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1.
Pediatr Blood Cancer ; 67(8): e28319, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32543116

RESUMO

OBJECTIVE: To review the treatment and revaccination of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK). PROCEDURE: Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma-associated OMAS followed at MSK from 2000 to 2016. RESULTS: Fourteen patients (nine female) were 9-21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n = 12), stage 2B, or intermediate-risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in two, and unknown in one patient. No patient had amplified MYCN. All patients underwent tumor resection at diagnosis. Anti-neuroblastoma treatment was limited to chemotherapy in one patient. Overall survival is 100% at 3-16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab, and one received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, five patients received low-dose cyclophosphamide and two received rituximab. The mean total OMAS treatment was 20-96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other six experienced OMAS relapse. To date, six patients have been revaccinated at a minimum of 2 years after completion of OMAS therapy without OMAS recurrence. CONCLUSIONS: Patients with neuroblastoma-associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg, and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neuroblastoma , Síndrome de Opsoclonia-Mioclonia , Hormônio Adrenocorticotrópico/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Síndrome de Opsoclonia-Mioclonia/diagnóstico , Síndrome de Opsoclonia-Mioclonia/mortalidade , Síndrome de Opsoclonia-Mioclonia/terapia , Estudos Retrospectivos , Rituximab/administração & dosagem , Taxa de Sobrevida
2.
Medicine (Baltimore) ; 99(25): e20853, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569234

RESUMO

INTRODUCTION: Neuroblastoma (NB) with MYCN amplification has a poor prognosis and high mortality. The potential molecular biological relationship between clinical features and MYCN amplification should be explored. METHODS: NB patients were examined by fluorescence in situ hybridization (FISH) for MYCN amplification in the tumor mass or bone marrow samples to determine whether MYCN was amplified. A series of eleven MYCN-amplified NB patients were included. The age, primary site, tumor size, specific biomarkers, and invaded organs were analyzed. All patients accepted standardized treatment of surgery, chemotherapy, and radiotherapy. Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: The median age at diagnosis was 24 months. Nine patients (81.8%) were in stage IV, with high serum neuron-specific enolase (NSE) expression, normal urine vanillylmandelic acid (VMA) level and extensive metastases. All patients accepted a chemotherapy protocol with 8 to 10 cycles, and 9 patients (81.8%) were sensitive to the initial chemotherapy protocol. At the end of follow-up, four patients (36.3%) died with a median OS of 15 months. Five patients (45%) survived with a median PFS of 13 months. Two patients were still receiving chemotherapy. CONCLUSION: Given the effect of MYCN amplification on poor outcome in NB, novel treatments targeting MYCN should be developed for patients with NB.


Assuntos
Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/patologia , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Análise de Sobrevida
3.
Medicine (Baltimore) ; 99(23): e20639, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502048

RESUMO

Retroperitoneal neuroblastoma is a rare subtype of neuroblastoma and the role of age in its clinical prognosis is still unknown.To describe the age distribution and investigate the association between age and survival outcomes in patients diagnosed with retroperitoneal neuroblastoma.We retrospectively analyzed patients registered for retroperitoneal neuroblastoma in the Surveillance, Epidemiology, and End Results (SEER) national database from 1973 to 2015. Age distribution was described and Cox proportional hazard regression was used to evaluate the measured effect of age on overall survival and disease-specific survival.A total of 399 retroperitoneal neuroblastoma patients with a median follow-up of 53.0 (interquartile range 17.0-133.5) months were included. We found a unimodal distribution of age with a median age of diagnosis to be 1.0 (interquartile range 0.0-4.0) years. Univariate analysis suggested that transformed age was associated with an increased risk of total death and disease-specific death (OR = 4.2, 95% CI 3.0-5.9; OR = 4.7, 95% CI 3.2-6.8). Adjusted smoothed plots showed a nonlinear correlation between age and disease-specific death. The risk of disease-specific death did not increase sharply as the age increased until reaching the inflection point (age < 3 years, OR = 0.4, 95% CI 0.2-1.0; age ≥ 3 years, OR = 1.2, 95% CI 0.9-1.5). There was, however, a linear relationship between age and total deaths (OR = 1.0, 95% CI 0.7-1.2). Adjusted multivariate Cox regression analysis showed that ages ≥ 3 years were associated with a significant increased risks of disease-specific death and total death (OR = 2.5, 95% CI 1.7-3.8; OR = 2.3, 95% CI 1.6-3.3, respectively).There was a unimodal age distribution of retroperitoneal neuroblastoma usually presented in infants or younger child. Older age was associated with a lower chance of overall survival and the risk of disease-specific death increased sharply after 3 years of age.


