Neuroblastoma Biology Research Articles

Enrollment on upfront high-risk neuroblastoma trials by race, ethnicity, and poverty status: A report from the Children's Oncology Group.

It is not clear whether trial access disparities exist in the Children's Oncology Group (COG). Here, we leverage a cohort of children with high-risk neuroblastoma (HR-NBL) enrolled on the COG ANBL00B1 neuroblastoma biology study to examine subsequent enrollment to upfront COG therapeutic trials by race, ethnicity, and proxied poverty status. Among 1917 children with HR-NBL enrolled on ANBL00B1, 696 (36.3%) subsequently enrolled on an upfront therapeutic trial with no difference by race, ethnicity, or proxied poverty status. In neuroblastoma, trial access disparities are not comparable to adult oncology, and efforts to advance equity should prioritize other mechanisms of survival disparities.

Extracting Electronic Health Record Neuroblastoma Treatment Data With High Fidelity Using the REDCap Clinical Data Interoperability Services Module.

Although the International Neuroblastoma Risk Group Data Commons (INRGdc) has enabled seminal large cohort studies, the research is limited by the lack of real-world, electronic health record (EHR) treatment data. To address this limitation, we evaluated the feasibility of extracting treatment data directly from EHRs using the REDCap Clinical Data Interoperability Services (CDIS) module for future submission to the INRGdc. Patients enrolled on the Children's Oncology Group neuroblastoma biology study ANBL00B1 (ClinicalTrials.gov identifier: NCT00904241) who received care at the University of Chicago (UChicago) or the Vanderbilt University Medical Center (VUMC) after the go-live dates for the Fast Healthcare Interoperability Resources (FHIR)-compliant EHRs were identified. Antineoplastic drug orders were extracted using the CDIS module. To validate the CDIS output, antineoplastic agents extracted through FHIR were compared with those queried through EHR relational databases (UChicago's Clinical Research Data Warehouse and VUMC's Epic Clarity database) and manual chart review. The analytic cohort consisted of 41 patients at UChicago and 32 VUMC patients. Antineoplastic drug orders were identified in the extracted EHR records of 39 (95.1%) UChicago patients and 26 (81.3%) VUMC patients. Manual chart review confirmed that patients with missing (n = 8) or discontinued (n = 1) orders in the CDIS output did not receive antineoplastic agents during the timeframe of the study. More than 99% of the antineoplastic drug orders in the EHR relational databases were identified in the corresponding CDIS output. Our results demonstrate the feasibility of extracting EHR treatment data with high fidelity using HL7-FHIR via REDCap CDIS for future submission to the INRGdc.

AF1q is a universal marker of neuroblastoma that sustains N-Myc expression and drives tumorigenesis

Neuroblastoma is the most common extracranial malignant tumor of childhood, accounting for 15% of all pediatric cancer deaths. Despite significant advances in our understanding of neuroblastoma biology, five-year survival rates for high-risk disease remain less than 50%, highlighting the importance of identifying novel therapeutic targets to combat the disease. MYCN amplification is the most frequent and predictive molecular aberration correlating with poor outcome in neuroblastoma. N-Myc is a short-lived protein primarily due to its rapid proteasomal degradation, a potentially exploitable vulnerability in neuroblastoma. AF1q is an oncoprotein with established roles in leukemia and solid tumor progression. It is normally expressed in brain and sympathetic neurons and has been postulated to play a part in neural differentiation. However, no role for AF1q in tumors of neural origin has been reported. In this study, we found AF1q to be a universal marker of neuroblastoma tumors. Silencing AF1q in neuroblastoma cells caused proteasomal degradation of N-Myc through Ras/ERK and AKT/GSK3β pathways, activated p53 and blocked cell cycle progression, culminating in cell death via the intrinsic apoptotic pathway. Moreover, silencing AF1q attenuated neuroblastoma tumorigenicity in vivo signifying AF1q’s importance in neuroblastoma oncogenesis. Our findings reveal AF1q to be a novel regulator of N-Myc and potential therapeutic target in neuroblastoma.

