case only (Table 2a, 5th column) [17].
Patients are sorted by the presence of genomic aberrations in neuritogenesis genes (Neuritogenesis, n = 19), by MYCN amplification (MYCN, n = 23), and by INSS stage (high to low).
Validation of 1,014 candidate somatic small mutations (SNVs, substitutions, insertions, deletions), including 763 SNVs, established a specificity of 88% and a sensitivity of 85% at a somatic score cut-off of 0.1 (Supplementary Fig. Consistent with their occurrence in high-stage neuroblastoma, defects in neuritogenesis genes did not show an independent prognostic power in multivariate analysis with the clinical parameters age and stage.Here we report the first whole-genome sequence study of a comprehensive series of neuroblastoma including both low- and high-stage tumours. Therefore, at present no definite conclusions can be drawn on the optimal extent of surgery.This inconsistency can partly be attributed to the lack of a universal tumour staging system and to the diversity in surgical terminology before the INSS was introduced in 1988 [7].
Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. Analysis of the frequency of structural variations per chromosome revealed ten tumours with chromothripsis characteristics6 (see Methods).
Most of the structural variants affected only one allele of a gene (Supplementary Table 5).
Low-stage neuroblastoma lacked recurrent gene alterations (mutations and structural variations), raising the question whether they are primarily driven by chromosomal imbalances and the consequent gene dosage effects.
In conclusion, complete resection of the primary tumor with no residual disease was associated with improved survival in children with advanced neuroblastoma whose metastatic disease had been controlled by chemotherapy. The analysis and comparison of literature published before this date is therefore challenging. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours. Middle panel, amino-acid-changing mutations and structural variations are indicated for all genes having two or more events and that are involved in neuritogenesis (red, mutated or structural variant; grey, not affected).
SNVs above this score and all validated SNVs with lower scores were used for further analyses (total 586 genes, Supplementary Table 3). Chromothripsis is a localized shredding of a chromosomal region and subsequent random reassembly of the fragments.


This indicates that the tumour-driving mechanism of these defects is haploinsufficiency, possibly combined with epigenetic attenuation of the non-affected allele.
Tumours with defects in genes functioning in neuritogenesis or growth cone guidance mostly are aggressive high-stage tumours without MYCN amplification.
The sequence data identified an average of 12 somatic candidate amino-acid-affecting mutations per tumour (Fig.
On average, genes with structural variants resulting in loss of coverage indeed showed a reduced expression in tumours with these defects, as compared to tumours with normal alleles (Supplementary Fig. In addition, ODZ2 and ODZ4, two highly homologous members of the conserved ODZ family, were together affected three times.
Interestingly, there is indication that MYCN also inhibits neuritogenesis in neuroblastoma. CR led to significantly improved 5-year event-free survival when compared to less extensive surgery (26 vs.
With the introduction of the International Neuroblastoma Risk Group (INRG) Classification system in 2009, finally a consensus approach for pre-treatment risk stratification has been developed [31] and this will make future comparison less complicated. PTPRD and ODZ genes encode transmembrane receptors expressed in the developing nervous system and localizing to axons and axonal growth cones21. Currently, most studies are retrospective and in many cases patient numbers are small, making reported statistical differences occasionally questionable. Targeted silencing of ODZ homologues in Drosophila, Caenorhabditis elegans and mouse caused severe axon guidance defects9. Chamberlain studied 28 patients and concluded that complete surgical resection resulted in a clear survival benefit over less radical surgery.
In several studies the results may have been contaminated by pooling patients with INSS stage 3 and 4 tumours and determining survival rates for these groups as a whole [13, 16, 27, 32]. Although the SNP data have a much lower resolution than the sequence coverage plots, they supported the deletions and gains of sufficient size. Moreover, in spite of the adoption of the INSS, the definition of CR is still not always correctly applied [18, 19, 27] and the proposed subdivision of the extent of surgery [9, 10]a€”including GTRa€”is not universally used. A Japanese study described a series of patientsa€”twenty-four at stage 4 and nine at stage 3. In some of the studies that supposedly do seem to use the terms GTR or CR correctly, the actual level of excision is not described, so inaccuracies cannot be excluded.
2g).To identify relevant genes and pathways that contribute to neuroblastoma pathogenesis, we generated one list of all genes with amino-acid changing mutations (n = 586), mutations in splice junctions (n = 37) and structural variations (n = 451).
Total excision was defined as excision free of macroscopic residual tumour and can be considered identical to CR according to the INSS.
In addition, the comparison of literature is hampered by the fact that treatment for stage 3 and 4 neuroblastoma is multidisciplinary.