Assuntos
Neuroblastoma/mortalidade , Neoplasias Retroperitoneais/mortalidade , Distribuição por Idade , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neuroblastoma/terapia , Modelos de Riscos Proporcionais , Neoplasias Retroperitoneais/terapia , Estudos Retrospectivos , Programa de SEER/estatística & dados numéricos
4.
Medicine (Baltimore) ; 99(10): e19199, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150058

RESUMO

Neuroblastoma is the most prevalent malignancy in infants characterized by heterogeneous prognosis. It is critical to stratify the risks for patients with neuroblastoma. To stratify the risks for neuroblastoma, clinical characteristics of neuroblastoma patients were retrieved from the Therapeutically Applicable Research to Generate Effective Treatment program. All patients were randomly sampled into the development and validation sets. Cox regression was used to construct a prediction nomogram. The discrimination and calibration capacity of the nomogram was assessed. Prognostic index (PI) was calculated and tested to evaluate the performance of the nomogram. This nomogram demonstrated reasonable discrimination and calibration capacity. The nomogram derived PI exhibited acceptable accuracy in predicting the prognosis for neuroblastoma patients. The overall survival rate was significantly different between the PI discriminated high and low-risk patient subgroups. In conclusion, besides traditional staging systems, some newly defined risk factors could be involved in risk stratification for patients with neuroblastoma. Our nomogram may aid the risk stratification for neuroblastoma patients.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neuroblastoma/diagnóstico por imagem , Nomogramas , Área Sob a Curva , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Pré-Escolar , China , Bases de Dados Factuais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Prognóstico , Reprodutibilidade dos Testes , Risco , Análise de Sobrevida
5.
Am Surg ; 86(2): 127-133, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167055

RESUMO

Adrenal neuroblastoma (NB) is a relatively common malignancy in children. The Surveillance, Epidemiology, and End Results database was used to present demographic data and a survival analysis with the aim of making tumor management better. The Surveillance, Epidemiology, and End Results database was used to search pediatric patients (age ≤16 years) with NB from 2004 to 2013. The Kaplan-Meier method was used to calculate the overall survival. And, we used Cox regression analysis to determine hazard ratios for prognostic variables. Independent prognostic factors were selected into the nomogram to predict individual's three-, five-, and seven-year overall survival. The study included a total of 1870 pediatric patients with NB in our cohort. Overall, three-, five-, and seven-year survival rates for adrenal NB were 0.777, 0.701, and 0.665, respectively, whereas the rates for nonadrenal NB were 0.891, 0.859, and 0.832, respectively. The multivariate analysis identified age >1 year, no complete resection (CR)/CR, radiation, and regional/distant metastasis as independent predictors of mortality for adrenal NB. Concordance index of the nomogram was 0.665 (95% confidence interval, 0.627-0.703). Pediatric patients with adrenal NB have significantly worse survival than those with nonadrenal NB. Adrenal NB with age <1 year, treated with surgery, no radiation, and localized tumor leads to a better survival. There was no survival difference for patients to receive CR and no CR.


Assuntos
Neoplasias das Glândulas Suprarrenais/mortalidade , Neuroblastoma/mortalidade , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Nomogramas , Prognóstico , Análise de Regressão , Programa de SEER/estatística & dados numéricos , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo
6.
J Exp Clin Cancer Res ; 39(1): 41, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087738