Multi-modal 3-Dimensional Visualization of Pediatric Neuroblastoma: Aiding Surgical Planning Beyond Anatomical Information

BackgroundPatient-specific 3D models of neuroblastoma and relevant anatomy are useful tools for surgical planning. However, these models do not represent the heterogenous biology of neuroblastoma. This heterogeneity is visualized with the ADC and 123I-MIGB-SPECT-CT imaging. Combining these multi-modal data into preoperative 3D heatmaps, may allow differentiation of the areas of vital and non-vital tumor tissue. We developed a workflow to create multi-modal preoperative 3D models for neuroblastoma surgery. MethodsWe included 7 patients who underwent neuroblastoma surgery between 2022 and 2023. We developed 3D models based on the contrast enhanced T1-weighted MRI scans. Subsequently, we aligned the corresponding ADC and 123I-MIBG-SPECT-CT images using rigid transformation. We estimated registration precision using the Dice score and the target registration error (TRE). 3D heatmaps were computed based on ADC and 123I-MIBG uptake. ResultsThe registration algorithm had a median Dice score of 0.81 (0.75–0.90) for ADC and 0.77 (0.65–0.91) for 123I-MIBG-SPECT. For the ADC registration, the median TRE of renal vessels was 4.90 mm (0.86–10.18) and of the aorta 4.67 mm (1.59–12.20). For the 123I -MIBG-SPECT imaging the TRE of the renal vessels was 5.52 mm (1.71–10.97) and 5.28 mm (3.33–16.77) for the aorta. ConclusionsWe successfully developed a registration workflow to create multi-modal 3D models which allows the surgeon to visualize the tumor and its biological behavior in relation to the surrounding tissue. Future research will include linking of pathological results to imaging data, to validate these multi-modal 3D models. Level of EvidenceLevel IV. Type of StudyClinical Research.

Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression.

Neuroblastoma, a paediatric malignancy of the peripheral nervous system, displays a wide range of clinical outcomes, including regression to fatality despite extensive treatment. Neuroblastoma tumours display a complex interplay with their surrounding environment, known as the tumour microenvironment, which may affect disease progression and patient prognosis. This study aimed to dissect the ways in which neuroblastoma biology, treatment, prognosis, progression, and relapse are linked with the extracellular matrix, the dichotomous identities of neuroblastoma, various regulatory proteins and RNA, and extracellular vesicles within the backdrop of the tumour microenvironment. In addition, other aspects, such as immune cell infiltration, therapeutic options including monoclonal antibodies and small molecule inhibitors; and the ways in which these may affect disease progression and immunosuppression within the context of the neuroblastoma tumour microenvironment, are addressed. Such studies may shed light on useful therapeutic targets within the tumour microenvironment that may benefit groups of NB patients. Ultimately, a detailed understanding of these aspects will enable the neuroblastoma scientific community to improve treatment options, patient outcomes, and quality of life.

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.

A multicenter cooperative group study of late effects after high-risk neuroblastoma: COG ALTE15N2—LEAHRN study.

10002 Background: Aggressive therapies for high-risk neuroblastoma (HRNBL) have resulted in increased survival, but late effects have not been well-characterized. Methods: Comprehensive cross-sectional evaluation of health outcomes in HRNBL survivors enrolled on the COG Neuroblastoma Biology Study after 1/1/2000 and ≥ 5 years from primary diagnosis, using medical record abstraction and in-person clinical assessments. Descriptive and multivariable analyses identified extent of and risk factors for late toxicity. Results: There were 375 participants from 88 COG centers, 205 (55%) male; 92 (26%) non-white; 45 (13%) Hispanic. Median age at neuroblastoma diagnosis was 2.5 years (range: 0.2-15.8), at enrollment was 12.0 years (range: 5.0-24.0). All had received chemotherapy; 94% received cisplatin (median dose: 398 mg/m2). Other exposures included: radiation (95%), isotretinoin (91%), anti-GD2 antibody therapy (64%), MIBG (7%), single (79%) or tandem autologous transplantation (ASCT; 20%). ASCT conditioning included: Busulfan/Melphalan (BuMel) (18%), Carboplatin/Etoposide/Melphalan (CEM) (73%), Thiotepa/Cytoxan (19%), and total body irradiation (5%). Severe ototoxicity (requiring hearing aids) was observed in 58% of participants. Physician-reported late effects included hypothyroidism (17%), pulmonary hypertension (1%), congestive heart failure (2%), and hypertension (6%). Pulmonary Function Studies revealed restrictive lung disease [RLD - Total Lung Capacity < 70% predicted] in 8% of subjects. Laboratory study showed elevated creatinine in 7% and Hemoglobin A1c in 7%. Growth failure (height Z-score < -1.7) was observed in 34%. Subsequent malignant neoplasms (SMN) developed in 15 participants (4%; 4 sarcomas, 3 MDS/t-AML, single instance of 8 other malignancies). Adjusting for sex, follow-up time, age, and race, there were no differences in risk of SMN, severe ototoxicity, growth failure, or RLD for participants who received BuMel vs. CEM-based condtioning, or among those who received anti-GD2 antibody therapy vs. those who did not. Use of carboplatin during ASCT was not assocoiated with increased ototoxicity risk for any category of cisplatin induction dose. Comparing subjects who received CEM as a component of tandem ASCT (vs. single CEM), there was increased risk of growth failure [OR (95%CI) = 4.2(2.1, 8.4); p < 0.0001], but not RLD. Exposure to isotretinoin was not associated with increased risk of growth failure. Further multivariable analyses will be presented, exploring risks for late toxicity associated with conditioning regimens, radiation therapy, surgical approaches, and acute and chronic complications of therapy. Conclusions: The burden of late toxicity in HRNBL survivors is substantial. Anti-GD2 immunotherapy and isotretinoin do not appear to be associated with SMN, ototoxicity, growth failure, or RLD.

