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Frontiers in Oncology 2019Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a... (Review)
Review
Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a transient population of NC cells that undergo an epithelial-mesenchymal transition (EMT) and generate diverse cell-types and tissues. Patients with neuroblastoma are characterized by their extreme heterogeneity ranging from spontaneous regression to malignant progression. More than half of newly diagnosed patients present highly metastatic tumors and are stratified into a high-risk group with dismal outcome. As many as 20% of high-risk patients have residual disease that is refractory or progressive during induction chemotherapy. Although a majority of high-risk patients achieve remission, larger part of those patients has minimal residual disease (MRD) that causes relapse even after additional consolidation therapy. MRD is composed of drug-resistant tumor cells and dynamically presented as cancer stem cells (CSCs) in residual tumors, circulating tumor cells (CTCs) in peripheral blood (PB), and disseminated tumor cells (DTCs) in bone marrow (BM) and other metastatic sites. EMT appears to be a key mechanism for cancer cells to acquire MRD phenotypes and malignant aggressiveness. Due to the restricted availability of residual tumors, PB and BM have been used to isolate and analyze CTCs and DTCs to evaluate MRD in cancer patients. In addition, recent technical advances make it possible to use circulating tumor DNA (ctDNA) shed from tumor cells into PB for MRD evaluation. Because MRD can be detected by tumor-specific antigens, genetic or epigenetic changes, and mRNAs, numerous assays using different methods and samples have been reported to detect MRD in cancer patients. In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. Given the extreme heterogeneity of neuroblastoma, dynamics of MRD in neuroblastoma patients will hold a key to the clinical validation. In this review, we summarize the biology and detection methods of cancer MRD in general and evaluate the available assays and clinical significance of neuroblastoma MRD to clarify its dynamics in neuroblastoma patients.
PubMed: 31214500
DOI: 10.3389/fonc.2019.00455 -
Journal of Pediatric Hematology/oncology Jul 2019Congenital neuroblastoma with placental involvement is exceptionally rare, but mortality is high. Detailed examination of placenta including MYCN amplification and...
Congenital neuroblastoma with placental involvement is exceptionally rare, but mortality is high. Detailed examination of placenta including MYCN amplification and segmental chromosomal aberrations should be performed in all suspected cases, as it is noninvasive and readily available. Maternal dissemination has not been reported. In this manuscript, we describe an infant with placental diagnosis of MYCN nonamplified congenital neuroblastoma. This is the first report of a recurrence of congenital 4S neuroblastoma following resolution in which MYCN amplification is only detected in the recurrence. Germline sequencing using a large comprehensive cancer panel did not reveal variants in candidate cancer predisposition genes.
Topics: Adult; Chromosome Aberrations; Female; Gene Amplification; Humans; Infant; N-Myc Proto-Oncogene Protein; Neuroblastoma; Placenta Diseases; Pregnancy; Recurrence
PubMed: 31094905
DOI: 10.1097/MPH.0000000000001515 -
Frontiers in Molecular Neuroscience 2019In the developing organism, complex molecular programs orchestrate the generation of cells in adequate numbers, drive them to migrate along the correct pathways towards... (Review)
Review
In the developing organism, complex molecular programs orchestrate the generation of cells in adequate numbers, drive them to migrate along the correct pathways towards appropriate territories, eliminate superfluous cells, and induce terminal differentiation of survivors into the appropriate cell-types. Despite strict controls constraining developmental processes, malignancies can emerge in still immature organisms. This is the case of neuroblastoma (NB), a highly heterogeneous disease, predominantly affecting children before the age of 5 years. Highly metastatic forms represent half of the cases and are diagnosed when disseminated foci are detectable. NB arise from a transient population of embryonic cells, the neural crest (NC), and especially NC committed to the establishment of the sympatho-adrenal tissues. The NC is generated at the dorsal edge of the neural tube (NT) of the vertebrate embryo, under the action of NC specifier gene programs. NC cells (NCCs) undergo an epithelial to mesenchymal transition, and engage on a remarkable journey in the developing embryo, contributing to a plethora of cell-types and tissues. Various NCC sub-populations and derived lineages adopt specific migratory behaviors, moving individually as well as collectively, exploiting the different embryonic substrates they encounter along their path. Here we discuss how the specific features of NCC in development are re-iterated during NB metastatic behaviors.
PubMed: 30881286
DOI: 10.3389/fnmol.2019.00052 -
Pediatric Blood & Cancer Jun 2019
Topics: Congresses as Topic; Humans; Information Dissemination; Neuroblastoma; Publications; Societies, Scientific
PubMed: 30848089
DOI: 10.1002/pbc.27696 -
Acta Biomaterialia Apr 2019Metastasis of tumor cells in the bone marrow (BM) is a multi-step and highly dynamic process during which cells succumb important phenotypic changes. Behavior of...