RESUMO

BACKGROUND: The oncogene MYCN is critical for tumorigenesis of several types of cancers including neuroblastoma. We previously reported that miR-506-3p repressed MYCN expression in neuroblastoma cells. However, the mechanism underlying such regulation was undetermined since there is no miR-506-3p target site in MYCN 3'UTR. METHODS: By a systematic investigation combining microarray, informatics and luciferase reporter assay, we identified that the transcriptional factor pleiomorphic adenoma gene-like 2 (PLAGL2) is a direct target of miR-506-3p that mediates its regulation on MYCN expression. Using CHIP-PCR and luciferase reporter assay, we validated the transcriptional regulation of MYCN by PLAGL2 and we further demonstrated the transcriptional regulation of PLAGL2 by MYCN. We examined the function of PLAGL2 in regulating neuroblastoma cell fate by cell viability assay, colony formation and Western blotting of differentiation markers. We examined the effect of retinoic acid, the differentiation agent used in neuroblastoma therapy, on miR-506-3p, PLAGL2 and MYCN expressions by quantitative PCR and Western blots. We investigated the clinical relevance of PLAGL2 expression by examining the correlation of tumor PLAGL2 mRNA levels with MYCN mRNA expression and patient survival using public neuroblastoma patient datasets. RESULTS: We found that miR-506-3p directly down-regulated PLAGL2 expression, and we validated a PLAGL2 binding site in the MYCN promoter region responsible for promoting MYCN transcription, thereby establishing a mechanism through which miR-506-3p regulates MYCN expression. Conversely, we discovered that MYCN regulated PLAGL2 transcription through five N-Myc-binding E-boxes in the PLAGL2 promoter region. We further confirmed the reciprocal regulation between endogenous PLAGL2 and MYCN in multiple neuroblastoma cell lines. Moreover, we found that PLAGL2 knockdown induced neuroblastoma cell differentiation and reduced cell proliferation, and combined knockdown of PLAGL2 and MYCN showed a synergistic effect. More strikingly, we found that high tumor PLAGL2 mRNA levels were significantly correlated with high MYCN mRNA levels and poor patient survival in neuroblastoma patients. Furthermore, we found that retinoic acid increased expression of miR-506-3p and repressed expression of MYCN and PLAGL2. CONCLUSIONS: Our findings altogether suggest that the interplay network formed by PLAGL2, MYCN and miR-506-3p is an important mechanism in regulating neuroblastoma cell fate, determining neuroblastoma prognosis, and mediating the therapeutic function of retinoic acid.


Assuntos
Proteínas de Ligação a DNA/genética , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Regiões 3' não Traduzidas , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/metabolismo , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia
8.
J Surg Res ; 249: 8-12, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31918331

RESUMO

BACKGROUND: Pelvic neuroblastomas are rare and often present in children as massive tumors whose surgical resection can be associated with significant morbidity, given sacral nerve root involvement and close proximity to pelvic vascular structures. We sought to examine the characteristics of patients with pelvic neuroblastoma and the effect of extent of surgical resection on survival and surgical outcomes. MATERIALS AND METHODS: After institutional review board approval, a retrospective chart review was performed at Children's Hospital Los Angeles from 2000 to 2018. Collected data included tumor location, size, image-defined risk factors histology, stage and risk classification, amplification of the oncogene MYCN or N-myc, use of preoperative chemotherapy, and extent of surgical resection. Outcome variables included postoperative complications and survival. RESULTS: Ten patients with primary pelvic neuroblastoma tumors were identified. The median age at diagnosis was 4.2 y (3 mo to 11 y). Four patients presented with a localized pelvic tumor (stage I or stage II) and underwent upfront tumor resection. Six patients presented with advanced disease (stage III or stage IV) and underwent neoadjuvant chemotherapy, followed by partial resection (30%-90% debulked). One patient experienced a complication: lower extremity hypotonia after tumor resection. One patient died from extensive metastatic disease for which no resection was attempted. The mean postoperative follow-up was 3.9 y with 90% overall survival. CONCLUSIONS: Our data show that patients who undergo gross total resection for localized pelvic neuroblastoma or neoadjuvant chemotherapy, followed by partial resection for advanced disease have excellent survival. We recommend that small localized pelvic neuroblastoma undergo gross total resection and large unresectable tumors undergo neoadjuvant chemotherapy, followed by partial debulking resection to avoid neurovascular morbidity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Procedimentos Cirúrgicos de Citorredução/métodos , Terapia Neoadjuvante/métodos , Neuroblastoma/terapia , Neoplasias Pélvicas/terapia , Criança , Pré-Escolar , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neoplasias Pélvicas/diagnóstico , Neoplasias Pélvicas/mortalidade , Neoplasias Pélvicas/patologia , Pelve/irrigação sanguínea , Pelve/diagnóstico por imagem , Pelve/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
J Clin Pathol ; 73(3): 154-161, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31542727

