This nonrandomized, multi center cohort, open label clinical trial evaluated theefficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in childrenwith stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosedwith NB and assessed as stage 4/M and received either traditional chemotherapy or ATOcombined with chemotherapy according to their own wishes. Twenty two patients wereenrolled i n the trial group (ATO combined with chemotherapy) and thirteen patientswere enrolled in the control group (traditional chemotherapy). Objective response rate(ORR) at 4 weeks after completing induction chemotherapy was defined as the mainoutcome and adv erse events were monitored and graded in the meantime. Data cutoffdate was Dec. 31, 2019. Finally, we found that p patients who received ATO combined with chemotherapy had a significantly higher response rate than those who treated with traditional chemotherapy (ORR: 86.36% vs 46.16%, P=0.020). Reversible cardiotoxicity was just observed in 3 patients who treated with ATO and no other differential adverse events were observed between two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk neuroblastoma and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with arsenic trioxide, which creates new opportunity for prolonging survival. Besides, this treatment protocol furthest minimizes therapeutic costs compared with anti-GD2 therapy, MIBG and proton therapy, and can decrease the burden to families and society. However, we also need to bring into more cases to consolidate our conclusion.
Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations.
Background. Neuroblastoma (NB) is one of the most common extracranial tumors with limited therapeutic options. Retinoic acid (RA) has been identified to play anticancer role against NB cells by inducing the differentiation and apoptosis of immature neuroblasts. However, silencing HoxC9 promoter by EZH2-induced H3K27me3 hypermethylation can lead to RA resistance. Previous studies have suggested that arsenic trioxide (ATO), an inhibitor of DNA methylation, could downregulate the expression of EZH2 in breast cancer cells.Objectives. In our study, we attempted to obtain some insight into the mechanisms of differentiation of RA-resistant NB cells by detecting the expressions of HoxC9 and EZH2 in NB cells treated with ATO, so as to provide a basis for the subsequent treatment of RA-resistant NB by ATO. Materials and methods.Two NB cell lines, SK-N-AS (retinoic acid-resistant neuroblastoma cells) and SK-N-SH (retinoic acid-sensitive neuroblastoma cells), were used in our experiments. Cell proliferation and apoptosis were respectively determined with Cell Counting Kit-8 (CCK-8) assay kit and Annexin V staining. The inverted phase contrast microscope was used to observe cell growth and measure the total length of nerve synapses. We employed label-free quantitative proteomic analysis to profile ATO-dependent changes in the proteome of NB cells. Western blot was used to detect the expressions of HoxC9, HoxD8 and EZH2.Results. Arsenic trioxide inhibited the cell proliferation and increased apoptosis and total length of synapses in two NB cell lines. The expressions of HoxC9 and HoxD8 were upregulated, while the expression of EZH2 was downregulated in the SK-N-AS cell line. No significant changes in the 3 proteins mentioned above were observed in the SK-N-SH cell line after ATO treatment.Conclusions. Arsenic trioxide may reactivate the expression of HoxC9 by downregulating EZH2, which leads to restoring RA sensitivity and promoting the differentiation and apoptosis of RA-resistant NB cells.
BackgroundAlveolar rhabdomyosarcoma (ARMS) is a subtype of rhabdomyosarcoma characterized by its aggressive behavior and poor prognosis, highlighting the need for novel treatment options. Arsenic trioxide (ATO) has been shown to specifically inhibit tumor growth and the metastasis of ARMS in vitro by acting on the hedgehog pathway. Here we report on a pilot clinical study to evaluate the activity of an ATO-combined chemotherapy approach for the treatment of ARMS patients.MethodsWe designed a therapeutic schedule of an ATO-combined chemotherapy, incorporating comprehensive management according to the Intergroup Rhabdomyosarcoma Study Group protocol. ATO was administered at 0.16 mg/kg per day over 8 h via an IV for 10 days combined with a chemotherapeutic regimen of vincristine, actinomycin, and cyclophosphamide (VAC regimen) on the third day, which was repeated every 21 days. A total of eight cycles of ATO-combined chemotherapy were applied throughout the entire scheme.ResultsA total of three refractory/recurrent and one untreated ARMS patient, three male and one female, with a median age of 5.8 years (range, 5.1 to 12.5 years), were enrolled in the present study. All patients were sensitive to combined chemotherapy with ATO and achieved partial or complete remission during treatment. Except for reversible gastrointestinal reaction and myelosuppression, no other adverse events were observed during the process of treatment.ConclusionsThe combined chemotherapy of ATO and the VAC regimen exhibited beneficial activities against ARMS in pediatrics and was well tolerated, but prospective large-scale clinical trials are warranted to determine the long-term efficacy, optimal courses, and late toxicity in this population.
Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.
Background Neuroblastoma (NB) is a childhood malignant tumor,50% of high-risk NB children still have recurrence, and the long-term survival rate is very low. NB tumors expressing high levels of BDNF/TrkB are associated with poor survival outcomes.In this study, we show that the trends of serum concentration of BDNF at different growth stages after birth, and explore the relationship with NB replase. Methods In experiment 1, 87 subjects were enrolled and divided into four groups, neonates group、 children group、adults group and NB patients. The distribution of serum concentration of BDNF by ELISA. In experiment 2, we studied BDNF in stage 4 NB patients to determine their frequency, correlation with clinical parameters, and prognostic impact. Results First, we identified that serum BDNF concentration decreased from the newborn to childhood in healthy subjects, while it was relatively high in children(age > 1 year) with NB. In the second phase our studies showed no significant increase in serum BDNF concentration in these NB patients, with adverse pathologic features, large tumor maximum diameter, and MYCN amplification. After comprehensive treatment, levels of BDNF gradually increased in children with recurrence and decreased in the remission group. High serum BDNF concentration was associated with relapse. Of 21 stage 4 neuroblastoma patients, adopted a comprehensive treatment approach including ATO-basic modified chemotherapy, traditional radiotherapy,stem cell transplatation and immunotherapy. 76% of alive patients having > 3 years follow-up. Conclusion:The aim is to show that BDNF is a predictor of recurrence risk of NB.
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