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Annals of the New York Academy of... Jan 2015Arising from neural crest cells, neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The clinical presentation of NB is heterogeneous, ranging from... (Review)
Review
Arising from neural crest cells, neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The clinical presentation of NB is heterogeneous, ranging from patients with asymptomatic tumor masses, who require minimal treatment, to patients with metastatic disease who are treated with multimodal therapies. Clinical outcome is also variable, with overall survival ranging from 98% to 100% in infants with stage 1 NB, to less than 30% in patients with stage 4 MYCN-amplified NB. More than 50% of patients show metastasis at diagnosis, with the involvement of different vascularized tissues, including the bone marrow (BM). In this paper, we focus on BM infiltration by NB cells, which is considered an adverse prognostic factor. In particular, we discuss the role of different biological factors that may favor the dissemination of NB cells in the BM, such as chromosomic abnormalities, gene amplification, transcription factors, cell-surface receptors, products of oncogenes, and, more importantly, cytokines and chemokines. In addition, we analyze different techniques to evaluate BM infiltration by malignant cells (i.e., flow cytometry, immunocytochemistry, and quantitative reverse transcriptase polymerase chain reaction). Finally, we review recent data regarding phenotypic and genetic characterization of BM-infiltrating malignant cells and characterization of the BM microenvironment in NB patients compared to healthy subjects.
Topics: Animals; Bone Marrow; Bone Marrow Neoplasms; Cell Movement; Humans; Neuroblastoma
PubMed: 25315505
DOI: 10.1111/nyas.12554 -
Der Radiologe Aug 2014Germ cell tumors, which constitute approximately 3-5% of tumors of the central nervous system (CNS), can be subdivided into germinomas, embryonal carcinomas, yolk sac...
Germ cell tumors, which constitute approximately 3-5% of tumors of the central nervous system (CNS), can be subdivided into germinomas, embryonal carcinomas, yolk sac tumors, choriocarcinomas, teratomas and mixed germ cell tumors. The diagnosis of intracranial germ cell tumor is based on the clinical symptoms, detection of tumor markers, such as alpha fetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (beta-hCG) in blood and cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) of the brain and spinal cord, CSF cytology and histology. The diagnosis of a secreting germ cell tumor, i.e. a non-germinoma, can be made by the determination of AFP and hCG as tumor markers. Germinomas are radiosensitive but are equally as sensitive to chemotherapy. Teratomas of the CNS are mostly diagnosed in newborns and infants. The most decisive role in the treatment of teratomas is played by as complete a resection as possible. Chemotherapy and irradiation play a subordinate role.Embryonal tumors, which constitute approximately 15-20% of CNS tumors, include medulloblastomas, primitive neuroectodermal tumors (PNET) of the CNS and the atypical teratoid rhabdoid tumor of the CNS. Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. The incidence peak is the fifth year of life with a male predisposition in a ratio of 1.5:1. Medulloblastomas constitute 12-25% of all pediatric CNS tumors and 30-40% of pediatric tumors of the posterior cranial fossa. At the time of diagnosis evidence of dissemination in the CSF cavity is found in approximately 40% of patients. The extreme cell density makes medulloblastomas hyperdense in computed tomography (CT) and can therefore be differentiated from hypodense astrocytomas. The PNETs are histologically related to medulloblastomas, pineoblastomas, atypical teratoid rhabdoid tumors and peripheral neuroblastomas. They are relatively rare in children constituting less than 5% of supratentorial neoplasms. Patients are mostly clinically conspicuous due to macrocephalus and signs of brain pressure and/or seizures. In native CT the solid components of PNETs show a hyperdensity compared to the surrounding brain parenchyma probably due to the high cell density. Cysts and calcification are often detectable. The survival rate of children with CNS tumors has continuously increased in recent years. When corresponding clinical symptoms appear, such as headache, nausea or vomiting when fasting, all of which are evidence of increased intracranial pressure, MRI should be carried out as quickly as possible. Children should be treated in centers with departments of pediatric oncology and hematology and within the framework of studies.