Analysis of Serial Neuroblastoma PDX Passages in Mice Allows the Identification of New Mediators of Neuroblastoma Aggressiveness.

Neuroblastoma is a neural crest cell-derived pediatric tumor characterized by high inter- and intra-tumor heterogeneity, and by a poor outcome in advanced stages. Patient-derived xenografts (PDXs) have been shown to be useful models for preserving and expanding original patient biopsies in vivo, and for studying neuroblastoma biology in a more physiological setting. The maintenance of genetic, histologic, and phenotypic characteristics of the original biopsy along serial PDX passages in mice is a major concern regarding this model. Here we analyze consecutive PDX passages in mice, at both transcriptomic and histological levels, in order to identify potential changes or highlight similarities to the primary sample. We studied temporal changes using mRNA and miRNA expression and correlate those with neuroblastoma aggressiveness using patient-derived databases. We observed a shortening of tumor onset and an increase in proliferative potential in the PDXs along serial passages. This behavior correlates with changes in the expression of genes related to cell proliferation and neuronal differentiation, including signaling pathways described as relevant for neuroblastoma malignancy. We also identified new genes and miRNAs that can be used to stratify patients according to survival, and which could be potential new players in neuroblastoma aggressiveness. Our results highlight the usefulness of the PDX neuroblastoma model and reflect phenotypic changes that might be occurring in the mouse environment. These findings could be useful for understanding the progression of tumor aggressiveness in this pathology.

Exosomes in Neuroblastoma Biology, Diagnosis, and Treatment.

Neuroblastoma is an extracranial solid tumour of the developing sympathetic nervous system accounting for circa 15% of deaths due to cancer in paediatric patients. The clinical course of this cancer may be variable, ranging from aggressive progression to regression, while the amplification of MYCN in this cancer is linked to poor patient prognosis. Extracellular vesicles are a double membrane encapsulating various cellular components including proteins and nucleic acids and comprise exosomes, apoptotic bodies, and microvesicles. The former can act as mediators between cancer, stromal and immune cells and thereby influence the tumour microenvironment by the delivery of their molecular cargo. In this study, the contribution of extracellular vesicles including exosomes to the biology, prognosis, diagnosis and treatment of neuroblastoma was catalogued, summarised and discussed. The understanding of these processes may facilitate the in-depth dissection of the complexity of neuroblastoma biology, mechanisms of regression or progression, and potential diagnostic and treatment options for this paediatric cancer which will ultimately improve the quality of life of neuroblastoma patients.

Abstract 5214: Copper chelation overcomes the immunosuppressive tumor microenvironment in neuroblastoma

