[Effect of Low-Dose Recombinant Interleukin-2 Therapy on Immunocyte Subsets in Children with Solid Tumor].

OBJECTIVE: To evaluate the effect of low-dose recombinant interleukin-2 (rIL-2) therapy on immunocyte subsets and its side effects in children with solid tumor. METHODS: A total of 22 children (11 males and 11 females) with solid tumor in our department from December 2012 to November 2017 were selected, with a median age of 9 (3-16) years old when starting IL-2 therapy. ALL surgeries and chemotherapy of children had been completed before low-dose rIL-2 therapy, and 17 cases achieved complete remission (CR) and 5 cases achieved partial remission (PR). A low-dose rIL-2 therapy was given 1 month after chemotherapy for 1 year: 4×105 IU/(m2·d), s.c. for every other day, 3 times per week. The immunocyte subsets were detected every 3 months until the end of treatment, meanwhile, disease condition and therapy-related side effects were followed up. RESULTS: After low-dose rIL-2 therapy in 22 children, the absolute values of CD3+ T cells, CD3-CD56+ natural killer cells, CD3+CD4+ helper T cells (Th) and CD3+CD8+ cytotoxic T cells were up-regulated remarkably, as well as Th/suppressor T cells (all P < 0.05). While, there were no significant differences in absolute value and proportion of CD4+CD25+CD127- Treg cells during therapy. Among the 17 children who achieved CR before rIL-2 therapy, 14 cases continued to maintain CR after therapy, while 3 cases relapsed, and with 2 died after treatment abandonment. The 5 children who achieved PR before low-dose rIL-2 therapy were evaluated CR by PET/CT scan after treatment. In the early stage of low-dose rIL-2 therapy, 1 child developed skin rashes at the injection sites, and 2 children ran a slight to mild transient fever. Their symptoms disappeared without any organ damage after symptomatic treatment. CONCLUSION: Low-dose rIL-2 therapy has good drug tolerance, and changes the distribution of anti-tumor immune-cell subgroup in peripheral blood of children with solid tumor remarkably without up-regulation of absolute value and ratio of Treg cells.

Local Treatment of Children Suffering From Parameningeal Rhabdomyosarcoma: A Retrospective Single-Center Study From China.

BACKGROUND: Treatment for parameningeal rhabdomyosarcoma (PM-RMS) has been a challenge since local control is difficult. The goal of this study was to analyse the impact of different local treatment approaches on childhood PM-RMS patients and help dispel the doubt that whether secondary radical surgery (SRS) should be encouraged in the management of PM-RMS. METHODS: A total of 17 children with PM-RMS who received unified systemic chemotherapy and individualized local therapy such as radiotherapy (RT) and/or SRS were included in this retrospective study. The overall survival (OS) and event free survival (EFS) were compared between groups adopting different local strategies. RESULTS: The 3-year OS and EFS of our PM-RMS patients was 75.5% and 56.5% respectively. The OS and EFS of patients who received SRS were both significantly lower than that of the non-SRS group (3-year OS: 50.0% vs 90.0%, P = .031; 3-year EFS: 33.3% vs 60.6%, P = .020). The OS and EFS of the patients who received RT was higher than that of the patients of the non-RT group (3-year OS: 85.6% vs 0%, P = .001; 3-year EFS: 64.0% vs 0%, P = .011). CONCLUSION: This study illustrates that SRS was associated with poor prognosis of PM-RMS and should not be routinely performed. Optimized RT strategies along with more intensive chemotherapy may be alternative options to improve the survival of patients with PM-RMS. Multi-center, large sample and prospective studies are needed to further validate these findings.

Influence of Calcareous Deposits on Hydrogen Embrittlement Susceptibility of Q460 Steel.

Cathodic protection is widely used to protect structural steel from corrosion in marine environments. However, an inappropriate cathodic potential may lead to hydrogen embrittlement (HE). Therefore, this study investigates the relationship between cathodic protection potential, structure and composition of calcareous deposits, and hydrogen embrittlement susceptibility of Q460 steel. The slow strain rate test results and fracture analysis reveal that Q460 steel had the smallest HE susceptibility when covered with the calcareous deposits formed under -1.1 VSCE. The deposits have a relatively thin calcium-rich inner layer and a condensed magnesium-rich outer layer, which can significantly inhibit hydrogen entry. A sustained deposition reaction during slow strain rate testing (SSRT) in artificial seawater can also decrease the HE susceptibility of Q460 steel.