Topics: Brain Neoplasms; Child; Child, Preschool; Diagnosis, Differential; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Neoplasm Staging; Neoplasms, Germ Cell and Embryonal
PubMed: 25119569
DOI: 10.1007/s00117-014-2667-x -
Scientific Reports Oct 2017Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been...
Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been started in pediatric cancers, including high-risk/relapsing neuroblastoma (NB). Therefore, we studied the effects of anti-PD-1/PD-L1 mAbs in two syngeneic models of disseminated NB generated by the injection of either Neuro2a or NXS2 cells, which express PD-L1. In addition, we tested the combination of these agents with the immune-enhancing cytokine IL-21, the Ecto-NTPDase inhibitor POM-1, an anti-CD25 mAb targeting Treg cells, or an anti-CD4 mAb. We previously showed that CD4-transient depletion removes CD4CD25 Treg cells and other CD4CD25 regulatory subsets. Here we show that mono-therapy with anti-PD-1/PD-L1 mAbs had no effect on systemic NB progression in vivo, and also their combination with IL-21, POM-1 or anti-CD25 mAb was ineffective. The combined use of anti-PD-1 with an anti-CD4 mAb mediated a very potent, CD8-dependent, synergistic effect leading to significant elongation of tumor-free survival of mice, complete tumor regression and durable anti-NB immunity. Similar results were obtained by combining the anti-PD-L1 and anti-CD4 mAbs. These findings indicate that both PD-1/PD-L1 and CD4 T cell-related immune-regulatory mechanisms must be simultaneously blocked to mediate therapeutic effects in these models.
Topics: Animals; Antibodies, Monoclonal; Apoptosis; B7-H1 Antigen; CD4 Antigens; Cell Proliferation; Cytotoxicity, Immunologic; Female; Immunologic Factors; Immunotherapy; Interleukins; Lymphocyte Depletion; Mice; Mice, Inbred A; Neuroblastoma; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Tumor Cells, Cultured
PubMed: 29070883
DOI: 10.1038/s41598-017-14417-6 -
Cell Biology and Toxicology Jun 2023Neuroblastoma (NB) progression is branded with hematogenous metastasis and frequent relapses. Despite intensive multimodal clinical therapy, outcomes for patients with...
MMP-9 reinforces radiation-induced delayed invasion and metastasis of neuroblastoma cells through second-signaling positive feedback with NFκB via both ERK and IKK activation.
Neuroblastoma (NB) progression is branded with hematogenous metastasis and frequent relapses. Despite intensive multimodal clinical therapy, outcomes for patients with progressive disease remain poor, with negligible long-term survival. Therefore, understanding the acquired molecular rearrangements in NB cells with therapy pressure and developing improved therapeutic strategies is a critical need to improve the outcomes for high-risk NB patients. We investigated the rearrangement of MMP9 in NB with therapy pressure, and unveiled the signaling that facilitates NB evolution. Radiation-treatment (RT) significantly increased MMP9 expression/activity, and the induced enzyme activity was persistently maintained across NB cell lines. Furthermore, RT-triggered NFκB transcriptional activity and this RT-induced NFκB were required/adequate for MMP9 maintenance. RT-triggered NFκB-dependent MMP9 actuated a second-signaling feedback to NFκB, facilitating a NFκB-MMP9-NFκB positive feedback cycle (PFC). Critically, MMP9-NFκB feedback is mediated by MMP9-dependent activation of IKKβ and ERK phosphotransferase activity. Beyond its tumor invasion/metastasis function, PFC-dependent MMP9 lessens RT-induced apoptosis and favors survival pathway through the activation of NFκB signaling. In addition, PFC-dependent MMP9 regulates 19 critical molecular determinants that play a pivotal role in tumor evolution. Interestingly, seven of 19 genes possess NFκB-binding sites, demonstrating that MMP9 regulates these molecules by activating NFκB. Collectively, these data suggest that RT-triggered NFκB-dependent MMP9 actuates feedback to NFκB though IKKβ- and ERK1/2-dependent IκBα phosphorylation. This RT-triggered PFC prompts MMP9-dependent survival advantage, tumor growth, and dissemination. Targeting therapy-pressure-driven PFC and/or selective inhibition of MMP9 maintenance could serve as promising therapeutic strategies for treatment of progressive NB.