RESUMO

AIMS: To investigate the relations between anaplastic lymphoma kinase (ALK) and v-myc myelocytomatosis viral related oncogene neuroblastoma derived homolog (MYCN) protein expression and their prognostic roles in neuroblastoma tumours. METHODS: Sixty-one neuroblastoma tumours obtained at diagnosis were stained with anti-MYCN and anti-ALK antibodies by immunohistochemical staining. The correlations between protein expression of MYCN, ALK and clinicopathological and biological variables of neuroblastoma tumours were analysed. RESULTS: High expression of ALK protein could be detected in 25 (41%) and high expression of MYCN protein could be detected in 24 (39.3%) of the 61 neuroblastoma tumours, respectively. The majority of neuroblastoma tumours with evident of ALK or MYCN protein high expression exhibited undifferentiated or poorly differentiated histology (30/35, 85.7%). ALK or MYCN protein high expression in neuroblastoma tumours was associated with adverse clinical prognostic factors and ALK protein high expression was significantly associated with MYCN protein high expression. In addition, either ALK or MYCN protein high expression in neuroblastoma tumours was the independent adverse prognostic factor and also predicted worse survival outcomes for neuroblastoma patients with MYCN non-amplified status or non-high-risk Children's Oncology Group grouping. CONCLUSIONS: Our study showed a novel coordinately prognostic role of ALK and MYCN protein expression in neuroblastoma and is the first report to demonstrate the correlation between ALK and MYCN protein expression in primary neuroblastoma tumours.


Assuntos
Quinase do Linfoma Anaplásico/análise , Biomarcadores Tumorais/análise , Proteína Proto-Oncogênica N-Myc/análise , Neuroblastoma/enzimologia , Adolescente , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/terapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Regulação para Cima
10.
Pediatr Blood Cancer ; 67(2): e28066, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31736249

RESUMO

OBJECTIVE: This study aims to explore prognostic factors for high-risk neuroblastoma patients with response failure to tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT). METHODS: Survival outcomes were compared according to characteristics at initial diagnosis, at relapse/progression, and after relapse/progression in patients who experienced relapse/progression after tandem HDCT/auto-SCT from 2006 to 2018. RESULTS: Forty-nine patients experienced relapse/progression after tandem HDCT/auto-SCT during the study period: 43 received salvage treatment and 30 underwent allogeneic SCT (allo-SCT) after reinduction treatment. Although all six patients who did not undergo salvage treatment died, 13 of the 43 patients who did remain alive. The 3-year probabilities of event-free survival (EFS) and overall survival (OS) from initial relapse/progression among the 49 patients were 14.4% ± 5.2% and 21.2% ± 6.4%, respectively. A higher neuron-specific enolase (NSE) level (>24 ng/mL) at relapse/progression was an independent prognostic factor for worse OS. Nine of 30 patients who underwent allo-SCT remain alive, and the 3-year probabilities of EFS and OS from allo-SCT were 16.5% ± 7.2% and 21.6% ± 8.3%, respectively. A higher NSE level and no incorporation of high-dose 131 I-metaiodobenzylguanidine (HD-MIBG) treatment into allo-SCT were independent prognostic factors for worse EFS and OS after allo-SCT. CONCLUSION: The results suggest that a higher serum NSE level at relapse/progression is a predictor of worse prognosis in patients with response failure to tandem HDCT/auto-SCT, and that incorporation of HD-MIBG treatment into allo-SCT may improve outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Transplante de Células-Tronco Hematopoéticas/mortalidade , Quimioterapia de Indução/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neuroblastoma/mortalidade , Fosfopiruvato Hidratase/sangue , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neuroblastoma/sangue , Neuroblastoma/patologia , Neuroblastoma/terapia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Transplante Autólogo
11.
PLoS One ; 14(12): e0225998, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31834883

RESUMO

INTRODUCTION: Under the hypothesis that early natural killer cell infusion (NKI) following haploidentical stem cell transplantation (haplo-SCT) will reduce relapse in the early post-transplant period, we conducted a pilot study to evaluate the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed previous tandem high-dose chemotherapy and autologous SCT. METHODS: We used the high-dose 131I-metaiodobenzylguanidine and cyclophosphamide/fludarabine/anti-thymocyte globulin regimen for conditioning and infused 3 × 107/kg of ex-vivo expanded NK cells derived from a haploidentical parent donor on days 2, 9, and 16 post-transplant. Interleukin-2 was administered (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20 post-transplant. RESULTS: Seven children received a total of 19 NKIs, and NKI-related acute toxicities were fever (n = 4) followed by chills (n = 3) and hypertension (n = 3); all toxicities were tolerable. Grade ≥II acute GVHD and chronic GVHD developed in two and five patients, respectively. Higher amount of NK cell population was detected in peripheral blood until 60 days post-transplant than that in the reference cohort. Cytomegalovirus and BK virus reactivation occurred in all patients and Epstein-Barr virus in six patients. Six patients died of relapse/progression (n = 5) or treatment-related mortality (n = 1), and one patient remained alive. CONCLUSION: NKI following haplo-SCT was relatively safe and feasible in patients with recurrent neuroblastoma. Further studies to enhance the graft-versus-tumor effect without increasing GVHD are needed.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Neuroblastoma/imunologia , Neuroblastoma/terapia , Transplante Haploidêntico , Biomarcadores , Contagem de Células , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunofenotipagem , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Quimeras de Transplante , Resultado do Tratamento
12.
J Exp Clin Cancer Res ; 38(1): 498, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856871