Accordingly, their prognostic impact is not independent of age and stage in multivariate analyses. Various and continuously changing chemotherapy and irradiation regiments are used and this may obscure the effects of surgery on overall survival. Chromothripsis-related structural aberrations frequently affected genes involved in neuroblastoma pathogenesis and were associated with amplification of MYCN or CDK4 and loss of heterozygosity of 1p (Supplementary Fig. Surgeon-dependent factors, such as experience and skills, and the chosen surgical approach are presumably also of importance.
Within high-stage neuroblastoma, MYCN amplification status did not correlate to mutation frequency (Supplementary Fig.
Four genes belonged to the MYCN amplicons (MYCN, MYCNOS, DDX1 and NBAS) and except for MYCN probably play no role in pathogenesis.
These results have to be interpreted with caution because they are derived from both stage 3 and stage 4 patients. The timing of the surgery itself, which varies considerably between studies, could influence survival as well.
In one tumour, chromothripsis resulted in amplification and very strong overexpression of MYC (c-Myc) (Supplementary Fig. Interestingly, CSMD1, which showed structural variants in three tumours, is also a transmembrane protein expressed on nerve growth cones7. From another study of 26 patients, it was concluded that complete surgical resection, defined by the authors as the absence of microscopic residual disease, leads to significant survival benefit. Moreover, it cannot be excluded that selection bias has occurred in the comparative studies that we reviewed. As the frequencies of PTPRD and ODZ3 defects exclude that they were found by chance, we propose that the function of these genes and of ODZ2, ODZ4 and CSMD1 in neuronal growth cones might hold a clue to their function in neuroblastoma pathogenesis.The second analysis that we performed for the list for 1,041 affected genes was a gene ontology study to identify enrichment of genes with defects in specific molecular processes. It is possible that CR was attempted in patients with a better overall condition and that, in an effort to reduce the risks of surgery, patients in a more incapacitated state underwent GTR or incomplete resection.
Chromosome 5 had undergone chromothripsis in three tumours, but no clear tumorigenic target on this chromosome was identified.
Furthermore, in the majority of the studies that compare various levels of surgery only two groups are studied: patients undergoing the most extensive type of surgery and the remainder of the patients undergoing less aggressive surgery.
To identify genetic defects that allowed chromothripsis and subsequent survival of the cell, we searched for defects in DNA damage response pathways in tumours with chromothripsis.
La Quaglia [18] demonstrated a clear survival benefit in 39 patients undergoing CR in 1994.
The second group is obviously very heterogeneous and could contain patients with abundant tumour load. This strongly indicates that at least the defects in PTPRD, ATRX and ODZ3 did not accumulate due to for example, the genomic length of the genes, but that they were selected for during the process of tumorigenesis. As a consequence, the favourable results of the group undergoing extensive surgery may be relatively exaggerated.
2a and 2b) showed an inactivating deletion in FANCM and another chromothripsis tumour sample (N576) had a missense mutation in FAN1, predicted to be damaging by the polyphen2 program16.
It functions as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac and is, together with Rac, central to regulation of cellular polarity and neuritogenesis24, 25. GTR was defined as removal of all visible and palpable tumour from the primary site and regional lymphatics. Finally, the presence or absence of unfavourable tumour characteristics could obscure the relevance of the surgical procedures. These findings might suggest involvement of inactivating events in the Fanconi anaemia signalling pathway to allow chromothripsis17. The W1285S* mutation creates a premature stop-codon in the carboxy-terminal pleckstrin homology domain required for Rac activation, whereas the other mutations were predicted to be damaging by polyphen2 analysis16.
This is the same definition used by the INSS for complete resection [7] and therefore the level of surgery was considered to be CR in this review. Due to variation in histological and biological features the prognosis of seemingly comparable tumours, both in mass and in growth, can differ dramatically.
In a more recent study by the same team the survival benefit in patients undergoing CR was reconfirmed. In addition, these tumour characteristics may influence the operative method that is chosen, thus resulting in selection bias. In this respect it is for instance conceivable, as suggested by von Schweinitz [6], that GTR may be suitable for stage 4 disease if MYCN is not amplified but that complete excision may be beneficial in case of MYCN amplification. We identified a total of eight alterations in six GEFs specific for Rac (including TIAM1), but none in GAPs specific for Rac (Supplementary Tables 7, 8 and 10 for functional consequences).
However, important prognostic data, such as the MYCN amplification and the Shimada histology [33, 34] were either not determined or not incorporated in the results of most studies.The question whether survival is determined more by recurrence of locoregional disease or by recurrent metastases cannot be answered definitely due to the lack of relevant data on this subject.