Abstract Immunotherapy remains a promising approach in the treatment of high-risk neuroblastoma, however efficacy is hampered by the immunosuppressive tumor microenvironment. We previously reported a link between intratumoral copper levels and Programmed Death-Ligand 1 (PD-L1) expression and therefore sought to elucidate the wider impact of copper chelation on immune evasion strategies (Voli et al 2020). Here we profile key elements of the neuroblastoma tumor microenvironment which work in concert to promote immunosuppression and tumor progression. Using the murine TH-MYCN model, animals were treated daily with the copper chelation agent tetraethylenepentamine (TEPA) for seven days before tumor resection and processing. Transcriptome analyses using single-cell RNA-sequencing revealed copper chelation positively skewed the functional status of tumor, immune and stromal compartments to enhance the anti-tumor immune response. This was supported by a tissue microarray screen using NanoString Digital Spatial Profiling which identified increased immune cell infiltration and regions of active tumor killing. High-resolution mass-spectrometry detected upregulation of major histocompatibility complex (MHC) proteins and exclusive antigenic signatures in peptide repertoires. A multiplex cytokine array indicated an improved anti-tumorigenic response underscored by T cell and Natural Killer cell activation. Importantly, combination of copper chelation and anti-GD2 antibody therapy led to tumor regression and significantly improved survival in vivo. Collectively, this study demonstrates the ability of copper chelation to successfully mitigate tumoral immune evasion strategies while providing remarkable insight into neuroblastoma biology. Findings provide crucial evidence in support of combining clinically approved copper chelators with immunotherapy to improve outcomes for neuroblastoma patients. Citation Format: Jourdin R. Rouaen, Daniele Mercatelli, Federica Saletta, Ensieh M. Poursani, Jayne E. Murray, Nicodemus Tedla, Federico M. Giorgi, Orazio Vittorio. Copper chelation overcomes the immunosuppressive tumor microenvironment in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5214.

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma.

Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.

MYCN in Neuroblastoma: "Old Wine into New Wineskins".

MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) has been one of the most studied genes in neuroblastoma. It is known for its oncogenetic mechanisms, as well as its role in the prognosis of the disease and it is considered one of the prominent targets for neuroblastoma therapy. In the present work, we attempted to review the literature, on the relation between MYCN and neuroblastoma from all possible mechanistic sites. We have searched the literature for the role of MYCN in neuroblastoma based on the following topics: the references of MYCN in the literature, the gene’s anatomy, along with its transcripts, the protein’s anatomy, the epigenetic mechanisms regulating MYCN expression and function, as well as MYCN amplification. MYCN plays a significant role in neuroblastoma biology. Its functions and properties range from the forming of G-quadraplexes, to the interaction with miRNAs, as well as the regulation of gene methylation and histone acetylation and deacetylation. Although MYCN is one of the most primary genes studied in neuroblastoma, there is still a lot to be learned. Our knowledge on the exact mechanisms of MYCN amplification, etiology and potential interventions is still limited. The knowledge on the molecular mechanisms of MYCN in neuroblastoma, could have potential prognostic and therapeutic advantages.

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.

Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group.

Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker. Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2). Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (MYCN) or 12-18 months (MYCN, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively. A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.

Association Between Participation in Clinical Trials and Overall Survival Among Children With Intermediate- or High-risk Neuroblastoma

Participants in clinical trials may experience benefits associated with new therapeutic strategies as well as tight adherence to best supportive care practices. To investigate whether participation in a clinical trial is associated with improved survival among children with neuroblastoma and investigate potential recruitment bias of patients in clinical trials. This cohort study included pediatric patients with intermediate- or high-risk neuroblastoma in North American studies who were included in the International Neuroblastoma Risk Group Data Commons and who received a diagnosis between January 1, 1991, and March 1, 2020. Enrollment in a clinical trial. Event-free survival and overall survival (OS) of patients with intermediate- or high-risk neuroblastoma enrolled in an up-front Children's Oncology Group (COG) clinical trial vs a biology study alone were analyzed using log-rank tests and Cox proportional hazards regression models. The racial/ethnic composition and the demographic characteristics of the patients in both groups were compared. The cohort included 3058 children with intermediate-risk neuroblastoma (1533 boys [50.1%]; mean [SD] age, 10.7 [14.7] months) and 6029 children with high-risk neuroblastoma (3493 boys [57.9%]; mean [SD] age, 45.8 [37.4] months) who were enrolled in a Children's Oncology Group or legacy group neuroblastoma biology study between 1991 and 2020. A total of 1513 patients with intermediate-risk neuroblastoma (49.5%) and 2473 patients with high-risk neuroblastoma (41.0%) were also enrolled in a clinical trial, for a cohort total of 3986 of 9087 children (43.9%) enrolled in a clinical trial. The prevalence of prognostic markers for the clinical trial and non-clinical trial cohorts differed, although representation of patients from racial/ethnic minority groups was similar in both cohorts. Among patients with intermediate-risk neuroblastoma, OS was higher among those who participated in a clinical trial compared with those enrolled only in a biology study (OS, 95% [95% CI, 94%-96%] vs 91% [95% CI, 89%-94%]; P = .01). Among patients with high-risk neuroblastoma, participation in a clinical trial was not associated with OS (OS, 38% [95% CI, 35%-41%] in the clinical trial group vs 41% [95% CI, 38%-44%] in the biology study group; P = .23). Approximately 44% of patients in this large cohort of patients with neuroblastoma were enrolled in up-front clinical trials. Compared with children not enrolled in clinical trials, a higher prevalence of favorable prognostic markers was identified among patients with intermediate-risk neuroblastoma enrolled in clinical trials, and unfavorable features were more prevalent among patients with high-risk neuroblastoma enrolled in clinical trials. No evidence of recruitment bias according to race/ethnicity was observed. Participation in a clinical trial was not associated with OS in this cohort, likely reflecting the common practice of treating nontrial participants with therapeutic and supportive care regimens used in a previous therapeutic trial.

Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT).

Simple SummaryNeuroblastoma arises in the developing sympathetic nervous system and represents the most common extracranial pediatric solid tumor. High-risk patients often experience relapse despite intensive multimodal therapies. Consistent with previous reports describing various phenotypes in neuroblastoma cell lines, recent studies precisely characterized two distinct cell identities based on transcriptomic and epigenetic profiles. In this review, we focus on the description of these two cell states, which we define as noradrenergic (NOR) and mesenchymal (MES), and discuss the plasticity between them. The differences in chemoresistance and invasion/migration properties of these two identities may have important clinical relevance. Deciphering the mechanisms of transdifferentiation from a NOR to a MES identity, which is reminiscent of the well-known epithelial-to-mesenchymal transition, is a key step to better understand neuroblastoma biology and improve therapeutic management of patients.Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition.

The quest to develop an effective therapy for neuroblastoma.

Neuroblastoma (NB) is a common solid extracranial tumor developing in pediatric populations. NB can spontaneously regress or grow and metastasize displaying resistance to therapy. This tumor is derived from primitive cells, mainly those of the neural crest, in the sympathetic nervous system and usually develops in the adrenal medulla and paraspinal ganglia. Our understanding of the molecular characteristics of human NBs continues to advance documenting abnormalities at the genome, epigenome, and transcriptome levels. The high-risk tumors have MYCN oncogene amplification, and the MYCN transcriptional regulator encoded by the MYCN oncogene is highly expressed in the neural crest. Studies on the biology of NB has enabled a more precise risk stratification strategy and a concomitant reduction in the required treatment in an expanding number of cases worldwide. However, newer treatment strategies are mandated to improve outcomes in pediatric patients who are at high-risk and display relapse. To improve outcomes and survival rates in such high-risk patients, it is necessary to use a multicomponent therapeutic approach. Accuracy in clinical staging of the disease and assessment of the associated risks based on biological, clinical, surgical, and pathological criteria are of paramount importance for prognosis and to effectively plan therapeutic approaches. This review discusses the staging of NB and the biological and genetic features of the disease and several current therapies including targeted delivery of chemotherapy, novel radiation therapy, and immunotherapy for NB.

Molecular Basis and Clinical Features of Neuroblastoma.

Neuroblastoma, a neoplasm of the sympathetic nervous system, originates from neuroblastoma stem cells during embryogenesis. It exhibits unique clinical features including a tendency for spontaneous regression of tumors in infants and a high frequency of metastatic disease at diagnosis in patients aged over 18 months. Genetic risk factors and epigenetic dysregulation also play a significant role in the development of neuroblastoma. Over the past decade, our understanding of this disease has advanced considerably. This has included the identification of chromosomal copy number aberrations specific to neuroblastoma development, risk groups, and disease stage. However, high-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. New therapeutic approaches have been developed, either as alternatives to conventional chemotherapy or in combination, to overcome the dismal prognosis. Particularly promising strategies are targeted therapies that directly affect cancer cells or cancer stem cells while exhibiting minimal effect on healthy cells. This review summarizes our understanding of neuroblastoma biology and prognostic features and focuses on novel therapeutic strategies for this intractable disease.

India neuroblastoma registration and biology study (INPOG-NB-18-01): Barriers to childhood cancer research in a lower-middle income country

India neuroblastoma registration and biology study (INPOG-NB-18-01): Barriers to childhood cancer research in a lower-middle income country

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group.

PURPOSEFor localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.PATIENTS AND METHODSDiagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children’s Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.RESULTSPatients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038).CONCLUSIONGenomic aberrations of resectable non–MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.