RESUMO

BACKGROUND: The MYCN amplification is a defining hallmark of high-risk neuroblastoma. Due to irregular oncogenes orchestration, tumor cells exhibit distinct fatty acid metabolic features from non-tumor cells. However, the function of MYCN in neuroblastoma fatty acid metabolism reprogramming remains unknown. METHODS: Gas Chromatography-Mass Spectrometer (GC-MS) was used to find the potential target fatty acid metabolites of MYCN. Real-time PCR (RT-PCR) and clinical bioinformatics analysis was used to find the related target genes. The function of the identified target gene ELOVL2 on cell growth was detected through CCK-8 assay, Soft agar colony formation assay, flow Cytometry assay and mouse xenograft. Chromatin immunoprecipitation (ChIP) and Immunoprecipitation-Mass Spectrometer (IP-MS) further identified the target gene and the co-repressor of MYCN. RESULTS: The fatty acid profile of MYCN-depleted neuroblastoma cells identified docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid with anti-tumor activity, significantly increased after MYCN depletion. Compared with MYCN single-copy neuroblastoma cells, DHA level was significantly lower in MYCN-amplified neuroblastoma cells. RT-PCR and clinical bioinformatics analysis discovered that MYCN interfered DHA accumulation via ELOVL fatty acid elongase 2 (ELOVL2) which is a rate-limiting enzyme of cellular DHA synthesis. Enforced ELOVL2 expression in MYCN-amplified neuroblastoma cells led to decreased cell growth and counteracted the growth-promoting effect of MYCN overexpression both in vitro and vivo. ELOVL2 Knockdown showed the opposite effect in MYCN single-copy neuroblastoma cells. In primary neuroblastoma, high ELOVL2 transcription correlated with favorable clinical tumor biology and patient survival. The mechanism of MYCN-mediated ELOVL2 inhibition contributed to epigenetic regulation. MYCN recruited PRC1 (Polycomb repressive complex 1), catalysed H2AK119ub (histone 2A lysine 119 monoubiquitination) and inhibited subsequent ELOVL2 transcription. CONCLUSIONS: The tumor suppressive properties of DHA and ELOVL2 are repressed by the MYCN and PRC1 jointly, which suggests a new epigenetic mechanism of MYCN-mediated fatty acid regulation and indicates PRC1 inhibition as a potential novel strategy to activate ELOVL2 suppressive functions.


Assuntos
Ácidos Docosa-Hexaenoicos/biossíntese , Elongases de Ácidos Graxos/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Histonas/metabolismo , Humanos , Camundongos , Modelos Biológicos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Complexo Repressor Polycomb 1/genética
13.
Zhonghua Er Ke Za Zhi ; 57(11): 863-869, 2019 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-31665841