Topics: Humans; Matrix Metalloproteinase 9; I-kappa B Kinase; Feedback; Cell Line, Tumor; NF-kappa B; Neuroblastoma; Protein Serine-Threonine Kinases
PubMed: 34626302
DOI: 10.1007/s10565-021-09663-4 -
Proceedings of the National Academy of... Aug 2017Neuroblastoma is a childhood cancer that is fatal in almost half of patients despite intense multimodality treatment. This cancer is derived from neuroendocrine tissue...
Neuroblastoma is a childhood cancer that is fatal in almost half of patients despite intense multimodality treatment. This cancer is derived from neuroendocrine tissue located in the sympathetic nervous system. Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite outgrowth. In this study, we find that GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression. We demonstrate that silencing of GPC2 by CRISPR-Cas9 or siRNA results in the inhibition of neuroblastoma tumor cell growth. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. We have isolated human single-domain antibodies specific for GPC2 by phage display technology and found that the single-domain antibodies can inhibit active β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a. To explore GPC2 as a potential target in neuroblastoma, we have developed two forms of antibody therapeutics, immunotoxins and chimeric antigen receptor (CAR) T cells. Immunotoxin treatment was demonstrated to inhibit neuroblastoma growth in mice. CAR T cells targeting GPC2 eliminated tumors in a disseminated neuroblastoma mouse model where tumor metastasis had spread to multiple clinically relevant sites, including spine, skull, legs, and pelvis. This study suggests GPC2 as a promising therapeutic target in neuroblastoma.
Topics: Animals; Antineoplastic Agents, Immunological; Cell Line, Tumor; Female; Gene Silencing; Glypicans; HEK293 Cells; Humans; Mice; Mice, Nude; N-Myc Proto-Oncogene Protein; Neuroblastoma; Single-Chain Antibodies; Wnt Signaling Pathway; Wnt3A Protein; Xenograft Model Antitumor Assays
PubMed: 28739923
DOI: 10.1073/pnas.1706055114 -
Head and Neck Pathology Sep 2021Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the... (Review)
Review
Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the head and neck region is rare. Here, we present two cases of metastatic neuroblastoma of childhood, in which a mandibular swelling was the first sign of disseminated disease. Case 1 describes a 4-year-old boy with a 2-week history of painful swelling in the left mandibular region, body soreness and weakness. Panoramic radiography and computed tomography showed a destructive lesion in the left mandibular ramus. Case 2 describes a 3-year-old boy with a 1-month history of swelling in the right mandibular area. Panoramic radiograph and cone-beam computed tomography showed a destructive lesion in the right body and ramus of the mandible, displacing tooth germs, with the destruction of vestibular and lingual bone cortices. In both cases, microscopic analyses revealed a diffuse proliferation of small, round, and blue cells with hyperchromatic nuclei and scant cytoplasm. While Case 1 was more undifferentiated, Case 2 presented eosinophilic areas suggestive of neuropil. A large immunohistochemical panel was performed, showing expression of neural markers such as CD56, neuron-specific enolase (in Case 2), chromogranin, and synaptophysin. Both lesions presented a high proliferation index (Ki67 > 70% and 80%, respectively). Positron emission tomography-computed tomography revealed ipsilateral adrenal primary lesions in both cases, with multiple bone metastatic lesions. Besides the mandible, multiple sites of the axial and appendicular skeleton were affected. Treatment consisted of induction chemotherapy, adrenalectomy, consolidation chemoradiotherapy, and post-consolidation therapy.
Topics: Adrenal Gland Neoplasms; Child, Preschool; Humans; Male; Mandibular Neoplasms; Neuroblastoma
PubMed: 33394374
DOI: 10.1007/s12105-020-01277-2 -
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... Jan 2023Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required...