Arsenic trioxide induces ferroptosis in neuroblastoma by mediating GPX4 transcriptional inhibition.

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, significantly contributes to cancer-related mortality, presenting a dearth of efficacious treatment strategies. Previously, our studies have substantiated the potent cytotoxicity of arsenic trioxide (ATO) against NB cells, however, the specific underlying mechanism remains elusive. Here, we first identified ATO as a novel GPX4 inhibitor, which could trigger the ferroptosis in NB cells. In vitro, ATO significantly inhibited the proliferation and migration ability of NB cells SK-N-AS and SH-SY5Y, and induced ferroptosis. Furthermore, the iron chelator deferoxamine reversed ATO-mediated intracellular reactive oxygen species accumulation and hindered the generation of the lipid peroxidation product malondialdehyde. Conversely, ferric ammonium citrate notably intensified its cytotoxic effects, especially on retinoic acid (RA)-resistant SK-N-AS cells. Subsequently, the quantitative real-time polymerase chain reaction results showed ATO significantly inhibited the transcription of GPX4 in NB cells. Remarkably, immunoblotting analysis revealed that MG132 exhibited a notable effect on elevating GPX4 levels in NB cells. Nevertheless, pretreatment with MG132 failed to reverse the ATO-mediated decrease in GPX4 levels. These findings suggested that ATO reduced the GPX4 expression level in NB cells by mediating GPX4 transcriptional repression rather than facilitating ubiquitinated degradation. In conclusion, our research has successfully indicated that ATO could induce ferroptosis and initiate lipid peroxidation by regulating the transcriptional repression of GPX4, and ATO holds promise as a potential anti-tumor agent in NB, specifically for patients with RA-resistant HR-NB.

AURKA inhibition induces Ewing's sarcoma apoptosis and ferroptosis through NPM1/YAP1 axis.

Ewing's sarcoma (ES) is a rare and highly aggressive malignant tumor arising from bone and soft tissue. Suffering from intractable or recurrent diseases, the patients' therapy options are very limited. It is extremely urgent to identify novel potential therapeutic targets for ES and put them into use in clinical settings. In the present study, high-throughput screening of a small molecular pharmacy library was performed. The killing effect of the Aurora kinase A (AURKA) inhibitor TCS7010 in ES cells was identified, and AURKA was selected as the research object for further study. Disparate suppressants were adopted to study the cell death manner of TCS7010. TCS7010 and RNA silencing were used to evaluate the functions of AURKA in the apoptosis and ferroptosis of ES cells. Co-immunoprecipitation assay was used to investigate the correlation of AURKA and nucleophosmin1 (NPM1) in ES. Nude-mice transplanted tumor model was used for investigating the role of AURKA in ES in vivo. Investigations into the protein activities of AURKA were conducted using ES cell lines and xenograft models. AURKA was found to be prominently upregulated in ES. The AURKA expression level was remarkably connected to ES patients' shorter overall survival (OS) and event-free survival (EFS). Furthermore, AURKA inhibition markedly induced the apoptosis and ferroptosis of ES cells and attenuated tumorigenesis in vivo. On the part of potential mechanisms, it was found that AURKA inhibition triggered the apoptosis and ferroptosis of ES cells through the NPM1/Yes1 associated transcriptional regulator (YAP1) axis, which provides new insights into the tumorigenesis of ES. AURKA may be a prospective target for clinical intervention in ES patients.

SARS-CoV-2 Neutralization by Cell Membrane-Coated Antifouling Nanoparticles.

The global outbreak of the COVID-19 pandemic has indisputably wreaked havoc on societies worldwide, compelling the scientific community to seek urgently needed therapeutic agents with low-cost and low-side effect profiles. Numerous approaches have been investigated in the quest to prevent or treat COVID-19, but many of them exhibit unwelcome side effects, such as dysfunctional viral immune responses and inflammation. Herein, we present the preparation of solid natural human pulmonary alveolar epithelial cell (ATII) membrane-coated PLGA NPs (PLGA NPs@ATII-M), which demonstrate remarkable affinity and competitiveness to neutralize the SARS-CoV-2 S1 protein-coated NPs (SCMMA NPs-S1), which are employed as a surrogate for coronavirus particles. In addition, we first considered the antifouling properties of these types of NPs, and we found that this membrane-coated NP formulation boasts excellent antifouling capabilities, which serve to protect their neutralization properties out of shielding by protein coronas in blood circulation. Moreover, this formulation is easily prepared and stored with a low-cost profile and exhibits good specificity, high targeting efficiency, and potentially side effect avoiding, thus making it a highly promising candidate for COVID-19 treatment.