RESUMO

Objective: To analyze the clinical characteristics of newly treated high-risk group neuroblastoma (NB) patients with bone marrow metastasis and to explore the prognostic factors. Methods: The clinical features (sex, age, stage, risk group, pathological type, metastatic site, etc.) of 203 newly treated high-risk NB patients with bone marrow metastasis admitted to Hematology Oncology Center, Beijing Children's Hospital from January 2007 to December 2016 were analyzed retrospectively. There were 118 males (58.1%) and 85 females (41.9%). Kaplan-Meier method was used for survival analysis and Cox regression was used to analyze the prognostic factors. Results: The age at onset of the 203 patients was 41 months (9-147 months). The metastatic sites at diagnosis were as follows: bone in 195 cases (96.1%), distant lymph nodes in 104 cases (51.2%), skull and endomeninx in 61 cases (30.0%), orbit in 30 cases (14.8%), pleura in 16 cases (7.9%), liver in 13 cases(6.4%), canalis spinalis in 13 cases (6.4%), other sites in 11 cases (5.4%) and skin and soft tissue in 10 cases (4.9%). In all, 194 cases were enrolled for prognostic analysis. The follow-up time was 36 months (1 day-138 months) , and the 5-years event free survival (EFS) and overall survival (OS) were 36.1% and 39.7%, respectively. A total of 118 patients (60.8%) had events (first relapse or death) with the time to event occurrence was 15 months (1 day-72 months), whereas 112 patients (57.7%) died with the event occurrence to death time was 3 months (1 day-21 months). There was no significant difference in 5-years OS between radiotherapy group and non-radiotherapy group (42.3% vs. 38.3%, χ(2)=3.671, P=0.055). The 5-years OS in transplantation group was significantly better than the non-transplantation group (44.3% vs. 35.5%, χ(2)=8.878, P=0.003), and the radiotherapy combined transplantation group also had a better 5-years OS rate than the non-radiotherapy combined transplantation group (45.8% vs. 37.3%, χ(2)=5.945, P=0.015). Univariate survival analysis showed lactate dehydrogenase ≥ 1 500 U/L, the amplification of MYCN, the metastatic sites of orbit, canalis spinalis and pleura were associated with poor prognosis of newly diagnosed high-risk NB patients (χ(2)=21.064, 13.601, 3.998, 6.183, 15.307, all P<0.05). The amplification of MYCN and the metastatic sites of pleura were risk factors for prognosis of newly diagnosed high-risk NB patients by Cox regression models (HR=1.896,1.100, 95%CI: 1.113-3.231, 1.020-1.187, both P<0.05). Conclusions: The prognosis is unfavorable in high-risk group NB patients with BM metastasis. Radiotherapy combined with transplantation can further improve the prognosis of these patients. The amplification of MYCN and the metastatic sites of pleura were the poor prognostic factors for high-risk NB patients with bone marrow metastasis.


Assuntos
Neoplasias da Medula Óssea/patologia , Neuroblastoma/patologia , Neoplasias da Medula Óssea/mortalidade , Neoplasias da Medula Óssea/radioterapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Metástase Neoplásica , Neuroblastoma/mortalidade , Neuroblastoma/radioterapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
14.
Medicina (B Aires) ; 79(4): 280-283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31487248

RESUMO

The purpose of the study was to evaluate the outcome of patients under 18 months diagnosed with neuroblastoma. Between April 2006 and December 2013, 45 consecutive patients followed in Hospital de Pediatría Garrahan, were retrospectively reviewed. With a median age of 9.3 months (1-18 months) N-myc amplification was detected in 5 out of 38 patients, 1p deletion (del1p) in 4 patients, and 11q aberration in one patient. With a median follow-up of 53 (range: 6-109 months), at 24 months the event free survival (EFS) of all patients was 83% (SE 6%) and overall survival (OS) of 88% (SE 5%). Significant difference was found in OS and EFS between patients with stages L1, L2 and Ms vs. stage M (p = 0.01 and p = 0.01 respectively). EFS for each stage: L1 85% (SE 7%), L2 100%, MS 100%, vs. M 55% (SE 16%). OS: L1 90% (SE 6%), L2 100%, MS 100%, vs. M 66% (SE 15%). OS and EFS results are similar to those reported in international studies. However, better identification of biological prognostic factors will warr ant accurate staging and consequently an appropriate treatment.


Assuntos
Antineoplásicos/administração & dosagem , Neuroblastoma/diagnóstico , Neuroblastoma/tratamento farmacológico , Protocolos Antineoplásicos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Prognóstico , Estudos Retrospectivos
15.
Int J Mol Sci ; 20(19)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557970

RESUMO

Neuroblastoma (NB) is an aggressive, relapse-prone infancy tumor of the sympathetic nervous system and is the leading cause of death among preschool age diseases, so the search for novel therapeutic targets is crucial. Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development, and in the DNA damage response, of various human cancers. Golgi dispersal is a common feature of DNA damage response in mammalian cells. Understanding how cells react to DNA damage is essential in order to recognize the systems used to escape from elimination. We induced DNA damage in two human neuroblastoma cell lines by curcumin. The exposure of neuroblastoma cells to curcumin induced: (a) up-regulation of GOLPH3+ cells; (b) augmentation of double-strand breaks; (c) Golgi fragmentation and dispersal throughout the cytoplasm; (d) increase of apoptosis and autophagy; (e) increased expression of TPX2 oncoprotein, able to repair DNA damage. Primary neuroblastoma samples analysis confirmed these observations. Our findings suggest that GOLPH3 expression levels may represent a clinical marker of neuroblastoma patients' responsiveness to DNA damaging therapies-and of possible resistance to them. Novel molecules able to interfere with GOLPH3 and TPX2 pathways may have therapeutic benefits when used in combination with standard DNA damaging therapeutic agents in neuroblastoma.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Biomarcadores Tumorais , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Curcumina/farmacologia , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Lactente , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Transporte Proteico , Resultado do Tratamento
16.
J Pediatr Surg ; 54(12): 2589-2594, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31522796