Whereas activation of Rac1 stimulates neuritogenesis, activation of its small GTPase antagonist RhoA promotes axon retraction and growth cone collapse (Fig.
In an article analysing 291 stage 4 patients, Sultan demonstrated that CR could be achieved in 58 %. However, several authors do report that the final outcome of high-risk neuroblastoma patients is more related to the evolution of metastases than to the extent of resection [9, 27, 28, 30]. Because it is conceivable that, compared to GTR, CR may not only lead to higher peri-operative morbidity and mortality, but also to more late complications (such as renal failure or chronic diarrhoea) [25] this is an important issue to address. Strikingly, we detected seven alterations in five GAPs for RhoA, but only one GEF specific for RhoA (ARHGEF12) showed a translocation with unknown functional consequences (Fig. A study by Escobar of 104 operated patients also favours CR, showing significant survival benefit [21]. Interestingly, a recent large study suggests that the degree of resection may not be related to the rate of complications.
The complication rate in high-risk patients was reported to be 29, 38 and 36 % in complete resections, minimal residual resections and partial resections, respectively [14].
Based on data from the late seventies and early eighties, Shorter concluded that CR is not a prerequisite for optimal treatment of stage 4 neuroblastoma [26].
Following incomplete resection, survival rates were even better than after CR with a 4-year survival of 45 and 15 %, respectively. If GTR can be considered an adequate level of resection in stage 4 disease, this could lead to an increase in the percentage of successfully performed operations.
Of note, transgenic mice with ATRX mutations causing mental retardation in humans showed abnormal dendritic spine formation with increased TIAM1 phosphorylation and Rac1 signalling27. The authors hypothesized that the biological characteristics of the tumour, rendering them favourable or unfavourable, were far more important prognostic markers than the extent of the resection. Likewise, based on a small series, Kiely [25] suggested that incomplete excision may be enough and that more extensive surgery does not necessarily prolong survival. From a series of 71 procedures, Castel reported no differences in event-free 5-year survival between patients undergoing various levels of resection. Only four publications explicitly make a comparison between CR and GTR, while keeping other variables stable. The only significant difference in survival was found when these patients were compared to patients solely undergoing biopsy [9]. The authors conclude that the final outcome is determined more by metastatic relapses than by the degree of resection. With the development of uniformly applied treatment protocols the opportunity to study the effects of surgery, independently of other factors, has finally emerged. In 2010 in The Netherlands, the Dutch Childhood Oncology Group (DCOG) NBL 2009 Treatment Protocol, which is based on the GPOH (Gesellschaft fA?r PA¤diatrische Onkologie und HA¤matologie) NB2004 High-risk Protocol, was adopted. In that study the term GTR was used, but this was identical to the definition of complete resection used by the INSS.
In the DCOG HR neuroblastoma patients, we will perform preoperative imaging by MRI and digital postoperative photographs of the operation field.
In this way, all image defined risk factors can be determined and the digital photographs will be reviewed by a board of surgeons to definitively define the ultimate level of resection.
This will be done in a prospective study, so we will hopefully be able to compare outcome of surgery with preoperative IRDS and biological characteristics such as MYCN-status, histology and ploidy.
Local recurrence occurred in patients undergoing less extensive surgery, but not in patients undergoing CR. Event-free and overall survival (60 %) were not influenced by the extent of resection [27]. In contrast, survival in stage 4 patients did not diminish after incomplete resection compared with CR [6]. In a large study Matsumura reported that removal of approximately 100 % of the tumour (which can be interpreted as GTR by INSS standards) can only lead to a slightly improved survival (not significant) when compared with less radical resection.
A publication by Browne, primarily aimed at accomplishing CR, showed a lower metastatic recurrence rate following CR compared to incomplete resection and better survival (68 vs.
55 %, respectively), but this was not significant and may have been caused by differences in tumour biology or undetected micrometastasis in the bone marrow.
The authors state that aggressive surgical resection, including removal of organs, is no longer necessary due to improved medical therapies [30].
Likewise, Kaneko postulated that highly extensive surgery may not be required due to better pre-and postoperative chemotherapy protocols [24]. In ten operated patients the 5-year overall and relapse-free survival was 56 and 46 %, respectively. Instead, seven of the patients underwent GTR, while in two gross macroscopic residual was left. Although not enough patients undergoing CR were available to make a comparison with GTR in this study, it indicates that substantial survival can be achieved if tumour mass is left behind after surgery. Contrary to these positive results, we found one study that demonstrated no difference in survival following GTR or following less extensive surgery [10].



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