BACKGROUND
Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required thromboelastometry-guided surgery.
OBSERVATION
A 6-year-old female diagnosed with intermediate risk adrenal neuroblastoma developed tumor-related DIC after chemotherapy first cycle. She remained stable without clinical bleeding and emergent tumor resection guided by intraoperative-thromboelastometry was decided. DIC resolved early after surgery and complete remission was achieved.
CONCLUSION
Treatment of the underlying condition is critical to manage DIC. Thromboelastometry can guide goal-directed therapy, including surgery in pediatric patients. However, larger studies are needed to examine its applicability in different clinical settings, such as cancer related DIC.
Topics: Female; Humans; Child; Thrombelastography; Disseminated Intravascular Coagulation; Neuroblastoma
PubMed: 36629349
DOI: 10.54847/cp.2023.01.20 -
Journal of Pediatric Hematology/oncology Nov 2014Neuroblastoma in the adult is rare. No established therapeutic guidelines exist for these patients and the literature on this issue is scant and contradictory.
BACKGROUND
Neuroblastoma in the adult is rare. No established therapeutic guidelines exist for these patients and the literature on this issue is scant and contradictory.
MATERIALS AND METHODS
Between 1986 and 2011, 21 adults (18 to 38 y; median, 23) diagnosed with neuroblastoma were referred to our hospital. Three of the 21 were classified as neuroblastoma, not otherwise specified, 13 as neuroblastoma, schwannian stroma-poor, and 5 as ganglioneuroblastoma, nodular. Nine patients had a resectable (stage 1/2) and 6 an unresectable primary tumor (stage 3); 6 had disseminated disease (stage 4).
RESULTS
Of 9 stage 1/2 patients, 6 underwent surgery alone (2 survive, 4 died), 2 received adjuvant chemotherapy (both survive), and 1 received radiation therapy (alive). Four of the 6 stage 3 patients received chemotherapy and died, 1 underwent partial tumor resection only and died, and 1 received radiation therapy after partial tumor resection and is alive. The 6 stage 4 patients received chemotherapy with/without radiotherapy, and all died. Event-free survival at 10 years was 33.3% for stage 1/2, 16.7% for stage 3, and 0% for stage 4 patients. The 10-year overall and event-free survival rates were 39.8% and 19.1%, respectively.
CONCLUSIONS
The outcome of neuroblastoma in adults is poorer than in younger patients at all stages. The clinical course seems modestly influenced by therapy.
Topics: Adolescent; Adult; Combined Modality Therapy; Disease-Free Survival; Female; Ganglioneuroblastoma; Humans; Italy; Male; Neurilemmoma; Neuroblastoma; Population Surveillance; Prevalence; Prognosis; Young Adult
PubMed: 24633299
DOI: 10.1097/MPH.0000000000000144 -
Cancer Reports (Hoboken, N.J.) May 2022Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma.
BACKGROUND
Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma.
AIMS
The present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma.
METHODS AND RESULTS
The medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO ≤55 mmHg). Possible predictive factors on admission were first screened for using univariate analyses with P = .05, then models of the predictive power of the outcome were evaluated by generating receiver operating characteristic (ROC) curves. Eleven patients (14.7%) had the outcome, including three (4.0%) who required respiratory support in the intensive care unit. The area under the curve of the ROC for the predictive factors screened by univariate analyses was 0.84 (95% confidence interval [CI]: 0.73-0.95) for lactate dehydrogenase (LDH) and 0.90 (95% CI: 0.82-0.98) for the disseminated intravascular coagulation (DIC) score.
CONCLUSION
The LDH value and DIC score on admission may be clinically useful predictors of ARE during initial induction chemotherapy in patients with advanced neuroblastoma.
Topics: Disseminated Intravascular Coagulation; Humans; Hypoxia; Induction Chemotherapy; Neuroblastoma; Retrospective Studies
PubMed: 34255936
DOI: 10.1002/cnr2.1499