RESUMO

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in childhood. In this work, the clinical value of long noncoding RNA LINC01296 was evaluated in patients with neuroblastoma. METHODS: LncRNA microarray was conducted to identify differentially expressed lncRNAs in 5 early stage and 5 advanced stage tumor tissues of neuroblastoma. RT-qPCR was carried out to validate the result of microarray. Clinical information was reviewed to analyze the relationship between lncRNA and clinical characteristics. The public database R2 was used to analyze prognosis. RESULTS: 765 differentially expressed lncRNAs were identified. LINC01296 was the most overexpressed lncRNA in advanced stage patients. RT-qPCR was conducted in 28 tumor tissues, confirming the tendency with microarray. Higher expression of LINC01296 was associated with age > 18 months (p = 0.004) and advanced stage (p = 0.021). Furthermore, LINC01296 was correlated with tumor size (r = 0.4060, p = 0.0321), LDH level (r = 0.6904, p = 0.0002), and NSE level (r = 0.5772, p = 0.0013). The neuroblastoma dataset shows patients with overexpression of LINC01296 obtained a shorter overall survival than low expression (n = 88, log-rank: P < 0.0001). CONCLUSION: LINC01296 is associated with clinical characteristics of neuroblastoma and may function as a prognostic predictor. LEVEL OF EVIDENCE: II.


Assuntos
Neuroblastoma , RNA Longo não Codificante , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Neuroblastoma/epidemiologia , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Prognóstico , RNA Longo não Codificante/análise , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
17.
Pediatr Blood Cancer ; 66(11): e27944, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31368239

RESUMO

BACKGROUND: Outcome data for neuroblastoma in sub-Saharan Africa are minimal, whereas poor outcome is reported in low- and middle-income countries. A multi-institutional retrospective study across South Africa was undertaken to determine outcome. METHODS: Patients treated between January 2000 and December 2014 in nine South African pediatric oncology units were included. Kaplan-Meier curves and Cox regression models were employed to determine two-year survival rates and to identify prognostic factors. RESULTS: Data from 390 patients were analyzed. The median age was 39.9 months (range, 0-201 months). The majority presented with stage 4 disease (70%). The main chemotherapy regimens were OPEC/OJEC (44.8%), St Jude NB84 protocol (28.96%), and Rapid COJEC (22.17%). Only 44.4% had surgery across all risk groups, whereas only 16.5% of high-risk patients received radiotherapy. The two-year overall survival (OS) for the whole cohort was 37.6%: 94.1%, 81.6%, and 66.7%, respectively, for the very-low-risk, low-risk, and intermediate-risk groups and 27.6% for the high-risk group (P < 0.001, 95% CI). The median survival time for the whole group was 13 months (mean, 41.9 months; range, 0.1-209 months). MYCN-nonamplified patients had a superior two-year OS of 51.3% in comparison with MYCN-amplified patients at 37.3% (P = 0.002, 95% CI). CONCLUSIONS: Limited disease had an OS comparable with high-income countries, but advanced disease had a poor OS. South Africa should focus on early diagnosis and implementation of a national protocol with equitable access to treatment.


Assuntos
Neuroblastoma/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Comorbidade , Procedimentos Cirúrgicos de Citorredução , Países em Desenvolvimento , Amplificação de Genes , Genes myc , Acesso aos Serviços de Saúde , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico , Neuroblastoma/patologia , Neuroblastoma/terapia , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia/métodos , Estudos Retrospectivos , África do Sul/epidemiologia , Transplante de Células-Tronco , Taxa de Sobrevida , Transplante Autólogo
18.
Biol Direct ; 14(1): 16, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443736