Nano-induced endothelial leakiness-reversing nanoparticles for targeting, penetration and restoration of endothelial cell barrier.

Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. STATEMENT OF SIGNIFICANCE.

Arsenic Trioxide inhibits Activation of Hedgehog Pathway in Human Neuroblastoma Cell Line SK-N-BE(2) Independent of Itraconazole.

BACKGROUND: Neuroblastoma (NB) remains associated with a low overall survival rate over the long term. Abnormal activation of the Hedgehog (HH) signaling pathway can activate the transcription of various downstream target genes that promote NB. Both arsenic trioxide (ATO) and itraconazole (ITRA) can inhibit tumor growth. OBJECTIVE: To determine whether ATO combined with ITRA can be used to treat NB with HH pathway activation, we examined the effects of ATO and ITRA monotherapy or combined inhibition of the HH pathway in NB. METHODS: Analysis of CCK8 and flow cytometry showed cell inhibition and cell cycle, respectively. Real-time PCR analysis was conducted to assess the mRNA expression of HH pathway. RESULTS: We revealed that as concentrations of ATO and ITRA increased, the killing effects of both agents on SK-N-BE(2) cells became more apparent. During G2/M, the cell cycle was largely arrested by ATO alone and combined with ITRA, and in the G0/G1 phase by ITRA alone. In the HH pathway, ATO inhibited the transcription of the SHH, PTCH1, SMO and GLI2 genes, however, ITRA did not. Instead of showing synergistic effects in a combined mode, ITRA decreased ATO inhibitory effects. CONCLUSION: We showed that ATO is an important inhibitor of HH pathway but ITRA can weaken the inhibitory effect of ATO. This study provides an experimental evidence for the clinical use of ATO and ITRA in the treatment of NB with HH pathway activation in cytology.

Serum brain-derived neurotrophic factor (BDNF) as predictors of childhood neuroblastoma relapse.

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.

Serum levels of soluble interleukin 2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-α), and immunoglobulin M are correlated with the disease extent in childhood Langerhans cell histiocytosis.

PURPOSE: This study aimed to identify peripheral parameters associated with the severity of Langerhans cell histiocytosis (LCH) and to look for indicators associated with improvement in LCH patients with risk-organ involvement. METHODS: This study enrolled LCH patients who were assessed as active disease-better (AD-B) after treatment. Patients were divided into the single system (SS) group, multisystem disease without risk-organ involvement (RO- MS) group, and multisystem disease with risk-organ involvement (RO + MS) group. Serum cytokines, immunoglobulins, and lymphocyte subsets were measured at admission for all three groups. Changes in these indicators after treatment were also analyzed. RESULTS: From January 2015 to January 2022, a total of 46 patients were recruited in the present study, including 19 patients (41.3%) in the SS group, 16 patients (34.8%) in the RO- MS group, and 11 patients (23.9%) in the RO + MS group. Serum levels of soluble interleukin 2 receptor (sIL-2R) (> 912.5 U/mL), tumor necrosis factor-alpha (TNF-α) (> 20.3 pg/mL), and immunoglobulin M (< 1.12 g/L) were found to be effective in identifying patients in the RO + MS group. Furthermore, the levels of sIL-2R (SS vs RO + MS: P = 0.002, RO- MS vs RO + MS: P = 0.018) and CD8 + T-cell count (SS vs RO + MS: P = 0.028) significantly declined in the RO + MS group after treatment, indicating disease improvement. CONCLUSIONS: The levels of sIL-2R and TNF-α were positively correlated with the extent of disease, while the levels of IgM were negatively correlated with the extent of disease. Additionally, the levels of sIL-2R and CD8 + T-cell count could serve as useful indicators to evaluate the treatment response in RO + MS-LCH patients.

Effect of Mo Content on Hydrogen Evolution Reaction of 1400 MPa-Grade High-Strength Bolt Steel.

