The Diagnostic And Therapeutic Value Of Serum Neuron-specific Enolase In High-risk Neuroblastoma

Objective Neuroblastoma(NB)is a malignant solid tumor in childhood which is characterized by remarkable heterogeneity.Treatment based on risk-group embodies the principle of individual therapy,which significantly improves the effect and reduces the toxicity of treatment.However,long-term survival is still less than 50% in the high-risk group.It is not the primary tumor that affects long-term survival,but the recurrence of the tumor.Because it is difficult to obtain serial tumor biopsies,at the same time,imaging examination has radioactive hazard,current risk stratification methods mainly focus on pretreatment factors.Serum neuron-specific enolase(NSE)is one of the tumor markers of NB,which can be continuously collected during treatment to reflect the change of tumor burden and therapeutic response.In this study,the early change of serum NSE in treatment were monitored dynamically to explore its application value in NB diagnosis and treatment.Methods Clinicopathological data of 155 children with a confirmed diagnosis of neuroblastoma at Tianjin Medical University Cancer Institute and Hospital from September 30,2011 to September 11,2019 were collected.The value of serum NSE in NB treatment was discussed from the following aspects:1.A comparative study on analysis of serum NSE and urine vanillymandelic acid(VMA)levels in children with different clinical features: Including age,gender,tumor size and location,pathological pattern,International Neuroblastoma Staging System staging(INSS),risk grouping,metastasis,MYCN gene amplification,and image-defined risk factors(IDRFs).Differences between groups were compared using a nonparametric rank-sum test.P-value <0.05 was considered statistically significant.2.Comparison of the diagnostic value between serum NSE and urine VMA in children at high risk:Receiver operating characteristic(ROC)curves and prediction models were used to determine the accuracy of serum NSE and urine VMA in identifying high-risk children.3.Early decline of neuron-specific enolase during neuroblastoma chemotherapy is a predictive factor of clinical outcome: A line chart was drawn to illustrate the changing trend of early serum NSE level in patients with progress/relapsed and those non-progress/relapsed.Meanwhile,the level of early NSE was correlated with the therapeutic effect.Survival analysis was used to find out the independent risk factors which affected Event-free survival(EFS)and Overall survival(OS).Results1.A comparative study on analysis of serum NSE and urine vanillymandelic acid(VMA)levels in children with different clinical features: Serum NSE and urine VMA levels were significantly increased in children with an INSS stage 4 classification,a COG high-risk grouping,metastases,and with presence of IDRFs(P<0.05).Specifically,the NSE level was significantly higher in children with tumors >500 cm3,an unfavorable prognosis based on the International Neuroblastoma Pathologic(INPC),a pathological pattern of neuroblastoma,and a retroperitoneal primary tumor focus than in children of other groups(P<0.001).2.Comparison of the diagnostic value between serum NSE and urine VMA in children at high risk: The ROC curves revealed that a serum NSE cut-off level of 98.50 ng/m L with an area under the curve(AUC)of 0.943(95%confidence interval [CI],0.906-0.991)and a urine VMA cut-off level of62.28 μmol/24 h with an AUC of 0.791(95% CI,0.705-0.878)could identify high-risk children.When the two indicators were combined to identify high-risk children,the AUC was 0.948(95% CI,0.900-0.997).3.Early decline of neuron-specific enolase during neuroblastoma chemotherapy is a predictive factor of clinical outcome: During the first 3cycles of chemotherapy,serum NSE consistently remained at lower level in patients with non-progress/relapsed than with progress/relapsed.At the end of the third cycle of chemotherapy(C3),serum NSE was at a higher level in patients with stable disease(SD)and positive bone marrow metastasis.The2-year EFS and OS of patients whose C3 NSE were higher than 20.89ng/ml were 30.6%(95% CI 20.9%–40.1%)and 51.3%(95% CI 44.2%–61.4%),respectively.In multivariable analysis,only C3 serum NSE was a significant independent predictive factor for EFS and OS.Conclusion Compared with urine VMA,serum NSE levels correlated with more clinical features of neuroblastoma;thus,serum NSE could better assist in the diagnosis and evaluation of the disease by providing more comprehensive results.While both serum NSE and urine VMA levels are significantly higher in high-risk children,the accuracy,sensitivity,and specificity of serum NSE are all higher than those of urine VMA in identifying high-risk children.A combination of the two indicators does not improve diagnostic accuracy.In high-risk group,C3 NSE is not only related with the early change of tumor burden and therapeutic response,but also an independent prognostic factors for relapsed NB.After three cycles of chemotherapy,Patients whose serum NSE remain at higher level need to take more intensive treatment as early as possible to resist recurrence.