RESUMO

BACKGROUND: Neuroblastoma is one of the most common types of pediatric cancer. In current neuroblastoma prognosis, patients can be stratified into high- and low-risk groups. Generally, more than 90% of the patients in the low-risk group will survive, while less than 50% for those with the high-risk disease will survive. Since the so-called "high-risk" patients still contain patients with mixed good and poor outcomes, more refined stratification needs to be established so that for the patients with poor outcome, they can receive prompt and individualized treatment to improve their long-term survival rate, while the patients with good outcome can avoid unnecessary over treatment. METHODS: We first mined co-expressed gene modules from microarray and RNA-seq data of neuroblastoma samples using the weighted network mining algorithm lmQCM, and summarize the resulted modules into eigengenes. Then patient similarity weight matrix was constructed with module eigengenes using two different approaches. At the last step, a consensus clustering method called Molecular Regularized Consensus Patient Stratification (MRCPS) was applied to aggregate both clinical information (clinical stage and clinical risk level) and multiple eigengene data for refined patient stratification. RESULTS: The integrative method MRCPS demonstrated superior performance to clinical staging or transcriptomic features alone for the NB cohort stratification. It successfully identified the worst prognosis group from the clinical high-risk group, with less than 40% survived in the first 50 months of diagnosis. It also identified highly differentially expressed genes between best prognosis group and worst prognosis group, which can be potential gene biomarkers for clinical testing. CONCLUSIONS: To address the need for better prognosis and facilitate personalized treatment on neuroblastoma, we modified the recently developed bioinformatics workflow MRCPS for refined patient prognosis. It integrates clinical information and molecular features such as gene co-expression for prognosis. This clustering workflow is flexible, allowing the integration of both categorical and numerical data. The results demonstrate the power of survival prognosis with this integrative analysis workflow, with superior prognostic performance to only using transcriptomic data or clinical staging/risk information alone. REVIEWERS: This article was reviewed by Lan Hu, Haibo Liu, Julie Zhu and Aleksandra Gruca.


Assuntos
Redes Reguladoras de Genes , Neuroblastoma/genética , Transcriptoma , Criança , Pré-Escolar , Análise por Conglomerados , Biologia Computacional , Humanos , Lactente , Recém-Nascido , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Prognóstico , Análise de Sobrevida
19.
Exp Oncol ; 41(2): 179-181, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31262150

RESUMO

The article represents current literature data on epidemiological, clinical-morphological features and diagnostic criteria of neuroblastoma. The case of large congenital neuroblastoma with multiple metastases in the newborn child is presented. The histological picture and immunohistochemical profile of the tumor allowed us to consider this type of neuroblastoma as the least differentiated variant (subtype, "neuroblastoma rich in Schwann stroma"), with rapid progression and metastasizing started before the birth of the child.


Assuntos
Neuroblastoma/congênito , Neuroblastoma/patologia , Neoplasias Retroperitoneais/congênito , Neoplasias Retroperitoneais/patologia , Feminino , Humanos , Recém-Nascido , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Neoplasias Retroperitoneais/terapia
20.
Cochrane Database Syst Rev ; 4: CD012442, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31016728

RESUMO

BACKGROUND: Neuroblastoma is a rare malignant disease that primarily affects children. The tumours mainly develop in the adrenal medullary tissue, and an abdominal mass is the most common presentation. High-risk disease is characterised by metastasis and other primary tumour characteristics resulting in increased risk for an adverse outcome. The GD2 carbohydrate antigen is expressed on the cell surface of neuroblastoma tumour cells and is thus a promising target for anti-GD2 antibody-containing immunotherapy. OBJECTIVES: To assess the efficacy of anti-GD2 antibody-containing postconsolidation immunotherapy after high-dose chemotherapy (HDCT) and autologous haematopoietic stem cell transplantation (HSCT) compared to standard therapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. Our primary outcomes were overall survival and treatment-related mortality. Our secondary outcomes were progression-free survival, event-free survival, early toxicity, late non-haematological toxicity, and health-related quality of life. SEARCH METHODS: We searched the electronic databases CENTRAL (2018, Issue 9), MEDLINE (PubMed), and Embase (Ovid) on 20 September 2018. We searched trial registries and conference proceedings on 28 October 2018. Further searches included reference lists of recent reviews and relevant articles as well as contacting experts in the field. There were no limits on publication year or language. SELECTION CRITERIA: Randomised controlled trials evaluating anti-GD2 antibody-containing immunotherapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, abstracted data on study and participant characteristics, and assessed risk of bias and GRADE. Any differences were resolved by discussion, with third-party arbitration unnecessary. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, that is study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. MAIN RESULTS: We identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin.The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate. AUTHORS' CONCLUSIONS: The evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Neuroblastoma/terapia , Criança , Quimioterapia de Consolidação , Intervalo Livre de Doença , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neuroblastoma/imunologia , Neuroblastoma/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto
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