The effect of Mo content of 1400 MPa-grade high-strength bolt steel on hydrogen diffusion behavior and the hydrogen evolution reaction were studied using a hydrogen permeation experiment, potentiodynamic polarization tests, thermal desorption spectroscopy, and the first-principle calculation. Two 1400 MPa-grade high-strength bolt steels with different Mo content were used. Based on the potentiodynamic polarization tests, both steels' electrochemical behavior was similar in the test range. The hydrogen permeation experiment showed that the process of hydrogen adsorption and absorption was significantly promoted, and hydrogen desorption and recombination were slightly promoted, with the Mo content increasing from 0.70 to 1.09 wt%. The thermal desorption spectroscopy showed the overall reaction of hydrogen permeation and evolution. The increasing Mo content facilitated hydrogen entry behavior and increased the hydrogen content. According to the first-principle calculation and the density functional theory, this phenomenon is induced by the stronger bonding ability of Mo-H than Fe-H. This work could guide the design of 1400 MPa-grade high-strength bolt steel.

Arsenic trioxide increases apoptosis of SK-N-BE (2) cells partially by inducing GPX4-mediated ferroptosis.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial tumor in central nervous system threatening children's health with limited therapeutic options. Arsenic trioxide (ATO) has been identified the cytotoxicity in NB cells but the potential mechanism remains unclear. In this study, we attempted to obtain some insight into the mechanisms of cell death induced by ATO in NB cells. METHODS AND RESULTS: Proteomic analyses found that ATO can affect the signaling pathway associated with ferroptosis, including the upregulation of iron absorption (FTL, FTH1, HO-1), ferritinophagy (LC3, P62, ATG7, NCOA4) and modifier of glutathione synthesis (GCLM); downregulation of glutamine synthetase (GS) and GPX4, which was the critical inhibitor of ferroptosis. Western blot analysis revealing GPX4 expression in SK-N-BE (2) cells decreased after treatment with ATO (7.3 µM), resulting in a loss of GPX4 activity. Furthermore, Ferroptosis inhibitor ferrostatin-1 partially blocked ATO-induced cell death. CONCLUSIONS: Our study revealed that ATO may induce ferroptosis in neuroblastoma cell SK-N-BE (2) by facilitating the downregulation of GPX4, ultimately resulting in iron-dependent oxidative death.

Arsenic trioxide induces the differentiation of retinoic acid-resistant neuroblastoma cells via upregulation of HoxC9.

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. MATERIAL 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.

Encouraging Early Outcomes of Treatment With Arsenic Trioxide Combined With Chemotherapy for Alveolar Rhabdomyosarcoma in Children: 4 Case Reports.

BACKGROUND: Alveolar 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: The 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.

Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series.

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.

Immune Microenvironment in Langerhans Cell Histiocytosis: Potential Prognostic Indicators.

In this study, the immune microenvironment in Langerhans cell histiocytosis (LCH) was characterized to determine if immune indices are predictive of severity. Serum samples from 54 treatment-naïve patients were analyzed quantitatively for inflammatory cytokines and immunoglobulins before and after the induction of chemotherapy. The initial serum sIL-2R, TNF-α, and IL-10 of untreated LCH patients with risk organ involvement (RO+) were significantly higher than those with single-system (SS) involvement. LCH patients with hematologic involvement exhibited a significantly higher sIL-2R, TNF-α, IL-10, and IL-1ß expression, as compared to the group without involvement. sIL-2R, TNF-α, and IL-10 were increased in patients with liver or spleen involvement. Th cells have decreased in the liver+ and spleen+ group, and Ts cells were significantly decreased in non-response group after induction chemotherapy. The serum level of immune indices represents, to some extent, the severity of the disease. Pertinent laboratory inspections can be used to improve risk stratification and guide immunotherapy.

Excellent Early Outcomes of Combined Chemotherapy With Arsenic Trioxide for Stage 4/M Neuroblastoma in Children: A Multicenter Nonrandomized Controlled Trial.

This nonrandomized, multicenter cohort, open-label clinical trial evaluated the efficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in children with stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosed with NB and assessed as stage 4/M and received either traditional chemotherapy or ATO combined with chemotherapy according to their own wishes. Twenty-two patients were enrolled in the trial group (ATO combined with chemotherapy), and 13 patients were enrolled in the control group (traditional chemotherapy). Objective response rate (ORR) at 4 weeks after completing induction chemotherapy was defined as the main outcome, and adverse events were monitored and graded in the meantime. Data cutoff date was December 31, 2019. Finally, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who were treated with traditional chemotherapy (ORR: 86.36% vs. 46.16%, p=0.020). Reversible cardiotoxicity was just observed in three patients who were treated with ATO, and no other differential adverse events were observed between the two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk NB, and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with ATO, which creates new opportunity for prolonging survival. In addition, this treatment protocol 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 evaluate more cases to consolidate our conclusion.