Metastasis of tumor cells in the bone marrow (BM) is a multi-step and highly dynamic process during which cells succumb important phenotypic changes. Behavior of disseminated tumor cells in BM is strictly regulated by three-dimensional (3D) cell-cell and cell-matrix interactions. In this study, we explored whether the β-tricalcium-phosphate (β-TCP) scaffolds with a tailored interconnecting channel structure could enable appropriate 3D mimetic BM microenvironment for the growth of metastatic neuroblastoma cells. The scaffolds provided the mechanical support for human mesenchymal stromal cells (hMSC) allowing them to proliferate, differentiate towards osteoblasts, and produce the deposits of extracellular matrix inside the interconnected channels. The in vitro microenvironment shaped by stromal cells was then tailored by neuroblastoma tumor cells. Immunohistological analyses confirmed the organization of tumor cells into the forms of spheres only when co-cultured with hMSC-derived osteoblasts. The growing rate of tumor cells in 3D conditions was less marked comparing to the one of the cells grown as 2D monolayer as confirmed by decreased Ki-67 expression. Instead, the 3D culturing of neuroblastoma cells inside supportive stroma promoted cell quiescence as sustained by increased p27 level. A balance between cell proliferation, survival, and differentiation was more evident for tumor cells grown inside the 3D scaffolds, thus mirroring better the situation that occurs in vivo where the cells do not follow the exponential growth rate. We conclude that the proposed 3D β-TCP scaffold type provides a mimetic 3D in vitro niche suitable for studying behavior of BM metastasized tumor cells. STATEMENT OF SIGNIFICANCE: Bone marrow (BM) niche is a favorite target of metastatic neuroblastoma cells. To better address the molecular mechanisms that sustain spatiotemporal organization of neuroblastoma cells in the marrow we mimicked the three-dimensional (3D) assembly of stromal and tumor cells inside β-tricalcium-phosphate (β-TCP) scaffolds. β-TCP scaffolds with a tailored interconnecting channel structure provided mechanical support to mesenchymal stromal cells allowing them to differentiate towards osteoblasts and to produce extracellular matrix. A dynamic cell-matrix interplay favored the characteristic rosette-like growth of metastatic neuroblastoma cells and triggered their quiescence. With our study, we confirmed the potential of β-TCP scaffolds with reproduced BM niche as a cost-effective in vitro model for the growth of disseminated tumor cells, and for related biological and pharmacological surveys.
Topics: Biocompatible Materials; Bone Marrow Neoplasms; Calcium Phosphates; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Humans; Mesenchymal Stem Cells; Neuroblastoma; Osseointegration; Osteoblasts; Porosity; Reproducibility of Results; Spheroids, Cellular; Stem Cell Niche; Tissue Scaffolds
PubMed: 30797105
DOI: 10.1016/j.actbio.2019.02.030 -
PloS One 2019The consistent focus of 'Advances in Neuroblastoma Research' congresses on the topic neuroblastoma sets it as a model for a circumscribed scientific community.
BACKGROUND
The consistent focus of 'Advances in Neuroblastoma Research' congresses on the topic neuroblastoma sets it as a model for a circumscribed scientific community.
METHODS
The contributions of authors, institutions and countries to congress abstracts and their collaborations were compared to the Hirsch index (h-index) calculated from the Web of Science publication output on the topic 'neuroblastoma'.
RESULTS
From 1975 to 2016, 18 congresses were held. 8459 authors affiliated to 553 institutions of 53 countries presented 3,993 abstracts. The number of coauthors increased over the years from 2 to 7. A considerable proportion of authors, institutions and countries presented only once (53.7%/25.7%/13.2%). Authors with a high number of abstracts and with a large local network were often among those with a higher publication rate and success (R2 = 0.508 for Pearson's correlation between weight and h-index, R2 = 0.474 for degree centrality, R2 = 0.364 for lobby-index). Closeness and betweenness centralities were less correlated (R2 = 0.127/R2 = 0.33, resp.). The institutions showed a similar impact of local interactions on publication success (degree centrality R2 = 0.417, weight R2 = 0.308), while countries demonstrated a higher correlation of betweenness centrality and h-Index (R2 = 0.704) emphasizing their brokerage role. Of 553 institutions, 520 collaborated within 13 communities and belonged to the large scientific network. 33 satellite institutions had no connections to the central network. They attended 1-4 congresses over a period of 1-16 years.
CONCLUSION
A large scientific network has been developed during the recent 42 years. Growth and interaction at congresses were correlated to publication success. Weight is suggested as a useful and simple estimate.
Topics: Authorship; Bibliometrics; Child; Congresses as Topic; Humans; Information Dissemination; Medical Oncology; Neoplasms; Neuroblastoma; Pediatrics; Publications; Publishing
PubMed: 30682100
DOI: 10.1371/journal.pone.0210994 -
Frontiers in Oncology 2018Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal... (Review)
Review
Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside G on the cell surface of neuroblastomas which derive from G-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentiation, adhesion and cell death. In addition, transformation of human cells to cancer cells can be associated with distinct glycosylation profiles which provide advantages for tumor growth and dissemination and can serve as immune targets. Both gangliosides and aberrant glycosylation of proteins escape the direct molecular and proteomic screening strategies currently applied to identify further immune targets in cancers. Due to their highly restricted expression and their functional roles in the malignant behavior, they are attractive targets for immune engineering strategies. G-redirected CAR T cells have shown activity in clinical phase I/II trials in neuroblastoma and next-generation studies are ongoing. Further carbohydrate targets for CAR T cells in preclinical development are O-acetyl-G, NeuGc-GM3 (N-glycolyl GM3), G, SSEA-4, and oncofetal glycosylation variants. This review summarizes knowledge on the role and function of some membrane-expressed non-protein antigens, including gangliosides and abnormal protein glycosylation patterns, and discusses their potential to serve as a CAR targets in pediatric solid cancers.