Using sternal angle as anatomic landmark for right internal jugular vein catheterization in pediatrics.

BACKGROUND: Many formulas based on the patient's height, weight and/or age exist to determine central venous catheter (CVC) depth in children. However, this information is unavailable in some emergency conditions. Therefore, direct methods should be developed to guide catheter position in children. METHODS: Eighty patients aged 1-10 y were enrolled from July 2015 to August 2016 and seventy-five were completed; fifty were male, and twenty-five were female. The exclusion criteria were inability to identify the sternal angle or failure to use the right internal jugular vein approach. The catheter was inserted using the right internal jugular vein approach, the distance from the skin puncture point to the midpoint of the sternal angle plane was measured, and the catheter tip was positioned to this distance minus 1 cm. Chest radiography were performed for those children after catheter insertion. The relative position between the catheter tip and carina was confirmed and the longitudinal distance from the catheter tip to the carina was calculated on radiographic images, and related complications were recorded. RESULTS: All catheter tips were above the carina, and the average distance from the catheter tip to the carina was 9.8 mm. No patients experienced serious complications. CONCLUSION: The sternal angle is a useful and reliable anatomic landmark for guiding CVC position in children. Using this landmark, the catheter can be quickly and conveniently placed at a safety position in right internal jugular vein, especially in some emergency conditions.

Cytokine-induced killer cells/natural killer cells combined with anti-GD2 monoclonal antibody increase cell death rate in neuroblastoma SK-N-SH cells.

Neuroblastoma (NB) is one of the most common extracranial, solid, pediatric malignancies. Despite improvements in conventional therapies, including surgery, chemotherapy and radiation therapy, the prognosis of stage IV NB remains poor, indicating that novel treatment strategies are required. Immunotherapies, such as anti-GD2 monoclonal antibodies, used alone or in combination with cytokines, and peripheral blood mononuclear cells or cord blood mononuclear cells (CBMNCs), have been indicated to cause NB cell death and to prolong patient survival in high-risk NB; however, they remain limited by severe cytotoxicity and side effects. In the present study, it was determined that anti-GD2 monoclonal antibody alone or CBMNC-isolated cytokine-induced killer (CIK)/natural killer (NK) cells alone significantly induced cell death of NB SK-N-SH cells, and the combination of anti-GD2 antibody and CIK/NK cells could significantly increase the cell death rate compared with either treatment alone. In addition, based on a method referred to our previous study, it was identified that a two-cytokine culture system, using interleukin IL-2 and IL-7, effectively stimulated the proliferation of CIK/NK cells. These results serve to suggest a novel treatment strategy for relapsed/refractory NB with high efficiency and few side effects.

Pre-application of arsenic trioxide may potentiate cytotoxic effects of vinorelbine/docetaxel on neuroblastoma SK-N-SH cells.

BACKGROUND: Arsenic trioxide is effective in the treatment of acute promyelocytic leukemia and is currently in use in clinical trials for the treatment of solid tumor types. Given that arsenic trioxide is able to arrest neuroblastoma cell cycle in the G2/M phase, the present study is, to the best of our knowledge, the first to investigate whether the combination of arsenic trioxide with mitosis-phase-specific antineoplastic agents (vinorelbine or docetaxel) or non-mitosis-phase-specific antineoplastic agents (etoposide or cisplatin) exert synergistic effects in cytotoxicity on the human SK-N-SH neuroblastoma cell line. METHODS: Neuroblastoma cells were either incubated with one of the four drugs individually, or preincubated with arsenic trioxide and then followed by another drug when cell cycle was arrested at the G2/M phase with the highest proportion. RESULTS: The results of the present study revealed that arsenic trioxide potentiated the apoptotic rate of neuroblastoma cells induced by chemotherapeutic drugs. The present study further demonstrated that preincubation with arsenic trioxide followed by a mitosis-phase-specific antineoplastic agent result in a higher cytotoxicity effect compared with a non mitosis-phase-specific antineoplastic agent. Along with the enhanced cytotoxicity in combination group, the cell cycle distribution demonstrated a decreased proportion of G2/M phase in the combination group. CONCLUSION: The in vitro study revealed that the pre-application of arsenic trioxide followed by mitosis-phase-specific antineoplastic agents potentiate the cytotoxic effects on neuroblastoma cells, therefore arsenic trioxide may be a promising therapeutic option for treating neuroblastoma.