PubMed: 30483473
DOI: 10.3389/fonc.2018.00513 -
The Pediatric Infectious Disease Journal May 2019We report an 8-year-old boy with disseminated, life-threatening, drug treatment-resistant varicella zoster infection occurring during standard treatment for...
We report an 8-year-old boy with disseminated, life-threatening, drug treatment-resistant varicella zoster infection occurring during standard treatment for neuroblastoma in whom viral clearance and cure was effected by donor Lymphocyte infusion from his HLA (Human leukocyte antigen)-identical twin sibling.
Topics: Child; Drug Resistance, Viral; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunotherapy, Adoptive; Lymphocytes; Male; Neuroblastoma; Treatment Outcome
PubMed: 30461572
DOI: 10.1097/INF.0000000000002252 -
Molecular Imaging 2018Metastasis is the most common cause of death for patients with cancer. To fully understand the steps involved in metastatic dissemination, in vivo models are required,...
Metastasis is the most common cause of death for patients with cancer. To fully understand the steps involved in metastatic dissemination, in vivo models are required, of which murine ones are the most common. Therefore, preclinical imaging methods such as magnetic resonance imaging (MRI) have mainly been developed for small mammals and their potential to monitor cancer growth and metastasis in nonmammalian models is not fully harnessed. We have here used MRI to measure primary neuroblastoma tumor size and metastasis in a chick embryo model. We compared its sensitivity and accuracy to end-point fluorescence detection upon dissection. Human neuroblastoma cells labeled with green fluorescent protein (GFP) and micron-sized iron particles were implanted on the extraembryonic chorioallantoic membrane of the chick at E7. T RARE, T-weighted fast low angle shot (FLASH) as well as time-of-flight MR angiography imaging were applied at E14. Micron-sized iron particle labeling of neuroblastoma cells allowed in ovo observation of the primary tumor and tumor volume measurement noninvasively. Moreover, T weighted and FLASH imaging permitted the detection of small metastatic deposits in the chick embryo, thereby reinforcing the potential of this convenient, 3R compliant, in vivo model for cancer research.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Disease Models, Animal; Embryonic Development; Humans; Iron; Magnetic Resonance Imaging; Neoplasm Metastasis; Particle Size; Tumor Burden
PubMed: 30392458
DOI: 10.1177/1536012118809585 -
Cirugia Pediatrica : Organo Oficial de... Aug 2018The aim of the paper is to describe the experience in our center with the use of minimally invasive surgery (MIS) of neural tumors in childhood.
PURPOUSE
The aim of the paper is to describe the experience in our center with the use of minimally invasive surgery (MIS) of neural tumors in childhood.
METHODS
Descriptive and retrospective study of patients diagnosed with neural neoplasia (neuroblastoma and neuroganglioma) on whom MIS technique surgery has been performed between October 2012 and December 2017. The inclusion criteria were patients with a neural tumor diagnosis who, at the time of the intervention, did not have imaging-defined risk factors (IDRFs). Patients with a different diagnosis than neural tumor or with IDRFs were excluded from the study.
RESULTS
The study comprises 19 cases (6 female and 13 male) with a median age of 47 months. According to the International Neuroblastoma Risk Group Staging System (INRGSS) classification, nine cases were in L1 stage, six in L2, two in M and two in MS. Laparoscopy was used in 14 patients (12 adrenal and 2 abdominal tumors) and thoracoscopy was used in the other 5. In 4 of the 19 cases (21%), conversion to open surgery was needed due to fibrosis in 2 cases and vascular structures entrapment in another 2 (3 in laparoscopy and 1 in thoracoscopy). There were no surgical complications, achieving complete resection in all cases. Three cases showed postsurgical adverse effects grade I and II, according to Clavien-Dindo classification. After a median of 27 months of follow up, two patients showed disease progression without local recurrence.
CONCLUSIONS
In conclusion, MIS are useful techniques in the surgical exeresis of non-disseminated neural tumors without IDRFs.
Topics: Abdominal Neoplasms; Adolescent; Adrenal Gland Neoplasms; Child; Child, Preschool; Disease Progression; Female; Follow-Up Studies; Ganglioneuroma; Humans; Infant; Laparoscopy; Male; Minimally Invasive Surgical Procedures; Neuroblastoma; Retrospective Studies; Risk Factors; Thoracoscopy
PubMed: 30260107
DOI: No ID Found